Roy M. Gulick

Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

BACKGROUND CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Early Versus Standard Antiretroviral Therapy for HIV Infected Adults in Haiti

BACKGROUND For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)

Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals

Context Neurologic toxicity is the most commonly reported adverse effect of the antiretroviral drug efavirenz. Contribution In this substudy of a randomized, controlled trial, 12 of 200 (6%) HIV-infected individuals discontinued treatment with efavirenz because of central nervous system symptoms or mood disorders versus 0 of 103 individuals (0%) who were not receiving the drug. Although patients taking efavirenz had more neuropsychological symptoms, such as bad dreams, in the first week of therapy, no statistically significant neuropsychological differences were found at weeks 4, 12, and 24. Implications Some adverse neuropsychological effects associated with efavirenz are probably transient. The Editors Efavirenz is a non-nucleoside reverse transcriptase inhibitor approved for treatment of HIV infection. The drug is potent, is generally well tolerated, and can be administered once daily, making it a preferred treatment option for HIV infection (1, 2). The most commonly reported adverse effect with efavirenz is neurologic toxicity, with more than 50% of patients reporting symptoms in open-label studies (1, 3). Our randomized, controlled study prospectively characterized aspects of the neurologic toxicity of 3 protease inhibitorsparing antiretroviral regimens for the initial treatment of HIV infection. Methods This investigator-initiated trial was a substudy of the AIDS Clinical Trials Group study A5095, a randomized, double-blind trial of 3 antiretroviral regimens: zidovudine and lamivudine in combination with efavirenz; abacavir; or abacavir and efavirenz in combination (4). For simplicity, we will refer to 2 groups: patients who received efavirenz (with or without abacavir) and those who did not. Randomization was performed centrally without reference to center. The study was supported by the National Institutes of Health (NIH) and was approved by the institutional review boards at each of the participating institutions, with each patient providing informed consent to participate in the substudy. All patients at sites taking part in the substudy were invited to participate before randomization for the parent study (Figure 1). Unblinding and within-class substitutions were allowed in cases of treatment-limiting toxicity (we substituted stavudine for zidovudine, didanosine for abacavir, and nevirapine for efavirenz). Participants had not previously received antiretroviral therapy, and their baseline plasma HIV-1 RNA levels were greater than 400 copies/mL. Parent study A5095 enrolled 1147 participants, of whom 303 at 36 clinical trials units volunteered to participate in the additional evaluations for A5097s. Participants were recruited between March 2001 and January 2002. Figure 1. CONSORT diagram of substudy 5097s. The primary measures of neuropsychological performance were the Trail Making Tests (Parts A and B) and the Digit Symbol Substitution Test (part of the Wechsler Adult Intelligence Scale III [5]). A summary neuropsychological Z score (NPZ3) was derived from the sum of the scores from these 3 tests and standardized for age. Positive scores indicated above-normal function, whereas negative scores indicated below-normal function. The entire score was coded as missing if any component of the NPZ3 was not available. The Neurologic AIDS Research Consortium provided administrator training at each site. These tests assessed functioning in the areas of motor persistence, sustained attention, response speed, visuomotor coordination, and conceptual shifting and tracking. Neuropsychometric measures were collected at baseline and at weeks 1, 4, 12, and 24. Testing was performed at each time point to assess symptoms that might be associated with efavirenz use, sleep disorders, anxiety, depression, and history of drug abuse. The instruments are summarized in Table 1. The symptom questionnaire developed for this study is shown in the Appendix Figure. Appendix Figure. Sample participant questionnaire. Table 1. Testing Instruments Whole blood was collected from all participants to determine efavirenz trough concentrations in plasma (13). These data were used to explore relationships between drug exposure and other variables that were evaluated in the study. Statistical Analysis Our substudy was designed to compare neurologic changes from baseline in patients who received efavirenz with changes in those who did not. The study had 90% power to detect a standard deviation of 0.4 for change in the summary neuropsychological performance score from baseline to week 1. We presented descriptive statistics for the study sample and used nonparametric tests to determine treatment differences. Using the nonparametric methods of Hodges and Lehmann (14) and Proc-StatXact software, version 4.0.1 (Cytel Software Corp., Cambridge, Massachusetts), we estimated treatment differences for continuous outcomes with corresponding exact confidence intervals. Generalized estimating equation modeling (a regression method) and the Wei-Johnson test (a nonparametric method for analyzing incomplete 2-sample data) (15) were used to compare treatment groups longitudinally; both methods assumed that data were missing completely at random. We used the Spearman correlation coefficient, a rank-based method that is robust to extreme observations, to evaluate correlations. All significance testing was performed at an level of 0.05 with no adjustment for multiple testing. All reported P values were 2-sided. To assess the potential effect of any missing data, we performed multiple imputation, analyzed 2 worst-case scenarios (Appendix Table 1 and Appendix Table 2), and conducted an as-treated analysis that excluded patients who discontinued efavirenz therapy. We used SAS software (SAS Institute, Inc., Cary, North Carolina) to perform statistical analyses. Test sources included Elsevier Science (Oxford, United Kingdom) for the Pittsburgh Sleep Quality Index, Mind Garden (Redwood City, California) for the State-Trait Anxiety Inventory for Adults, and the National Institute of Mental Health (Bethesda, Maryland) for the Center for Epidemiologic Studies Depression Scale. Role of the Funding Sources This investigator-initiated protocol was supported by the NIH. Drugs used in the study were donated by pharmaceutical companies whose representatives participated in team discussions. The study was monitored by NIH-contracted monitors and was supervised by a data safety monitoring committee that was appointed by the National Institute of Allergy and Infectious Diseases. The NIH-supported biostatistical team working with the AIDS Clinical Trials Group and the Neurologic AIDS Research Consortium performed the statistical analyses. The protocol team, led by the first author, had final responsibility for the study protocol, case report forms, statistical analysis plan, progress of the study, analysis, and reporting of the data, regardless of outcome. The final version was the sole responsibility of the authors. The team had full access to the data files of the study. Results Baseline Evaluations Recruitment characteristics are displayed in Figure 1; demographic characteristics of the study participants are presented in Table 2. The treatment groups were balanced at baseline with respect to demographic characteristics, neuropsychological measures, and responses to the symptom questionnaire. The sleep disturbance component of the global sleep index demonstrated a baseline difference; the patients who eventually received efavirenz had marginally more sleep disturbances (P= 0.048) (data not shown). Other components of the sleep index, including quality, latency, duration, efficiency, use of sleeping medication, and daytime dysfunction, were similar between groups. Alcohol abuse, drug use, and affective disturbances were infrequent and similar for both groups. Table 2. Baseline Characteristics and Evaluations by Treatment Group Disposition of Study Participants The study allowed for drug substitution from the same class of antiretroviral agents in cases of treatment-limiting toxicity. Table 3 summarizes the modifications that occurred and the respective reasons. Appendix Table 3 gives further details of timing of modifications and the ethnicity of the individuals. Primary end point data (the change in NPZ3 from baseline to week 1) were observed in 283 of the 303 (93.4%) participants. Table 3. Reasons for Modification of Treatment Appendix Table 1. Neuropsychological Performance Appendix Table 2. Results of Sensitivity Analysis by Generalized Estimating Equation Method Appendix Table 3. Status and Ethnicity of Patients Requiring Modification of Treatment Prospective Evaluations Median NPZ3 scores improved in both groups during the study, with the greatest change occurring in the first week of treatment (Figure 2). No statistically significant differences in changes in neuropsychological performance were observed between the groups at any time point. We conducted conventional longitudinal analyses to further investigate differences in neuropsychological scores between the treatment groups. On the basis of these analyses, we had insufficient evidence to conclude that there were treatment differences (generalized estimating equation modeling in which treatment was the only independent variable and an exchangeable correlation structure was assumed, P= 0.176; Wei-Johnson test, P= 0.196). Multiple sensitivity analyses were performed, including single and multiple imputation methods, as-treated analyses, and 2 forms of worst-case scenarios. Details of these analyses are shown in Appendix Table 1. Multiple imputation and as-treated analyses generally provided similar results to observed data at specific weeks; however, the worst-case analyses at weeks 4, 12, and 24 displayed significant differences between groups. These results suggest that differences between groups might exist if the worst-case scenario were true, that is, if patients without data who were receiving efavirenz had wors

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

BACKGROUND Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study. METHODS 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. RESULTS 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. CONCLUSIONS 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.

ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-Week results

ObjectiveTo evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals. DesignProspective, randomized, double-blind, multicenter. MethodsEligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68). ResultsMean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 × 106/l and 310 × 106/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50–100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound. ConclusionsABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.

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.

Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo.

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.

HIV Type 1 Chemokine Coreceptor Use among Antiretroviral-Experienced Patients Screened for a Clinical Trial of a CCR5 Inhibitor: AIDS Clinical Trial Group A5211

BACKGROUND Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors. METHODS We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression. RESULTS Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P<.001). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 (10%) had D/M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug. CONCLUSIONS Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/M group had significantly lower CD4(+) cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors.

Pre-existing Minority Drug-Resistant HIV-1 Variants, Adherence, and Risk of Antiretroviral Treatment Failure

BACKGROUND The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain. METHODS To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants. RESULTS The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90-6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58-3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression. CONCLUSIONS In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy. CLINICAL TRIALS REGISTRATION NCT00013520.

Preexisting Resistance to Nonnucleoside Reverse-Transcriptase Inhibitors Predicts Virologic Failure of an Efavirenz-Based Regimen in Treatment-Naive HIV-1–Infected Subjects

A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure. Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%. The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance (hazard ratio 2.27 [95% confidence interval], 1.15-4.49; P = .018). These results support resistance testing before starting antiretroviral therapy.