Michael N. Robertson

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.

BACKGROUND Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. METHODS We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. FINDINGS In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. INTERPRETATION This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis

BACKGROUND In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. METHODS To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5. FINDINGS We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases. INTERPRETATION Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial

Context Various oral interferon- and ribavirin-free regimens are becoming available to treat chronic hepatitis C virus (HCV) infection. A grazoprevirelbasvir combination regimen has shown promise in phase 2 trials. Contribution This phase 3 trial found a once-daily grazoprevirelbasvir regimen to be effective and well-tolerated in patients with HCV genotype 1, 4, or 6 infection. Outcomes were similar in patients with and without cirrhosis. Caution The study did not include an active comparator, so how this regimen compares with others is unknown. Implication Grazoprevirelbasvir represents a new therapeutic option for chronic HCV infection. Chronic hepatitis C virus (HCV) infection remains a growing cause of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver transplantation (1). Effective therapy for HCV infection diminishes long-term liver-related complications and mortality (2). Convenient, oral, direct-acting antiviral regimens are being investigated for chronic HCV infection (3). Grazoprevir is an NS3/4A protease inhibitor that has high potency in vitro against HCV genotype (GT) 1, GT2, GT4, GT5, and GT6 but is less active against GT3 (4). Grazoprevir retains substantial activity against resistance-associated variants (RAVs) commonly detected after failed therapy with first-generation protease inhibitors (4, 5). Elbasvir is an NS5A inhibitor active against GT1, GT2a, GT3, GT4, GT5, and GT6, even in the presence of RAVs associated with failure of other NS5A inhibitors, such as daclatasvir and ledipasvir (6, 7). Grazoprevirelbasvir has been evaluated in an extensive phase 2 clinical development program (5, 810). The C-WORTHY study indicated that grazoprevirelbasvir with or without ribavirin for 12 weeks provided efficacious and well-tolerated therapy for monoinfected and HIVco-infected patients, treatment-naive and treatment-experienced patients, and noncirrhotic and cirrhotic patients (9, 10). The objective of the phase 3 C-EDGE Treatment-Naive trial was to evaluate the efficacy and safety profile of a once-daily, fixed-dose, oral, 12-week regimen of grazoprevirelbasvir without interferon or ribavirin in treatment-naive monoinfected patients with and without cirrhosis and with GT1, GT4, or GT6 infection. Methods Study Design The C-EDGE Treatment-Naive study was an international, randomized, blinded, placebo-controlled, parallel-group trial of a fixed-dose combination of grazoprevir 100 mg/elbasvir 50 mg for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV GT1, GT4, or GT6 infections. A historical SVR12 rate was used as the comparator for efficacy. A deferred-treatment group was included as a concurrent placebo group to assess safety; after the follow-up period, placebo recipients received open-label grazoprevirelbasvir so that all participants would receive therapy during the study. Recruitment of Study Participants Patients were recruited from general medical clinics at 60 trial centers: 4 in Australia, 4 in the Czech Republic, 5 in France, 5 in Germany, 5 in Israel, 3 in Puerto Rico, 3 in South Korea, 4 in Sweden, 3 in Taiwan, and 24 in the United States. Patients who fulfilled inclusion criteria were asked to participate in the trial. Selected clinical sites were experienced in the management and care of HCV-infected patients, with a history of successful study conduct and the capability for rapid enrollment. Sites were chosen to allow a wide geographic distribution and to ensure that requirements for minority representation, enrollment of patients with cirrhosis, and genotype distribution were met. Eligibility Criteria Adults (aged >18 years) with HCV RNA levels greater than 104 IU/mL were eligible. Hepatic fibrosis was staged by biopsy or noninvasive assessment (Appendix 1) (11). Exclusion criteria were decompensated liver disease, hepatocellular carcinoma, HIV or hepatitis B virus co-infection, uncontrolled diabetes mellitus (hemoglobin A1c level >10%), elevated prothrombin time unrelated to anticoagulation, creatinine clearance less than 50 mL/min, hemoglobin level less than 95 g/L, thrombocytopenia (platelet count <50109 cells/L), aminotransferase levels more than 10 times the upper limit of normal, or hypoalbuminemia (albumin level <30 g/L). Enrollment was constrained to meet the following targets: 20% of the participants having cirrhosis and 15% having GT4 or GT6 infection. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent ethics committees reviewed and approved the protocol and applicable amendments for each institution. Randomization and Masking After stratification by presence or absence of cirrhosis and GT1, GT4, or GT6, patients were randomly assigned in a 3:1 ratio to receive immediate or deferred therapy with grazoprevirelbasvir through a central interactive voice-response system according to a computer-generated random allocation schedule. Patients took 1 fixed-dose combination tablet of grazoprevirelbasvir (immediate-treatment group) or matching placebo (deferred-treatment group) once daily at approximately the same time, without regard to food, for 12 weeks. Patients, clinical site, and sponsor personnel were blinded to treatment assignment (except for a separate unblinded medical team that monitored virologic failures and serious adverse events). Four weeks after completion of therapy, treatment allocation was unblinded, and patients in the deferred-treatment group then received open-label grazoprevirelbasvir for 12 weeks. All patients were to be followed for 24 weeks after cessation of active study therapy (Figure 1). Figure 1. Diagram of study design. DFW = deferred follow-up week; DTW = deferred-treatment week; FU = follow-up; FW = follow-up week; GZREBR = grazoprevirelbasvir; TW = treatment week. Outcome Measures This report describes the efficacy among patients enrolled in the immediate-treatment group through 12 weeks after treatment and the safety findings among patients enrolled in both groups through 14 days after the end of therapy in the initial treatment period. Efficacy and safety results for both groups through follow-up week 24 are still being collected and will be presented in a future report. The primary efficacy outcome variable was the proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after the end of study treatment (SVR12). Virologic failures encompassed breakthrough viremia (confirmed HCV RNA level at or above the lower limit of quantification [LLOQ] during treatment after previously being below the LLOQ) and relapse (confirmed HCV RNA level at or above the LLOQ subsequent to cessation of study therapy after becoming undetectable at the end of treatment). Viral and Resistance Assays Plasma HCV RNA levels were measured by the COBAS AmpliPrep/COBAS TaqMan HCV test, version 2.0 (Roche Molecular Diagnostics, Branchburg, NJ), with an LLOQ of 15 IU/mL. Specimens for viral load measurements were collected at screening; baseline; treatment weeks 4, 8, and 12; and follow-up weeks 4, 12, and 24. Circulating viral quasi-species at baseline or at the time of virologic failure underwent population sequencing with a detection limit for variants of approximately 25% prevalence (12). The complete NS3 and NS5A genes were amplified from samples with RNA levels of 1000 IU/mL or greater by using reverse transcription polymerase chain reaction (5, 12, 13). Resultant amino acid sequences were compared with wild-type GT1a (H77; accession number NC004102), GT1b (Con1; AJ238799), GT4a (ED43; GU814265), or GT6a (EUHK2; Y12083) reference sequences. To assess the effect of baseline NS3 variants, specific amino acid loci prone to selection by early-generation NS3/4A protease inhibitors (positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175) were studied in replicon cell lines encoding mutations in a GT1a backbone (5, 14). These substitutions were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to grazoprevir. Likewise, to assess the effect of baseline NS5A variants, amino acid loci selected by NS5A inhibitors (positions 28, 30, 31, 58, and 93) were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to elbasvir in the replicon assay. Statistical Analysis The C-EDGE Treatment-Naive study was designed to randomly assign approximately 400 patients, with 300 patients in the immediate-treatment group and 100 patients in the deferred-treatment group (which served as the placebo control group for the first 12 weeks). After a 4-week follow-up period, placebo recipients were unblinded at study week 16 and received open-label grazoprevirelbasvir. The primary efficacy hypothesis exclusively applied to patients in the immediate-treatment group. Assuming a response rate of 85% or greater, the study had more than 99% power to demonstrate an SVR12 rate superior to the reference rate of 73% at an overall 1-sided value of 0.025. The historical reference rate of 73% was derived from phase 3 trials of simeprevir/peginterferon + ribavirin in treatment-naive monoinfected patients, after adjustment for the expected proportion of cirrhotic patients and the anticipated improved tolerability with an interferon-free regimen (Appendix 1) (15, 16). The primary efficacy and safety analyses were performed on the full data set, which included all patients receiving at least 1 dose of the study treatment. The primary efficacy end point was prespecified as the proportion of patients with an HCV RNA level below the LLOQ 12 weeks after the end of treatment (SVR12) (17). Missing outcome data were imputed as failures unless the values immediately before and after the missing result were both successes, in which case the absent value was imputed as a success. The 95% CIs were computed by the conservative ClopperPear

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C.BACKGROUND The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. METHODS We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. FINDINGS 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. INTERPRETATION The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. FUNDING The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.

Safety and Immunogenicity of a Replication-Incompetent Adenovirus Type 5 HIV-1 Clade B gag/pol/nef Vaccine in Healthy Adults

BACKGROUND The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.

Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial

We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.

Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

BACKGROUND Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection. METHODS In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING Merck Sharp & Dohme Corp.

Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial

BACKGROUND Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. METHODS In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. FINDINGS From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. INTERPRETATION Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. FUNDING Merck.

Extended Follow-up Confirms Early Vaccine-Enhanced Risk of HIV Acquisition and Demonstrates Waning Effect Over Time Among Participants in a Randomized Trial of Recombinant Adenovirus HIV Vaccine (Step Study)

BACKGROUND The Step Study tested whether an adenovirus serotype 5 (Ad5)-vectored human immunodeficiency virus (HIV) vaccine could prevent HIV acquisition and/or reduce viral load set-point after infection. At the first interim analysis, nonefficacy criteria were met. Vaccinations were halted; participants were unblinded. In post hoc analyses, more HIV infections occurred in vaccinees vs placebo recipients in men who had Ad5-neutralizing antibodies and/or were uncircumcised. Follow-up was extended to assess relative risk of HIV acquisition in vaccinees vs placebo recipients over time. METHODS We used Cox proportional hazard models for analyses of vaccine effect on HIV acquisition and vaccine effect modifiers, and nonparametric and semiparametric methods for analysis of constancy of relative risk over time. RESULTS One hundred seventy-two of 1836 men were infected. The adjusted vaccinees vs placebo recipients hazard ratio (HR) for all follow-up time was 1.40 (95% confidence interval [CI], 1.03-1.92; P= .03). Vaccine effect differed by baseline Ad5 or circumcision status during first 18 months, but neither was significant for all follow-up time. The HR among uncircumcised and/or Ad5-seropositive men waned with time since vaccination. No significant vaccine-associated risk was seen among circumcised, Ad5-negative men (HR, 0.97; P=1.0) over all follow-up time. CONCLUSIONS The vaccine-associated risk seen in interim analysis was confirmed but waned with time from vaccination.