Bio

Clinical Focus


  • HIV/AIDS
  • Infectious Disease

Academic Appointments


Administrative Appointments


  • Acting Chief of Infectious Diseases, Stanford University, School of Medicine (2008 - Present)

Professional Education


  • Residency:Santa Clara Valley Medical Center (1988) CA
  • Internship:Santa Clara Valley Medical Center (1985) CA
  • Fellowship:Stanford University School of Medicine (1992) CA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1988)
  • Medical Education:UCLA School of Medicine (1984) CA

Community and International Work


  • Rwanda/Stanford HIV Mentoring Program, Rwanda Africa

    Topic

    HIV/AIDS

    Partnering Organization(s)

    Rwanda Ministry of Health

    Populations Served

    HIV infected Rwandans

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Dr. Zolopas research applies a variety of clinical epidemiologic methods in an effort to optimize antiretroviral therapy and understand the impact of drug resistance on response to ARV. Areas of focus include the clinical application of resistance testing in optimizing antiretroviral therapy, clinical cohorts, trials of antiretroviral therapies and population-based epidemiologic evaluation of HIV resistance and efficacy of ARV therapy. As the Principal Investigator of Stanford's NIH sponsored AIDS Clinical Trials Unit Dr. Zolopa is engaged in a variety of clinical trials focused on the optimization of ART both in the US and in income limited settings.
More recently studies focused on premature aging in HIV infected popultaions. This work will involve detailed immunologic evaluations and evaluation of end organ complications including heart disease, bone disease, renal disease and neuro-cognitive decline.
Finally, Dr. Zolopa is involved in HIV research in collaboration with the Rwandan Ministry of Health in Africa.

Clinical Trials


  • Bone, Immunologic, and Virologic Effects of a Antiretroviral Regimen Not Recruiting

    There are now several HIV treatment options for a person with HIV infection who has not yet been treated. Most people who receive treatment and take their medications as directed have a good result. This is usually determined by measuring the amount of HIV in the blood (viral load). The best response is when HIV cannot be found (less than 50 copies/mL) in the blood. However, it has recently become clear that some people with HIV who are receiving effective HIV drugs continue to have more health problems than people without HIV infection. Sometimes, there is damage to organs in the body, including bone, kidneys, and the brain. The main purpose of this study is to compare the effects on bones of the following two drug combinations: - maraviroc (MVC), emtricitabine (FTC), plus darunavir/ritonavir (DRV/r) - tenofovir (TDF) plus emtricitabine (FTC) plus darunavir/ritonavir (DRV/r) Additional reasons this study is being done are the following: - To see how the drug combinations affect the brain and kidneys. - To see how well the drug combinations lower the HIV viral load. - To see how safe the drug combinations are, how well people are able to take the study drug combinations, and how well their immune systems respond to the study drugs. - To see how well the drug combinations get into the blood.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, RN, BSN, ACRN, (650) 723-2804.

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  • A Study to Treat Subjects With Telaprevir, Ribavirin, and Peginterferon Who Are Coinfected With HIV and Hepatitis C Virus (HCV) Not Recruiting

    The purpose of this study is to treat HIV and HCV coinfected subjects with telaprevir, peg-interferon alfa-2a, and ribavirin to achieve undetectable HCV RNA 12 weeks after the last planned dose of study drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723-2804.

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  • Safety of and Immune Response to an Investigational HIV-1 Vaccine With or Without Interleukin-12 (IL-12) in HIV-1 Infected Adults Not Recruiting

    Therapeutic HIV vaccines are designed to control HIV infection by boosting the body's natural immune response. There are currently no FDA-approved therapeutic HIV vaccines. This study will test whether giving an HIV-1 vaccine together with or without interleukin 12 (IL-12) is safe and effective. This study will also test a new way of giving the vaccine called electroporation (EP).

    Stanford is currently not accepting patients for this trial.

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  • Evaluating the Effectiveness of Boceprevir, Pegylated-Interferon Alfa 2b and Ribavirin in Treating Hepatitis C Virus (HCV) Infection in Adults With HIV and HCV Infection Recruiting

    Hepatitis C virus (HCV) infection is a leading cause of death and illness in people with HIV-1. Currently, the standard treatment for people with HIV-1 and HCV coinfection includes two drugs?pegylated-interferon alfa 2b (PEG-IFN) and ribavirin (RBV). The purpose of this study is to evaluate the effectiveness of giving boceprevir (BOC) together with standard treatment in treating HCV infection in people with HIV-1 and HCV coinfection.

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  • Stanford Universities: The Stanford HIV Aging Cohort Recruiting

    A research study to evaluate the effect of aging and HIV on neurocognitive dysfunction (declining ability to process information), physical frailty and heart disease. HIV-infected participants whose virus is controlled on antiretroviral medications will be studied to determine the rates and risk factors of developing these conditions.

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  • Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/GS-7340 Single Tablet Regimen Versus Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Single Tablet Regimen in HIV 1 Infected, Antiretroviral Treatment-Naive Adults Not Recruiting

    This study is to evaluate the safety, efficacy, and tolerability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single tablet regimen (STR) versus E/C/F/tenofovir disoproxil fumarate (TDF; E/C/F/TDF) STR in HIV-1 infected, antiretroviral treatment-naive adults as determined by the achievement of HIV-1 RNA < 50 copies/mL at Week 24.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723-8014.

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  • Consent for Use of Stored Patient Specimens for Future Testing Not Recruiting

    The purpose of this study is to obtain informed consent to use stored human biological materials (HBM) (e.g., blood and other tissues) for future studies that may include genetic testing.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Evaluating the Effectiveness of the Quadrivalent Human Papillomavirus (HPV) Vaccine at Preventing Anal HPV Infection in HIV-Infected Men and Women Recruiting

    Men who have sex with men (MSM) have an increased risk of developing anal human papillomavirus (HPV) infections, which can be a risk factor for anal cancer. HIV-infected women are also at risk of anal cancer. This study will evaluate the effectiveness of the Food and Drug Administration (FDA)-approved quadrivalent HPV vaccine, Gardasil, at preventing anal HPV infection in HIV-infected MSM and HIV-infected women.

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  • Phase 3b Open Label Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV 1 Infected Patients Not Recruiting

    This study will evaluate the non-inferiority of stribild (elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate [EVG/COBI/FTC/TDF]) single-tablet regimen relative to regimens consisting of a ritonavir-boosted protease inhibitor (PI/r) plus truvada (FTC/TDF) fixed-dose combination in maintaining HIV-1 RNA < 50 copies/mL at Week 48 in virologically suppressed, HIV-1 infected adults. This study will also evaluate the safety, tolerability, and efficacy of the two regimens through 96 weeks of treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 7232804.

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  • High Dose Vitamin D and Calcium for Bone Health in Individuals Initiating HAART Not Recruiting

    This study was done with people who were infected with HIV and needed to start treatment for their HIV disease. The purpose of this study is to see if taking vitamin D and calcium will help prevent the bone loss that sometimes happens when people start HIV treatment. For this study, the following HIV treatment (or HAART) were provided in the form of a single tablet that contains three different drugs: efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). These drugs are approved by the FDA to treat HIV infection. The HIV treatment provided is common for people who are taking HIV drugs for the first time. The risks seen with this HIV treatment are the same that you would encounter when taking these drugs outside of the study. The lists of risks of this HIV treatment are included in this document because the drugs are provided by the study, not because the drugs are being tested. The purpose of the study is only to look at the impact of high doses of vitamin D and calcium in preventing bone loss. There are no study objectives related to HIV treatment (EFV/FTC/TDF).

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Investigation of The Effect of Cenicriviroc (CVC) Plus FTC/TDF on Cardiovascular Disease Risk Factors Not Recruiting

    This is a single-site substudy, "Investigation of the Effect of Cenicriviroc (CVC) plus Emtricitabine/Tenofovir (FTC/TDF) on Atherosclerosis Risk Factors", open to all patients enrolled in the primary study, "A Phase 2b Randomized, Double-Blind, Double-Dummy Trial of 100 or 200 mg Once-Daily Doses of Cenicriviroc (CVC, TBR-652) or Once-Daily EFV, Each With Open-Label FTC/TDF, in HIV-1-Infected, Antiretroviral Treatment-Nave, Adult Patients With Only CCR5-Tropic Virus", in the San Francisco Bay area to evaluate changes in brachial flow mediated dilation in patients in one of three treatment groups: 1. Cenicriviroc (CVC) at 100mg (2 tablets, 50mg each) QD + CVC matching placebo (2 tablets) QD + Efavirenz (EFV) matching placebo (1 capsule) QHS + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (1 tablet) QD; 2. CVC at 200mg (4 tablets, 50mg each) QD + EFV matching placebo (1 capsule) QHS + FTC/TDF (1 tablet) QD; 3. CVC matching placebo (4 tablets) QD + EFV 600 mg (1 capsule) QHS + FTC/TDF (1 tablet) QD. The substudy will run for the duration of the primary study. 50 patients of the 150 total enrolled in the primary study will be referred to and enrolled in the cardiovascular substudy. Patients enrolled in the substudy and substudy protocol staff will be blinded to study treatment. Data obtained on this substudy will be analyzed in conjunction with laboratory data for cardiovascular disease risk factors and HIV-1 RNA levels obtained on the primary study. The primary study is a randomized, double-blind, double-dummy, 48-week, comparative study in approximately 150 HIV-1-infected, treatment-nave patients with CCR5-tropic virus. Patients will be stratified by Screening HIV-1 RNA level (?100,000 copies/mL versus <100,000 copies/mL) and randomized 2:2:1 to one of the three treatment groups. Patients will receive all medications from the primary study, and thus the primary study site will be responsible for any adverse outcomes with the drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723 - 2804.

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  • Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults Not Recruiting

    This study is to evaluate the safety and tolerability of cobicistat-boosted darunavir plus two fully active nucleoside analogue reverse transcriptase inhibitors in HIV 1 infected, antiretroviral treatment-naive and treatment-experienced adults with no darunavir (DRV) resistance-associated mutations.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Study to Evaluate the Safety and Efficacy of Stribild Versus Ritonavir-Boosted Atazanavir Plus Truvada in Human Immunodeficiency Virus, Type 1 (HIV-1) Infected, Antiretroviral Treatment-Naive Adults Not Recruiting

    To evaluate the safety and efficacy of Stribild, a single tablet regimen (STR) containing fixed doses of elvitegravir (EVG)/GS-9350 (cobicistat; COBI)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) versus ritonavir-boosted atazanavir (ATV/r) plus the standard of care nucleoside reverse transcriptase inhibitor (NRTI) backbone FTC/TDF (Truvada). Ritonavir-boosted atazanavir + Truvada was selected as the active comparator for this study as it is a preferred protease inhibitor-based regimen in guidelines for the treatment of HIV-1 infected, antiretroviral treatment-naive adults.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Safety and Efficacy of T Cell Genetic Immunotherapy for HIV Not Recruiting

    This study uses autologous (one's own) CD4 T cells modified with a viral vector expressing a genetic antisense targeting HIV, this vector is called VRX496. Study treatment is by intravenous infusion of vector modified cells and infusions will be provided every other week for a total of 4 or 8 doses. These modified cells, once infused, may provide immune support and are not destroyed by HIV, and thus may delay or reverse HIV disease progression. The study will enroll up to 40 male and female HIV-positive subjects in up to 8 centers. Subjects will be 18 years of age and over who have failed or are intolerant to at least one triple combination of antiretroviral drugs. Subjects must have a viral load between 5,000 and 200,000 copies/ml and a CD4+ count of ?150, be in good health and have no evidence of active opportunistic infection, heart disease, or bleeding disorders. Subjects must not be on corticosteroids, immunomodulating agents or hydroxyurea. Subjects must not have received an AIDS vaccine or any investigational gene therapy product at any time. Females must not be pregnant or breastfeeding.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Stribild Versus Atripla in Human Immunodeficiency Virus, Type 1 (HIV-1) Infected, Antiretroviral Treatment-Naive Adults Not Recruiting

    To evaluate the safety and efficacy of Stribild, a single tablet regimen (STR) containing fixed doses of elvitegravir (EVG)/GS-9350 (cobicistat; COBI)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/FTC/TDF (Atripla) in HIV-1 infected, antiretroviral treatment-naive adults. Stribild offers an alternative STR for patients who are not candidates for non-nucleoside reverse transcriptor (NNRTI)-based STRs.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

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  • Open-label Safety Study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen in HIV-1 Positive Patients With Mild to Moderate Renal Impairment Recruiting

    This open-label, multicenter, multi-cohort study is to assess the safety, tolerability, and efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) in treatment-naive and treatment-experienced HIV-positive, adult participants with mild to moderate renal impairment. The primary objective of this study is to evaluate the effect of E/C/F/TAF STR on renal parameters at Week 24. The proportion of subjects achieving virologic response of HIV-1 RNA < 50 copies/mL will also be assessed. At sites able to conduct the appropriate testing, approximately 30 participants will be enrolled into an intensive pharmacokinetic/pharmacodynamic (PK/PD) substudy to evaluate the PK/PD parameters of the individual components of E/C/F/TAF as well as tenofovir diphosphate (TFV-DP).

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  • Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment-Nave Adults Recruiting

    The purpose of this study is to evaluate the efficacy of a single-tablet regimen (STR)containing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) versus a STR containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) in HIV-1 positive, antiretroviral treatment nave adult participants as determined by the achievement of HIV-1 RNA < 50 copies/mL at Week 48.

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  • A Phase 2 Study of the Safety of Ritonavir-Boosted Elvitegravir Administered in Combination With Other Antiretroviral Agents for the Treatment of HIV-1 Infected Subjects Not Recruiting

    This study is being initiated to provide continued access to ritonavir-boosted elvitegravir (EVG/r; GS-9137/r) for those participants currently benefiting from their participation in an ongoing EVG/r study. This study will also provide initial access to EVG/r for those participants who have completed a EVG/r study in which the participant was participating in a treatment arm that did not include EVG/r. While on study, participants will be monitored for safety using periodic assessments of concomitant medications, adverse events and laboratory tests. Participants will be seen once every 8 weeks for the first 48 weeks of the study. Upon completion of 48 weeks, study visits will occur once every 12 weeks until EVG becomes commercially available, or until Gilead elects to terminate the study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723-2804.

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  • Safety and Efficacy of Darunavir/Cobicistat/Emtricitabine/GS-7340 Single Tablet Regimen Versus Cobicistat-boosted Darunavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate Fixed Dose Combination in HIV-1 Infected, Antiretroviral Treatment Naive Adults Not Recruiting

    This study is to evaluate the efficacy darunavir/cobicistat/emtricitabine/GS-7340 (D/C/F/TAF) single-tablet regimen (STR) versus darunavir (DRV)+cobicistat (COBI)+emtricitabine(FTC)/tenofuvir disoproxil fumarate (TDF) in HIV-1 infected, antiretroviral treatment-naive adults as determined by the achievement of HIV-1 RNA < 50 copies/mL at Week 24.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723-2804.

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  • Study to Evaluate the Safety and Efficacy of a Single Tablet Regimen of Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Compared With a Single Tablet Regimen of Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults Not Recruiting

    The purpose of the study was to evaluate the safety and efficacy of the emtricitabine (FTC)/rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF) single-tablet regimen (STR) compared with the efavirenz (EFV)/FTC/TDF STR in HIV-1 infected adults who had not previously received treatment with antiretroviral medications. The FTC/RPV/TDF STR offers an alternative treatment option to patients who wish to simplify or improve the tolerability of their treatment regimen. Participants were randomized in a 1:1 ratio to receive one of the study treatments. Randomization was stratified by HIV-1 RNA level (? 100,000 copies/mL or > 100,000 copies/mL) at screening. A treatment duration of 96 weeks was planned, with the option for subjects in FTC/RPV/TDF STR arm to receive treatment following the Week 96 visit until FTC/RPV/TDF STR is commercially available or until Gilead Sciences elects to terminate development in that country.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, (650) 723-2804.

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  • Prospective Observational Epidemiologic Study of Maraviroc's Safety Recruiting

    The study will assess if use of maraviroc along with an optimized background regimen of antiretroviral drugs in usual clinical practice is as safe as using only an optimized regimen of antiretroviral drugs.

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  • FTC/RPV/TDF on T-Cell Activation, CD4 Cell Count, Inflammatory Biomarkers and Viral Reservoir Recruiting

    This study is being done with people who are infected with HIV, but do not show any signs of having HIV. They are also feeling well without taking HIV medication and have low or undetectable levels of the virus in the blood. The purpose of this study is to see if taking HIV medication (antiretroviral therapy [ART]) will reduce immune activation (a signal that the body is fighting an infection) in people who have HIV, but do not show symptoms. Also this study will help determine how safe the drug is and how well people react to the drug. For this study, the following antiretroviral therapy (ART) will be provided in the form of a single tablet that contains three different drugs: emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF). These drugs are combined as one tablet which is approved by the Food and Drug Administration (FDA) as a single pill to treat HIV infection. The HIV medication provided is one of the recommended treatments for HIV, including people with low viral loads (how much HIV you have in your body) who are taking HIV drugs for the first time. The risks seen with this HIV medication are the same that one would encounter when taking these drugs outside of the study.

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  • HIV Prevention and Care of Psychological Trauma in Vulnerable Rwandan Youth Not Recruiting

    The investigators propose a prospective single arm pilot cohort study of 100 youth (ages 15-25) to evaluate the feasibility of this project. A convenience sample of subjects will be enrolled on a voluntary basis from those who come to the day care center located in Nyanza, a district of the Southern province, in Rwanda.

    Stanford is currently not accepting patients for this trial. For more information, please contact Deborah Slamowitz, 7232804.

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  • Long-Term Data Collection From Participants in Adult AIDS Clinical Trials Not Recruiting

    The purpose of this study is to determine what combinations of anti-HIV drugs work best in patients treated over several years. The study will also assess the occurrence of side effects and opportunistic infections in patients with low viral loads compared to those with higher viral loads.

    Stanford is currently not accepting patients for this trial. For more information, please contact Debbie Slamowitz, 650-723-2804.

    View full details

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Low Baseline CD4+ Count Is Associated With Greater Bone Mineral Density Loss After Antiretroviral Therapy Initiation. Clinical infectious diseases Grant, P. M., Kitch, D., McComsey, G. A., Dube, M. P., Haubrich, R., Huang, J., Riddler, S., Tebas, P., Zolopa, A. R., Collier, A. C., Brown, T. T. 2013; 57 (10): 1483-1488

    Abstract

    Background.?Bone mineral density (BMD) decreases 2%-6% in the 2 years after antiretroviral therapy (ART) initiation. Pre-ART immune deficiency and early immune recovery may contribute to this loss. Methods.?We pooled data from 3 studies of ART initiation in treatment-naive patients in which serial whole-body dual-energy X-ray absorptiometry scans were performed. We used linear regression to evaluate effects of baseline CD4(+) and 16-week CD4(+) change (both absolute and relative) on 96-week total BMD change from baseline. We performed multivariable linear regression to assess associations between baseline variables of age, sex, race/ethnicity, body mass index (BMI), hepatitis C status, parent study, human immunodeficiency virus type 1 (HIV-1) RNA level, and assignment to a protease inhibitor (PI)- or tenofovir-containing regimen on 96-week total BMD change. Results.?The included 796 subjects had mean 96-week total BMD loss of 2.0%. In multivariable analysis, baseline CD4(+) cell count was significantly associated with 96-week BMD loss; individuals with baseline CD4(+) <50 cells/L lost significantly more BMD compared to those with CD4(+) ?500 cells/L. A greater relative, but not absolute, 16-week increase in CD4(+) count was significantly associated with greater declines in BMD, but not after controlling for baseline CD4(+) count. In multivariable analysis, older age, female sex, lower BMI, higher HIV-1 RNA levels, and PI and tenofovir assignment were also associated with greater BMD decline. Conclusions.?Low pretreatment CD4(+) count, but not greater CD4(+) count increase, is a strong and independent risk factor for bone loss after ART initiation. ART initiation at higher CD4(+) counts may reduce the burden of osteoporosis and fragility fractures.

    View details for DOI 10.1093/cid/cit538

    View details for PubMedID 23943825

  • A Randomized Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate for Initial Treatment of HIV-1 Infection: Analysis of Week 96 Results JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Zolopa, A., Sax, P. E., deJesus, E., Mills, A., Cohen, C., Wohl, D., Gallant, J. E., Liu, H. C., Plummer, A., White, K. L., Cheng, A. K., Rhee, M. S., Szwarcberg, J. 2013; 63 (1): 96-100

    Abstract

    We report week 96 results from a phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, n = 348) vs efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF, n = 352). At week 48, EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% confidence interval: -1.6% to 8.8%). Virologic success (HIV-1 RNA <50 copies/mL) was maintained at week 96 (84% vs 82%, difference +2.7%, 95% CI: -2.9% to 8.3%). Discontinuation due to adverse events was low (5% vs 7%). Median changes in serum creatinine (mg/dL) at week 96 were similar to week 48. These results support the durable efficacy and long-term safety of EVG/COBI/FTC/TDF.

    View details for DOI 10.1097/QAI.0b013e318289545c

    View details for Web of Science ID 000319112200022

    View details for PubMedID 23392460

  • Test performance of blood beta-glucan for Pneumocystis jirovecii pneumonia in patients with AIDS and respiratory symptoms AIDS Wood, B. R., Komarow, L., Zolopa, A. R., Finkelman, M. A., Powderly, W. G., Sax, P. E. 2013; 27 (6): 967-972

    Abstract

    The objective of this study was to define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients with respiratory symptoms.Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms.Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164 trial, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if at least 80?pg/ml and negative if less than 80?pg/ml.Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% [95% confidence interval (CI) 87.2-96.5], and specificity 75.0% (95% CI 50.9-91.3). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (95% CI 91.5-98.8). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (95% CI 38.7-78.9).Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool on the basis of the pretest probability of PCP in such patients.

    View details for DOI 10.1097/QAD.0b013e32835cb646

    View details for Web of Science ID 000316417900013

    View details for PubMedID 23698062

  • Patient monitoring and follow-up in lentiviral clinical trials JOURNAL OF GENE MEDICINE McGarrity, G. J., Hoyah, G., Winemiller, A., Andre, K., Stein, D., Blick, G., Greenberg, R. N., Kinder, C., Zolopa, A., Binder-Scholl, G., Tebas, P., June, C. H., Humeau, L. M., Rebello, T. 2013; 15 (2): 78-82

    Abstract

    Lentiviral vectors are being used with increasing frequency in human clinical trials. We were the first to use lentiviral vectors in clinical trials in 2003. Our lentiviral vector encoded a long RNA antisense sequence to the HIV-1 envelope and was used in an ex vivo autologous setting to provide viral load control in HIV-1 positive subjects failing anti-HIV therapy. A total of 65 subjects have been treated in Phase 1 and Phase 2 trials in six institutions.Good manufacturing practices (GMP) lots of the lentiviral vector used in our clinical trials were assayed for the presence of replication competent lentivirus (RCL). RCL assays were conducted at two stages. The first testing was performed on samples collected immediately following bulk harvest of the GMP product lot and consisted of 1??10(8) cells used in production. RCL assays were also performed on aliquots of the final fill of the vector by the inoculation of at least 5% of the GMP final fill volume into C8166 cells, passaged for at least ten passages and tested for RCL by p24 enzyme-linked immunosorbent assay and vesicular stomatitis virus-G envelope DNA.Following 263 infusions of autologous, transduced cells, no adverse events have been detected in these subjects, with some followed for more than 8?years following infusions. More than 4.3??10(12) VRX496 proviral copies were administered to these 65 subjects.Data from this small population suggest that there is no apparent risk for serious adverse events with the use of lentiviral vectors.

    View details for DOI 10.1002/jgm.2691

    View details for Web of Science ID 000315494400003

    View details for PubMedID 23322669

  • Elevated Interleukin 8 and T-Helper 1 and T-Helper 17 Cytokine Levels Prior to Antiretroviral Therapy in Participants Who Developed Immune Reconstitution Inflammatory Syndrome During ACTG A5164 JOURNAL OF INFECTIOUS DISEASES Grant, P. M., Komarow, L., Lederman, M. M., Pahwa, S., Zolopa, A. R., Andersen, J., Asmuth, D. M., Devaraj, S., Pollard, R. B., Richterman, A., Kanthikeel, S., Sereti, I. 2012; 206 (11): 1715-1723

    Abstract

    Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus-infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear.We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels.Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-?, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-? and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-? at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS.Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.

    View details for DOI 10.1093/infdis/jis604

    View details for Web of Science ID 000310968700013

    View details for PubMedID 23002445

  • When to start ART in the setting of acute AIDS-related opportunistic infections: the time is now! Current HIV/AIDS reports Grant, P. M., Zolopa, A. R. 2012; 9 (3): 251-258

    Abstract

    Despite the substantial benefits of combination antiretroviral therapy (ART), a significant proportion of HIV-infected individuals still present with advanced disease and active AIDS-related opportunistic infections (OIs). The weight of evidence from recent studies supports the early initiation of ART (ie, within 2 weeks of initiating treatment for the acute OIs). Initiating ART early in acutely ill patients can reduce AIDS-related progression and death. Early ART has not been associated with increased rates of immune reconstitution inflammatory syndrome in prospective studies of non-tuberculosis OIs, although this concern is frequently cited as a reason to delay ART. Nor has early ART been associated with increased adverse outcomes. Nonetheless, initiating ART early in acute care settings can be challenging to implement and requires a well-coordinated multidisciplinary team with expertise in ART management.

    View details for DOI 10.1007/s11904-012-0126-8

    View details for PubMedID 22733609

  • Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks LANCET Sax, P. E., deJesus, E., Mills, A., Zolopa, A., Cohen, C., Wohl, D., Gallant, J. E., Liu, H. C., Zhong, L., Yale, K., White, K., Kearney, B. P., Szwarcberg, J., Quirk, E., Cheng, A. K. 2012; 379 (9835): 2439-2448

    Abstract

    The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection.In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796.700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (876%) versus 296/352 (841%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 36%, 95% CI -16% to 88%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 ?mol/L, IQR 5 to 20 vs 1 ?mol/L, -6 to 8; p<0001).If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection.Gilead Sciences.

    View details for Web of Science ID 000305915900028

    View details for PubMedID 22748591

  • Standardized Comparison of the Relative Impacts of HIV-1 Reverse Transcriptase (RT) Mutations on Nucleoside RT Inhibitor Susceptibility ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Melikian, G. L., Rhee, S., Taylor, J., Fessel, W. J., Kaufman, D., Towner, W., Troia-Cancio, P. V., Zolopa, A., Robbins, G. K., Kagan, R., Israelski, D., Shafer, R. W. 2012; 56 (5): 2305-2313

    Abstract

    Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative effect of an RT mutation on susceptibility to different NRTIs. In this study, we analyzed 1,273 genotyped HIV-1 isolates for which phenotypic results were obtained using the PhenoSense assay (Monogram, South San Francisco, CA). We used a parsimonious feature selection algorithm, LASSO, to assess the possible contributions of 177 mutations that occurred in 10 or more isolates in our data set. We then used least-squares regression to quantify the impact of each LASSO-selected mutation on each NRTI. Our study provides a comprehensive view of the most common NRTI resistance mutations. Because our results were standardized, the study provides the first analysis that quantifies the relative phenotypic effects of NRTI resistance mutations on each of the NRTIs. In addition, the study contains new findings on the relative impacts of thymidine analog mutations (TAMs) on susceptibility to abacavir and tenofovir; the impacts of several known but incompletely characterized mutations, including E40F, V75T, Y115F, and K219R; and a tentative role in reduced NRTI susceptibility for K64H, a novel NRTI resistance mutation.

    View details for DOI 10.1128/AAC.05487-11

    View details for Web of Science ID 000302790400015

    View details for PubMedID 22330916

  • Association of Low Level Viremia with Inflammation and Mortality in HIV-Infected Adults PLOS ONE Eastburn, A., Scherzer, R., Zolopa, A. R., Benson, C., Tracy, R., Do, T., Bacchetti, P., Shlipak, M., Grunfeld, C., Tien, P. C. 2011; 6 (11)

    Abstract

    Whether HIV viremia, particularly at low levels is associated with inflammation, increased coagulation, and all-cause mortality is unclear.The associations of HIV RNA level with C-reactive protein (CRP), fibrinogen, interleukin (IL)-6 and mortality were evaluated in 1116 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. HIV RNA level was categorized as undetectable (i.e., "target not detected"), 1-19, 20-399, 400-9999, and ? 10,000 copies/ml. Covariates included demographics, lifestyle, adipose tissue, and HIV-related factors.HIV RNA level had little association with CRP. Categories of HIV RNA below 10,000 copies/ml had similar levels of IL-6 compared with an undetectable HIV RNA level, while HIV RNA ? 10,000 copies/ml was associated with 89% higher IL-6 (p<0.001). This association was attenuated by ~50% after adjustment for CD4+ cell count. Higher HIV RNA was associated with higher fibrinogen. Compared to an undetectable HIV RNA level, fibrinogen was 0.6%, 1.9%, 4.5%, 4.6%, and 9.4% higher across HIV RNA categories, respectively, and statistically significant at the highest level (p = 0.0002 for HIV RNA ? 10,000 copies/ml). Higher HIV RNA was associated with mortality during follow-up in unadjusted analysis, but showed little association after adjustment for CD4+ cell count and inflammation.HIV RNA ? 10,000 copies/ml was associated with higher IL-6 and fibrinogen, but lower levels of viremia appeared similar, and there was little association with CRP. The relationship of HIV RNA with IL-6 was strongly affected by CD4 cell depletion. After adjustment for CD4+ cell count and inflammation, viremia did not appear to be substantially associated with mortality risk over 5 years.

    View details for DOI 10.1371/journal.pone.0026320

    View details for Web of Science ID 000297154900017

    View details for PubMedID 22073156

  • Blood (1 -> 3)-beta-D-Glucan as a Diagnostic Test for HIV-Related Pneumocystis jirovecii Pneumonia CLINICAL INFECTIOUS DISEASES Sax, P. E., Komarow, L., Finkelman, M. A., Grant, P. M., Andersen, J., Scully, E., Powderly, W. G., Zolopa, A. R. 2011; 53 (2): 197-202

    Abstract

    (See the editorial commentary by Morris and Masur, on pages 203-204.)Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 ? 3)-?-D-glucan (?-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for ?-glucan, with standard assay reference values defining ? 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.A total of 252 persons had a ?-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median ?-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of ?-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.Blood (1 ? 3)-?-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

    View details for DOI 10.1093/cid/cir335

    View details for Web of Science ID 000293024000014

    View details for PubMedID 21690628

  • Cost-effectiveness of antiretroviral regimens in the World Health Organization's treatment guidelines: a South African analysis AIDS Bendavid, E., Grant, P., Talbot, A., Owens, D. K., Zolopa, A. 2011; 25 (2): 211-220

    Abstract

    the World Health Organization (WHO) recently changed its first-line antiretroviral treatment guidelines in resource-limited settings. The cost-effectiveness of the new guidelines is unknown.comparative effectiveness and cost-effectiveness analysis using a model of HIV disease progression and treatment.using a simulation of HIV disease and treatment in South Africa, we compared the life expectancy, quality-adjusted life expectancy, lifetime costs, and cost-effectiveness of five initial regimens. Four are currently recommended by the WHO: tenofovir/lamivudine/efavirenz; tenofovir/lamivudine/nevirapine; zidovudine/lamivudine/efavirenz; and zidovudine/lamivudine/nevirapine. The fifth is the most common regimen in current use: stavudine/lamivudine/nevirapine. Virologic suppression and toxicities determine regimen effectiveness and cost-effectiveness.choice of first-line regimen is associated with a difference of nearly 12 months of quality-adjusted life expectancy, from 135.2 months (tenofovir/lamivudine/efavirenz) to 123.7 months (stavudine/lamivudine/nevirapine). Stavudine/lamivudine/nevirapine is more costly and less effective than zidovudine/lamivudine/nevirapine. Initiating treatment with a regimen containing tenofovir/lamivudine/nevirapine is associated with an incremental cost-effectiveness ratio of $1045 per quality-adjusted life year compared with zidovudine/lamivudine/nevirapine. Using tenofovir/lamivudine/efavirenz was associated with the highest survival, fewest opportunistic diseases, lowest rate of regimen substitution, and an incremental cost-effectiveness ratio of $5949 per quality-adjusted life year gained compared with tenofovir/lamivudine/nevirapine. Zidovudine/lamivudine/efavirenz was more costly and less effective than tenofovir/lamivudine/nevirapine. Results were sensitive to the rates of toxicities and the disutility associated with each toxicity.among the options recommended by WHO, we estimate only three should be considered under normal circumstances. Choice among those depends on available resources and willingness to pay. Stavudine/lamivudine/nevirapine is associated with the poorest quality-adjusted survival and higher costs than zidovudine/lamivudine/nevirapine.

    View details for DOI 10.1097/QAD.0b013e328340fdf8

    View details for Web of Science ID 000285501900012

    View details for PubMedID 21124202

  • Inflammation and Mortality in HIV-Infected Adults: Analysis of the FRAM Study Cohort JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Tien, P. C., Choi, A. I., Zolopa, A. R., Benson, C., Tracy, R., Scherzer, R., Bacchetti, P., Shlipak, M., Grunfeld, C. 2010; 55 (3): 316-322

    Abstract

    To determine the association of inflammatory markers, fibrinogen, and C-reactive protein (CRP), with 5-year mortality risk.Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios after adjustment for demographic, cardiovascular, and HIV-related factors.Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile (>406 mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile (<319 mg/dL). Those with high CRP (>3 mg/L) had 2.7-fold higher adjusted odds of death than those with CRP <1 mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [odds ratio (95% confidence intervals)] per 100 mg/dL increase in fibrinogen: 1.93 (1.57 to 2.37); 1.43 (1.14 to 1.79); 1.43 (1.14 to 1.81); and 1.30 (1.04 to 1.63) for CD4 <200, 200-350, >350 to 500, and >500 cells per microliter, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500 cells per microliter, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.

    View details for DOI 10.1097/QAI.0b013e3181e66216

    View details for Web of Science ID 000283847400007

    View details for PubMedID 20581689

  • Concerns Regarding a Randomized Study of the Timing of Antiretroviral Therapy in Zimbabweans with AIDS and Acute Cryptococcal Meningitis CLINICAL INFECTIOUS DISEASES Grant, P. M., Aberg, J. A., Zolopa, A. R. 2010; 51 (8): 984-985

    View details for DOI 10.1086/656435

    View details for Web of Science ID 000282036700018

    View details for PubMedID 20858075

  • HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Rhee, S., Taylor, J., Fessel, W. J., Kaufman, D., Towner, W., Troia, P., Ruane, P., Hellinger, J., Shirvani, V., Zolopa, A., Shafer, R. W. 2010; 54 (10): 4253-4261

    Abstract

    The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.

    View details for DOI 10.1128/AAC.00574-10

    View details for Web of Science ID 000281907200028

    View details for PubMedID 20660676

  • Early Antiretroviral Therapy for Patients With Acute AIDS-Related Opportunistic Infections: A Cost-Effectiveness Analysis of ACTG A5164 HIV CLINICAL TRIALS Sax, P. E., Sloan, C. E., Schackman, B. R., Grant, P. M., Rong, J., Zolopa, A. R., Powderly, W., Losina, E., Freedberg, K. A. 2010; 11 (5): 248-259

    Abstract

    ACTG A5164 demonstrated that early antiretroviral therapy (ART) in HIV-infected patients with acute opportunistic infections (OIs) reduced death and AIDS progression compared to ART initiation 1 month later. We project the life expectancies, costs, and incremental cost-effectiveness ratios (ICERs) of these strategies.using an HIV simulation model, we compared 2 strategies for patients with acute OIs: (1) an intervention to deliver early ART, and (2) deferred ART. Parameters from ACTG A5164 included initial mean CD4 count (47/microL), linkage to outpatient care (87%), and immune reconstitution inflammatory syndrome 1 month after ART initiation (7%). The estimated intervention cost was $1,650/patient.early ART lowered projected 1-year mortality from 10.4% to 8.2% and increased life expectancy from 10.07 to 10.39 quality-adjusted life-years (QALYs). Lifetime costs increased from $385,220 with deferred ART to $397,500 with early ART, primarily because life expectancy increased, producing an ICER of $38,600/QALY. Results were most sensitive to increased intervention cost and decreased virologic efficacy in the early ART strategy.an intervention to initiate ART early in patients with acute OIs improves survival and meets US cost-effectiveness thresholds. Programs should be developed to implement this strategy at sites where HIV-infected patients present with OIs.

    View details for DOI 10.1310/hct1105-248

    View details for Web of Science ID 000284681400002

    View details for PubMedID 21126955

  • Optimal antiretroviral therapy: HIV-1 treatment strategies to avoid and overcome drug resistance CURRENT OPINION IN INVESTIGATIONAL DRUGS Grant, P. M., Zolopa, A. R. 2010; 11 (8): 901-910

    Abstract

    Potent antiretroviral therapy (ART) has transformed HIV infection into a chronic manageable disease, but drug resistance remains a common problem that limits the effectiveness and clinical benefits of treatment. With increasing experience with ART, the understanding of viral dynamics of HIV improved, and researchers learned how challenging HIV can be to control. With new-class and new-generation drugs, it is hoped that the lessons learned will be useful for limiting drug resistance and optimizing the use of ART for long-term management of HIV infection.

    View details for Web of Science ID 000280192200005

    View details for PubMedID 20721832

  • Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome in a Randomized Study of Early vs. Deferred ART during an Opportunistic Infection PLOS ONE Grant, P. M., Komarow, L., Andersen, J., Sereti, I., Pahwa, S., Lederman, M. M., Eron, J., Sanne, I., Powderly, W., Hogg, E., Suckow, C., Zolopa, A. 2010; 5 (7)

    Abstract

    Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI).A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS.In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART.ClinicalTrials.gov NCT00055120.

    View details for DOI 10.1371/journal.pone.0011416

    View details for Web of Science ID 000279465500005

    View details for PubMedID 20617176

  • Predicting Tipranavir and Darunavir Resistance Using Genotypic, Phenotypic, and Virtual Phenotypic Resistance Patterns: an Independent Cohort Analysis of Clinical Isolates Highly Resistant to All Other Protease Inhibitors ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Talbot, A., Grant, P., Taylor, J., Baril, J., Liu, T. F., Charest, H., Brenner, B., Roger, M., Shafer, R., Cantin, R., Zolopa, A. 2010; 54 (6): 2473-2479

    Abstract

    Genotypic interpretation systems (GISs) for darunavir and tipranavir susceptibility are rarely tested by the use of independent data sets. The virtual phenotype (the phenotype determined by Virco [the "Vircotype"]) was used to interpret all genotypes in Qubec, Canada, and phenotypes were determined for isolates predicted to be resistant to all protease inhibitors other than darunavir and tipranavir. We used multivariate analyses to predict relative phenotypic susceptibility to darunavir and tipranavir. We compared the performance characteristics of the Agence Nationale de Recherche sur le Sida scoring algorithm, the Stanford HIV database scoring algorithm (with separate analyses of the discrete and numerical scores), the Vircotype, and the darunavir and tipranavir manufacturers' scores for prediction of the phenotype. Of the 100 isolates whose phenotypes were determined, 89 and 72 were susceptible to darunavir and tipranavir, respectively. In multivariate analyses, the presence of I84V and V82T and the lack of L10F predicted that the isolates would be more susceptible to darunavir than tipranavir. The presence of I54L, V32I, and I47V predicted that the isolates would be more susceptible to tipranavir. All GISs except the system that provided the Stanford HIV database discrete score performed well in predicting the darunavir resistance phenotype (R(2) = 0.61 to 0.69); the R(2) value for the Stanford HIV database discrete scoring system was 0.38. Other than the system that provided the Vircotype (R(2) = 0.80), all GISs performed poorly in predicting the tipranavir resistance phenotype (R(2) = 0.00 to 0.31). In this independent cohort harboring highly protease inhibitor-resistant HIV isolates, reduced phenotypic susceptibility to darunavir and tipranavir was rare. Generally, GISs predict susceptibility to darunavir substantially better than they predict susceptibility to tipranavir.

    View details for DOI 10.1128/AAC.00096-10

    View details for Web of Science ID 000277756000025

    View details for PubMedID 20368406

  • International Cohort Analysis of the Antiviral Activities of Zidovudine and Tenofovir in the Presence of the K65R Mutation in Reverse Transcriptase ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Grant, P. M., Taylor, J., Nevins, A. B., Calvez, V., Marcelin, A., Wirden, M., Zolopa, A. R. 2010; 54 (4): 1520-1525

    Abstract

    A K65R mutation in HIV-1 reverse transcriptase can occur with the failure of tenofovir-, didanosine-, abacavir-, and, in some cases, stavudine-containing regimens and leads to reduced phenotypic susceptibility to these drugs and hypersusceptibility to zidovudine, but its clinical impact is poorly described. We identified isolates with the K65R mutation within the Stanford Resistance Database and a French cohort for which subsequent treatment and virological response data were available. The partial genotypic susceptibility score (pGSS) was defined as the genotypic susceptibility score (GSS) excluding the salvage regimen's nucleoside reverse transcriptase inhibitor (NRTI) component. A three-part virologic response variable was defined (e.g., complete virologic response, partial virologic response, and no virologic response). Univariate, multivariate, and bootstrap analyses evaluated factors associated with the virologic response, focusing on the contributions of zidovudine and tenofovir. Seventy-one of 130 patients (55%) achieved a complete virologic response (defined as an HIV RNA level of <200 copies/ml). In univariate analyses, pGSS and zidovudine use in the salvage regimen were predictors of the virologic response. In a multivariate analysis, pGSS and zidovudine and tenofovir use were associated with the virologic response. Bootstrap analyses showed similar reductions in HIV RNA levels with zidovudine or tenofovir use (0.5 to 0.9 log(10)). In the presence of K65R, zidovudine and tenofovir are associated with similar reductions in HIV RNA levels. Given its tolerability, tenofovir may be the preferred agent over zidovudine even in the presence of the K65R mutation.

    View details for DOI 10.1128/AAC.01380-09

    View details for Web of Science ID 000275662700017

    View details for PubMedID 20124005

  • Activity of Elvitegravir, a Once-Daily Integrase Inhibitor, against Resistant HIV Type 1: Results of a Phase 2, Randomized, Controlled, Dose-Ranging Clinical Trial JOURNAL OF INFECTIOUS DISEASES Zolopa, A. R., Berger, D. S., Lampiris, H., Zhong, L., Chuck, S. L., Enejosa, J. V., Kearney, B. P., Cheng, A. K. 2010; 201 (6): 814-822

    Abstract

    This phase 2, randomized, active-controlled, 48-week study assessed the noninferiority of the human immunodeficiency virus (HIV) integrase inhibitor elvitegravir to comparator ritonavir-boosted protease inhibitor (CPI/r) in treatment-experienced subjects.Subjects had HIV RNA levels 1000 copies/mL and 1 protease resistance mutation. Subjects received nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) with or without T-20 and either CPI/r or once-daily elvitegravir at a dose of 20 mg, 50 mg, or 125 mg (blinded to dose) with ritonavir. After week 8, the independent data monitoring committee stopped the elvitegravir 20 mg arm and allowed subjects in the elvitegravir 50 mg and 125 mg arms to add protease inhibitors. The primary end point was the time-weighted average change from baseline in HIV RNA level through week 24 (DAVG(24)).A total of 278 subjects with a median of 11 protease and 3 thymidine analog mutations were randomized and treated. One-half of subjects received NRTIs without expected antiviral activity. Compared with the DAVG(24) for the CPI/r arm (-1.19 log(10) copies/mL), the elvitegravir 50 mg arm was noninferior (-1.44 log(10) copies/mL), and the elvitegravir 125 mg arm was superior (-1.66 log(10) copies/mL; P = .021). Efficacy was impacted by activity of background agents. There was no relationship between elvitegravir dosage and adverse events.Elvitegravir was well-tolerated and produced rapid virologic suppression that was durable with active background therapy. Trial registration. ClinicalTrials.gov identifier number: NCT00298350.

    View details for DOI 10.1086/650698

    View details for Web of Science ID 000274664900004

    View details for PubMedID 20146631

  • Development of a didanosene genotypic resistance interpretation system based on large derivation and validation datasets AIDS Assoumou, L., Cozzi-Lepri, A., Brun-Vezinet, F., DeGruttola, V., Kuritzkes, D. R., Phillips, A., Zolopa, A., Miller, V., Flandre, P., Costagliola, D. 2010; 24 (3): 365-371

    Abstract

    To assess the genotypic determinants of the virological response to didanosine (ddI) in HIV-infected patients.The Forum database on ddI was randomly divided into a derivation set (n = 1000) and a validation set (n = 453). Linear regression models and bootstrap sampling were used to select resistance mutations and to estimate their resistance scores. Linear regression models, accounted for the censoring of viral load measurements due to assay lower limits, of the week 8 reduction in viral load from baseline were adjusted for baseline viral load, the exact number of weeks between baseline and the week 8 viral load measurements, and the Stanford genotypic sensitivity score.The ddI resistance mutations and their resistance scores based on the derivation set were as follows: M41L (score of 14), T69D (24), D123S (40), T139M (54), I180V (53), M184V (-12), V189I (55), Q207K (37), L210W (25), and T215Y (eight). The total score is obtained by adding the individual scores. Viruses with scores of 19 or less, 20-59, and 60 or more are considered sensitive, intermediate, and resistant, respectively. In the validation set, respectively, 58.7, 36.9, and 4.4% of viruses were predicted to be sensitive, intermediate, and resistant to ddI. The observed viral load reductions at week 8 were, respectively, 1.51 log10 copies/ml [interquartile range (IQR) 1.26-1.76] (P = 0.0001 versus resistant), 1.11 (0.94-1.30) (P = 0.0077 versus sensitive), and 0.46 (0.32-0.74) (P = 0.0079 versus intermediate).We developed a genotypic resistance score for didanosine including four mutations never previously used.

    View details for DOI 10.1097/QAD.0b013e32833338ba

    View details for Web of Science ID 000274374900007

    View details for PubMedID 19864933

  • Association of HIV Infection, Demographic and Cardiovascular Risk Factors With All-Cause Mortality in the Recent HAART Era JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Cockerham, L., Scherzer, R., Zolopa, A., Rimland, D., Lewis, C. E., Bacchetti, P., Grunfeld, C., Shlipak, M., Tien, P. C. 2010; 53 (1): 102-106

    Abstract

    To determine the relationship of HIV infection, demographic, and cardiovascular disease (CVD) risk factors with mortality in the recent highly active antiretroviral therapy era.Vital status was ascertained from 2004 to 2007 in 922 HIV infected and 280 controls in the Study of Fat Redistribution and Metabolic Change in HIV infection; 469 HIV infected were included in analysis comparing HIV with similar age controls. Multivariable exponential survival regression (adjusting for demographic and CVD factors) estimated hazard ratios (HRs) for death.After 5 years of follow-up, the overall adjusted mortality HR was 3.4 [95% confidence interval (CI): 1.35-8.5]; HR was 6.3 among HIV infected with CD4 < 200 (95% CI: 2.2-18.2), 4.3 with CD4 200-350 (95% CI: 1.14-16.0), and 2.3 with CD4 > 350 (95% CI: 0.78-6.9). Among HIV infected, current smoking (HR = 2.73 vs. never smokers, 95% CI: 1.64-4.5) and older age (HR = 1.61 per decade, 95% CI: 1.27-2.1) were independent risk factors for death; higher baseline CD4 count was associated with lower risk (HR = 0.65 per CD4 doubling, 95% CI: 0.58-0.73).HIV infection was associated with a 3-fold mortality risk compared with controls after adjustment for demographic and CVD risk factors. In addition to low baseline CD4 count, older age and current smoking were strong and independent predictors of mortality in a US cohort of HIV-infected participants in clinical care.

    View details for Web of Science ID 000273182400015

    View details for PubMedID 19738484

  • The evolution of HIV treatment guidelines: Current state-of-the-art of ART ANTIVIRAL RESEARCH Zolopa, A. R. 2010; 85 (1): 241-244

    Abstract

    Expert panels have provided guidelines for the treatment of HIV infection for more than a decade. The guidelines have evolved rapidly reflecting the remarkable improvements in HIV therapeutics over this time. From guidelines based mostly on expert opinion - the current guidelines are now primarily evidence-based recommendations - which the vast majority of treating clinicians accept and follow. We will highlight the major guideline recommendations for initiation of antiretroviral therapy - focusing on new data for the asymptomatic patient and those presenting with acute AIDS-related opportunistic infections. Given the number of new drugs available, we are currently able to offer virtually all patients in practice - a fully suppressive regimen, even in patients with substantial multi-drug resistant HIV. A remarkable achievement since AZT was first introduced for the treatment of HIV. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.

    View details for DOI 10.1016/j.antiviral.2009.10.018

    View details for Web of Science ID 000274978200018

    View details for PubMedID 19883695

  • Switch from enfuvirtide to raltegravir in virologically suppressed HIV-1 infected patients: Effects on level of residual viremia and quality of life JOURNAL OF CLINICAL VIROLOGY Grant, P. M., Palmer, S., Bendavid, E., Talbot, A., Slamowitz, D. C., Cain, P., Kobayashi, S. S., Balamane, M., Zolopa, A. R. 2009; 46 (4): 305-308

    Abstract

    Raltegravir is a potential treatment option for virologically suppressed HIV-1 infected patients on enfuvirtide with injection site reactions.To characterize safety and efficacy of an enfuvirtide to raltegravir switch including changes in T-cells, quality of life, and residual viremia.In patients with viral load <50 copies/mL and injection site reactions, enfuvirtide was switched to raltegravir without additional changes to the antiretroviral regimen. Virologic failure was defined as a viral load >1000 copies/mL or two consecutive viral load measurements between 50 and 1000 copies/mL (low-level viremia). Over the 24 week study, we compared changes in T-cells, injection site reactions, quality of life, and residual viremia, as measured through the single-copy assay which can detect plasma virus down to a single copy, using paired t-tests.Fourteen patients with a median CD4+ T-cell count of 420 cells/microL were enrolled. After the switch, two patients experienced virologic failure due to confirmed low-level viremia. However, both patients subsequently were re-suppressed, one without any changes to his regimen. There was no change in CD4+ T-cell count. Injection site reactions resolved. However, there was little reported change in quality of life. The baseline median level of residual viremia was 6 copies/mL and did not change after the switch to raltegravir.A switch to raltegravir in virologically suppressed patients on enfuvirtide is effective in maintaining immunologic and virologic control at 24 weeks but did not result in a change in residual viremia.

    View details for DOI 10.1016/j.jcv.2009.09.025

    View details for Web of Science ID 000272460900002

    View details for PubMedID 19819183

  • Nonpolymorphic Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Treatment-Selected Mutations ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Shahriar, R., Rhee, S., Liu, T. F., Fessel, W. J., Scarsella, A., Towner, W., Holmes, S. P., Zolopa, A. R., Shafer, R. W. 2009; 53 (11): 4869-4878

    Abstract

    The spectrum of human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase (RT) mutations selected by antiretroviral (ARV) drugs requires ongoing reassessment as ARV treatment patterns evolve and increasing numbers of protease and RT sequences of different viral subtypes are published. Accordingly, we compared the prevalences of protease and RT mutations in HIV-1 group M sequences from individuals with and without a history of previous treatment with protease inhibitors (PIs) or RT inhibitors (RTIs). Mutations in protease sequences from 26,888 individuals and in RT sequences from 25,695 individuals were classified according to whether they were nonpolymorphic in untreated individuals and whether their prevalence increased fivefold with ARV therapy. This analysis showed that 88 PI-selected and 122 RTI-selected nonpolymorphic mutations had a prevalence that was fivefold higher in individuals receiving ARVs than in ARV-nave individuals. This was an increase of 47% and 77%, respectively, compared with the 60 PI- and 69 RTI-selected mutations identified in a similar analysis that we published in 2005 using subtype B sequences obtained from one-fourth as many individuals. In conclusion, many nonpolymorphic mutations in protease and RT are under ARV selection pressure. The spectrum of treatment-selected mutations is changing as data for more individuals are collected, treatment exposures change, and the number of available sequences from non-subtype B viruses increases.

    View details for DOI 10.1128/AAC.00592-09

    View details for Web of Science ID 000270881200040

    View details for PubMedID 19721070

  • The use of resistance testing in the management of HIV-1-infected patients CURRENT OPINION IN HIV AND AIDS Grant, P. M., Zolopa, A. R. 2009; 4 (6): 474-480

    Abstract

    Resistance testing has become an important component of the recommended care for treatment-naive and treatment-experienced HIV-infected patients in the developed world, and their use has been shown to improve clinical outcomes. Despite the widespread use of resistance testing, the clinician faces a number of challenges in optimally applying these technologies to antiretroviral management.Even with the aid of a genotypic interpretation system, the interpretation of a genotype is complex and benefits from expert input. Phenotypic resistance testing is limited by cost and availability for many patients. Standard resistance testing (both genotypes and phenotypes) is unable to detect minority species. The presence of resistant minority populations has been associated with virologic failure. However, the current techniques available to detect their presence are cumbersome and not soon likely to become part of routine clinical care. The development of the chemokine (C-C motif) receptor 5 antagonists has provided new challenges in quantifying antiretroviral resistance.Resistance testing plays a central role in the management of treatment-experienced patients. Further progress in the interpretation of resistance testing, especially as new agents are developed, will continue to add value to the care of HIV-infected patients.

    View details for DOI 10.1097/COH.0b013e328331c14f

    View details for Web of Science ID 000208083400003

    View details for PubMedID 20048713

  • Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial PLOS ONE Zolopa, A. R., Andersen, J., Komarow, L., Sanne, I., Sanchez, A., Hogg, E., Suckow, C., Powderly, W. 2009; 4 (5)

    Abstract

    Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.A5164 was a randomized strategy trial of "early ART"--given within 14 days of starting acute OI treatment versus "deferred ART"--given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. THE DIFFERENCE IN THE PRIMARY ENDPOINT DID NOT REACH STATISTICAL SIGNIFICANCE: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.ClinicalTrials.gov NCT00055120.

    View details for DOI 10.1371/journal.pone.0005575

    View details for Web of Science ID 000266107500006

    View details for PubMedID 19440326

  • Initiation of antiretroviral therapy in the hospitalized patient with an acute AIDS-related opportunistic infection and other conditions: no time to lose. Current HIV/AIDS reports Grant, P., Zolopa, A. 2009; 6 (2): 63-67

    Abstract

    Treatment guidelines have recently become more definitive regarding the optimal timing for initiation of combination antiretroviral therapy (ART) in the setting of an acute AIDS-related opportunistic infection (OI). These recent changes reflect new data from a prospective, randomized study and several retrospective studies, all of which support earlier initiation of ART during an OI. These studies focus on OIs for which effective antimicrobial therapy exists. For AIDS-related conditions that lack effective antimicrobial therapy, there are few studies to help inform the optimal timing to initiate ART, but most clinicians initiate ART early, as little else can be offered to these patients. For patients with HIV admitted for non-AIDS-related conditions, there are few data that directly address the optimal timing for ART. Initiating ART in the hospitalized patient can be challenging and requires a well-coordinated multidisciplinary team with expertise in ART management.

    View details for PubMedID 19358776

  • Maintaining Reduced Viral Fitness and CD4 Response in HIV-Infected Patients with Viremia Receiving a Boosted Protease Inhibitor CLINICAL INFECTIOUS DISEASES Grant, P., Taylor, J., Cain, P., Short, W., Gallant, J., Farthing, C., Thal, G., Coakley, E., Zolopa, A. 2009; 48 (5): 680-682

    Abstract

    When fully suppressive regimens are not available, incompletely suppressive regimens also provide immunologic benefits. In this study, with stable background therapy, human immunodeficiency virus (HIV)-infected patients who were randomized to receive atazanavir or boosted atazanavir, compared with those who continued boosted protease inhibitor therapy, maintained similar virologic and immunologic control, resistance-mutation patterns, and replication capacities with reduced use of lipid-lowering medication.

    View details for DOI 10.1086/597008

    View details for Web of Science ID 000263061700026

    View details for PubMedID 19191657

  • Hepatotoxicity and Gastrointestinal Intolerance When Healthy Volunteers Taking Rifampin Add Twice-Daily Atazanavir and Ritonavir JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Haas, D. W., Koletar, S. L., Laughlin, L., Kendall, M. A., Suckow, C., Gerber, J. G., Zolopa, A. R., Bertz, R., Child, M. J., Hosey, L., Alston-Smith, B., Acosta, E. P. 2009; 50 (3): 290-293

    Abstract

    Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P4503A by rifampin markedly lowers HIV protease inhibitor plasma concentrations.This phase 1, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included 3 sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours.Upon adding atazanavir and ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated.Coadministration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies, which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.

    View details for Web of Science ID 000263920800007

    View details for PubMedID 19194314

  • Safety and Efficacy of Enfuvirtide in Combination with Darunavir-Ritonavir and an Optimized Background Regimen in Treatment-Experienced Human Immunodeficiency Virus-Infected Patients: the Below the Level of Quantification Study ANTIMICROBIAL AGENTS AND CHEMOTHERAPY DeJesus, E., Gottlieb, M. S., Gathe, J. C., Greenberg, M. L., Guittari, C. J., Zolopa, A. R. 2008; 52 (12): 4315-4319

    Abstract

    Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treatment. This prospective, open-label, 24-week, single-arm trial assessed the efficacy and safety of enfuvirtide (90 mg injected subcutaneously twice daily) in combination with darunavir-ritonavir (600/100 mg administered orally twice daily) in triple-antiretroviral-class-experienced adults failing their current regimen. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA loads of <50 copies/ml. Other virological and immunological measures were also evaluated, as were the effects of the baseline viral coreceptor tropism and darunavir phenotype sensitivity scores on the outcomes. At week 24, 60.3%, 72.5%, and 84.0% of 131 participants achieved viral loads of <50 copies/ml and <400 copies/ml and a change from the baseline load of > or =1 log(10) copies/ml, respectively. A baseline viral load of < or =5 log(10) copies/ml was a significant predictor of achieving a viral load of <50 copies/ml at 24 weeks; however, neither background genotype sensitivity nor darunavir phenotype sensitivity was a significant predictor of the achievement of viral loads of <50 copies/ml. Although these findings are limited by the relatively small numbers of participants with darunavir susceptibility changes of > or =10-fold, they suggest that combining enfuvirtide and darunavir-ritonavir with an optimized background regimen in triple-class experienced participants nave to these agents can result in positive virological and immunological responses regardless of most baseline parameters.

    View details for DOI 10.1128/AAC.00467-08

    View details for Web of Science ID 000261029800014

    View details for PubMedID 18809940

  • Evaluation of high-protein supplementation in weight-stable HIV-positive subjects with a history of weight loss: a randomized, double-blind, multicenter trial AMERICAN JOURNAL OF CLINICAL NUTRITION Sattler, F. R., Rajicic, N., Mulligan, K., Yarasheski, K. E., Koletar, S. L., Zolopa, A., Alston, B., Zackin, S. R., Bistrian, B. 2008; 88 (5): 1313-1321

    Abstract

    HIV patients with wasting are at increased risk of opportunistic complications and fatality.We hypothesized that augmenting dietary intake with high-biologic-value protein would enhance weight and lean tissue in weight-stable subjects with a prior unintentional weight loss of >3%.Fifty-nine subjects with HIV RNA concentrations <5000 copies/mL were randomly assigned to receive a 280-kcal supplement containing 40 g whey protein or a matched isocaloric control supplement without added protein twice daily for 12 wk.Before the study, intake of total energy and protein exceeded estimated requirements (44.3 +/- 12.6 kcal x kg(-1) x d(-1) and 1.69 +/- 0.55 g x kg(-1) x d(-1), respectively). Both supplements failed to increase total energy intake because of decreases in self-selected food intake. Changes in weight (0.8 +/- 2.4 and 0.7 +/- 2.4 kg) and lean body mass (0.3 +/- 1.4 and 0.3 +/- 1.5 kg) did not differ significantly between the whey protein and control groups, respectively. Waist-to-hip ratio improved more with whey protein (-0.02 +/- 0.05) than with the control (0.01 +/- 0.03; P = 0.025) at week 6 but not at week 12. Fasting triacylglycerol increased by 39 +/- 98 mg/dL with the control supplement and decreased by 16 +/- 62 mg/dL with whey protein at week 12 (P = 0.03). CD4 lymphocytes increased by 31 +/- 84 cells/mm(3) with whey protein and decreased by 5 +/- 124 cells/mm(3) with the control supplement at 12 wk (P = 0.03). Gastrointestinal symptoms occurred more often with whey protein.A whey protein supplement did not increase weight or lean body mass in HIV-positive subjects who were eating adequately, but it did increase CD4 cell counts. The control supplement with rapidly assimilable carbohydrate substituted for protein increased cardiovascular disease risk factors. Careful dietary and weight history should be obtained before starting nutritional supplements in subjects with stable weight loss and good viral control.

    View details for DOI 10.3945/ajcn.2006.23583

    View details for Web of Science ID 000260770600020

    View details for PubMedID 18996868

  • Virologic Response to Lopinavir-Ritonavir-Based Antiretroviral Regimens in a Multicenter International Clinical Cohort: Comparison of Genotypic Interpretation Scores ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Grant, P., Wong, E. C., Rode, R., Shafer, R., De Luca, A., Nadler, J., Hawkins, T., Cohen, C., Harrington, R., Kempf, D., Zolopa, A. 2008; 52 (11): 4050-4056

    Abstract

    Several genotypic interpretation scores have been proposed for the evaluation of susceptibility to lopinavir/ritonavir (LPV/r) but have not been compared using an independent data set. This study was a retrospective multicenter cohort of patients initiating LPV/r-based therapy. The virologic response (VR) was defined as a viral load of <500 copies/ml at week 24. The genotypic interpretation scores surveyed were the LPV mutation score, the ViroLogic score, the ATU score, the Stanford database score, and the International AIDS Society-USA mutation list. Of the 103 patients included in the analysis, 76% achieved VR at 24 weeks. For scores with clinical breakpoints defined (LPV mutation, ATU, ViroLogic, and Stanford), over 80% of the patients below the breakpoints achieved VR, while 50% or less above the breakpoints responded. Protease mutations at positions 10, 54, and 82 and at positions 54, 84, and 90 were associated with a lack of VR in the univariate and multivariate analyses, respectively. The area under the receiver-operator characteristic curves for the five genotypic interpretation scores studied ranged from 0.73 to 0.76. The study confirms that the currently available genotypic interpretation scores which are widely used by clinicians performed similarly well and can be effectively used to predict the virologic activity of LPV/r in treatment-experienced patients.

    View details for DOI 10.1128/AAC.00605-08

    View details for Web of Science ID 000260305600032

    View details for PubMedID 18710915

  • Initiatives for developing and comparing genotype interpretation systems: External validation of existing systems for didanosine against virological response JOURNAL OF INFECTIOUS DISEASES Assoumou, L., Brun-Vezinet, F., Cozzi-Lepri, A., Kuritzkes, D., Phillips, A., Zolopa, A., DeGruttola, V., Miller, V., Costagliola, D. 2008; 198 (4): 470-480

    Abstract

    This study was performed to investigate the concordance between commonly used human immunodeficiency virus type 1 (HIV-1) drug resistance interpretation systems for didanosine (ddI) and their ability to predict responses at weeks 8 and 24.The study included drug-experienced HIV-infected patients who had viral loads >500 copies/mL and who underwent a genotypic resistance test when beginning a ddI-containing therapy. The interpretations of the level of resistance to ddI were compared for the 6 interpretation systems. Linear and logistic regression were used to assess their ability to predict responses for weeks 8 and 24, respectively.The 1453 patients had a median viral load of 4.3 log10 copies/mL, and 31% were preexposed to ddI. Complete concordance was found for 19% of samples, partial discordance for 49%, and complete discordance for 32%. The median viral load reduction at week 8 was 1.36 log10 copies/mL, and 56% of patients had viral loads > 400 copies/mL at week 24. At week 8, all systems correctly predicted a greater viral load reduction in patients with susceptible viruses than in those with resistant viruses, but only the Stanford system was able to discriminate between patients with resistant, intermediately resistant, and susceptible viruses. No systems predicted virological response correctly at week 24.Our results show the need for standardized methods to establish genotypic interpretation systems.

    View details for DOI 10.1086/590156

    View details for Web of Science ID 000257893300004

    View details for PubMedID 18598191

  • Integrase inhibitors: a clinical review of raltegravir and elvitegravir. Journal of HIV therapy Grant, P., Zolopa, A. 2008; 13 (2): 36-39

    View details for PubMedID 18953272

  • Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Acosta, E. P., Kendall, M. A., Gerber, J. G., Alston-Smith, B., Koletar, S. L., Zolopa, A. R., Agarwala, S., Child, M., Bertz, R., Hosey, L., Haas, D. W. 2007; 51 (9): 3104-3110

    Abstract

    The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C(12 h)) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C(12 h) values for atazanavir were 44 ng/ml (range, <25 to 187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.

    View details for DOI 10.1128/AAC.00341-07

    View details for Web of Science ID 000249175400009

    View details for PubMedID 17576825

  • Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment experienced patients: AIDS clinical trials group 5211 JOURNAL OF INFECTIOUS DISEASES Gulick, R. M., Su, Z., Flexner, C., Hughes, M. D., Skolnik, P. R., Wilkin, T. J., Gross, R., Krambrink, A., Coakley, E., Greaves, W. L., Zolopa, A., Reichman, R., Godfrey, C., Hirsch, M., Kuritzkes, D. R. 2007; 196 (2): 304-312

    Abstract

    Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study.The present study was a double-blind, randomized phase 2 study of vicriviroc in treatment-experienced, human immunodeficiency virus (HIV)-infected subjects experiencing virologic failure while receiving a ritonavir-containing regimen with an HIV-1 RNA level >or=5000 copies/mL and CCR5-using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV-1 RNA levels at day 14; secondary end points included safety/tolerability and HIV-1 RNA changes at week 24.One hundred eighteen subjects were randomized with a median HIV-1 RNA level of 36,380 (4.56 log(10)) copies/mL and a median CD4 cell count of 146 cells/mm(3). At 14 days and 24 weeks, mean changes in HIV-1 RNA level (log(10) copies/mL) were greater in the vicriviroc groups (-0.87 and -1.51 [5 mg], -1.15 and -1.86 [10 mg], and -0.92 and -1.68 [15 mg]) than in the placebo group (+0.06 and -0.29) (P<.01). Grade 3/4 adverse events were similar across groups. Malignancies occurred in 6 subjects randomized to vicriviroc and in 2 to placebo.In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

    View details for DOI 10.1086/518797

    View details for Web of Science ID 000247803100019

    View details for PubMedID 17570119

  • A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024) JOURNAL OF INFECTIOUS DISEASES Kilby, J. M., Bucy, R. P., Mildvan, D., Fischl, M., Santana-Bagur, J., Lennox, J., Pilcher, C., Zolopa, A., Lawrence, J., Pollard, R. B., El Habib, R., Sahner, D., Fox, L., Aga, E., Bosch, R. J., Mitsuyasu, R. 2006; 194 (12): 1672-1676

    Abstract

    Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty-two subjects reached the study end point. ALVAC recipients had 0.5 log(10) lower virologic rebounds (P=.033). IL-2 plus vaccine boosted CD4(+) T cell counts (P<.001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design.

    View details for Web of Science ID 000242656000008

    View details for PubMedID 17109338

  • N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure AIDS RESEARCH AND HUMAN RETROVIRUSES Mitsuya, Y., Winters, M. A., Fessel, W. J., Rhee, S., Hurley, L., Horberg, M., Schiffer, C. A., Zolopa, A. R., Shafer, R. W. 2006; 22 (12): 1300-1305

    Abstract

    Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the co-occurrence of D30N and L90M. Third, D30N+N88D+L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N-->D30N+N88D-->D30N+N88D+L90M-->D30N+N88D+L90M+(L33F+/-I84V or M46I/L+/-I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.

    View details for Web of Science ID 000243398800014

    View details for PubMedID 17209774

  • Incorporating drug-resistance measurements into the clinical management of HIV-1 infection JOURNAL OF INFECTIOUS DISEASES Zolopa, A. R. 2006; 194: S59-S64

    Abstract

    Testing for resistance to antiretrovirals is considered to be standard of care and is widely used in the management of human immunodeficiency virus (HIV)-infected persons. Despite the widespread use of resistance testing, the clinician still faces a number of challenges when applying these technologies in the optimal management of antiretroviral therapy. Both genotype and phenotype tests require interpretation, and available interpretative algorithms for genotypes and resistance cutoffs for phenotypes are incomplete and evolving. Even experts in HIV resistance do not completely agree in their interpretation of genotypes. Moreover, discordant results between genotypes and phenotypes are a common source of confusion when both tests are used to evaluate resistance in a patient. Finally, newer indicators, such as replication capacity, are clinically available and appear to have prognostic value, but how this in vitro measure should be used in the management of antiretroviral therapy remains to be fully defined.

    View details for Web of Science ID 000240317800010

    View details for PubMedID 16921474

  • The study of fat redistribution and metabolic change in HIV infection (FRAM): Methods, design, and sample characteristics AMERICAN JOURNAL OF EPIDEMIOLOGY Tien, P. C., Benson, C., Zolopa, A. R., Sidney, S., Osmond, D., Grunfeld, C. 2006; 163 (9): 860-869

    Abstract

    The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.

    View details for DOI 10.1093/aje/kwj111

    View details for Web of Science ID 000237174600008

    View details for PubMedID 16524955

  • The effect of diagnosis with HIV infection on health-related quality of life QUALITY OF LIFE RESEARCH Honiden, S., Sundaram, V., Nease, R. F., Holodniy, M., Lazzeroni, L. C., Zolopa, A., Owens, D. K. 2006; 15 (1): 69-82

    Abstract

    We sought to understand how diagnosis with HIV affects health-related quality of life. We assessed health-related quality of life using utility-based measures in a Department of Veterans Affairs (VA) clinic and a University-based clinic. Respondents assessed health-related quality of life regarding their current health, and retrospectively assessed their health 1 month prior to and 2 months after diagnosis with HIV infection. Sixty-six patients completed the study. The overall mean utilities for health 1 month before and 2 months after diagnosis were 0.87 (standard error 0.037), and 0.80 (0.043) (p<0.005 by rank sign test), but the effect of diagnosis differed between the two clinics, with a substantial decrease in the university clinic and a small non-significant decrease in the VA clinic. The overall mean utility for current health was 0.85 (0.034), assessed on average 7.5 years after diagnosis. When asked directly whether diagnosis of HIV decreased health-related quality of life, 47% agreed, but 35% stated that HIV diagnosis positively affected health-related quality of life. Diagnosis with HIV decreased health-related quality of life at 2 months on average, but this effect diminished over time, and differed among patient populations. Years after diagnosis, although half of the patients believed that diagnosis reduced health-related quality of life, one-third reported improved health-related quality of life.

    View details for DOI 10.1007/s11136-005-8485-x

    View details for Web of Science ID 000234601400007

    View details for PubMedID 16411032

  • Case files from Stanford University Medical Center: the initial presentation of HIV-1 infection--where public and personal health meet. MedGenMed : Medscape general medicine Liu, M., Holodniy, M., Zolopa, A. R., Shafer, R. W. 2006; 8 (1): 24-?

    View details for PubMedID 16915154

  • Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers CLINICAL PHARMACOLOGY & THERAPEUTICS Glesby, M. J., Aberg, J. A., Kendall, M. A., Fichtenbaum, C. J., Hafner, R., Hall, S., Grosskopf, N., Zolopa, A. R., Gerber, J. G. 2005; 78 (2): 143-153

    Abstract

    Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir.Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19.Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed.Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.

    View details for DOI 10.1016/j.clpt.2005.04.005

    View details for Web of Science ID 000231110700007

    View details for PubMedID 16084849

  • HIV-1 protease and reverse-transcriptase mutations: Correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance JOURNAL OF INFECTIOUS DISEASES Rhee, S. Y., Fessel, W. J., Zolopa, A. R., Hurley, L., Liu, T., Taylor, J., Nguyen, D. P., Slome, S., Klein, D., Horberg, M., Flamm, J., Follansbee, S., Schapiro, J. M., Shafer, R. W. 2005; 192 (3): 456-465

    Abstract

    Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.

    View details for Web of Science ID 000230387500013

    View details for PubMedID 15995959

  • Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection CLINICAL INFECTIOUS DISEASES Campbell, T. B., Shulman, N. S., Johnson, S. C., Zolopa, A. R., Young, R. K., Bushman, L., Fletcher, C. V., Lanier, E. R., Merigan, T. C., Kuritzkes, D. R. 2005; 41 (2): 236-242

    Abstract

    Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance.Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection.Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study.In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

    View details for Web of Science ID 000229890800016

    View details for PubMedID 15983922

  • Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: An international comparison (The GUESS Study) CLINICAL INFECTIOUS DISEASES Zolopa, A. R., Lazzeroni, L. C., Rinehart, A., Vezinet, F. B., Clavel, F., Collier, A., Conway, B., Gulick, R. M., Holodniy, M., Perno, C. F., Shafer, R. W., Richman, D. D., Wainberg, M. A., Kuritzkes, D. R. 2005; 41 (1): 92-99

    Abstract

    Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

    View details for Web of Science ID 000229530400015

    View details for PubMedID 15937768

  • Detection of minority populations of HIV-1 expressing the K103N resistance mutation in patients failing nevirapine JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Lecossier, D., Shulman, N. S., Morand-Joubert, L., Shafer, R. W., Joly, V., Zolopa, A. R., Clavel, F., Hance, A. J. 2005; 38 (1): 37-42

    Abstract

    Salvage therapy with efavirenz is often ineffective in patients having failed nevirapine treatment, even when mutations associated with efavirenz resistance are not detected by standard population-based genotyping. The presence of minority viral populations expressing efavirenz cross-resistance could explain these observations, and such populations were sought in plasma from patients failing nevirapine for whom genotyping revealed the presence of the Y181C mutation (usually associated with limited efavirenz cross-resistance) but not the K103N mutation (which produces high-level efavirenz resistance). Viral populations expressing K103N (>1% total virus) were detected by sequence-selective polymerase chain reaction in 4 of 16 patients failing nevirapine, although, in retrospect, the mutation was not perceptible in the original genotype in only 2 cases. Both patients with detectable K103N mutations who received efavirenz failed treatment, and virus expressing K103N emerged. Four of 5 patients without detectable K103N mutations also failed efavirenz, associated with the emergence of nonnucleoside reverse transcriptase mutations that included K103N in 2 cases. The emergence of a minority viral population expressing K103N was identified in 1 patient from a separate study group subsequent to discontinuing treatment with nevirapine. These findings support the idea that minority viral populations with distinct resistance genotypes, although undetectable by standard genotyping, can contribute to the failure of salvage regimens.

    View details for Web of Science ID 000226179400007

    View details for PubMedID 15608522

  • Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study INTERNATIONAL JOURNAL OF STD & AIDS Holodniy, M., Charlebois, E. D., Bangsberg, D. R., Zolopa, A. R., Schulte, M., Moss, A. R. 2004; 15 (8): 543-551

    Abstract

    We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV nave, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

    View details for Web of Science ID 000223453900010

    View details for PubMedID 15307966

  • Clinically validated genotype analysis: guiding principles and statistical concerns ANTIVIRAL THERAPY Brun-Vezinet, F., Costagliolo, D., Khaled, M. A., Calvez, V., Clavel, F., Clotet, B., Haubrich, R., Kemp, D., King, M., Kuritzkes, D., Lanier, R., Miller, M., Miller, V., Phillips, A., Pillay, D., Schapiro, J., Scott, J., Shafer, R., Zazzi, M., Zolopa, A., DeGruttola, V. 2004; 9 (4): 465-478

    Abstract

    Whereas previously the output of HIV resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virological outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and analytical methodology used to derive it. For genotyping, the most widely used resistance tool in clinical practice, these considerations are further complicated by the range of mutational patterns present in the treated population. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. This review discusses the processes involved in constructing such tools, with particular emphasis on establishing validated mutation score rules, and examines the key issues and confounding factors that influence predictive accuracy outside the originating dataset. Since the size of the sample is a key influence on the statistical power to determine an effect, it is hoped that a greater understanding of the influence of study design and methodology will assist the development of standardized outcome measures and reporting formats that allow data pooling at the international level.

    View details for Web of Science ID 000231615600002

    View details for PubMedID 15456077

  • High levels of adherence do not prevent accumulation of HIV drug resistance mutations AIDS Bangsberg, D. R., Charlebois, E. D., Grant, R. M., Holodniy, M., Deeks, S. G., Perry, S., Conroy, K. N., Clark, R., Guzman, D., Zolopa, A., Moss, A. 2003; 17 (13): 1925-1932

    Abstract

    To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence.Adherence was measured with unannounced pill counts performed at the participant's usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2.High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92-100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79-100%).Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.

    View details for DOI 10.1097/01.aids.0000076320.42412.fd

    View details for Web of Science ID 000185067700008

    View details for PubMedID 12960825

  • Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation JOURNAL OF INFECTIOUS DISEASES Gonzales, M. J., Delwart, E., Rhee, S. Y., Tsui, R., Zolopa, A. R., Taylor, J., Shafer, R. W. 2003; 188 (3): 397-405

    Abstract

    We examined consecutive protease (PR) and reverse transcriptase (RT) sequences from human immunodeficiency virus (HIV) type 1-infected individuals, to distinguish changes resulting from sequence evolution due to possible superinfection. Between July 1997 and December 2001, >/=2 PR and RT samples from 718 persons were sequenced at Stanford University Hospital. Thirty-seven persons had highly divergent sequence pairs characterized by a nucleotide distance of >4.5% in PR or >3.0% in RT. In 16 of 37 sequence pairs, divergence resulted from the loss of mutations during a treatment interruption or from the gain of mutations with reinstitution of treatment. tat and/or gag sequencing of HIV-1 from cryopreserved plasma samples could be performed on 15 of the 21 divergent isolate pairs from persons without a treatment interruption. The sequences of these genes, unaffected by selective drug pressure, were monophyletic. Although HIV-1 PR and RT genes from treated persons may become highly divergent, these changes usually are the result of sequence evolution, rather than superinfection.

    View details for Web of Science ID 000184316900008

    View details for PubMedID 12870121

  • Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors AIDS Gonzales, M. J., Wu, T. D., Taylor, J., Belitskaya, F., Kantor, R., Israelski, D., Chou, S., Zolopa, A. R., Fessel, W. J., Shafer, R. W. 2003; 17 (6): 791-799

    Abstract

    To characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI.A total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published.Chi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini-Hochberg procedure was used to correct for multiple comparisons.Mutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228.Mutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts.

    View details for DOI 10.1097/01.aids.0000050860.71999.23

    View details for Web of Science ID 000182779700005

    View details for PubMedID 12660525

  • Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments JOURNAL OF VIROLOGY Wu, T. D., Schiffer, C. A., Gonzales, M. J., Taylor, J., Kantor, R., Chou, S. W., Israelski, D., Zolopa, A. R., Fessel, W. J., Shafer, R. W. 2003; 77 (8): 4836-4847

    Abstract

    Although many human immunodeficiency virus type 1 (HIV-1)-infected persons are treated with multiple protease inhibitors in combination or in succession, mutation patterns of protease isolates from these persons have not been characterized. We collected and analyzed 2,244 subtype B HIV-1 isolates from 1,919 persons with different protease inhibitor experiences: 1,004 isolates from untreated persons, 637 isolates from persons who received one protease inhibitor, and 603 isolates from persons receiving two or more protease inhibitors. The median number of protease mutations per isolate increased from 4 in untreated persons to 12 in persons who had received four or more protease inhibitors. Mutations at 45 of the 99 amino acid positions in the protease-including 22 not previously associated with drug resistance-were significantly associated with protease inhibitor treatment. Mutations at 17 of the remaining 99 positions were polymorphic but not associated with drug treatment. Pairs and clusters of correlated (covarying) mutations were significantly more likely to occur in treated than in untreated persons: 115 versus 23 pairs and 30 versus 2 clusters, respectively. Of the 115 statistically significant pairs of covarying residues in the treated isolates, 59 were within 8 A of each other-many more than would be expected by chance. In summary, nearly one-half of HIV-1 protease positions are under selective drug pressure, including many residues not previously associated with drug resistance. Structural factors appear to be responsible for the high frequency of covariation among many of the protease residues. The presence of mutational clusters provides insight into the complex mutational patterns required for HIV-1 protease inhibitor resistance.

    View details for DOI 10.1128/JVI.77.8.4836-4847.2003

    View details for Web of Science ID 000181970200037

    View details for PubMedID 12663790

  • Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Shulman, N., Zolopa, A., Havlir, D., Hsu, A., Renz, C., Boller, S., Jiang, P., Rode, R., Gallant, J., Race, E., Kempf, D. J., Sun, E. 2002; 46 (12): 3907-3916

    Abstract

    Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.

    View details for DOI 10.1128/AAC.46.12.3907-3916.2002

    View details for Web of Science ID 000179376000032

    View details for PubMedID 12435695

  • Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Shulman, N. S., Hughes, M. D., Winters, M. A., Shafer, R. W., Zolopa, A. R., Hellmann, N. S., Bates, M., Whitcomb, J. M., Katzenstein, D. A. 2002; 31 (2): 121-127

    Abstract

    To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility

    View details for DOI 10.1097/01.QAI.0000038335.74605.52

    View details for Web of Science ID 000178884500001

    View details for PubMedID 12394789

  • Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Kantor, R., Fessel, W. J., Zolopa, A. R., Israelski, D., Shulman, N., Montoya, J. G., Harbour, M., Schapiro, J. M., Shafer, R. W. 2002; 46 (4): 1086-1092

    Abstract

    In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively; P < 0.001) and V82A/F/T (50% versus 81%, respectively; P = 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.

    View details for DOI 10.1128/AAC.46.4.1086-1092.2002

    View details for Web of Science ID 000174597000022

    View details for PubMedID 11897594

  • Characterization of the HIV-1 specific humoral immune response during highly active antiretroviral therapy (HAART) JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Morris, M. K., Katzenstein, D. A., Israelski, D., Zolopa, A., Hendry, R. M., Hanson, C. V. 2001; 28 (5): 405-415

    Abstract

    Plasma samples from 19 patients were analyzed for HIV-1 directed humoral immune responses prior to and 1 year after initiation of HAART. Eight of the subjects were classified as virologic successes, defined by a >100-fold decrease in viral load (VL) over the 1-year study period and a final VL <500 copies/ml. The eleven HAART failures were defined as subjects with <10-fold decrease in VL. At study entry (before HAART), VL and CD4 counts were similar between the two groups. Humoral immune responses before therapy and after 1 year of therapy were measured by V3 peptide antibody binding titers and neutralization of HIV-1 MN and four subtype B clinical isolates. Before HAART, neutralizing antibody titers to the clinical isolates and HIV(MN), as well as HIV V3 envelope binding titers to several V3 peptides, were significantly higher among treatment successes compared with treatment failures. After 1 year on HAART, neutralization declined in titer and narrowed in specificity among the HAART successes. In contrast, a significant increase in both neutralizing titer and breadth was seen among HAART failures.

    View details for Web of Science ID 000172932000001

    View details for PubMedID 11744827

  • HIV drug resistance testing: an update for the clinician. AIDS clinical care RICE, H. L., Zolopa, A. R. 2001; 13 (10): 89-?

    View details for PubMedID 11590921

  • Genotypic correlates of a virologic response to stavudine after zidovudine monotherapy JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Shulman, N. S., Machekano, R. A., Shafer, R. W., Winters, M. A., Zolopa, A. R., Liou, S. H., Hughes, M., Katzenstein, D. A. 2001; 27 (4): 377-380

    Abstract

    Prior evidence suggests that resistance to zidovudine (ZDV) confers some degree of cross-resistance to stavudine (d4T), but no genotypic correlates of clinical d4T susceptibility and resistance exist. To identify the genotypic correlates of a virologic response to d4T, reverse transcriptase (RT) sequencing of archived plasma HIV isolates was performed on 31 subjects who received d4T monotherapy in the AIDS Clinical Trials Group 302 study, all of whom received more than 3 years of ZDV monotherapy. Baseline characteristics and all RT mutations were analyzed for impact on virologic suppression. Eight of 31 subjects (27%) achieved a virologic response of greater than 0.3 log reduction in plasma HIV RNA after 8 weeks of d4T. Responders were more likely to have lower median baseline viral loads (4.2 vs. 4.7; p =.01) and a trend toward fewer ZDV-associated mutations (median: 1 vs. 2; p =.09). No subject with greater than one ZDV mutation had a virologic response to d4T. Seven of the 8 responders had only a K70R mutation at baseline. We conclude that in patients with prior ZDV treatment, those with only one ZDV mutation, particularly at position 70, can still get reasonable virologic activity from d4T. Those with more mutations are not likely to have much benefit.

    View details for Web of Science ID 000170145500008

    View details for PubMedID 11468426

  • Non-adherence to highly active antiretroviral therapy predicts progression to AIDS AIDS Bangsberg, D. R., Perry, S., Charlebois, E. D., Clark, R. A., Roberston, M., Zolopa, A. R., Moss, A. 2001; 15 (9): 1181-1183

    View details for Web of Science ID 000169319400015

    View details for PubMedID 11416722

  • Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy AIDS Shulman, N., Zolopa, A. R., Passaro, D., Shafer, R. W., Huang, W., KATZENSTEIN, D., Israelski, D. M., Hellmann, N., Petropoulos, C., Whitcomb, J. 2001; 15 (9): 1125-1132

    Abstract

    Enhanced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) was recently described in association with increased resistance to nucleoside analogs (nucleoside reverse transcriptase inhibitors; NRTI).To determine the prevalence of NNRTI hypersusceptibility, the genotypic correlates, and its impact on virologic response to efavirenz-based salvage therapy.Genotype and phenotype testing was performed retrospectively on baseline isolates from 30 patients who received salvage therapy containing efavirenz. NNRTI hypersusceptibility was defined as a 50% inhibitory concentration (IC(50)) of < 0.5 that of the wild-type control.Eight isolates had major NNRTI mutations. Among the 22 isolates with no major NNRTI mutations, 11 (50%) were hypersusceptible to efavirenz, 10 (45%) to delavirdine, and eight (36%) to nevirapine. Among eight isolates with NNRTI mutations, NNRTI resistance was present, but at lower than expected levels. The number of NRTI mutations was correlated inversely with the fold decrease in susceptibility to efavirenz (Spearman's rho, -0.57; P = 0.005), delavirdine (rho, -0.43; P = 0.04), and nevirapine (rho, -0.69; P < 0.001). Excluding subjects with NNRTI mutations, subjects with efavirenz hypersusceptibility at baseline had significantly better virologic suppression over 24 weeks than those without efavirenz hypersusceptibility (P < 0.001).NNRTI hypersusceptibility is common in heavily treated but NNRTI naive patients and is related directly to NRTI resistance mutations. Among patients receiving efavirenz-containing regimens, NNRTI hypersusceptibility was associated with an improved virologic outcome after 24 weeks of therapy. A reversal of phenotypic resistance was seen in patients with NNRTI mutations in the presence of multiple NRTI mutations, but no obvious virologic benefit of this phenomenon was seen in this study.

    View details for Web of Science ID 000169319400007

    View details for PubMedID 11416714

  • High degree of interlaboratory reproducibility of human immunodeficiency virus type 1 protease and reverse transcriptase sequencing of plasma samples from heavily treated patients JOURNAL OF CLINICAL MICROBIOLOGY Shafer, R. W., Hertogs, K., Zolopa, A. R., Warford, A., Bloor, S., Betts, B. J., Merigan, T. C., Harrigan, R., Larder, B. A. 2001; 39 (4): 1522-1529

    Abstract

    We assessed the reproducibility of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequencing using cryopreserved plasma aliquots obtained from 46 heavily treated HIV-1-infected individuals in two laboratories using dideoxynucleotide sequencing. The rates of complete sequence concordance between the two laboratories were 99.1% for the protease sequence and 99.0% for the RT sequence. Approximately 90% of the discordances were partial, defined as one laboratory detecting a mixture and the second laboratory detecting only one of the mixture's components. Only 0.1% of the nucleotides were completely discordant between the two laboratories, and these were significantly more likely to occur in plasma samples with lower plasma HIV-1 RNA levels. Nucleotide mixtures were detected at approximately 1% of the nucleotide positions, and in every case in which one laboratory detected a mixture, the second laboratory either detected the same mixture or detected one of the mixture's components. The high rate of concordance in detecting mixtures and the fact that most discordances between the two laboratories were partial suggest that most discordances were caused by variation in sampling of the HIV-1 quasispecies by PCR rather than by technical errors in the sequencing process itself.

    View details for Web of Science ID 000167946500053

    View details for PubMedID 11283081

  • Highly active antiretroviral therapy results in HIV type 1 suppression in lymph nodes, increased pools of naive T cells, decreased pools of activated T cells, and diminished frequencies of peripheral activated HIV type 1-specific CD8(+) T cells AIDS RESEARCH AND HUMAN RETROVIRUSES Gray, C. M., Lawrence, J., Ranheim, E. A., Vierra, M., Zupancic, M., Winters, M., Altman, J., Montoya, J., Zolopa, A., Schapiro, J., Haase, A. T., Merigan, T. C. 2000; 16 (14): 1357-1369

    Abstract

    This study examines sequential lymph nodes from 13 drug-naive patients before and after 24 weeks of highly active antiretroviral therapy (HAART). A multipronged approach was used to study changes in HIV-1 RNA in each paired lymph node in relation to tissue architecture and frequency of naive T cells. After 24 weeks, all patients showed significant suppression of plasma viral load and 12 of 13 showed concordant viral suppression in the lymph node (p = 0.001). Using in situ hybridization and quantitative image analysis, we showed that HIV-1 RNA was reduced to below detectable levels (two copies per cell) in follicular dendritic cell (FDC) and mononuclear cell pools. Independent immunohistochemical analysis of lymph node sections revealed that 5 of 13 patients displayed increased FDC networks and 6 of 13 showed no change and all patients showed increases in tissue-resident CD4+ cells. All lymph node biopsies at 24 weeks showed increased proportions of CD4+ and CD8+ cells coexpressing the naive markers CD45RA and CD62L when compared with baseline values. Significant correlations existed between viral load suppression and loss of activated CD8+ T cells after 24 weeks in both lymph node and blood, which was mirrored by significantly lowered frequencies of activated peripheral Gag peptide/MHC tetramer+ CD8+ cells. Overall, these data show that a potent and successful treatment strategy that significantly suppresses and removes FDC-resident HIV-1 results in improvements in lymphoid architecture and by so doing provides the structures available for increased numbers of naive cells to interact with cognate antigen. In addition, our article shows that suppression of HIV-1 replication results in diminished frequencies of peripherally activated antigen-specific CD8+ cells.

    View details for Web of Science ID 000089593100004

    View details for PubMedID 11018855

  • Adherence to isoniazid prophylaxis in the homeless - A randomized controlled trial ARCHIVES OF INTERNAL MEDICINE Tulsky, J. P., Pilote, L., Hahn, J. A., Zolopa, A., Burke, M., Chesney, M., Moss, A. R. 2000; 160 (5): 697-702

    Abstract

    To test 2 interventions to improve adherence to isoniazid preventive therapy for tuberculosis in homeless adults. We compared (1) biweekly directly observed preventive therapy using a $5 monetary incentive and (2) biweekly directly observed preventive therapy using a peer health adviser, with (3) usual care at the tuberculosis clinic.Randomized controlled trial in tuberculosis-infected homeless adults. Outcomes were completion of 6 months of isoniazid treatment and number of months of isoniazid dispensed.A total of 118 subjects were randomized to the 3 arms of the study. Completion in the monetary incentive arm was significantly better than in the peer health adviser arm (P = .01) and the usual care arm (P = .04), by log-rank test. Overall, 19 subjects (44%) in the monetary incentive arm completed preventive therapy compared with 7 (19%) in the peer health adviser arm (P = .02) and 10 (26%) in the usual care arm (P = .11). The median number of months of isoniazid dispensed was 5 in the monetary incentive arm vs 2 months in the peer health adviser arm (P = .005) and 2 months in the usual care arm (P = .04). In multivariate analysis, independent predictors of completion were being in the monetary incentive arm (odds ratio, 2.57; 95% CI, 1.11-5.94) and residence in a hotel or other stable housing at entry into the study vs residence on the street or in a shelter at entry (odds ratio, 2.33; 95% CI, 1.00-5.47).A $5 biweekly cash incentive improved adherence to tuberculosis preventive therapy compared with a peer intervention or usual care. Living in a hotel or apartment at the start of treatment also predicted the completion of therapy.

    View details for Web of Science ID 000085808300014

    View details for PubMedID 10724056

  • Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population AIDS Bangsberg, D. R., Hecht, F. M., Charlebois, E. D., Zolopa, A. R., Holodniy, M., Sheiner, L., Bamberger, J. D., Chesney, M. A., Moss, A. 2000; 14 (4): 357-366

    Abstract

    To examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy.A cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels.Thirty-four HIV-infected people with a median of 12 months of PI therapy.Adherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance.Median adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36-65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03).A substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

    View details for Web of Science ID 000086155800008

    View details for PubMedID 10770537

  • The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan ANTIVIRAL THERAPY DeGruttola, V., Dix, L., D'Aquila, R., Holder, D., Phillips, A., Ait-Khaled, M., Baxter, J., Clevenbergh, P., Hammer, S., Harrigan, R., KATZENSTEIN, D., Lanier, R., Miller, M., Para, M., Yerly, S., Zolopa, A., Murray, J., Patick, A., Miller, V., Castillo, S., Pedneault, L., Mellors, J. 2000; 5 (1): 41-48

    Abstract

    To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.

    View details for Web of Science ID 000087183000009

    View details for PubMedID 10846592

  • Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: Clinical and genotypic predictors of virologic response JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Shulman, N. S., Zolopa, A. R., Passaro, D. J., Murlidharan, U., Israelski, D. M., Brosgart, C. L., Miller, M. D., Van Doren, S., Shafer, R. W., Katzenstein, D. A. 2000; 23 (3): 221-226

    Abstract

    To determine the impact of prior nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy, genotypic resistance, and other variables on response to efavirenz (EFV)- and adefovir dipivoxil (ADV)-based salvage therapy.Retrospective clinical cohort study.One university and one community-based HIV clinic.All 33 patients who were coenrolled in both the EFV and ADV expanded access programs.Patients received EFV 600 mg/day and ADV 120 mg/day in addition to other antiretroviral agents.HIV viral load (<500 copies/ml) at 12 and 24 weeks.10 of 33 (30%) patients at 12 weeks and 8 of 33 (24%) patients at 24 weeks had viral loads <500 copies/ml. Prior NNRTI use and a history of any NNRTI-associated mutations predicted failure. Patients with Y181C or G190A single mutations had an initial greater magnitude of viral load suppression than those with K103N, but this advantage was short lived. No one with any NNRTI mutations responded with a viral load <500 copies/ml at 12 or 24 weeks.EFV/ADV-based salvage yielded viral load suppression at 24 weeks in 42% (8 of 19) of patients who were highly NRTI and protease inhibitor experienced but NNRTI naive. NNRTI-experienced study subjects had a poor response regardless of the specific NNRTI resistance mutation they harbored.

    View details for Web of Science ID 000086883600002

    View details for PubMedID 10839657

  • HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed ANNALS OF INTERNAL MEDICINE Zolopa, A. R., Shafer, R. W., Warford, A., Montoya, J. G., Hsu, P., KATZENSTEIN, D., Merigan, T. C., Efron, B. 1999; 131 (11): 813-?

    Abstract

    Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed.To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation.Retrospective clinical cohort study.University-based HIV clinic.54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months.HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL.In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included.In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.

    View details for Web of Science ID 000084053200002

    View details for PubMedID 10610625

  • Invasive fungal sinusitis due to Scedosporium apiospermum in a patient with AIDS CLINICAL INFECTIOUS DISEASES Eckburg, P. B., Zolopa, A. R., Montoya, J. G. 1999; 29 (1): 212-213

    View details for Web of Science ID 000081685300042

    View details for PubMedID 10433595

  • Association between time homeless and perceived health status among the homeless in San Francisco JOURNAL OF COMMUNITY HEALTH White, M. C., Tulsky, J. P., Dawson, C., Zolopa, A. R., Moss, A. R. 1997; 22 (4): 271-282

    Abstract

    The purpose of this study was to describe the perceived health of the homeless, and to measure the effect of time homeless on perceived health status, after controlling for sociodemographic characteristics and health conditions. The design was cross-sectional; the population was a representative sample of homeless in San Francisco, interviewed on health issues. Analysis of predictors of poor or fair health status was by logistic regression. In this sample of 2780 persons, 37.4% reported that their health status was poor or fair as compared to good or excellent. Reporting poor or fair health status was significantly associated with time homeless, after controlling for sociodemographic variables and health problems including results from screening for HIV and TB (OR = 1.49, 95% CI 1.24-1.79). Comparisons with data from the National Health Interview Survey (NHIS) showed poorer health status among the homeless persons in this study. Standardized morbidity ratios were highest for asthma; there was twice the number of homeless persons reporting asthma, in younger as well as older adults, as would be expected using NHIS rates. There was also an excess of arthritis, high blood pressure and diabetes in those age 18-44 as compared to adults in the Health Interview Survey. The time spent homeless remains associated with self-reported health status, after known contributors to poor health are controlled. Persons who have been homeless for longer periods of time may be the persons to whom health care interventions should be aimed.

    View details for Web of Science ID A1997XL31900005

    View details for PubMedID 9247850

  • PREVALENCE OF MEASLES ANTIBODIES IN ADULTS WITH HIV-INFECTION - POSSIBLE RISK-FACTORS OF MEASLES SERONEGATIVITY AIDS Kemper, C. A., Zolopa, A. R., Hamilton, J. R., Fenstersheib, M., Bhatia, G., Deresinski, S. C. 1992; 6 (11): 1321-1325

    Abstract

    To determine the prevalence of measles (rubeola) immunity in a group of HIV-1-infected adults and to examine predictors of measles seronegativity in this population.County hospital outpatient clinic and public-health department early HIV intervention clinic.A total of 262 HIV-infected adults presenting to outpatient clinics between September 1990 and January 1991.Patients were screened for the presence of measles immunoglobulin G antibody, as measured by an enzyme-linked immunosorbent assay (ELISA). Pertinent clinical and immunologic information was recorded. Univariate and multivariate analyses were performed to identify possible risk factors for measles seronegativity.Measles seronegativity, as defined by a lack of detectable antibody (ELISA predicted index value < 1.0).Thirteen (5%) patients lacked serologic evidence of immunity. Risk factors for measles seronegativity included year of birth in 1957 or later, Caucasian (non-Hispanic) race and oral hairy leukoplakia. Factors associated with progressive HIV disease (other than hairy leukoplakia) were not associated with a lack of existing immunity.A high prevalence (95%) of measles antibody was found in this large group of HIV-infected adults. Young, white individuals born in 1957 or later were at the greatest risk for measles seronegativity, but declining immunity due to progressive HIV infection did not appear to be associated with a lack of antibody. Self-reported histories of measles infection or immunization were not reliable predictors of measles immunity.

    View details for Web of Science ID A1992JY79600013

    View details for PubMedID 1472336

Conference Proceedings


  • Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons Lawrence, J., Schapiro, J., Winters, M., Montoya, J., Zolopa, A., Pesano, R., Efron, B., Winslow, D., Merigan, T. C. UNIV CHICAGO PRESS. 1999: 1356-1364

    Abstract

    The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.

    View details for Web of Science ID 000080561100007

    View details for PubMedID 10228055

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