A Randomized, Placebo-Controlled Trial Assessing the Effect of VISBIOME ES Probiotic in People With HIV on Antiretroviral Therapy.

BACKGROUND: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function. METHODS: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test. RESULTS: Overall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, -48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, -94.1 to 176.2 µg/L; P=.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed (P>.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria (P=.044) in the Visbiome ES arm. CONCLUSIONS: Visbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy-treated people with HIV.

Hepatotoxicity and Liver-Related Mortality in Women of Childbearing Potential Living With Human Immunodeficiency Virus and High CD4 Cell Counts Initiating Efavirenz-Containing Regimens.

BACKGROUND: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens. METHODS: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/µL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation. RESULTS: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70]). CONCLUSIONS: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.

Characteristics of REPRIEVE Trial Participants Identifying Across the Transgender Spectrum.

Because persons who identify across the transgender spectrum (PATS) are a key population in human immunodeficiency virus (HIV) yet are underreported in HIV and cardiovascular research, we aimed to characterize this population within the REPRIEVE global clinical trial (n = 7770). Acceptance of gathering gender identity was high (96%). Participation by PATS was 1.7% overall, 2.4% among natal males, 0.3% among natal females, and varied across geographic regions (from 0% in sub-Saharan Africa to 2.3% in High Income Region). Thirty percent of natal male PATS identified other than transgender. Some characteristics differed by gender. Most notably, 38% of natal male PATS receiving gender-affirming treatment had waist circumference >102 cm (compared with ≤25% in other groups). Given that PATS is a key population, HIV research should routinely report trial participation and outcomes by gender in addition to natal sex, to provide the results needed to optimize medical care to PATS.

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination.

Background: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities.Objective: To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process.Methods: Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support.Results: Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino.Conclusions: REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams.

Screening and Enrollment by Sex in Human Immunodeficiency Virus Clinical Trials in the United States.

BACKGROUND: Women are underrepresented in human immunodeficiency virus (HIV) research in the United States. To determine if women screening for HIV clinical trials enrolled at lower rates than men, we performed a retrospective, cross-trial analysis. METHODS: We conducted an analysis of screening and enrollment during 2003-2013 to 31 clinical trials at 99 AIDS Clinical Trials Group network research sites in the United States. Random-effects meta regression estimated whether sex differences in not enrolling ("screen out") varied by various individual, trial, or site characteristics. RESULTS: Of 10 744 persons screened, 18.9% were women. The percentages of women and men who screened out were 27.9% and 26.5%, respectively (P = .19); this small difference did not significantly vary by race, ethnicity, or age group. Most common reasons for screening out were not meeting eligibility criteria (30-35%) and opting out (23%), and these did not differ by sex. Trial and research site characteristics associated with variable screen-out by sex included HIV research domain and type of hemoglobin eligibility criterion, but individual associations did not persist after adjustment for multiple testing. CONCLUSIONS: In the absence of evidence of significantly higher trial screen-out for women, approaching more women to screen may increase female representation in HIV trials.

Time to viral rebound and safety after antiretroviral treatment interruption in postpartum women compared with men.

OBJECTIVE(S): The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials. DESIGN: Prospective evaluation of time to virologic rebound. METHODS: One thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4 cell counts at least 350 cells/µl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population). RESULTS: In PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4 cell count to less than 350 cells/µl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (<400 copies/ml) at 12 weeks compared with ACTG NWCS 371 participants (6.4%). CONCLUSION: Temporary treatment interruptions in healthy, HIV-infected women with high CD4 cell counts can be well tolerated. Potential sex differences need to be considered in cure studies examining time to virologic rebound.

Antiretroviral Activity of AMD11070 (An Orally Administered CXCR4 Entry Inhibitor): Results of NIH/NIAID AIDS Clinical Trials Group Protocol A5210.

AMD11070 binds to the chemokine receptor CXCR4, with anti-HIV-1 activity in vitro and in vivo. We conducted a phase IB/IIA proof-of-concept dose-escalating, open-label study to determine safety and antiviral activity of AMD11070 administered over 10 days to HIV-1-infected participants who harbored CXCR4-tropic virus. Primary endpoints were ≥1 log10 rlu (relative luminescence units) reduction in CXCR4-tropic virus during 10 days of AMD11070 treatment or in the 7 days following treatment discontinuation, rlu changes over 10 days of treatment, and safety. Plasma pharmacokinetic parameters, HIV-1 RNA, and safety labs were obtained over 90 days of study. The study was stopped early due to emerging AMD11070 animal toxicity data. Six HIV-infected participants with plasma HIV-1 RNA ≥5,000 copies/mL on no antiretroviral therapy for 14 days before entry were treated. AMD11070 was well-tolerated when administered at 200 mg orally every 12 h for 10 days. All enrolled participants had dual/mixed (D/M) viruses. Reductions of almost 1 log10 rlu or more in CXCR4 virus were seen in three of six participants after 10 days of treatment. No participants had ≥1 log10 decline in plasma HIV-1 RNA from baseline at day 10. No clear relationship between pharmacokinetic parameters and response to therapy (X4 log rlu reduction) was observed. AMD11070 demonstrated in vivo activity as measured by reductions in CXCR4 rlu signal. Despite the finding of discordant rlu and plasma HIV RNA responses in these participants with D/M viruses, exploration of other HIV-1 CXCR4 antagonist therapies is possible.

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

BACKGROUND: People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown. METHODS: REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40-75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally. RESULTS: To date the Mechanistic Substudy has completed planned enrollment, with 805 participants. CONCLUSION: This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin's effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.

Rationale and design of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).

BACKGROUND: Cardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population. METHODS: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7,500 PWH, 40-75 years of age, on stable antiretroviral therapy, will be randomized to pitavastatin calcium (4 mg/d) or identical placebo and followed for up to 8 years. Participants are enrolled based on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score and low-density lipoprotein cholesterol (LDL-C) level with a goal to identify a low- to moderate-risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible based on decreasing LDL-C thresholds for increasing risk score >7.5% (LDL-C <190 mg/dL for risk score <7.5%, LDL-C <160 mg/dL for risk score 7.6%-10%, and LDL-C<130 mg/dL for risk score 10.1%-15%). The primary objective is to determine effects on a composite end point of MACE. Formal and independent adjudication of clinical events will occur using standardized criteria. Key secondary end points include effects on MACE components, all-cause mortality, specified non-CVD events, AIDS and non-AIDS events, and safety. RESULTS: To date, REPRIEVE has enrolled >7,500 participants at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH to investigate the primary objective of the trial. CONCLUSIONS: REPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIV-infected participants on antiretroviral therapy and provide critical information on CVD mechanisms and non-CVD events in PWH.

Adverse Pregnancy Outcomes Among Women Who Conceive on Antiretroviral Therapy.

Background: Adverse pregnancy outcomes for women who conceive on antiretroviral therapy (ART) may be increased, but data are conflicting. Methods: Human immunodeficiency virus-infected, nonbreastfeeding women with pre-ART CD4 counts ≥400 cells/µL who started ART during pregnancy were randomized after delivery to continue ART (CTART) or discontinue ART (DCART). Women randomized to DCART were recommended to restart if a subsequent pregnancy occurred or for clinical indications. Using both intent-to-treat and as-treated approaches, we performed Fisher exact tests to compare subsequent pregnancy outcomes by randomized arm. Results: Subsequent pregnancies occurred in 277 of 1652 (17%) women (CTART: 144/827; DCART: 133/825). A pregnancy outcome was recorded for 266 (96%) women with a median age of 27 years (interquartile range [IQR], 24-31 years) and median CD4+ T-cell count 638 cells/µL (IQR, 492-833 cells/µL). When spontaneous abortions and stillbirths were combined, there was a significant difference in events, with 33 of 140 (23.6%) in the CTART arm and 15 of 126 (11.9%) in the DCART arm (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.1-3.5]; P = .02). In the as-treated analysis, the RR was reduced and no longer statistically significant (RR, 1.4 [95% CI, .8-2.4]). Conclusions: Women randomized to continue ART who subsequently conceived were more likely to have spontaneous abortion or stillbirth, compared with women randomized to stop ART; however, the findings did not remain significant in the as-treated analysis. More data are needed on pregnancy outcomes among women conceiving on ART, particularly with newer regimens.

Women have enhanced bone loss associated with phosphaturia and CD4+ cell restoration during initial antiretroviral therapy.

OBJECTIVE: We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF). METHODS: Covariates in linear regression models of 48-week hip and spine %BMD changes, by dual energy X-ray absorptiometry, included baseline and 48-week changes in plasma viral load, CD4 cells, plasma C-terminal telopeptide, procollagen 1 N-terminal propeptide and glomerular filtration rates, and the 48-week area under the curve of fractional excretion of phosphate. RESULTS: Despite overall hip and spine BMD declines of 2.8 and 2.9%, respectively, plasma viral load suppression to less than 50 vs. at least 50 copies/ml was associated 1.0% (P = 0.02) and 0.8% (P = 0.01) less BMD decline. Women had lower baseline spine (P = 0.04; n = 59 women, 418 men) and hip BMD (P = 0.01) in adjusted models, with 1.7% more hip decline on ART than men (P = 0.001). Serum phosphate was positively associated with baseline spine BMD in women (P = 0.03) but not men, and area under the curve of fractional excretion of phosphate was negatively associated with spine BMD changes, particularly in women randomized to TDF regimens (P = 0.03 and 0.054 for interactions by sex, and randomization to TDF vs. non-TDF regimens, respectively; n = 44 women, 326 men). Women also had 0.6% (P = 0.004) more hip BMD decline than men associated with each 100 CD4 cells/µl increase on ART (P = 0.02; n = 49 women, 379 men). CONCLUSION: Women randomized to TDF-containing ART had accentuated spine loss associated with phosphaturia, and accentuated hip loss associated with CD4 restoration, regardless of TDF exposure. Viral load suppression reduced bone loss.

Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial.

Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results: Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

Maternal health outcomes among HIV-infected breastfeeding women with high CD4 counts: results of a treatment strategy trial.

BACKGROUND: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery. METHODS: Women with pre-ART CD4+ cell counts ≥350 cells/mm3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat. FINDINGS: 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61). INTERPRETATION: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.

Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.

BACKGROUND: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). OBJECTIVE: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. DESIGN: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114). SETTING: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. INTERVENTION: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control). MEASUREMENTS: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. RESULTS: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. LIMITATIONS: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. CONCLUSION: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1-infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275).

BACKGROUND: Persistent immune activation and inflammation in virologically suppressed human immunodeficiency virus (HIV) infection are linked to excess cardiovascular risk. OBJECTIVE: To evaluate atorvastatin as a strategy to reduce cardiovascular risk. METHODS: A5275 was a multicenter, prospective, randomized, double-blind, placebo-controlled, cross-over pilot study of atorvastatin (10 mg/day for 4 weeks then 20 mg/day for 16 weeks) with a planned enrollment of 97 HIV-infected participants ≥18 years old, receiving boosted protease inhibitor-based antiretroviral therapy for ≥6 months, with plasma HIV-1 RNAs below limits of quantification ≥180 days, and fasting low-density lipoprotein (LDL) cholesterol ≥70 and <130 mg/dL. Primary endpoints were differences of changes ([week 44-week 24]-[week 20-baseline]) in CD4+ and CD8+ T-lymphocyte activation (% CD38+/DR+) and plasma levels of IL-6 and D-dimer. Arms were compared using the Wilcoxon rank-sum tests and also summarized changes pre-to-post atorvastatin treatment. Analyses were as-treated. RESULTS: Ninety-eight participants were enrolled at 31 U S sites and 73 completed study treatment. Atorvastatin treatment did not decrease T-lymphocyte or monocyte activation, circulating biomarker levels (interleukin-6, D-dimer, soluble CD14, soluble CD163, monocyte chemoattractant protein-1, interferon-gamma-induced protein-10, high-sensitivity C-reactive protein, CD40L, and P-selectin) or white blood cell Krüppel-like Factor 2/4 messenger RNA levels. Pre-to-post atorvastatin reductions in calculated LDL (-38%), oxidized-LDL (-33%), and lipoprotein-associated phospholipase A2 (-31%) were significant (P < .01). CONCLUSION: In virologically suppressed individuals with HIV infection, atorvastatin did not significantly decrease levels of soluble or cellular biomarkers of immune activation and inflammation but resulted in robust reductions in LDL cholesterol, oxLDL, and lipoprotein-associated phospholipase A2, biomarkers associated with cardiovascular risk.

Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per µL: secondary outcome results from a randomised controlled trial.

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per µL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per µL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per µL higher, and average CD4 cell count 194 cells per µL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).

BACKGROUND: Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis. METHODS: Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat. RESULTS: Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations. CONCLUSIONS: MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis. CLINICAL TRIALS REGISTRATION: NCT01505114.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).