In this randomized, controlled trial in Africa and India, combination antiretroviral therapy was more effective than standard therapy in preventing mother-to-child transmission of HIV but was ...associated with increased toxic effects.
Antiretroviral regimens used for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV) have evolved from the first successful trial that used zidovudine single-drug prophylaxis in 1994 to current triple-drug regimens.
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Although there are clear benefits of combination antiretroviral therapy (ART) for the mother and infant, these do not come without risks; some studies have shown higher rates of adverse pregnancy outcomes with maternal ART than with regimens containing fewer antiretroviral agents.
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The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial compared the relative efficacy and safety of various proven antiretroviral strategies for the prevention of . . .
When to start antiretroviral therapy for HIV infection on the basis of the CD4+ count has been controversial. In a global randomized trial, treatment of patients with a CD4+ count of more than 500 ...cells per cubic millimeter showed significant benefit.
The immune compromise caused by the human immunodeficiency virus (HIV) is characterized by a loss of CD4+ T cells. Rates of HIV-associated complications and death increase as the number of these cells in peripheral blood (CD4+ count) declines.
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It has been general practice to defer the initiation of antiretroviral therapy in asymptomatic patients with a CD4+ count above a certain threshold level. The applicable threshold has changed over time, and recommendations remain inconsistent across various guidelines.
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Randomized studies that have assessed the benefits and risks of treating patients with HIV infection sooner rather than later have largely enrolled patients . . .
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.
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.
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.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Several regimens are used as initial antiretroviral therapy for HIV-1 infection, but few direct comparisons are available. In this randomized, open-label study, efavirenz plus two nucleoside ...reverse-transcriptase inhibitors (NRTIs), lopinavir–ritonavir plus two NRTIs, and lopinavir–ritonavir plus efavirenz were compared. Initial therapy with efavirenz plus two NRTIs was associated with less virologic failure than was lopinavir–ritonavir plus two NRTIs. The NRTI-sparing regimen of lopinavir–ritonavir plus efavirenz had virologic efficacy similar to that of efavirenz plus two NRTIs but was more likely to select for drug resistance.
Initial therapy with efavirenz plus two NRTIs was associated with less virologic failure than was lopinavir–ritonavir plus two NRTIs. The NRTI-sparing regimen of lopinavir–ritonavir plus efavirenz had virologic efficacy similar to that of efavirenz plus two NRTIs but was more likely to select for drug resistance.
Current practice guidelines recommend the use of efavirenz or ritonavir-boosted protease inhibitor regimens containing two nucleoside reverse-transcriptase inhibitors (NRTIs) for initial therapy of human immunodeficiency virus type 1 (HIV-1) infection.
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These recommendations are derived from expert opinion and the results of clinical trials, but to our knowledge well-powered, head-to-head comparisons of these regimens have not been performed.
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Although NRTIs are included in all recommended antiretroviral regimens, toxic effects, especially lipoatrophy associated with the thymidine analogues,
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has raised interest in regimens that do not contain NRTIs. Pilot studies of NRTI-sparing regimens have shown good virologic efficacy, but adequately . . .
Abstract
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.
We compared the incidence of suicidal behavior between human immunodeficiency virus-positive adults with high CD4 count started on antiretroviral therapy immediately or after CD4 count fell below 350 cell/mL. Participants started on efavirenz-based, but not other combinations, had increased risk of suicidal behavior.
Abstract
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.
A retrospective cross-protocol analysis of 31 AIDS network trials did not find evidence that women screening to trials subsequently enrolled at significantly lower rates than men. Efforts to recruit more women to HIV trials are needed to close knowledge gaps.
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.
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.
To date the Mechanistic Substudy has completed planned enrollment, with 805 participants.
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.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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.
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).
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.
Addressing Standards of Care in Resource-Limited Settings Dawson, Liza; Klingman, Karin L; Marrazzo, Jeanne
Journal of acquired immune deficiency syndromes,
2014-January-1, Volume:
65 Suppl 1, Issue:
Supplement 1
Journal Article
Peer reviewed
Open access
The choice between “best-known” standards of care (SOC) or “best available” standards as the control arm in a clinical trial is a fundamental dilemma in clinical research in resource-limited settings ...(RLS). When the health system is delivering less than an optimal level of care, using highest standard of care in a clinical trial may produce results that cannot be implemented or sustained locally. On the other hand, using interventions that are more feasible in the local setting may involve suboptimal care, and clinical outcomes may be affected. The need for improved standards in health systems in RLS, and the difficulty in securing them, has led many researchers advocate for policy changes at the national or international level to improve clinical care more systemically. SOC decisions in a clinical trial affect the level of benefit provided to study participants and the policy implications of the trial findings. SOC choices should provide high-quality care to help advance the health care system in host countries participating in the trial, but balancing the scientific and ethical objectives of SOC choices is difficult, and there is no single formula for selecting the appropriate SOC. Despite the challenges, well-designed and conducted clinical trials can and should make significant contributions to health systems in RLS.
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.
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