Rebekah Puls

Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebo-controlled, non-inferiority trial

Background: The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. Methods: ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staffwere masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than-10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. Findings: The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4.75 log copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI-2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89.1%, efavirenz 600=88.4%; difference 0.75%, 95% CI-4.19 to 5.69; p=0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference-10.5%, 95% CI-18.2 to-2.8; p=0.01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference-3.96%, 95% CI-6.96 to -0.95; p=0.01). Interpretation: Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care.BACKGROUND The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. METHODS ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL (IQR 0·88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI -2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0·01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%, 95% CI -4·19 to 5·69; p=0·77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10·5%, 95% CI -18·2 to -2·8; p=0·01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3·96%, 95% CI -6·96 to -0·95; p=0·01). INTERPRETATION Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care. FUNDING Bill & Melinda Gates Foundation, University of New South Wales.

Does Choice of Combination Antiretroviral Therapy (cART) Alter Changes in Cerebral Function Testing after 48 Weeks in Treatment-Naive, HIV-1–Infected Individuals Commencing cART? A Randomized, Controlled Study

BACKGROUND Neurocognitive impairment remains prevalent, despite combination antiretroviral therapy (cART). Differences between changes in cerebral function and alternative cARTs have not been prospectively assessed. METHODS Treatment-naive, HIV-1-infected individuals randomly allocated to commence cART (tenofovir-emtricitabine plus either efavirenz [arm 1], atazanavir-ritonavir [arm 2], or zidovudine-abacavir [arm 3]) were eligible. Cerebral function tests included neurocognitive testing and assessment of cerebral metabolites using proton magnetic resonance spectroscopy in several anatomical voxels, including right frontal white matter and right basal ganglia, at baseline and after 48 weeks. N-acetylaspartate-to-creatine (NAA/Cr) ratios were calculated. Both the differences between changes in neurocognitive function and NAA/Cr ratios over 48 weeks and the study arms (arm 1 vs arm 2; arm 1 vs arm 3) were assessed. RESULTS Thirty subjects completed study procedures (9, 9, and 12 subjects in arms 1, 2, and 3, respectively). Mean CD4+ cell counts (+/- standard deviation) were 218 +/- 87 cells/microL at baseline and 342 +/- 145 cells/microL at week 48. The mean plasma HIV-1 RNA level was <50 copies/mL for 28 of the 30 subjects at week 48. Over 48 weeks, greater improvements in identification reaction time (P = .04) and executive function (P = .02) were observed in arm 3, compared with arm 1 (0.03, -0.30, -0.50 log10 ms change in identification reaction time, in arms 1, 2, and 3, respectively). Increases in the NAA/Cr ratio were observed in all voxels (maximum 38% in right basal ganglia), with greater increases observed in arm 1 than in arm 2 (P = .03) in frontal white matter (30%, -7%, and 0% change in the NAA/Cr ratio, in arms 1, 2, and 3, respectively). CONCLUSIONS To our knowledge, this is the first study to prospectively describe different changes in cerebral function testing parameters between different cARTs. Greater improvements in neuronal recovery (NAA/Cr ratio) were observed for recipients of tenofovir-emtricitabine plus efavirenz (arm 1), and greater improvements in neurocognitive function testing were observed for recipients of tenofovir-emtricitabine plus zidovudine-abacavir (arm 3).

Efavirenz versus Boosted Atazanavir or Zidovudine and Abacavir in Antiretroviral Treatment-Naive, HIV-Infected Subjects: Week 48 Data from the Altair Study

BACKGROUND Antiretroviral therapy is complicated by drug interactions and contraindications. Novel regimens are needed. METHODS This open label study randomly assigned treatment-naive, human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz (Arm I), with ritonavir-boosted atazanavir (Arm II), or with zidovudine/abacavir (Arm III). Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis. Treatment arms were noninferior if the upper limit of the 95% confidence interval (CI) was <0.5 log(10) copies/mL. Secondary objectives included virologic, immunologic and safety end points. RESULTS The intention-to-treat population comprised 322 patients (Arm I, n = 114; Arm II, n = 105; and Arm III, n = 103). Noninferiority for the primary end point was established. Analysis for superiority showed that Arm III was significantly less potent than Arm I (-0.20 log(10) copies/mL; 95% CI, -0.39 to -0.01 log(10) copies/mL; P = .038). The proportions of patients on each of Arm I (95%) and Arm II (96%) with <200 copies/mL were not different (P = .75), but the percentage of patients in Arm III with <200 copies/mL (82%) was significantly lower (P = .005). CD4+ cell counts did not differ. Serious adverse events were more frequent in Arm III (n = 30) than in Arm I or Arm II (n = 15 for each; P = .062). CONCLUSIONS A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication, compared with the suppression demonstrated by standard antiretroviral therapy regimens, although it did meet the predetermined formal definition of noninferiority. Secondary analyses indicated statistically inferior virologic and safety performance. Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety.

A randomized, placebo-controlled phase I trial of DNA prime, recombinant fowlpox virus boost prophylactic vaccine for HIV-1.

An HIV-vaccine consisting of a DNA prime, recombinant fowlpox virus (rFPV) boost was evaluated in a double-blind placebo controlled trial. One milligram of pHIS–HIV-B expressing mutated gag, pol, env, vpu, tat and rev was administered at weeks 0 and 4 boosted by 5 × 107 pfu rFPV–HIV-B expressing gag/pol at week 8. The vaccine regimen was safe, but there was no difference between vaccine (n = 18) and placebo recipients (n = 6) for Gag or Pol-specific T-cell immune responses at week 9.

Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study.

BACKGROUND The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks. METHODS ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (≥16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50-500 cells per μL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (≤ or >100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above -10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90·0%) of 321 patients in the efavirenz 400 mg group and 280 (90·6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference -0·6, 95% CI -5·2 to 4·0; p=0·72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0·48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0·03). The number of patients who reported serious adverse events did not differ between the groups (p=0·20). INTERPRETATION Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation. FUNDING Bill & Melinda Gates Foundation, and UNSW Australia.

Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment‐naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV‐RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68–0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid‐dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz‐related side effects (GMR; 90% CI: 0.95 (0.88–1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: A randomized, controlled study

Improvements in neurocognitive (NC) function have been associated with commencing antiretroviral therapy in HIV‐infected subjects. However, the dynamics of such improvements are poorly understood.

Randomized, placebo-controlled, phase I/IIa evaluation of the safety and immunogenicity of fowlpox virus expressing HIV gag-pol and interferon-gamma in HIV-1 infected subjects.

We conducted a randomised, placebo-controlled double-blind trial to examine the safety and immunogenicity of a candidate HIV therapeutic vaccine based upon a recombinant fowl pox virus capable of co-expressing the human cytokine interferon-gamma and/or genes from HIV-1. Thirty-five eligible subjects were randomised (12 placebo, 11 fowlpox + HIV genes, 12 fowl pox + HIV genes + interferon-?). All but one subject (placebo group) received three immunizations (by intramuscular injection on day 0, week 4 and week 12) and all completed 52 weeks of follow-up. All subjects continued to take combination antiretroviral therapy for the duration of study. There were no significant toxicity or safety concerns and the distribution of adverse events and their severity was consistent across each randomly assigned vaccine group. Comparison of placebo recipients with the combined recipients of the two vaccine constructs, in terms of anti-HIV gag ELISpot or lymphoproliferative responses, tended to favour the placebo group, but were not significantly different (difference in time-weighted mean change from baseline = 56 Spot forming units (sfu)/106 PBMC; p = 0.062 and 4.4 SI; p = 0.337). There were no significant changes in CTL responses by standard Cr51 release assay. Anti-FPV antibodies were detected by week 14 in 0 placebo and 20 (87%) vaccine recipients. Although safe, neither vaccine construct appeared to possess detectable T-cell mediated anti-HIV immunogenic properties in HIV infected individuals, as measured by standard T cell assays.

Therapeutic vaccination against HIV: current progress and future possibilities.

Although effective in reducing mortality, current antiretroviral therapy for HIV infection involves complex and expensive drug regimens that are toxic and difficult to take. Eradication of HIV reservoirs is not possible with existing therapies. The concept of therapeutic vaccination has been investigated to increase the potency and breadth of anti-HIV immune responses in order to delay or reduce antiretroviral therapy use. A variety of approaches targeted to both cell- and antibody-mediated immunity have been developed, including whole inactivated HIV-1, protein subunits and synthetic peptides, DNA vaccines and a number of viral vectors expressing HIV-1. These investigations have occurred in the absence of a clear understanding of disease pathogenesis or the correlates of protective immunity. At this time, there is no licensed therapeutic vaccine for any viral disease, including HIV; however, this review will consider recent progress in the field and summarize the challenges faced in the development of a therapeutic HIV vaccine.

Influence of IFN gamma co-expression on the safety and antiviral efficacy of recombinant fowlpox virus HIV therapeutic vaccines following interruption of antiretroviral therapy

Therapeutic immunization to stimulate host immune responses and control human immunodeficiency virus (HIV-1) replication is being investigated as a supplimentary treatment for the management of HIV infection. On completion of an earlier study involving three vaccinations while taking combination antiretroviral therapy (CART), twenty-five subjects with plasma viral load (pVL)