Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial.

Objectives: To determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults. Methods: In this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400-900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015. Results: We enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30-43) years. Baseline CD4 count was 592 (491-694) cells/mm3 and VL was 4.04 (3.5-4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (-1.2%/year versus -1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events. Conclusions: Unlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebo-controlled trial.

BACKGROUND: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. OBJECTIVE: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. METHODS: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI- II) score greater than 15, confirmed 2 weeks apart. RESULTS: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. CONCLUSIONS: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV.

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults.

INTRODUCTION: The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. METHODS: A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. RESULTS: 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥ 40 =  31-58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. CONCLUSION: Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00764998.