Katie Mollan

Abacavir–Lamivudine versus Tenofovir–Emtricitabine for Initial HIV-1 Therapy

BACKGROUND The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known. METHODS In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks). RESULTS A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48. CONCLUSIONS In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1: A Randomized Trial

BACKGROUND Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS Antiretroviral-naive patients. INTERVENTION Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine. MEASUREMENTS Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE National Institutes of Health.

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1

Few studies have compared once-daily treatment regimens for HIV-1. This randomized trial in antiretroviral-naive patients with HIV-1 showed that a once-daily ritonavir-boosted protease inhibitor re...

Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results.

BACKGROUND AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. METHODS Primary endpoints were times to virologic failure, regimen modification, and safety event. RESULTS In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). CONCLUSIONS In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.

Association Between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk for Suicidal Ideation or Attempted or Completed Suicide: An Analysis of Trial Data

Context Postmarketing reports have suggested that efavirenz increases risk for suicide. Contribution In an analysis of data from 4 large, randomized trials in which patients with HIV were randomly assigned to either efavirenz-containing or efavirenz-free regimens for initial therapy, efavirenz was associated with a doubling of risk for suicidality (a composite of suicide, suicide attempt, and suicidal ideation). Caution The clinical trials were not specifically designed to investigate suicidality. Implication An increased risk for suicidality should be considered when choosing efavirenz as part of an initial antiretroviral regimen. The Editors Efavirenz is a preferred nonnucleoside reverse transcriptase inhibitor for treatment of HIV (14). Although efavirenz is generally safe and effective, it is associated with central nervous system side effects (58); prescribing information contains warnings of rare but serious psychiatric experiences, including suicide, but also notes that a causal relationship cannot be determined from postmarketing reports (5). Likewise, published cases and case series report suicidal thoughts or behavior with efavirenz (917). A literature review stated that clear evidence of association between efavirenz and suicide was not available and thus psychiatric history should not exclude patients from efavirenz treatment (18). Given the widespread use of efavirenz and uncertainty about its relationship to suicide, suicide attempt, or suicidal ideation, we report an AIDS Clinical Trials Group cross-protocol analysis of 4 studies in which participants were randomly assigned to an initial efavirenz-containing or efavirenz-free antiretroviral regimen. Our primary goal was to compare the hazard of suicidality between participants assigned to an efavirenz-containing versus efavirenz-free antiretroviral regimen for initial treatment of HIV-1, a potential safety issue not reported in the original studies. Supplement. Original Version (PDF) Methods Study Design and Participants Individual-level data from antiretroviral-naive participants with HIV-1 in AIDS Clinical Trials Group studies conducted from 2001 to 2010 that involved random assignment to an efavirenz-containing or efavirenz-free regimen were included in this prespecified retrospective cross-study analysis. Four studies met these criteria: A5095 (ClinicalTrials.gov: NCT00013520) (19, 20), A5142 (NCT00050895) (21), A5175 (NCT00084136) (22), and A5202 (NCT00118898) (23). Components of the antiretroviral regimen were randomly assigned, except for the nucleoside analogue choice in A5142. The studies varied by antiretroviral regimen and slightly by duration and eligibility criteria (Table 1); each study excluded participants with substantially abnormal baseline laboratory values. Histories of suicidal ideation or attempt were not exclusion criteria. Studies A5095 and A5202 enrolled participants in the United States and Puerto Rico; A5142 enrolled participants in the United States and South Africa; and A5175 enrolled participants from 9 countries in North and South America, Africa, and Asia. Table 1. Summary of Included Studies* Study protocols required reporting of signs, symptoms, or diagnoses at each visit, which were recorded with both open-text and data-entry codes. In A5175, diagnosis reporting instructions included specific codes for suicidality; the other studies used general psychiatric event codes (for example, psychiatric disorder, specify) plus open-text description. Each study required reporting of severe and life-threatening graded signs or symptoms per the Division of AIDS grading table (24), as well as any sign or symptom, regardless of grade, that led to change in study treatment; diagnoses were not graded. Further, study A5142 required report of all moderate signs or symptoms, and A5095 and A5202 required report of all moderate central nervous system symptoms. Site institutional review boards approved each study; participants provided written informed consent. Randomization Each study used permuted-block randomization; stratification factors and treatment groups are listed in Table 1. Efavirenz was formulated as one 600-mg pill given once daily, with three 200-mg pills given initially in A5095. Efavirenz assignment was open-label in A5142, A5175, and A5202 and was blinded and placebo-controlled in A5095 before a data safety monitoring board (DSMB) recommendation to unblind efavirenz. The DSMB released recommendations mid-study about inferior efficacy in the efavirenz-free group of A5095 (20 February 2003) and A5175 (23 May 2008), after which participants in the efavirenz-free groups were given the option to switch treatment (19, 22). Outcomes The primary outcome of this cross-study analysis was suicidality, defined as suicidal ideation or attempted or completed suicide and identified from signs, symptoms, diagnoses, adverse events, and death data via Medical Dictionary for Regulatory Activities, version 15.0. Prespecified Medical Dictionary for Regulatory Activities preferred terms were completed suicide, suicide attempt, intentional overdose, multiple drug overdose intentional, poisoning deliberate, suicidal ideation, suicidal behaviour, and depression suicidal. Attempted or completed suicide was a secondary outcome. Clinical investigators, blinded to treatment and previous adverse events, independently reviewed death data categorized as suicide, substance abuse, homicide, accident, unknown cause, or other cause (for example, infection, cancer, or organ failure); a secondary outcome included suicidality or fatal injury attributed to substance abuse, homicide, or accident. Covariates Each study protocol required report of prescription medication ongoing within 30 days before entry (denoted recent prestudy); prestudy psychoactive and antidepressant medications were identified from a medication list on the National Institute of Mental Health Web site (25). Psychiatric history was defined as any event in the Medical Dictionary for Regulatory Activities system organ class psychiatric disorders, and depression-related events were classified according to review of psychiatric events data by a psychologist. Prestudy psychiatric measures included psychiatric event history, recent psychoactive medication, depression-related event history, and recent antidepressant medication; presence of event history or prestudy medication was combined into 1 covariate. Additional a priori baseline covariates included geographic region, sex, race or ethnic group, age, pretreatment CD4 count, history of AIDS-defining event, and history of injection drug use (IDU); pretreatment HIV-1 RNA levels, body weight, and body mass index (BMI) at study entry were evaluated post hoc (Appendix Table 1). Analysis of race or ethnic group was limited to white, black, and Hispanic from the United States because of potential social and ethnic differences among countries and low frequencies in other groups and was self-reported and classified according to National Institutes of Health categories. Covariate misclassification was possible; for example, history of psychiatric events or IDU could have been undisclosed or underreported. Appendix Table 1. Baseline Characteristics* Data Synthesis and Statistical Analysis The primary analysis approach was intention-to-treat (ITT). Participant-level data were analyzed according to randomized treatment allocation, with follow-up from randomization to last on-study contact or death; all follow-up in A5095 and A5175 was censored after a DSMB recommendation related to the efavirenz comparison (denoted ITT DSMB). In a sensitivity analysis, follow-up included time from randomization to last on-study contact or death, regardless of DSMB recommendations (denoted ITT); deaths were summarized using the ITT approach. As-treated analyses excluded participants who never started treatment and included follow-up from treatment initiation through the earliest of the following: discontinuation of the assigned efavirenz-containing or efavirenz-free strategy plus 28 days for washout, discontinuation of all antiretroviral therapy plus 28 days, or last on-study contact (denoted as-treated). A sensitivity approach further censored as-treated follow-up at the time of DSMB recommendations (denoted as-treated DSMB). Antiretroviral modifications were allowed for reasons such as toxicity, virologic failure, or DSMB recommendations. Missing baseline data were rare (<1%); thus, covariate-adjusted analyses used a complete-case approach. Crude incidence rates were calculated as the number of cases per total person-years (PYs) at risk, presented as events per 1000 PYs. Incidence rate difference (IR) between treatment groups was quantified by a Mantel-Haenszel estimate, stratified by study, with a 95% CI computed using a rare events variance estimator (26). The primary end point, time to suicidality, is presented with cumulative incidence curves and compared between groups with a Gray test (27), stratified by study, with nonsuicide death considered a competing risk. Estimated efavirenz and baseline covariate associations were quantified by a hazard ratio (HR) from a Cox proportional hazards model, stratified by study. Modification of efavirenz association by covariates was evaluated with interaction terms. The Cox model proportional hazards assumption was evaluated with a piecewise constant hazard with time (24 weeks vs. >24 weeks) and with a log-transformed time variable. An incidence rate ratio for the efavirenz association was estimated from an exact Poisson model, stratified by study, to evaluate sensitivity of the Cox model to low event frequencies. Analyses were conducted 2-sided with a significance level of 0.05, without adjustment for multiplicity, in SAS, versions 9.2 or 9.3 (phreg, genmod) (SAS Institute, Cary, North Carolina), and in R, version 2.15.1, competing risks package (cmprsk) (www.r-project.org). Role of the Funding Source The National Institute

Regimen Simplification to Atazanavir-Ritonavir Alone as Maintenance Antiretroviral Therapy: Final 48-Week Clinical and Virologic Outcomes

BACKGROUND Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety. METHODS Subjects with virologic suppression after > or = 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor (PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure (confirmed HIV-1 RNA level > or = 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing (SGS). Residual viremia (1.1-49 copies/mL) was measured by single-copy assay. RESULTS Thirty-four subjects simplified to ATV/RTV alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS. CONCLUSIONS In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy.

Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention.

Effective antiretroviral (ARV)‐based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co‐medications revealed significant (P < 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9‐fold > colorectal; vaginal ABCC2 2.9‐fold > colorectal; colorectal ABCC4 2.0‐fold > cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues.

Crowdsourcing HIV Test Promotion Videos: A Noninferiority Randomized Controlled Trial in China

BACKGROUND Crowdsourcing, the process of shifting individual tasks to a large group, may enhance human immunodeficiency virus (HIV) testing interventions. We conducted a noninferiority, randomized controlled trial to compare first-time HIV testing rates among men who have sex with men (MSM) and transgender individuals who received a crowdsourced or a health marketing HIV test promotion video. METHODS Seven hundred twenty-one MSM and transgender participants (≥16 years old, never before tested for HIV) were recruited through 3 Chinese MSM Web portals and randomly assigned to 1 of 2 videos. The crowdsourced video was developed using an open contest and formal transparent judging while the evidence-based health marketing video was designed by experts. Study objectives were to measure HIV test uptake within 3 weeks of watching either HIV test promotion video and cost per new HIV test and diagnosis. RESULTS Overall, 624 of 721 (87%) participants from 31 provinces in 217 Chinese cities completed the study. HIV test uptake was similar between the crowdsourced arm (37% [114/307]) and the health marketing arm (35% [111/317]). The estimated difference between the interventions was 2.1% (95% confidence interval, -5.4% to 9.7%). Among those tested, 31% (69/225) reported a new HIV diagnosis. The crowdsourced intervention cost substantially less than the health marketing intervention per first-time HIV test (US

Hepatitis C Virus (HCV) NS3 Sequence Diversity and Antiviral Resistance-Associated Variant Frequency in HCV/HIV Coinfection

131 vs US

Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS Clinical Trials Group Study A5202.

238 per person) and per new HIV diagnosis (US