Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial

Background

Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.

Methods and Findings

In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm³ were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log₁₀ below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm³, HIV RNA = 5.2 log₁₀copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.

Conclusions

Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm³.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00089505","term_id":"NCT00089505"}}NCT00089505 Please see later in the article for the Editors'' Summary     

Adverse Events in a Cohort of HIV Infected Pregnant and Non-Pregnant Women Treated with Nevirapine versus Non-Nevirapine Antiretroviral Medication

Background

Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women.

Methodology

AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses.

Principal Findings

Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant.

LEE

No significant difference was found between regimens in the development of new grade ≥2 LEE (p = 0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p = 0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm³ were not associated with this toxicity.

Rash

NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14–6.76), as was baseline CD4 >250 cells/mm³ when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19–6.02 p = 0.017).

Conclusions

CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication.     

A Randomized,Controlled, Trial of Short Cycle Intermittent Compared to Continuous Antiretroviral Therapy for the Treatment of HIV Infection in Uganda

Background

Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Methods

A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count ≥125 cells/mm³ and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection.

Results

Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39).

Conclusions

Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00339456","term_id":"NCT00339456"}}NCT00339456     

Reproductive Intentions and Outcomes among Women on Antiretroviral Therapy in Rural Uganda: A Prospective Cohort Study

Background

Antiretroviral therapy (ART) may influence the biological, social and behavioral determinants of pregnancy in HIV-infected women. However, there are limited longitudinal data on the reproductive intentions and outcomes among women on ART in Africa.

Methodology /Principal Findings

Using a prospective cohort design, we analyzed trends in desire for children and predictors of pregnancy among a cohort of 733 HIV-infected women in rural Uganda who initiated ART between May 2003 and May 2004 and were followed up in their homes until June 2006. Women answered in-depth social and behavioral questionnaires administered every quarter in year 1 after initiating ART, and every 6 to 12 months thereafter. Use of family planning methods was assessed at 18 and 24 months after starting ART. We tested for non-constant pregnancy incidence by using a shape parameter test from the Weibull distribution. We modeled repeated measurements of all variables related to the women''s desire for children over time using a generalized estimating equation (GEE) extension to the logistic regression model. Risk factors for pregnancy were examined using Cox proportional hazards model. 711 women eligible for the study were followed-up for a median time of 2.4 years after starting ART. During this time, less than 7% of women reported wanting more children at any time point yet 120 (16.9%) women experienced 140 pregnancies and pregnancy incidence increased from 3.46 per 100 women-years (WY) in the first quarter to 9.5 per 100 WY at 24 months (p<0.0001). This was paralleled by an increase in the proportion of women reporting sexual activity in the past 3 months, from 24.4% at baseline to 32.5% over 24 months of follow-up (p = 0.001). Only 14% of women used permanent or semi-permanent family planning methods by their second year on ART. In the multivariate model, younger age (HR = 2.71 per 10-year decrease, 95% CI: 2.95–3.78), having a BMI>18.5 (HR = 1.09, CI: 1.01–1.18) and not having used condoms consistently in the last 3 months (HR = 1.79, CI: 1.02–3.13) were independently associated with pregnancy.

Conclusion/Significance

Women on ART and their partners should be consistently counseled on the effects of ART in restoring fertility, and offered regularly free and comprehensive family planning services as part of their standard package of care.     

The APPLe Study: A Randomized,Community-Based,Placebo-Controlled Trial of Azithromycin for the Prevention of Preterm Birth,with Meta-Analysis

Background

Premature birth is the major cause of perinatal mortality and morbidity in both high- and low-income countries. The causes of preterm labour are multiple but infection is important. We have previously described an unusually high incidence of preterm birth (20%) in an ultrasound-dated, rural, pregnant population in Southern Malawi with high burdens of infective morbidity. We have now studied the impact of routine prophylaxis with azithromycin as directly observed, single-dose therapy at two gestational windows to try to decrease the incidence of preterm birth.

Methods and Findings

We randomized 2,297 pregnant women attending three rural and one peri-urban health centres in Southern Malawi to a placebo-controlled trial of oral azithromycin (1 g) given at 16–24 and 28–32 wk gestation. Gestational age was determined by ultrasound before 24 wk. Women and their infants were followed up until 6 wk post delivery. The primary outcome was incidence of preterm delivery, defined as <37 wk. Secondary outcomes were mean gestational age at delivery, perinatal mortality, birthweight, maternal malaria, and anaemia. Analysis was by intention to treat. There were no significant differences in outcome between the azithromycin group (n = 1,096) and the placebo group (n = 1,087) in respect of preterm birth (16.8% versus 17.4%), odds ratio (OR) 0.96, 95% confidence interval (0.76–1.21); mean gestational age at delivery (38.5 versus 38.4 weeks), mean difference 0.16 (−0.08 to 0.40); mean birthweight (3.03 versus 2.99 kg), mean difference 0.04 (−0.005 to 0.08); perinatal deaths (4.3% versus 5.0%), OR 0.85 (0.53–1.38); or maternal malarial parasitaemia (11.5% versus 10.1%), OR 1.11 (0.84–1.49) and anaemia (44.1% versus 41.3%) at 28–32 weeks, OR 1.07 (0.88–1.30). Meta-analysis of the primary outcome results with seven other studies of routine antibiotic prophylaxis in pregnancy (>6,200 pregnancies) shows no effect on preterm birth (relative risk 1.02, 95% confidence interval 0.86–1.22).

Conclusions

This study provides no support for the use of antibiotics as routine prophylaxis to prevent preterm birth in high risk populations; prevention of preterm birth requires alternative strategies.

Trial registration

Current Controlled Trials ISRCTN84023116 Please see later in the article for the Editors'' Summary     

Cellular Levels of HIV Unspliced RNA from Patients on Combination Antiretroviral Therapy with Undetectable Plasma Viremia Predict the Therapy Outcome

Background

Combination antiretroviral therapy (cART), the standard of care for HIV-1 infection, is considered to be successful when plasma viremia remains below the detection limit of commercial assays. Yet, cART fails in a substantial proportion of patients after the apparent success. No laboratory markers are known that are predictive of cART outcome in initial responders during the period of undetectable plasma viremia.

Methodology/Principal Findings

Here, we report the results of a retrospective longitudinal study of twenty-six HIV-infected individuals who initially responded to cART by having plasma viremia suppressed to <50 copies/ml. Eleven of these patients remained virologically suppressed, whereas fifteen experienced subsequent cART failure. Using sensitive methods based on seminested real-time PCR, we measured the levels of HIV-1 proviral (pr) DNA, unspliced (us) RNA, and multiply spliced RNA in the peripheral blood mononuclear cells (PBMC) of these patients at multiple time points during the period of undetectable plasma viremia on cART. Median under-therapy level of usRNA was significantly higher (0.43 log₁₀ difference, P = 0.0015) in patients who experienced subsequent cART failure than in successfully treated patients. In multivariate analysis, adjusted for baseline CD4⁺ counts, prior ART experience, and particular cART regimens, the maximal usRNA level under therapy was the best independent predictor of subsequent therapy failure (adjusted odds ratio [95% CI], 24.4 [1.5–389.5], P = 0.024). The only other factor significantly associated with cART failure was prior ART experience (adjusted odds ratio [95% CI], 12.3 [1.1–138.4], P = 0.042). Levels of usRNA under cART inversely correlated with baseline CD4⁺ counts (P = 0.0003), but did not correlate with either baseline usRNA levels or levels of prDNA under therapy.

Conclusion

Our data demonstrate that the level of HIV-1 usRNA in PBMC, measured in cART-treated patients with undetectable plasma viremia, is a strong predictive marker for the outcome of therapy.     

Effect of Peer Health Workers on AIDS Care in Rakai,Uganda: A Cluster-Randomized Trial

Background

Human resource limitations are a challenge to the delivery of antiretroviral therapy (ART) in low-resource settings. We conducted a cluster randomized trial to assess the effect of community-based peer health workers (PHW) on AIDS care of adults in Rakai, Uganda.

Methodology/Principal Findings

15 AIDS clinics were randomized 2∶1 to receive the PHW intervention (n = 10) or control (n = 5). PHW tasks included clinic and home-based provision of counseling, clinical, adherence to ART, and social support. Primary outcomes were adherence and cumulative risk of virologic failure (>400 copies/mL). Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART. Analysis was by intention to treat. From May 2006 to July 2008, 1336 patients were followed. 444 (33%) of these patients were already on ART at the start of the study. No significant differences were found in lack of adherence (<95% pill count adherence risk ratio [RR] 0.55, 95% confidence interval [CI] 0.23–1.35; <100% adherence RR 1.10, 95% CI 0.94–1.30), cumulative risk of virologic failure (RR 0.81, 95% CI 0.61–1.08) or in shorter-term virologic outcomes (24 week virologic failure RR 0.93, 95% CI 0.65–1.32; 48 week, RR 0.83, 95% CI 0.47–1.48; 72 week, RR 0.81, 95% CI 0.44–1.49). However, virologic failure rates ≥96 weeks into ART were significantly decreased in the intervention arm compared to the control arm (96 week failure RR 0.50, 95% CI 0.31–0.81; 120 week, RR 0.59, 95% CI 0.22–1.60; 144 week, RR 0.39, 95% CI 0.16–0.95; 168 week, RR 0.30, 95% CI 0.097–0.92; 192 week, RR 0.067, 95% CI 0.0065–0.71).

Conclusions/Significance

A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART, but did not affect cumulative risk of virologic failure, adherence measures, or shorter-term virologic outcomes. PHWs may be an effective intervention to sustain long-term ART in low-resource settings.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00675389","term_id":"NCT00675389"}}NCT00675389     

Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A C?te d'Ivoire Appraisal

Background

Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa.

Methods and Findings

We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of <3× gross domestic product per capita (3× GDP per capita = US$2,823 for Côte d''Ivoire) as a plausible threshold for “cost-effectiveness.” The main results are based on a reported 18% 1-y LTFU rate. With full retention in care, projected per-person discounted life expectancy starting from age 37 y was 144.7 mo (12.1 y). Survival losses from LTFU within 1 y of ART initiation ranged from 73.9 to 80.7 mo. The intervention costing US$22/person/year (e.g., eliminating ART co-payment) would be cost-effective with an efficacy of at least 12%. An intervention costing US$77/person/year (inclusive of all the components described above) would be cost-effective with an efficacy of at least 41%.

Conclusions

Interventions that prevent LTFU in resource-limited settings would substantially improve survival and would be cost-effective by international criteria with efficacy of at least 12%–41%, depending on the cost of intervention, based on a reported 18% cumulative incidence of LTFU at 1 y after ART initiation. The commitment to start ART and treat HIV in these settings should include interventions to prevent LTFU. Please see later in the article for the Editors'' Summary     

Oral Bisphosphonates and Risk of Atrial Fibrillation and Flutter in Women: A Self-Controlled Case-Series Safety Analysis

Background

A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.

Methodology/Principal Findings

We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195) was 1.07 (95% CI 0.94–1.21). The age-adjusted incidence rate ratio for alendronic acid (n = 1489) and risedronate sodium (n = 649) exposed individuals were 1.09 (95% CI 0.93–1.26) and 0.99 (95% CI 0.78–1.26) respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.

Conclusions/Significance

We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.     

Survival of Infants Born to HIV-Positive Mothers,by Feeding Modality,in Rakai,Uganda

Background

Data comparing survival of formula-fed to breast-fed infants in programmatic settings are limited. We compared mortality and HIV-free of breast and formula-fed infants born to HIV-positive mothers in a program in rural, Rakai District Uganda.

Methodology/Principal Findings

One hundred eighty two infants born to HIV-positive mothers were followed at one, six and twelve months postpartum. Mothers were given infant-feeding counseling and allowed to make informed choices as to whether to formula-feed or breast-feed. Eligible mothers and infants received antiretroviral therapy (ART) if indicated. Mothers and their newborns received prophylaxis for prevention of mother-to-child HIV transmission (pMTCT) if they were not receiving ART. Infant HIV infection was detected by PCR (Roche Amplicor 1.5) during the follow-up visits. Kaplan Meier time-to-event methods were used to compare mortality and HIV-free survival. The adjusted hazard ratio (Adjusted HR) of infant HIV-free survival was estimated by Cox regression. Seventy-five infants (41%) were formula-fed while 107 (59%) were breast-fed. Exclusive breast-feeding was practiced by only 25% of breast-feeding women at one month postpartum. The cumulative 12-month probability of infant mortality was 18% (95% CI = 11%–29%) among the formula-fed compared to 3% (95% CI = 1%–9%) among the breast-fed infants (unadjusted hazard ratio (HR)  = 6.1(95% CI = 1.7–21.4, P-value<0.01). There were no statistically significant differentials in HIV-free survival by feeding choice (86% in the formula-fed compared to 96% in breast-fed group (Adjusted RH = 2.8[95%CI = 0.67–11.7, P-value = 0.16]

Conclusions/Significance

Formula-feeding was associated with a higher risk of infant mortality than breastfeeding in this rural population. Our findings suggest that formula-feeding should be discouraged in similar African settings.     

Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants

Background

Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.

Methods/Findings

Standard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant''s blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.

Conclusions/Significance

Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00061321","term_id":"NCT00061321"}}NCT00061321     

Plasmodium falciparum Infection Significantly Impairs Placental Cytokine Profile in HIV Infected Cameroonian Women

Background

Placental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women.

Materials and Methods

P. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses.

Results

Placental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5–4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3–1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-α mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-α/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-α was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery.

Conclusions

These results show that P. falciparum infection profoundly modifies the placenta cytokine environment and acts as a confounding factor, masking the impact of HIV-1 in co-infected women. This interplay between the two infections might have implications in the in utero MTCT of HIV-1 in areas where HIV-1 and P. falciparum co-circulate.     

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background

Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

Methods and Findings

A5164 was a randomized strategy trial of “early ART” - given within 14 days of starting acute OI treatment versus “deferred ART” - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) ≥50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS.282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively.The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.

Conclusions

Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00055120","term_id":"NCT00055120"}}NCT00055120