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Vicriviroc Effective in Treatment-Experienced
Patients in Phase 2 Study VICTOR-E1
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"This study demonstrates vicriviroc's virologic and immunologic activity and safety in treatment-experienced patients infected with CCR5-tropic HIV. The results of this trial were comparable to those seen in similarly designed trials conducted with other CCR5 antagonists and new classes of drugs. The 30-mg once-daily vicriviroc dose tended to have superior virologic suppression while maintaining a favorable toxicity profile and is the dose currently being evaluated in phase 3 studies......The benefits of vicriviroc, especially 30 mg once daily, were demonstrated by reductions in viral load, a significant likelihood of achieving and maintaining full virologic suppression (HIV RNA level <50 copies/mL), a reduced incidence and longer time to virologic failure, and improvement in CD4 counts. The responses to vicriviroc were often apparent by week 12 and were sustained through weeks 24 and 48, supporting the durability of the early antiviral effect......The mean change in baseline HIV RNA level at week 48 was -1.77 log10 copies/mL for the vicriviroc 30 mg recipients and -1.75 log10 copies/mL for the vicriviroc 20 mg recipients; the placebo arm exhibited a mean decrease in baseline HIV RNA of -0.79 log10 copies/mL p=.002 and p=.003, respectively, compared with placebo).....The proportions of subjects with HIV RNA levels <50 copies/mL (modified intent-to-treat and noncompleter equals failure population) at week 48 were 56% (22 of 39), 53% (21 of 40), and 14% (5 of 35) in the vicriviroc 30 mg, vicriviroc 20 mg, and placebo groups, respectively (p=.001 for vicriviroc 30 mg and p=.001 for vicriviroc 20 mg, compared with placebo).....The magnitude of virologic suppression in subjects with fewer (<2) active drugs in the OBT appeared to favor the vicriviroc 30 mg group; the proportions of subjects with week 48 HIV RNA levels <50 copies/mL (modified intent-to-treat time to loss of virologic response analysis) were 57%, 29%, and 17%, respectively, for vicriviroc 30 mg, vicriviroc 20 mg, and placebo. A similar tendency to superior time to loss of virologic response with vicriviroc 30 mg appeared in subjects with baseline HIV RNA levels >100,000 copies/mL (33%, 17%, and 10%, respectively) or baseline CD4 count <200 cells/mm3 (50%, 36%, and 14%, respectively)......No seizures, malignancies, or hepatotoxicity were reported among vicriviroc recipients. Also, no consistent pattern in laboratory value abnormalities was apparent across treatment groups.....The most commonly reported adverse event was diarrhea; no trend in the rates was apparent across treatment arms. The numbers of adverse events overall were too small to draw conclusions"
Vicriviroc in Combination Therapy with an Optimized Regimen for Treatment-Experienced Subjects: 48-Week Results of the VICTOR-E1 Phase 2 Trial
The Journal of Infectious Diseases Feb 15 2010;201:590-599
Jamal Suleiman,1,a Barry S. Zingman,4,a Ricardo Sobhie Diaz,2 Jose Valdez Ramalho Madruga,3 Edwin DeJesus,5 Jihad Slim,6 Carmen Mak,7 Erin Lee,7 Michael C. McCarthy,7 Lisa M. Dunkle,7 and Sharon Walmsley8
1Brasilmed Assistencia Medica e Pesquisas, 2Laboratorio de Retrovirologia, Federal University of Sao Paulo, and 3Centro de Referencia e Treinamento em DST/AIDS, Sao Paulo, Brazil; 4Montefiore Medical Center and the Einstein-Montefiore Center for AIDS Research, Bronx, New York; 5Orlando Immunology Center, Orlando, Florida; 6St Michael's Medical Center-Infectious Diseases, Newark, 7Schering-Plough Research Institute, Kenilworth, New Jersey; and 8The University Health Network, Toronto, Ontario, Canada
ABSTRACT
Background. Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy.
Methods. This double-blind, dose-ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re-optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5-tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log10 HIV RNA level at 48 weeks, based on an intent-to-treat analysis.
Results. One hundred fourteen persons received vicriviroc at 30 mg (n=39), vicriviroc at 20 mg (n=40), or placebo (n=35). The mean change in baseline HIV RNA level at week 48 was -1.77 log10 copies/mL for 30 mg of vicriviroc and -1.75 log10 copies/mL for 20 mg of vicriviroc, compared with -0.79 log10 copies/mL for placebo (=.002 and , p=,003 respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm3 for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively ( and , respectively, compared with placebo). Rates of adverse events (mostly mild-to-moderate) were 111.4, 112.5, and 147.4 events per 100 subject-years, respectively.
Conclusions. Vicriviroc administered with a protease inhibitor plus ritonavir-containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment-experienced patients.
The life expectancy of people with human immunodeficiency virus (HIV) infection has steadily increased since the introduction of antiretroviral therapy >2 decades ago [1]. Current guidelines recommend that patients receive >3 antiretroviral drugs of at least 2 classes [2]. Although antiretroviral therapy is effective in suppressing viral replication in many patients, treatment failure is relatively frequent. Virologic failure is commonly associated with drug resistance, which often involves cross-resistance within classes of drugs [3, 4]. Many patients discontinue initial antiretroviral therapy because of adverse effects [5]. The need to replace drugs that are no longer effective or tolerable to maintain a fully active regimen creates an ongoing demand for agents from new classes with novel mechanisms of action and favorable adverse-effect profiles. One new class of antiretrovirals is the CCR5 antagonists. These agents block the CCR5 chemokine receptor, which most strains of HIV use as a coreceptor for gaining entry to CD4+ cells. Blockade of CCR5 has been shown to provide potent antiretroviral activity [6].
Vicriviroc is a novel, small-molecule CCR5 antagonist, which has demonstrated potent antiviral activity in early clinical studies. As a substrate of CYP3A4, vicriviroc may be administered in regimens containing a CYP3A4 inhibitor without dosage adjustment, and clinical development (including this protocol) has taken the strategy of vicriviroc use in regimens containing a ritonavir-boosted protease inhibitor. This approach provides the convenience of a single dose of 30 mg once daily with no adjustment required for concomitant medications. In a phase 2 trial evaluating vicriviroc in daily doses of 5, 10, and 15 mg added to a failing ritonavir-containing regimen, antiviral activity was observed in all 3 vicriviroc dosage groups [7]. However, because it was not clear that optimal antiviral benefit had been achieved and because no dose-limiting toxicities had been observed, testing at higher doses was deemed advisable. This trial was designed to evaluate the efficacy and safety of 2 dose levels of vicriviroc, compared with placebo, each in combination with optimized background therapy (OBT) containing a protease inhibitor with ritonavir.
Results
The study was conducted in North and Latin America, Europe, and South Africa from June 2006 through October 2007. One hundred sixteen persons were randomized to receive vicriviroc at 30 mg (n=40), vicriviroc at 20 mg (=39), and placebo (n=37). The treatment groups were balanced with respect to demographic and baseline characteristics. Consistent with other similarly designed studies reported recently, over one-half of subjects had <2 active drugs in their OBT (Table 1).
Subject disposition.
One hundred fourteen subjects received at least 1 dose of blinded study drug (modified intent-to-treat population) (Table 1). On the basis of a Kaplan-Meier analysis, time to discontinuation for any reason was significantly longer in the vicriviroc groups than in the placebo group (p=.001 and p<.0001 for the vicriviroc 30 mg and vicriviroc 20 mg arms, respectively, compared with placebo). Treatment failure, the most common reason for discontinuation, occurred most frequently in the placebo arm. Twenty-one (95%) of 22 treatment failures occurred by week 24 regardless of treatment assignment. No subject discontinued because of treatment-related safety or tolerability issues.
Virologic response.
The mean change in baseline HIV RNA level at week 48 was -1.77 log10 copies/mL for the vicriviroc 30 mg recipients and -1.75 log10 copies/mL for the vicriviroc 20 mg recipients; the placebo arm exhibited a mean decrease in baseline HIV RNA of -0.79 log10 copies/mL (p=.002 and p=.003, respectively, compared with placebo) (Figure 1). The superior antiviral efficacy of vicriviroc at either 30 mg or 20 mg was apparent at week 12 (p<.001 and p=.002, respectively, compared with placebo) and was sustained thereafter (Figure 1).
Analysis of week 48 secondary end points was consistent with these results. The proportions of subjects with HIV RNA levels <50 copies/mL (modified intent-to-treat and noncompleter equals failure population) at week 48 were 56% (22 of 39), 53% (21 of 40), and 14% (5 of 35) in the vicriviroc 30 mg, vicriviroc 20 mg, and placebo groups, respectively (p<.001 for vicriviroc 30 mg and p<.001 for vicriviroc 20 mg, compared with placebo) (Figure 2). The modified intent-to-treat time to loss of virologic response virologic response rates were 59% (23 of 39), 50% (20 of 40), and 26% (9 of 35) for vicriviroc 30 mg, vicriviroc 20 mg, and placebo, respectively p=.003( and p=.027 , respectively, compared with placebo). Virologic suppression (HIV RNA level <50 copies/mL) was sustained significantly longer in the vicriviroc 30 mg or 20 mg groups, compared with placebo (p=.003 and p=.018, respectively).
The benefit of vicriviroc in regimens regardless of the number of active drugs in the background regimen is suggested by the mean change in baseline log10 HIV RNA at week 48 (Figure 3). The magnitude of virologic suppression in subjects with fewer (<2) active drugs in the OBT appeared to favor the vicriviroc 30 mg group; the proportions of subjects with week 48 HIV RNA levels <50 copies/mL (modified intent-to-treat time to loss of virologic response analysis) were 57%, 29%, and 17%, respectively, for vicriviroc 30 mg, vicriviroc 20 mg, and placebo. A similar tendency to superior time to loss of virologic response with vicriviroc 30 mg appeared in subjects with baseline HIV RNA levels >100,000 copies/mL (33%, 17%, and 10%, respectively) or baseline CD4 count <200 cells/mm3 (50%, 36%, and 14%, respectively). Analyses of primary and secondary efficacy end point subgroups including age, sex, race, region, baseline HIV RNA, baseline CD4 count, overall sensitivity score, and use of enfuvirtide or darunavir yielded consistent results and supported the efficacy advantage of vicriviroc 30 mg over placebo (data not shown).
Immunologic response.
Mean CD4 counts increased by 102 cells/mm3 in the vicriviroc 30 mg group, 136 cells/mm3 in the vicriviroc 20 mg group, and by 63 cells/mm3 in the placebo group, but only the difference between the 20-mg dose group and placebo was statistically significant (p=.039), possibly because the sample size did not provide adequate statistical power to distinguish changes in CD4 counts (Figure 4).
Coreceptor tropism.
Six subjects (5%) had CXCR4 virus (dual-mixed or X4-only) detected at baseline before any drug exposure (3 in the vicriviroc 30 mg group, 1 in the vicriviroc 20 mg group, and 2 in the placebo group). Subsequently, 19 additional subjects (9 in the vicriviroc 30 mg group, 7 in the vicriviroc 20 mg group, and 3 in the placebo group) had detection of DM/X4 virus after receiving treatment, with 11 detectable at or before week 8. Of the 25 subjects in whom DM/X4 virus was detected, 17 (68%) met protocol-defined criteria for virologic failure, but only 9 discontinued the study. Four subjects who received vicriviroc and had detectable DM/X4 tropic virus experienced a >50% decrease in baseline CD4 count; 3 of these 4 subjects had detectable DM/X4 tropism at baseline (before receiving any study drug). One of these subjects discontinued the study.
Resistance.
One subject (3%) in the vicriviroc 30 mg group, 4 subjects (10%) in the 20 mg group, and no subjects in the placebo group developed vicriviroc-resistant HIV infection at the time of study discontinuation. Among the 15 subjects receiving vicriviroc who experienced virologic failure, 2 developed resistance to the single active drug in their OBT. Among subjects with 0 or 1 fully active drugs in their OBT, the 30-mg dose of vicriviroc appeared to confer an advantage, as resistance to vicriviroc developed less frequently (1 [4.3%] of 23 in the vicriviroc 30 mg group vs 4 [19%] of 21 in the vicriviroc 20 mg group).
Safety.
The mean duration of treatment for the 114 subjects who received study drug was 44, 45, and 33 weeks for the vicriviroc 30 mg, vicriviroc 20 mg, and placebo groups, respectively. Sixty-eight (86%) of the 79 subjects randomized to receive vicriviroc completed 48 weeks of blinded treatment, compared with only 18 (49%) of 37 subjects in the control group.
Most subjects (>90%) experienced at least one treatment-emergent adverse event; these occurred with similar frequencies across treatment groups (95% in vicriviroc 30 mg, 98% in vicriviroc 20 mg, and 94% in placebo group). Most adverse events were mild or moderate in severity and occurred at similar frequencies across treatment groups (74% in vicriviroc 30 mg, 78% in vicriviroc 20 mg, and 74% in placebo group). The rate of adverse events was higher among subjects in the placebo group (147.4 incidents per 100 subject-years) than in the vicriviroc 30 mg (111.4 incidents per 100 subject-years) and 20 mg (112.5 incidents per 100 subject-years) groups. Table 2 lists treatment-emergent adverse events occurring in >10% of patients, adjusted for subject-years of exposure.
The most commonly reported adverse event was diarrhea; no trend in the rates was apparent across treatment arms. The numbers of adverse events overall were too small to draw conclusions.
The proportion of subjects with severe (grade 3/4) adverse events was similar across treatment groups (21% in vicriviroc 30 mg, 20% in vicriviroc 20 mg, and 20% in placebo group). Most grade 3/4 adverse events were isolated events in a single subject. It is notable that no seizures occurred in vicriviroc recipients.
Other events of interest included malignancies, hepatotoxicity, and ischemic cardiovascular events. No confirmed malignancies were reported in either vicriviroc group during the 48-week treatment period of this study. The number of subjects who experienced liver-related events was similar across treatment groups (2 in vicriviroc 30 mg, 3 in vicriviroc 20 mg, and 2 in placebo group), with the rates lower in both vicriviroc arms (6.02, 8.65, and 8.93 incidents per 100 subject-years, respectively). Elevations in liver function test results (alanine aminotransferase or aspartate aminotransferase) were generally mild (grade 1 or 2) and were evenly distributed across treatment groups; none appeared to be dose-related. No grade 3 or 4 elevations in alanine aminotransferase or aspartate aminotransferase were observed in the vicriviroc arms, and no subjects met the criteria for drug-induced liver injury (Hy's law). No ischemic cardiac events were reported.
Four deaths were reported, involving the 4 subjects who discontinued the study because of to adverse events. Two of the subjects were in the placebo group; both deaths occurred 60 days after the patient discontinued the study. One death was attributed to cardiorespiratory failure in a subject with either central nervous system toxoplasmosis or central nervous system metastases from lung cancer, and the other to hypokalemia secondary to diarrhea. Two deaths were in the vicriviroc 20 mg group; 1 occurred while participating in the study and was attributed to bilateral atypical pneumonia; the other was attributed to presumed disseminated tuberculosis complicated by multiple organ failure and occurred 15 days after the end of treatment. All deaths were deemed unlikely to be related to study drug.
Discussion
This trial was designed to evaluate the efficacy and safety of 2 dosage levels of vicriviroc, higher than levels previously studied, compared with placebo in individuals infected with CCR5-tropic HIV who were experiencing failure of their current antiretroviral therapy regimen. Subjects were highly treatment-experienced with documented resistance to both nucleotide reverse-transcriptase inhibitor and protease inhibitor antiretroviral therapy classes. Although the majority of subjects were white men from Latin America, the study also enrolled 22% women and 17% black/African-American subjects. Demographic and baseline characteristics were generally well balanced across treatment arms.
Subjects randomized to receive vicriviroc, in addition to a newly optimized protease inhibitor plus ritonavir-containing OBT, experienced a substantial benefit, compared with the control group who received OBT alone. The benefits of vicriviroc, especially 30 mg once daily, were demonstrated by reductions in viral load, a significant likelihood of achieving and maintaining full virologic suppression (HIV RNA level <50 copies/mL), a reduced incidence and longer time to virologic failure, and improvement in CD4 counts. The responses to vicriviroc were often apparent by week 12 and were sustained through weeks 24 and 48, supporting the durability of the early antiviral effect. Vicriviroc appeared to be associated with greater reductions in plasma HIV RNA level regardless of baseline overall sensitivity score (even among those with 3 active drugs), and both vicriviroc dosage levels demonstrated superior efficacy over placebo. The efficacy findings in this study confirm those reported in an earlier phase 2 dose-ranging trial with vicriviroc, supporting the prolonged antiviral effect of a vicriviroc-containing regimen in treatment-experienced subjects with HIV infection [ 7].
Vicriviroc was well tolerated in this study population. When adverse events were adjusted for exposure to study drug, the rate (incidents per 100 subject-years) of treatment-emergent adverse events was higher among subjects in the placebo group. Most adverse events were mild or moderate in severity. All severe adverse events were considered by the investigators to be unlikely related to study medication. None of the 4 reported deaths were judged to be related to study drug.
Diarrhea was the most common treatment-emergent adverse event reported, and the rates were comparable across treatment groups. Gastrointestinal disorders are frequent in HIV infection, and diarrhea is a common cause of morbidity [10]. Also, diarrhea is a known adverse effect of ritonavir-boosted protease inhibitors, which all subjects received in their OBT [11]. Notably, other gastrointestinal complaints, such as dyspepsia, nausea, vomiting, gastroenteritis, and aphthous stomatitis, were reported across treatment groups, underscoring the advanced HIV disease in this study population [10].
Persons with HIV infection may be at greater risk of infection because of impaired humoral and cellular immunity [12]. Theoretical concerns about CCR5 receptor blockade and increased susceptibility to infection or other serious outcomes have also been raised [13]. Notably, the exposure-adjusted rate for all infections in the aggregate was slightly lower in both vicriviroc groups, compared with placebo, and no other serious outcomes appeared to be related to vicriviroc exposure. Further observation in larger populations will be required to evaluate this issue.
No seizures, malignancies, or hepatotoxicity were reported among vicriviroc recipients. Also, no consistent pattern in laboratory value abnormalities was apparent across treatment groups.
DM/X4 virus was detected at baseline before any drug exposure in 5% of subjects and in an additional 19 subjects (17%) after dosing. Another CCR5 antagonist study has reported similar findings [14]. The detection of DM/X4 virus prior to exposure to study drug likely reflects either the natural history of HIV disease or the sensitivity of the original tropism assay [15,16]. Detection of DM/X4 virus may reflect "uncovering" of previously undetected DM/X4 virus after suppression of R5 virus, as has been reported with maraviroc [14,16]. Detection of DM/X4 virus tended to occur earlier in the vicriviroc 30 mg arm, suggesting that this dosage may provide greater selective pressure of CCR5 virus; this hypothesis needs to be explored in future studies. A reanalysis of data from this trial with use of the newer version of the Trofile assay, which has greatly enhanced sensitivity, is currently in progress.
Vicriviroc resistance emerged in a single subject who experienced virologic failure in the vicriviroc 30 mg arm but occurred in 4 subjects in the 20 mg arm. The paucity of active drugs in the OBT and, in some instances, the emergence of detectable DM/X4-using variants appears to have contributed to virologic failure in a subset of subjects receiving vicriviroc.
This study demonstrates vicriviroc's virologic and immunologic activity and safety in treatment-experienced patients infected with CCR5-tropic HIV. The results of this trial were comparable to those seen in similarly designed trials conducted with other CCR5 antagonists and new classes of drugs. The 30-mg once-daily vicriviroc dose tended to have superior virologic suppression while maintaining a favorable toxicity profile and is the dose currently being evaluated in phase 3 studies.
Subjects, Materials, and Methods
Study subjects.
Eligible subjects were adults (aged >18 years) infected with CCR5-tropic HIV and experiencing failure of a 3-drug antiretroviral therapy regimen. Subjects must have received >3 classes of antiretroviral therapy for >3 months and been receiving a stable regimen for >8 weeks prior to randomization. Plasma HIV RNA levels of >1000 copies/mL and >1 HIV resistance mutation to the nucleotide reverse-transcriptase inhibitor class and >1 primary resistance mutation to the protease inhibitor class were required for enrollment.
Subjects had to be clinically stable, without active AIDS-defining illnesses and with acceptable laboratory values. Subjects with a history of a seizure disorder, central nervous system disease, or use of a drug that might predispose them to seizures were excluded, as were subjects with a history of malignancy or prior receipt of chemotherapy (except for cutaneous Kaposi sarcoma or basal cell carcinoma treated without chemotherapy). Subjects with chronic hepatitis B or C infection could enroll if they had stable liver disease and transaminase levels within the inclusion criteria range (<3 times the upper limit of normal). Previous receipt of a CCR5 inhibitor (for >4 weeks or <30 days prior to screening) was prohibited.
Written informed consent was obtained from patients and human experimentation guidelines of the United States Department of Health and Human Services and/or those of the authors' institutions were followed. The protocol and informed consent form were reviewed and approved by an Institutional Review Board prior to study initiation.
Study design.
This double-blind, dose-ranging trial randomized subjects in 1:1:1 fashion to receive 30 mg vicriviroc once daily, 20 mg vicriviroc once daily, or placebo, each with optimized OBT containing a protease inhibitor plus ritonavir. Randomization was stratified by baseline HIV RNA level <100,000 or 100,000 copies/mL and receipt of enfuvirtide in the OBT. Site investigators individualized OBTs were based on viral susceptibility at screening. End point assessments included plasma HIV RNA level (Amplicor HIV-1 Monitor Test version 1.5; Roche Molecular Diagnostics) and CD4/CD8 count (flow cytometry). Monogram Biosciences performed drug susceptibility testing (PhenoSense GT genotypic and phenotypic assay) and determined coreceptor tropism of HIV isolates (Trofile assay) and vicriviroc susceptibility (PhenoSense Entry assay, with a maximal percent inhibition value of <85% defined as resistance). The tropism test used to screen patients for this trial was the original version of the Trofile assay; the enhanced version Monogram Biosciences subsequently developed was not available at the time.
The screening tropism and genotype/phenotype resistance assays determined eligibility and guided selection of OBT. All subjects were tested for resistance to antiretroviral drugs in the OBT at baseline and at time of virologic failure or study discontinuation with use of the PhenoSense GT assay, which uses a combination of genotypic and phenotypic resistance techniques to determine an overall sensitivity score. The overall sensitivity score represents the total number of drugs in the OBT (not counting vicriviroc) to which the subject's virus was fully susceptible (partial sensitivity was not counted). Drug susceptibility testing was repeated in subjects who discontinued because of treatment failure. HIV coreceptor tropism and vicriviroc susceptibility were assayed at baseline; at weeks 8, 20, and 48; and at vicriviroc discontinuation for those with HIV RNA levels >1000 copies/mL, if applicable. Safety assessments included physical examinations, blood chemistries, hematology, and periodic electrocardiograms.
The primary end point was the mean change in baseline log10 HIV RNA level at week 48. Secondary end points included the proportion of subjects with HIV RNA levels <50 copies/mL, mean change in baseline CD4 count, time to loss of virologic response, frequency of emergence of viral resistance to vicriviroc or OBT components, detection of CXCR4-tropic virus, and detection of CXCR4-tropic virus accompanied by a 50% decrease in baseline CD4 count. Safety end points included adverse and AIDS-defining events and laboratory abnormalities. Planned interim analyses at weeks 12 and 24 were reviewed by an independent Data and Safety Monitoring Board.
Subjects continued to receive blinded treatment for 48 weeks unless they met criteria for discontinuation. Virologic failure was defined by 2 criteria confirmed on second testing: <0.5 log10 decrease in baseline HIV RNA at week 4 or rebound of HIV RNA to within 0.5 log10 below baseline level after week 4, after achieving maximal suppression. Either event resulted in discontinuation from the study unless the investigator (in consultation with the Schering-Plough physicians) requested the patient continue because of apparent clinical benefit. Subjects with detectable CXCR4 virus or dual/mixed CCR5/CXCR4 virus accompanied by 50% decrease in baseline CD4 count also discontinued the study. At week 48, subjects were offered open-label vicriviroc 30 mg once daily and persons who had discontinued prior to week 48 for reasons other than adverse events were allowed to be re-screened for the open-label protocol extension.
Statistics.
The planned sample size (40 per treatment arm) provided about 90% power to detect a difference of >0.7 log10 HIV RNA copies/mL between the vicriviroc 30 mg and placebo groups, assuming a pooled standard deviation of 0.9 log10 HIV RNA copies/mL. The primary efficacy and safety analyses were based on all randomized subjects receiving at least 1 dose of study medication (modified intent-to-treat population). Changes in baseline log10 HIV RNA and CD4 counts at week 48 were analyzed in analysis of variance models with baseline treatment and stratification factors as covariates. Proportions of virologic responders between treatments were compared with Cochran-Mantel-Haenszel tests, adjusting for baseline stratification factors. Kaplan-Meier estimates of time to study discontinuation and time to loss of virologic response by treatment were analyzed with log-rank tests. A step-down approach of data interpretation was used in the primary analysis: the vicriviroc 30 mg dose was first compared with placebo; if this comparison was significant, the 20 mg group was compared with placebo. The efficacy of the 2 vicriviroc doses relative to each other was not assessed statistically. All P values were 2-sided. Statistical significance was concluded if the P value was <.05.
Single missing values of HIV RNA or CD4 count were imputed with the geometric/arithmetic means of the immediately preceding and following values, if available. All other missing HIV RNA or CD4 values, including those missing because of treatment discontinuation, were imputed with baseline value (change, 0) at the point of discontinuation and onwards (noncompleter equals failure) [8]. A virologic responder was defined in 2 ways: (1) a subject with HIV RNA level <50 copies/mL at week 48 (primary analysis [noncompleter equals failure]); or (2) on the basis of the Food and Drug Administration time to loss of virologic response algorithm [9], which requires a responder to have 2 consecutive HIV RNA values <50 copies/mL at week 48, without prior viral rebound or a change in the subject's background treatment for reasons other than tolerability.
Efficacy in subjects in prespecified subgroups (age, sex, race, region, baseline HIV RNA level, baseline CD4 count, and enfuvirtide use) as well as characteristics identified post hoc (overall sensitivity score, darunavir use) were examined. Because of small sample sizes, analyses were restricted to sample statistics (N, mean), P values were not considered.
Adverse and AIDS-defining events, occurring up to week 48, were tabulated by treatment group. Adverse event incidences were adjusted for duration of exposure to provide rates attributable to differing lengths of treatment in each arm. AIDS-defining events were confirmed by an external Adjudication Committee of experts.
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