Clinical and population-based study design considerations to accelerate the investigation of new antiretrovirals during pregnancy.

INTRODUCTION: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies. DISCUSSION: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias. CONCLUSIONS: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.

Dosage of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in a Cohort of Zambian Pregnant Women in a Low Malaria Prevalence Region.

In Lusaka, Zambia, where malaria prevalence is low, national guidelines continue to recommend that all pregnant women receive sulfadoxine-pyrimethamine (SP) for malaria prophylaxis monthly at every scheduled antenatal care visit after 16 weeks of gestation. Human immunodeficiency virus (HIV)-positive women should receive co-trimoxazole prophylaxis for HIV and not SP, but many still receive SP. We sought to determine whether increased dosage of SP is still associated with a reduced risk of low birth weight (LBW) in an area where malaria transmission is low. Our secondary objective was to determine whether any association between SP and LBW is modified by receipt of antiretroviral therapy (ART). We analyzed data routinely collected from a cohort of HIV-positive pregnant women with singleton births in Lusaka, Zambia, between February 2006 and December 2012. We used a log-Poisson model to estimate the risk of LBW by dosage of SP and to determine whether the association between SP and LBW varied by receipt of ART. Risk of LBW declined as the number of doses increased and appeared lowest among women who received three doses (adjusted risk ratio [ARR] = 0.78; 95% confidence interval [CI] = 0.64-0.95). In addition, women receiving combination ART had a higher risk of delivering an LBW infant compared with women receiving no treatment or prophylaxis (ARR = 1.18; 95% CI = 1.09-1.28), but this risk was attenuated among women who were receiving SP (risk ratio = 1.09; 95% CI = 0.99-1.21). SP was associated with a reduced risk of LBW in HIV-positive women, including those receiving ART, in a low malaria prevalence region.

Health facility characteristics and their relationship to coverage of PMTCT of HIV services across four African countries: the PEARL study.

BACKGROUND: Health facility characteristics associated with effective prevention of mother-to-child transmission of HIV (PMTCT) coverage in sub-Saharan are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We conducted surveys in health facilities with active PMTCT services in Cameroon, Cote d'Ivoire, South Africa, and Zambia. Data was compiled via direct observation and exit interviews. We constructed composite scores to describe provision of PMTCT services across seven topical areas: antenatal quality, PMTCT quality, supplies available, patient satisfaction, patient understanding of medication, and infrastructure quality. Pearson correlations and Generalized Estimating Equations (GEE) to account for clustering of facilities within countries were used to evaluate the relationship between the composite scores, total time of visit and select individual variables with PMTCT coverage among women delivering. Between July 2008 and May 2009, we collected data from 32 facilities; 78% were managed by the government health system. An opt-out approach for HIV testing was used in 100% of facilities in Zambia, 63% in Cameroon, and none in Côte d'Ivoire or South Africa. Using Pearson correlations, PMTCT coverage (median of 55%, (IQR: 33-68) was correlated with PMTCT quality score (rho = 0.51; p = 0.003); infrastructure quality score (rho = 0.43; p = 0.017); time spent at clinic (rho = 0.47; p = 0.013); patient understanding of medications score (rho = 0.51; p = 0.006); and patient satisfaction quality score (rho = 0.38; p = 0.031). PMTCT coverage was marginally correlated with the antenatal quality score (rho = 0.304; p = 0.091). Using GEE adjustment for clustering, the, antenatal quality score became more strongly associated with PMTCT coverage (p<0.001) and the PMTCT quality score and patient understanding of medications remained marginally significant. CONCLUSIONS/RESULTS: We observed a positive relationship between an antenatal quality score and PMTCT coverage but did not identify a consistent set of variables that predicted PMTCT coverage.

Nevirapine for the prevention of mother-to-child transmission of HIV: a nation-wide coverage survey in Côte d'Ivoire.

BACKGROUND: Single-dose nevirapine (NVP) is the simplest antiretroviral regimen for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. We evaluated NVP coverage among HIV-infected delivering women in Côte d'Ivoire. METHODS: A cross-sectional survey of mother-infant pairs was conducted between November 2007 and September 2008 in 10 randomly selected facilities providing delivery services in the country. All sites used at least NVP for PMTCT. Anonymous HIV test and blood collection for NVP concentration measurement were performed in labor wards. NVP coverage was defined as the proportion of maternal and infant NVP intake confirmed by cord blood chromatography and direct observation. RESULTS: A total of 9953 deliveries were enrolled. Median maternal age was 25 years, and the median number of antenatal care (ANC) visits was 3. Of the 9747 women (97.9%) who made at least 1 ANC visit, 5880 (60.3%) received an HIV test proposal, 5135 (87.3%) accepted it, and 251 (4.9%) were diagnosed HIV infected; 176 of them (70.1%) received antiretroviral prophylaxis according to the medical record. Using anonymous cord blood surveillance, HIV prevalence was 5.9% (570 of 9646), maternal NVP coverage was 24.3% (138 of 570), and maternal and infant NVP coverage was 17.9% (102 of 570). In multivariate analysis, maternal NVP coverage was associated with 2-3 ANC visits [adjusted odds ratio (aOR): 2.61; 95% confidence interval (CI): 1.27 to 5.39] or ≥ 4 ANC visits (aOR: 3.84; 95% CI: 1.86 to 7.90) (ref. ≤ 1), and giving birth in clinic of first ANC visit (aOR: 2.21; 95% CI: 1.43 to 3.40). CONCLUSIONS: Maternal and infant NVP coverage was low irrespective of the method. Anonymous cord blood surveillance is more reliable for documenting PMTCT coverage.

Presumptive diagnosis of severe HIV infection to determine the need for antiretroviral therapy in children less than 18 months of age.

OBJECTIVE: To develop a new algorithm for the presumptive diagnosis of severe disease associated with human immunodeficiency virus (HIV) infection in children less than 18 months of age for the purpose of identifying children who require antiretroviral therapy (ART). METHODS: A conditional probability model was constructed and non-virologic parameters in various combinations were tested in a hypothetical cohort of 1000 children aged 6 weeks, 6 months and 12 months to assess the sensitivity, specificity, and positive and negative predictive values of these algorithms for identifying children in need of ART. The modelled parameters consisted of clinical criteria, rapid HIV antibody testing and CD4+ T-lymphocyte (CD4) count. FINDINGS: In children younger than 18 months, the best-performing screening algorithm, consisting of clinical symptoms plus antibody testing plus CD4 count, showed a sensitivity ranging from 71% to 80% and a specificity ranging from 92% to 99%. Positive and negative predictive values were between 61% and 97% and between 95% and 96%, respectively. In the absence of virologic tests, this alternate algorithm for the presumptive diagnosis of severe HIV disease makes it possible to correctly initiate ART in 91% to 98% of HIV-positive children who are at highest risk of dying. CONCLUSION: The algorithms presented in this paper have better sensitivity and specificity than clinical parameters, with or without rapid HIV testing, for the presumptive diagnosis of severe disease in HIV-positive children less than 18 months of age. If implemented, they can increase the number of HIV-positive children successfully initiated on ART.

Myths and misconceptions about cervical cancer among Zambian women: rapid assessment by peer educators.

OBJECTIVE: To make a rapid assessment of the common myths and misconceptions surrounding the causes of cervical cancer and lack of screening among unscreened low-income Zambian women. METHODS: We initiated a door-to-door community-based initiative, led by peer educators, to inform unscreened women about the existence of a new see-and-treat cervical cancer prevention program. During home visits peer educators posed the following two questions to women: 1. What do you think causes cervical cancer? 2. Why haven't you been screened for cervical cancer? The most frequent types of responses gathered in this exercise were analyzed thematically. RESULTS: Peer educators contacted over 1100 unscreened women over a period of two months. Their median age was 33 years, a large majority (58%) were not educated beyond primary school, over two-thirds (71%) did not have monthly incomes over 500,000 Zambian Kwacha (US$100) per month, and just over half (51%) were married and cohabiting with their spouses. Approximately 75% of the women engaged in discussions had heard of cervical cancer and had heard of the new cervical cancer prevention program in the local clinic. The responses of unscreened low-income Zambian women to questions posed by peer educators in urban Lusaka reflect the variety of prevalent 'folk' myths and misconceptions surrounding cervical cancer and its prevention methods. CONCLUSION: The information in our rapid assessment can serve as a basis for developing future educational and intervention campaigns for improving uptake of cervical cancer prevention services in Zambia. It also speaks to the necessity of ensuring that programs addressing women's reproductive health take into account societal inputs at the time they are being developed and implemented. Taking a community-based participatory approach to program development and implementation will help ensure sustainability and impact.