Trials In sub-Saharan Africa Research Articles

In Tanzania, Educating Religious Leaders Increases Uptake of Male Circumcision

Educating religious leaders about male circumcision may improve uptake of the procedure in Sub-Saharan African countries. (1) In a cluster randomized trial conducted in rural Tanzania, men had an elevated likelihood of undergoing circumcision during a government campaign if their village's religious leaders had attended a day-long educational seminar about circumcision (odds ratio, 3.2). Among men who had a circumcision, the proportion who attributed their decision to having heard about the procedure in church was substantially higher in intervention villages than in control villages (31% vs. 1%). Although randomized trials in Sub-Saharan Africa have shown that circumcision reduces the risk of HIV infection, uptake of the procedure has fallen short of goals in many countries. In Tanzania, one impediment has been religious objection, notably from Christians who view the practice as appropriate only for Muslims and sexually promiscuous individuals. Given that religion plays an important role in the lives of most Tanzanians, researchers designed a study to examine whether uptake of circumcision would increase if local religious leaders received education about the procedure. The study was conducted in 2014-2015 in rural northwest Tanzania in conjunction with a regional circumcision campaign administered by the Ministry of Health, in which circumcision and voluntary HIV testing and counseling were offered free of charge to all males aged 10 or older. Although the baseline prevalence of circumcision in the area was not known, it was thought to be low because most residents are Christian and belong to an ethnic group that traditionally does not circumcise youth. The researchers selected 16 villages, from which they formed eight pairs of villages that were within 60 kilometers of one another and would be targeted by the campaign at the same time; contact between each village and its counterpart was minimal because of poor infrastructure. One village in each pair was randomly chosen to receive the intervention, in which Christian church leaders (ideally at least one male and one female from each church) were invited to attend a day-long seminar that discussed the medical, historical, social and religious aspects of circumcision. Participants were encouraged to share the information they had received with their congregations. At about the same time, a team from the circumcision campaign began offering circumcisions and related outreach programs in both the intervention and the control villages, and documented the number of boys and men in each village who underwent the procedure. Information was collected on clients' demographic characteristics and reasons for circumcision. The researchers used client records and data from the 2012 census to estimate the proportion of males in each village who had been circumcised during the campaign. They used logistic regression models to identify differences between the intervention and control groups in circumcision levels and in the reasons men gave for wanting to be circumcised. …

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial.

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.

Acceptability and Safety of Hydroxyurea for Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria

Background: Nigeria has the highest prevalence of sickle cell disease (SCD), a common cause of pediatric ischemic stroke. In sub-Saharan Africa monthly blood transfusions for primary stroke prevention carries risks; hydroxyurea (HU) may be an alternative. We conducted the first, US NIH funded, SCD feasibility trial in sub-Saharan Africa (5R21NS080639-02) to: 1) assess the acceptability and willingness of families to participate in a HU trial; 2) develop a safety protocol for using HU in a trial setting in sub-Saharan Africa; and 3) prepare for a definitive phase III Trial. In the Sickle Cell Disease Stroke Prevention in Nigeria (SPIN) trial, our primary hypothesis in the internal feasibility trial is that 80% adherence for daily HU administration is feasible.Procedure: The internal pilot is a single site; single arm trial enrolling 40 children aged 5 to 12 years with hemoglobin SS or SB0 thalassemia at risk of developing stroke with a high transcranial Doppler (TCD) velocity in the middle cerebral artery (MCA) ≥ 200 cm/sec. Each participant is scheduled to receive low dose HU therapy (~20mg/kg/day) for 36 months. Acceptability was determined by the number of families who consented for screening. The adherence rate of HU was based on monthly parental assessment of the Morisky Medical Adherence Sore (MMAS) and monthly complete blood count (CBC) to monitor the serial change in mean corpuscular volume (MCV) from baseline level. Assessment of toxicity attributable to HU was based on comparing adverse events between the HU and control groups. Controls were identified as participants that met the criteria for the trial, but had TCD measurements < 200 cm/sec. From Baby HUG, adverse events were defined as hospitalization for any cause, severe anemia and myelosuppression (severe neutropenia and thrombocytopenia based on monthly CBC).Results: A total of 269 participants were approached, of which 96% (23 of 24) and 86% (211 of 245) with an elevated or normal TCD measurement agreed to enroll in the HU therapy or control groups with a median age of 8 and 7.6 years, respectively. At the current milestone, 100% of the participants enrolled in the treatment arm demonstrated at least average to high monthly adherence rate (MMAS of 6-8 points). This adherence rate was consistent with an increase in MCV from baseline to 3 months after starting HU therapy with a minimum increase in MCV of at least 3 fl in 8 of 11 participants. One child on HU therapy was hospitalized for 5 days for hypovolemia and dehydration associated with cholera. The table below shows no excessive rate of adverse events when HU therapy and control groups are compared.Conclusion: These early results demonstrate the ability for a sub-Saharan African clinical research team to plan and initiate a complex SCD trial. Our preliminary data provide strong evidence for acceptability and potential safety of low dose HU therapy in Nigerian children with SCD. Completion of the internal pilot should provide sufficient evidence to pursue a phase III trial of low dose HU therapy to prevent strokes in children living in sub-Saharan Africa.TableRates of Hospitalization within the first 12 months of the SCD Stroke Prevention in Nigeria (SPIN) Trial.Reason for HospitalizationHydroxyurea Therapy Group(15 total person years; n = 23)Rate per 100 patient yearsControl Group(52 total person years; n = 211)Rate per 100 patient yearsAcute Chest Syndrome02Osteomyelitis02Infection requiring hospitalization06Pain requiring hospitalization072Transfusion08Malaria requiring hospitalization734Fever requiring hospitalization70Other reasons for hospitalizations010 DisclosuresNeville:American Academy of Pediatrics; Food and Drug Administration; NICHD: Membership on an entity’s Board of Directors or advisory committees; Children’s Oncology Group; Therapeutic Advances in Childhood Leukemia; Neuroblastoma/Medulloblastoma Treatment Consortium; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Midwest Cancer Alliance; Dell; Braden’s Hope Foundation: Research Funding; Sanofi; Novartis; Amgen; Medimmune; United Therapeutics; Bristol Myers Squibb: IND for hydroxyurea, IND for hydroxyurea Other.

Women and ARV-based prevention: opportunities and challenges

ARV-based HIV prevention methods available in pill, gel or ring formulations (broadly referred to as microbicides) offer the possibility of protection against HIV for women who find it difficult because they cannot ask their partners to use condoms or even refuse sex. Partial efficacy of ARV-based medications has been demonstrated in a number of clinical trials around the world among various populations, building the evidence that ARV-based technologies will contribute to reducing the AIDS epidemic worldwide. Disappointing results, however, from two trials in sub-Saharan Africa, where poor adherence contributed to study closure due to futility, have raised questions about whether women at the centre of the epidemic are able to effectively use products that require routine use. Also, there are fears by some of risk compensation by decreased condom use because of the availability of microbicides when only partial efficacy has been demonstrated in microbicide trials to date. Of note, sub-analyses of biologic measures of adherence in trials where this was possible have shown a strong correlation between good adherence and efficacy, reinforcing the necessity of good adherence. Research conducted in conjunction with clinical trials and post-trials in advance of possible rollout of ARV-based products have examined social and cultural factors, gender-related and otherwise, influencing adherence and other aspects of women's use of products. These include HIV stigma, women's perception of risk, partner and community influences and the differing needs of women in various stages of life and in different circumstances. It is the purpose of this supplement to give voice to the needs of women who can benefit from woman-initiated methods by presenting research results and commentary to contribute to the global conversation about optimizing women's experience with ARV-based prevention.

Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa

BackgroundThe efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.MethodsIn this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir–ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%).ResultsGood HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).ConclusionsWhen given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.)

Modifying the multi-arm multi-stage (MAMS) design for use in a phase II tuberculosis trial in sub-Saharan Africa with a time-to-event primary outcome

Background Tuberculosis (TB) causes significant morbidity and mortality globally. High efficacy in clinical trials of the current 4-drug 6-month regimen does not always translate into practice due to a heavy pill burden and long duration. New drugs are in late-phase clinical development, so trials that evaluate novel and existing drugs in combination are urgently needed. A multi-arm multi-stage (MAMS) design, with planned interim analyses allowing stopping of arms not showing benefit, has been developed and used in oncology. We have adapted this approach to create the PanACEA MAMS-TB 5-arm 3-stage phase II trial evaluating new treatments for TB.

Pregnancy in HIV Clinical Trials in Sub Saharan Africa: Failure of Consent or Contraception?

ObjectiveHigher than expected pregnancy rates have been observed in HIV related clinical trials in Sub-Saharan Africa. We designed a qualitative study to explore the factors contributing to high pregnancy rates among participants in two HIV clinical trials in Sub-Saharan Africa.MethodsFemale and male participants enrolled in one of two clinical HIV trials in south-west Uganda were approached. The trials were a phase III microbicide efficacy trial among HIV negative women using vaginal gel (MDP); and a trial of primary prevention prophylaxis for invasive cryptococcal disease using fluconazole among HIV infected men and women in Uganda (CRYPTOPRO). 14 focus group discussions and 8 in-depth interviews were conducted with HIV positive and negative women and their male partners over a six month period. Areas explored were their experiences about why and when one should get pregnant, factors affecting use of contraceptives, HIV status disclosure and trial product use.ResultsAll respondents acknowledged being advised of the importance of avoiding pregnancy during the trial. Factors reported to contribute to pregnancy included; trust that the investigational product (oral capsules/vaginal gel) would not harm the baby, need for children, side effects that led to inconsistent contraceptive use, low acceptance of condom use among male partners. Attitudes towards getting pregnant are fluid within couples over time and the trials often last for more than a year. Researchers need to account for high pregnancy rates in their sample size calculations, and consider lesser used female initiated contraceptive options e.g. diaphragm or female condoms. In long clinical trials where there is a high fetal or maternal risk due to investigational product, researchers and ethics committees should consider a review of participants contraceptive needs/pregnancy desire review after a fixed period, as need for children, partners and health status of participants may alter over time.

Recent advances in hypertension in sub-Saharan Africa

BackgroundHypertension was once considered rare in sub-Saharan Africa (SSA), but currently it has become a widespread problem with immense socioeconomic importance. The purpose of this review is to summarise new...

Experience and challenges from clinical trials with malaria vaccines in Africa.

Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained.

Background Rates of Adverse Pregnancy Outcomes for Assessing the Safety of Maternal Vaccine Trials in Sub-Saharan Africa

BackgroundMaternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.MethodsWe developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed.FindingsAccounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%.InterpretationSome clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.

Conducting vaccine clinical trials in sub-Saharan Africa: Operational challenges and lessons learned from the Meningitis Vaccine Project

Group A Neisseria meningitidis epidemics have been an important and unresolved public health problem in sub-Saharan Africa for over a century. The Meningitis Vaccine Project (MVP) was established in 2001 with the goal of developing, testing, licensing, and introducing an affordable group A meningococcal conjugate vaccine for Africa. A monovalent group A conjugate vaccine, MenAfriVac™, was developed at the Serum Institute of India Ltd. and tested in clinical trials at multiple trial sites in sub-Saharan African countries.The setup and successful conduct of ICH-GCP standard vaccine trials across multiple trial sites located in low-resource settings are challenging. We describe the main operational issues encountered in three randomized, observer-blind, active controlled studies to evaluate the safety and immunogenicity of MenAfriVac™. The studies were conducted in parallel among 2700 subjects aged between 2 months and 29 years of age enrolled across four trial sites located in Mali, The Gambia, Senegal, and Ghana between September 2006 and August 2009.Many important lessons were learned during the preparation, setup, and implementation of the Meningitis Vaccine Project clinical program. They are summarized here to help vaccine development programs identify efficient pathways for successful implementation of clinical trials in low-resource settings.

A mixed-methods assessment of understanding (AoU) tool for AIDS vaccine trials in sub-Saharan Africa: results from a pilot study

Background Assessments of understanding (AoUs) in clinical trials are often composed of true/false multiple choice questions, however, these tools can be difficult for volunteers with limited education or without prior testing experience. Methods 35 adults were recruited at two research centers in Southern Africa. A within-subjects, repeated measures design was used, whereby each volunteer served as his/ her own control. An AoU tool with closed- and openended questions was administered within a hypothetical AIDS vaccine trial setting. Performance on closed- and open-ended questions was compared using correlations and repeated-measure t-tests, limited to 4 complex concepts: false sense of security, risk of false positive test, need for contraception, and potentially enhanced susceptibility.

Promoting good clinical laboratory practices and laboratory accreditation to support clinical trials in sub-Saharan Africa.

Laboratory capacity in the developing world frequently lacks quality management systems (QMS) such as good clinical laboratory practices, proper safety precautions, and adequate facilities; impacting the ability to conduct biomedical research where it is needed most. As the regulatory climate changes globally, higher quality laboratory support is needed to protect study volunteers and to accurately assess biological parameters. The University of Bamako and its partners have undertaken a comprehensive QMS plan to improve quality and productivity using the Clinical and Laboratory Standards Institute standards and guidelines. The clinical laboratory passed the College of American Pathologists inspection in April 2010, and received full accreditation in June 2010. Our efforts to implement high-quality standards have been valuable for evaluating safety and immunogenicity of malaria vaccine candidates in Mali. Other disease-specific research groups in resource-limited settings may benefit by incorporating similar training initiatives, QMS methods, and continual improvement practices to ensure best practices.

A Qualitative Study of Obstacles to Diaphragm and Condom Use in an HIV Prevention Trial in Sub-Saharan Africa

Consistent condom use and the substitution of condoms with potential HIV prevention methods of lower or unknown effectiveness are important concerns in the development of new prevention technologies. This qualitative study explored obstacles to consistent condom use with the diaphragm in MIRA, an HIV prevention trial in South Africa and Zimbabwe. We conducted 26 focus group discussions (FGDs) with 206 women and 7 FGDs and 10 in-depth interviews with 41 male partners of intervention-arm women. The belief that the diaphragm/gel prevented HIV, women's difficulties negotiating condom use, and men's unawareness that using the products together was recommended were obstacles to consistent condom use with the diaphragm/gel. Concerns about protection from HIV and pregnancy, recognition that the diaphragm was not yet proven to prevent HIV or sexually transmitted infections, and the trial context were facilitators. Understanding selective study product use in HIV prevention trials may inform improved adherence counseling and male involvement strategies.

Plasmodium falciparum msp1, msp2 and glurp allele frequency and diversity in sub-Saharan Africa

BackgroundThe efficacy of anti-malarial drugs is assessed over a period of 28-63 days (depending on the drugs' residence time) following initiation of treatment in order to capture late failures. However, prolonged follow-up increases the likelihood of new infections depending on transmission intensity. Therefore, molecular genotyping of highly polymorphic regions of Plasmodium falciparum msp1, msp2 and glurp loci is usually carried out to distinguish recrudescence (true failures) from new infections. This tool has now been adopted as an integral part of anti-malarial efficacy studies and clinical trials. However, there are concerns over its utility and reliability because conclusions drawn from molecular typing depend on the genetic profile of the respective parasite populations, but this profile is not systematically documented in most endemic areas. This study presents the genetic diversity of P. falciparum msp1, msp2 and glurp markers in selected sub-Saharan Africa countries with varying levels of endemicity namely Malawi, Tanzania, Uganda, Burkina Faso and São Tomé.MethodsA total 780 baseline (Day 0) blood samples from children less than seven years, recruited in a randomized controlled clinical trials done between 1996 and 2000 were genotyped. DNA was extracted; allelic frequency and diversity were investigated by PCR followed by capillary electrophoresis for msp2 and fragment sizing by a digitalized gel imager for msp1 and glurp.Results and ConclusionPlasmodium falciparum msp1, msp2 and glurp markers were highly polymorphic with low allele frequencies. A total of 17 msp1 genotypes [eight MAD20-, one RO33- and eight K1-types]; 116 msp2 genotypes [83 3D7 and 33 FC27- types] and 14 glurp genotypes were recorded. All five sites recorded very high expected heterozygosity (HE) values (0.68 - 0.99). HE was highest in msp2 locus (HE = 0.99), and lowest for msp1 (HE = 0.68) (P < 0.0001). The genetic diversity and allelic frequency recorded were independent of transmission intensity (P = 0.84, P = 0.25 respectively. A few genotypes had particularly high frequencies; however the most abundant showed only a 4% probability that a new infection would share the same genotype as the baseline infection. This is unlikely to confound the distinction of recrudescence from new infection, particularly if more than one marker is used for genotyping. Hence, this study supports the use of msp1, msp2 and glurp in malaria clinical trials in sub-Saharan Africa to discriminate new from recrudescent infections.

Challenges in PMTCT antiretroviral adherence in northern KwaZulu-Natal, South Africa

Background. Women living with HIV in sub-Saharan Africa face significant challenges in accessing HIV care and adhering to antiretroviral therapy. Most reports have focused on issues relating to long-term adherence such as those surrounding stigma and disclosure, hunger, cultural factors, lack of accurate health information, lack of social support, medication side effects and overcrowded health systems. Information related to the challenges facing pregnant women when taking antiretrovirals for prophylactic purposes is limited. The “Kesho Bora Study” is a multicentre prevention of mother-to-child transmission (PMTCT) trial in sub-Saharan Africa evaluating the PMTCT efficacy of triple therapy until cessation of breast feeding compared to short course zidovudine monotherapy in a predominantly breast feeding population. Following unexplained discrepancies during objective adherence assessments, a sub-study was conducted at one site to examine the underlying adherence issues. Methods. The counselling and clinical notes of all 100 enrolled Zulu women were examined. Extracted information was supplemented by unstructured, free-ranging interviews conducted by trained adherence counsellors on 43 consecutive women attending the trial clinic over a two-week period. Adherence was defined as good (>95% adherence), or poor (<95% adherence). Results. Reasons provided for sub-optimal adherence included therapy misconceptions/misunderstandings, antiretroviral use by relatives, domestic violence, poverty and issues relating to disclosure and stigma. About 61% (57/94) of antenatal women had good adherence with their PMTCT prophylaxis, with no significant difference shown between those taking the long and short course. Conclusion. Antenatal women in northern rural KwaZulu-Natal face significant challenges in taking antiretroviral PMTCT prophylaxis.

As Trials Advance for a Malaria Vaccine, Policy Makers Urged to Plan for Its Use

AS THE FIRST PROMISING MALARIA vaccine makes its way through phase 3 clinical trials in subSaharan Africa, stakeholders’ greatest fears go beyond the possibility that the vaccine may fail to meet safety and efficacy goals. They worry that even if the vaccine is licensed, inadequate planning for its distribution could leave it to languish in warehouses. “After decades of research and tens of millions of dollars invested . . . it would be scandalous if this vaccine just sits on the shelf,” said Yvette Collymore, MA, of the nonprofit PATH Malaria Vaccine Initiative (MVI), during a recent Washington, DC, conference. MVI and the vaccine’s creator, GlaxoSmithKline (GSK) Biologicals, partnered in 2001 to develop the vaccine for infants and young children in sub-Saharan Africa. But the origins of the vaccine, known as RTS,S, date back to 1984 when GSK collaborated on preclinical studies with researchers at the Walter Reed Army Institute of Research in Silver Spring, Md. Human trials in adults in the United States and Belgium began in 1992. The first African trials were launched in 1995. Since then, several published studies have shown that the vaccine has a favorable safety and efficacy profile. A phase 2b trial with 340 infants in Tanzania showed that the vaccine reduced the risk of Plasmodium falciparum infection by 65% (Abdulla S et al. N Engl J Med. 2008;359[24]:2533-2544). RTS,Senteredphase3clinical trials in 2009. Eleven sites in 7 countries will enroll 16 000 infants and children, constituting the largest malaria vaccine trial to date. As of late September, about 12 500 children were enrolled: nearly 9000 in a cohortaged6to12weeksandmore than 3000 in a second cohort aged 5 to 17 months. Efficacy data from the older cohort of children are expected in late 2011 and shouldbe followedupayear laterbydata from the younger children, said MarieChantalUwamwezi,MSc, senior regulatoryaffairsscientistatGSK.The30-month follow-updataareexpectedat theendof 2014. The earliest the vaccine could be available for general use would be 2015. Collymore said that efforts began in 2006 to prepare policy makers in Africa forthestepsneededtobringamalariavaccine to the public. “Policy makers need data, and they need it well before this intervention is available; otherwise, this decision can take decades,” she said. Someof thecountries thatmay implement immunization once a malaria vaccine is available are using a decisionmaking tool based on the World Health Organization’s (WHO’s) guidelines for the introduction of any new vaccine. “It looks at the disease burden and the existing interventions, because [the vaccine] will be used alongside other interventions,” Collymore said. “It looks at the efficacy and safety of the vaccine and the sociocultural context of countries where it will be introduced: what communities think about malaria, what some of their beliefs are, and what they think about immunizations.” Tsiri Agbenyega, MD, principal investigator at a clinical trial site in Ghana, said that as phase 3 results become available, clinical data provided for the licensing process will describe not only safety and efficacy, but also the immunogenicity and reactogenicity of RTS,S when given with other vaccines through a WHO program. Safety and efficacy data from HIV-infected children who receive the vaccine also will be provided. Even with phase 3 trial results pending,GSKhasbeeninvolvedforthelastfew years in licensure discussions with African regulatory authorities as well as officials at the WHO and the European Medicines Agency (EMA), which evaluates medical products. “We have an innovative, streamlinedregulatorystrategy toensure licensureandexpediteaccess,” said Uwamwezi. If phase 3 trials are successful, GSK would ask the EMA to review the vaccine and certify it as safe and effective. The certification would pave the way for GSK to apply to African regulatory authorities for marketing authorization. “We can’t overemphasize the major societal, economic, and public health impact this vaccine would have on subSaharan Africa,” said Agbenyega.

Male circumcision for HIV prevention: current research and programmatic issues

Randomized controlled trials in sub-Saharan Africa have shown that adult male circumcision reduces the risk of HIV acquisition in men by about 60%. In this article, we review recent data on the association of male circumcision and HIV/sexually transmitted infection in men and women. This includes a summary of data showing some evidence of an effect of male circumcision against genital ulcer disease, HSV-2 infection, human papillomavirus and Trichomonas vaginalis, but not Chlamydia trachomatis or Neisseria gonorrhoea in men. Longitudinal studies among HIV discordant couples suggest that male circumcision may provide some direct long-term benefit to women, which may start after complete wound healing. Circumcision may also protect against HIV acquisition in men who have sex with men (MSM) and those who practice unprotected anal intercourse (either exclusively or predominantly), although these data are not consistent. To date, there is little evidence from the few studies available of either unsafe practices or reported increases in risky behaviour, or adverse changes in sexual satisfaction and function. As countries in southern and eastern Africa scale up services, operational research will likely be useful to iteratively improve programme delivery and impact while identifying the best methods of integrating safe male circumcision services into HIV prevention strategies and strengthening health systems.

Therapeutic misconception and clinical trials in sub-saharan Africa: A review

To identify possible existence of therapeutic misconception and its effects on clinical trials in sub-Saharan Africa. Original research findings and reviews published in the English literature and author's professional experience with clinical trials in some East, Central and West African countries. Review of peer-reviewed articles. Online searches and requests for reprints from corresponding authors and institutional subscription. Information categorised accordingly. Therapeutic misconception, defined as a conflation by research subjects of research goals and those of routine health care is considered widely prevalent globally. The subjects misunderstand the disclosures during consenting process and enroll hoping to derive personal benefits from the study. Though no study has looked at therapeutic misconception specifically in sub-Saharan Africa, available evidence suggests that it is prevalent. Therapeutic misconception is incompatible with informed voluntary consent. It may affect participation in clinical trials, subjects' safety and well-being and possibly the research findings. There is need for studies to identify the prevalence and effects of therapeutic misconception in the region. Researchers in sub-Saharan Africa should be aware of its existence, thus design trials in which it will not have significant effects and strengthen the consent process to reduce it.

Male circumcision, HIV and sexually transmitted infections: a review

Three randomized controlled trials in sub-Saharan Africa have shown that circumcision reduces the risk of acquiring HIV infection in men by approximately 60%. In this paper, we review the evidence that male circumcision protects against infection with HIV and other sexually transmitted infections (STIs) in men and their female partners. Data from the clinical trials indicate that circumcision may be protective against genital ulcer disease, Herpes simplex type 2, Trichomonas vaginalis and human papillomavirus infection in men. No evidence exists of a protective effect against Chlamydia trachomatis or Neisseria gonorrhea. There is weak evidence that circumcision has a direct protective effect on HIV infection in women, although there is likely to be an indirect benefit, since HIV prevalence is likely to be lower in circumcised male partners. Although there is little evidence from the trials of serious adverse events from the procedure and of behavioural risk compensation among circumcised men, essential operational research is being conducted to evaluate these key issues outside the trial setting as circumcision services are expanded. Following the publication of the clinical trial results in early 2007, the World Health Organization/UNAIDS has advised that promotion of male circumcision should be included as an additional HIV strategy for the prevention of heterosexually acquired HIV infection in men in areas of high HIV prevalence. As circumcision services are expanded in settings where resources are limited, non-physician providers including nurses will play an important role in the provision of services.