Richard Haubrich

A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500 per Cubic Millimeter

BACKGROUND This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter. METHODS We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death. RESULTS Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment. CONCLUSIONS Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

Class-sparing regimens for initial treatment of HIV-1 infection.

BACKGROUND The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. METHODS In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups. RESULTS At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. CONCLUSIONS Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response

OBJECTIVE To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING Five university-affiliated HIV clinics. PATIENTS A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION Individualized, unrestricted antiretroviral therapy. MEASUREMENTS Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials.

BACKGROUND The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy

BACKGROUND Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Metabolic Outcomes in a Randomized Trial of Nucleoside, Nonnucleoside and Protease Inhibitor-Sparing Regimens for Initial HIV Treatment

Background:The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection. Methods:Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids. Results:Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25–39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12–24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5–14) in the NRTI-sparing arm (P ≤ 0.023 for all comparisons). Varying the definition of lipoatrophy (≥10 to ≥40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32–33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11–13%) in the NRTI-sparing arm. Conclusion:Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials.

Objective:To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. Design:DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. Methods:Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. Results:Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. Conclusion:At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 24.

Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems

Highly active antiretroviral therapy (HAART) delays disease progression and death. However, the treatments incompletely control HIV replication, only partially restore immune function, have significant shortand long-term toxicities, and eventually fail in many patients with consequent development of HIV drug resistance. Thus, there is increasing need for information to guide HIV-infected patients and their providers in making decisions regarding optimal use of antiretroviral therapies. Although clinical trials provide valuable information about efficacy and side effects of antiretroviral treatment, they have limited size, duration and power to detect effects on clinical outcomes, focusing instead on surrogate endpoints such as virologic failure, treatment discontinuation or composite outcome measures. Outside the clinical trial setting, there is tremendous heterogeneity among HIV-infected patients. The prevalence and impact of important health conditions such as hepatitis C virus (HCV) co-infection, mental illness and substance abuse likely contribute to increased toxicity and decreased clinical effectiveness of HAART regimens among the broader spectrum of patients treated in routine care. Cohorts with significant diversity in HIV disease severity, comorbidities and demographic distributions are required to provide information regarding long-term outcomes and complications of HIV infection in the modern HAART era. The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) was created to better define the relationship between patient and treatment factors and long-term clinical outcomes among HIV-infected patients in the HAART era. The CFARs are a national network of centres of excellence for HIV care and research established by the National Institutes of Health (NIH) whose mission is to support a multi-disciplinary environment for basic, clinical, epidemiologic, behavioural and translational research in the prevention, detection and treatment of HIV infection and AIDS. There are 19 CFARs located at academic and research institutions throughout the United States. The objective of the CNICS project is to integrate clinical data from the large and diverse population of HIV-infected persons receiving care at CFAR sites to investigate questions related to HIV disease management that cannot be readily addressed through traditional randomized controlled clinical trials and other cohort studies. Investigators with expertise in basic, clinical, translational and epidemiologic research, in addition to medical informatics, are collaborating on the CNICS project. The potential to build a comprehensive clinical data repository for HIV disease was greatly advanced by the work of CFAR investigators at the participating CNICS sites who had instituted point-of-care electronic medical record systems (EMRs) with the dual purpose of providing real-time clinical information to facilitate the delivery of HIV care and capturing standardized clinical data to support populationbased HIV research. The initial four CNICS sites were Case Western Reserve University, University of * Corresponding author. Center for AIDS Research, University of Washington, 325 9th Ave, MS 359931, Seattle, WA 98104, USA. E-mail: kitahata@u.washington.edu 1 Department of Medicine, University of Washington, Seattle, 98195, USA. 2 Department of Medicine, Case Western Reserve University, Cleveland, 44106, USA. 3 Department of Medicine, University of California, San Diego, 92110, USA. 4 Department of Medicine, Harvard University, Boston, 02115, USA. 5 Department of Medicine, Johns Hopkins University, Baltimore, 21218, USA. 6 Department of Medicine, University of Alabama, Birmingham, 35209, USA. 7 Department of Medicine, University of California, San Francisco, 94143, USA. Published by Oxford University Press on behalf of the International Epidemiological Association

Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection

A highly complex network of coinhibitory and costimulatory receptors regulates the outcome of virus-specific CD8(+) T-cell responses. Here, we report on the expression patterns of multiple inhibitory receptors on HIV-specific, cytomegalovirus-specific, and bulk CD8(+) T-cell memory populations. In contrast to cytomegalovirus-specific CD8(+) T cells, the majority of HIV-specific CD8(+) T cells exhibited an immature phenotype and expressed Programmed Death-1, CD160 and 2B4 but not lymphocyte activation gene-3. Notably, before antiretroviral therapy, simultaneous expression of these negative regulators correlated strongly with both HIV load and impaired cytokine production. Suppression of HIV replication by antiretroviral therapy was associated with reduced surface expression of inhibitory molecules on HIV-specific CD8(+) T cells. Furthermore, in vitro manipulation of Programmed Death-1 and 2B4 inhibitory pathways increased the proliferative capacity of HIV-specific CD8(+) T cells. Thus, multiple coinhibitory receptors can affect the development of HIV-specific CD8(+) T-cell responses and, by extension, represent potential targets for new immune-based interventions in HIV-infected persons.

HLA-Associated Immune Escape Pathways in HIV-1 Subtype B Gag, Pol and Nef Proteins

Background Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA)-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. Methodology/Principal Findings HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q≤0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association), followed by Gag then Pol (where ∼15–20% of codons exhibited HLA associations), confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q≤0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. Conclusions/Significance The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate research in HIV epitope discovery and host-pathogen co-evolution, and are relevant to the continued search for an effective CTL-based AIDS vaccine.