A single dose of nevirapine (sdNVP) administered to both mother and infant can decrease mother-to-child transmission of human immunodeficiency virus (HIV) by 47%, compared with ultra-short course zidovudine therapy (usZDV). There is limited data about the benefit of usZDV added to sdNVP to prevent mother-to-child transmission.
We performed a double-blind, randomized, placebo-controlled trial to determine whether usZDV combined with sdNVP improved neonatal outcome, compared with sdNVP alone. Mothers were randomized to 1 of 2 treatment groups. Mothers in the usZDV/sdNVP group received a loading dose of zidovudine (600 mg administered orally) and continued to receive 300-mg doses of zidovudine orally every 3 h while in labor, and their infants received zidovudine at a dosage of 2 mg per kg of body weight 4 times per day orally for 72 h. Mothers and infants in the sdNVP group received zidovudine placebo dosed in the same manner. All mothers also received nevirapine at a dosage of 200 mg orally while in labor, and all infants received nevirapine 2 mg per kg of body weight orally within 72 h of delivery.
The study was stopped on the basis of futility, because interim data showed that, at present trends, superiority would not be demonstrated. Results at 6 weeks of age were available for 609 infants. The primary end point of HIV RNA positivity or death occurred in 21.8% of infants in the usZDV/sdNVP arm and 23.6% of the infants in the sdNVP arm.
usZDV, when added to a standard 2-dose regimen of sdNVP, did not demonstrate a clinically important decrease in the combined end point of mother-to-child transmission or infant death. High rates of adverse maternal and infant outcome in both study arms suggest that improved approaches are necessary.
"Thirteen trials were terminated earlier than planned. Reasons for early termination included a significant effect of the intervention detected during data monitoring – and no significant effect during data monitoring –. In two of these trials, the results of data monitoring were confirmed in a recently published trial employing the same intervention , . "
[Show abstract][Hide abstract] ABSTRACT: To effectively address HIV/AIDS in Africa, evidence on preventing new infections and providing effective treatment is needed. Ideally, decisions on which interventions are effective should be based on evidence from randomized controlled trials (RCTs). Our previous research described African RCTs of HIV/AIDS reported between 1987 and 2003. This study updates that analysis with RCTs published between 2004 and 2008.
To describe RCTs of HIV/AIDS conducted in Africa and reported between 2004 and 2008.
We searched the Cochrane HIV/AIDS Specialized Register in September 2009. Two researchers independently evaluated studies for inclusion and extracted data using standardized forms. Details included location of trials, interventions, methodological quality, location of principal investigators and funders.
Our search identified 834 RCTs, with 68 conducted in Africa. Forty-three assessed prevention-interventions and 25 treatment-interventions. Fifteen of the 43 prevention RCTs focused on preventing mother-to-child HIV transmission. Thirteen of the 25 treatment trials focused on opportunistic infections. Trials were conducted in 16 countries with most in South Africa (20), Zambia (12) and Zimbabwe (9). The median sample size was 628 (range 33-9645). Methods used for the generation of the allocation sequence and allocation concealment were adequate in 38 and 32 trials, respectively, and 58 reports included a CONSORT recommended flow diagram. Twenty-nine principal investigators resided in the United States of America (USA) and 18 were from African countries. Trials were co-funded by different agencies with most of the funding obtained from USA governmental and non-governmental agencies. Nineteen pharmaceutical companies provided partial funding to 15 RCTs and African agencies co-funded 17 RCTs. Ethical approval was reported in 65 trials and informed consent in 61 trials.
Prevention trials dominate the trial landscape in Africa. Of note, few principal investigators and funders are from Africa. These findings mirror our previous work and continue to indicate a need for strengthening trial research capacity in Africa.
PLoS ONE 12/2011; 6(12):e28759. DOI:10.1371/journal.pone.0028759 · 3.23 Impact Factor
"Follow-up visits by mother and child were at two weeks, six weeks, three months, six months and one-year postpartum. Results were compared to a previous study performed at the same center from December 2002 to 2004, where mothers received intrapartum sdNVP 200 mg NVP only and infants received 2 mg/kg of NVP within 72 hours of delivery (Thistle et al. 2007). The hematology tests described for the current study were unavailable for the historical control group due to resource limitations at that time. "
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in preventing mother-to-child transmission (PMTCT) of HIV in breastfeeding women in rural Zimbabwe. During a severe socio-economic crisis in 2005-2007, 82 eligible HIV-positive pregnant women between 14-36 weeks gestation were initiated on HAART with AZT/3TC/nelfinavir combination therapy at a rural hospital and continued through to six months post-partum. In addition, mothers also received intrapartum single-dose nevirapine (sdNVP). Infants received sdNVP/AZT in the first 72 hours and were assessed for HIV infection at six weeks of age. Results were compared to historical controls of HIV-positive pregnant women who received sdNVP only at the same center. Of the 67 infants with available data on HIV status at six weeks postpartum, three (4.4%) were HIV positive by HIV RNA assay in the HAART + sdNVP group compared to 49/297 (16.5%) in the sdNVP group (p = 0.01). HAART given to HIV-infected mothers in pregnancy and during breastfeeding along with intrapartum sdNVP resulted in a lower postnatal HIV transmission at six weeks postpartum compared to sdNVP treatment. Our HAART regimen demonstrates that PMTCT of HIV can be effective even during times of socioeconomic crisis in resource-poor rural settings.
Medicine Conflict and Survival 09/2011; 27(3):165-76. DOI:10.1080/13623699.2011.631752
"In this case, the argument goes, continuing the trial may not be justifiable in terms of time, money, and effort. For example, Thistle et al. recently truncated their investigation of whether an ultrashort course of zidovudine therapy combined with a single dose of nevirapine would improve neonatal outcome compared with nevirapine alone . Third, new external information may arise during the conduct of the study that either convincingly answers the primary study question or that raises serious safety issues. "
[Show abstract][Hide abstract] ABSTRACT: To illustrate controversial issues associated with stopping randomized controlled trials (RCTs) early for apparent benefit.
The article presents our review of prior relevant work and our research group's reflections on early stopping.
Compelling evidence suggests that trials stopped early for benefit systematically overestimate treatment effects, sometimes by a large amount. Unresolved controversies in trials stopped early for benefit include ethical and statistical problems in the interpretation of results.
The best strategy to minimize the problems associated with early stopping of RCTs for benefit is not to stop early. As an alternative, we suggest a threefold approach: a low P-value as the threshold for stopping at the time of interim analyses, not to look before a sufficiently large number of events has accrued and continuation of enrollment and follow-up for a further period.
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