Camlin Tierney

Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202

BACKGROUND Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. METHODS A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fishers exact tests. RESULTS Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. CONCLUSIONS Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.

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.

Pharmacogenetics of Plasma Efavirenz Exposure after Treatment Discontinuation: An Adult AIDS Clinical Trials Group Study

BACKGROUND Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals. METHODS We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P<.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P<.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for >21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype. CONCLUSIONS The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.

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.

In vivo antagonism with zidovudine plus stavudine combination therapy.

Human immunodeficiency virus (HIV)-infected subjects receiving zidovudine were randomized either to add stavudine (d4T) or didanosine (ddI) to their current regimen or to switch to ddI or d4T monotherapy. After 16 weeks of therapy, the mean reduction in HIV RNA from baseline was 0.14 log(10) copies/mL in patients receiving d4T or zidovudine plus d4T. In subjects receiving ddI or ddI plus zidovudine, reductions were 0.39 and 0.56 log(10), respectively. CD4 cell counts remained stable or showed modest increases in all arms except the zidovudine plus d4T arm. Patients receiving zidovudine plus d4T showed progressive declines in CD4 cell counts with a median of 22 cells/mm(3) below baseline by 16 weeks. Examination of intracellular levels of d4T-triphosphate in 6 subjects was consistent with previous in vitro studies demonstrating pharmacologic antagonism between zidovudine and d4T. Analysis of these data suggests that zidovudine and d4T should not be prescribed in combination and that ddI provides greater antiviral activity than d4T in zidovudine-treated patients.

Multiple-Dose Escalation Study of the Safety, Pharmacokinetics, and Biologic Activity of Oral AMD070, a Selective CXCR4 Receptor Inhibitor, in Human Subjects

ABSTRACT AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P ≤ 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an Emax model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.

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

Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis

Objective: To evaluate treatment-mediated changes in HIV-1 RNA and CD3 count as prognostic markers and surrogate end points for disease progression (AIDS/death). Methods: Data from 13,045 subjects in all 16 randomized trials comparing nucleoside analogue reverse transcriptase inhibitors and having HIV-1 RNA measurements at 24 weeks were obtained. A total of 3146 subjects had HIV-1 RNA and CD3 count determinations at 24 weeks after starting treatment. Results: At Week 24, the percentage of subjects experiencing an HIV-1 RNA decrease of >1 log(10) copies/ml or a CD4 count increase of >33% was similar (22% vs 25%). Changes in both markers at Week 24 mere significant independent predictors of AIDS/death: across trials, the average reduction in hazard was 51% per 1 log(10) HIV-1 RNA copies/ml decrease (95% confidence interval: 41%, 59%) and 20% per 33% CD4 count increase (17%, 24%). In univariate analyses, the hazard ratio for AIDS/death in randomized treatment comparisons was significantly associated with differences between treatments in mean area under the curve of HIV-1 RNA changes to Weeks 8 and 24 (AUCMB) and mean CD3 change at Week 24, but, in multivariate analysis, only mean CD4 change was significant. Conclusions: Change in HIV-1 RNA, particularly using AUCMB, and in CD4 count should be measured to aid patient management and evaluation of treatment activity in clinical trials. However, short-term changes in these markers are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death.