Andrew Vallely

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial

Summary Background Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. Methods Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. Findings We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation. Interpretation Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. Funding UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands: challenges for malaria diagnostics in an elimination setting

BackgroundMany countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting.MethodsDuring the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared.ResultsA total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections.ConclusionAsymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Using serological measures to monitor changes in malaria transmission in Vanuatu

BackgroundWith renewed interest in malaria elimination, island environments present unique opportunities to achieve this goal. However, as transmission decreases, monitoring and evaluation programmes need increasingly sensitive tools to assess Plasmodium falciparum and Plasmodium vivax exposure. In 2009, to assess the role of serological markers in evaluating malaria transmission, a cross-sectional seroprevalence study was carried out in Tanna and Aneityum, two of the southernmost islands of the Vanuatu archipelago, areas where malaria transmission has been variably reduced over the past few decades.MethodsMalaria transmission was assessed using serological markers for exposure to P. falciparum and P. vivax. Filter blood spot papers were collected from 1,249 people from Tanna, and 517 people from Aneityum to assess the prevalence of antibodies to two P. falciparum antigens (MSP-119 and AMA-1) and two P. vivax antigens (MSP-119 and AMA-1). Age-specific prevalence was modelled using a simple catalytic conversion model based on maximum likelihood to generate a community seroconversion rate (SCR).ResultsOverall seropositivity in Tanna was 9.4%, 12.4% and 16.6% to P. falciparum MSP-119, AMA-1 and Schizont Extract respectively and 12.6% and 15.0% to P. vivax MSP-119 and AMA-1 respectively. Serological results distinguished between areas of differential dominance of either P. vivax or P. falciparum and analysis of age-stratified results showed a step in seroprevalence occurring approximately 30 years ago on both islands, indicative of a change in transmission intensity at this time. Results from Aneityum suggest that several children may have been exposed to malaria since the 2002 P. vivax epidemic.ConclusionSeroepidemiology can provide key information on malaria transmission for control programmes, when parasite rates are low. As Vanuatu moves closer to malaria elimination, monitoring changes in transmission intensity and identification of residual malaria foci is paramount in order to concentrate intervention efforts.

The Prevalence of Sexually Transmitted Infections in Papua New Guinea: A Systematic Review and Meta-Analysis

Background The potential for an expanded HIV epidemic in Papua New Guinea (PNG) demands an effective, evidence-based and locally-appropriate national response. As sexually transmitted infections (STIs) may be important co-factors in HIV transmission nationally, it is timely to conduct a systematic review of STI prevalences to inform national policy on sexual health and HIV/STI prevention. Methodology/Principal Findings We undertook a systematic review and meta-analysis of HIV and STI prevalences in PNG, reported in peer-reviewed and non-peer-reviewed publications for the period 1950–2010. Prevalence estimates were stratified by study site (community or clinic-based), geographic area and socio-demographic characteristics. The search strategy identified 105 reports, of which 25 studies (10 community-based; 10 clinic-based; and 5 among self-identified female sex workers) reported STI prevalences and were included in the systematic review. High prevalences of chlamydia, gonorrhoea, syphilis and trichomonas were reported in all settings, particularly among female sex workers, where pooled estimates of 26.1%, 33.6%, 33.1% and 39.3% respectively were observed. Pooled HIV prevalence in community-based studies was 1.8% (95% CI:1.2–2.4) in men; 2.6% (95% CI:1.7–3.5) in women; and 11.8% (95% CI:5.8–17.7) among female sex workers. Conclusions/Significance The epidemiology of STIs and HIV in PNG shows considerable heterogeneity by geographical setting and sexual risk group. Prevalences from community-based studies in PNG were higher than in many other countries in the Asia-Pacific. A renewed focus on national STI/HIV surveillance priorities and systems for routine and periodic data collection will be essential to building effective culturally-relevant behavioural and biomedical STI/HIV prevention programs in PNG.

A qualitative study on the acceptability and preference of three types of long-lasting insecticide-treated bed nets in Solomon Islands: implications for malaria elimination

BackgroundIn March 2008, the Solomon Islands and Vanuatu governments raised the goal of their National Malaria Programmes from control to elimination. Vector control measures, such as indoor residual spraying (IRS) and long-lasting insecticidal bed nets (LLINs) are key integral components of this programme. Compliance with these interventions is dependent on their acceptability and on the socio-cultural context of the local population. These factors need to be investigated locally prior to programme implementation.MethodTwelve focus group discussions (FGDs) were carried out in Malaita and Temotu Provinces, Solomon Islands in 2008. These discussions explored user perceptions of acceptability and preference for three brands of long-lasting insecticide-treated bed nets (LLINs) and identified a number of barriers to their proper and consistent use.ResultsMosquito nuisance and perceived threat of malaria were the main determinants of bed net use. Knowledge of malaria and the means to prevent it were not sufficient to guarantee compliance with LLIN use. Factors such as climate, work and evening social activities impact on the use of bed nets, particularly in men. LLIN acceptability plays a varying role in compliance with their use in villages involved in this study. Participants in areas of reported high and year round mosquito nuisance and perceived threat of malaria reported LLIN use regardless of any reported unfavourable characteristics. Those in areas of low or seasonal mosquito nuisance were more likely to describe the unfavourable characteristics of LLINs as reasons for their intermittent or non-compliance. The main criterion for LLIN brand acceptability was effectiveness in preventing mosquito bites and malaria. Discussions highlighted considerable confusion around LLIN care and washing which may be impacting on their effectiveness and reducing their acceptability in Solomon Islands.ConclusionProviding LLINs that are acceptable will be more important for improving compliance in areas of low or seasonal mosquito nuisance and malaria transmission. The implications of these findings on malaria elimination in Solomon Islands are discussed.

Intermittent preventive treatment for malaria in pregnancy in Africa: What's new, what's needed?

Falciparum malaria is an important cause of maternal, perinatal and neonatal morbidity in high transmission settings in Sub-Saharan Africa. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPT) has proven efficacious in reducing the burden of pregnancy-associated malaria but increasing levels of parasite resistance mean that the benefits of national SP-IPT programmes may soon be seriously undermined in much of the region. Hence, there is an urgent need to develop alternative drug regimens for IPT in pregnancy. This paper reviews published safety and efficacy data on various antimalarials and proposes several candidate combination regimens for assessment in phase II/III clinical trials.

Malaria elimination: moving forward with spatial decision support systems

Operational challenges facing contemporary malaria elimination have distinct geospatial elements including the need for high-resolution location-based surveillance, targeted prevention and response interventions, and effective delivery of essential services at optimum levels of coverage. Although mapping and geographical reconnaissance (GR) has traditionally played an important role in supporting malaria control and eradication, its full potential as an applied health systems tool has not yet been fully realised. As accessibility to global positioning system (GPS), geographic information system (GIS) and mobile computing technology increases, the role of an integrated spatial decision support system (SDSS) framework for supporting the increased operational demands of malaria elimination requires further exploration, validation and application; particularly in the context of resource-poor settings.

Mapping Malaria Risk in Bangladesh Using Bayesian Geostatistical Models

Background malaria-control programs are increasingly dependent on accurate risk maps to effectively guide the allocation of interventions and resources. Advances in model-based geostatistics and geographical information systems (GIS) have enabled researchers to better understand factors affecting malaria transmission and thus, more accurately determine the limits of malaria transmission globally and nationally. Here, we construct Plasmodium falciparum risk maps for Bangladesh for 2007 at a scale enabling the malaria-control bodies to more accurately define the needs of the program. A comprehensive malaria-prevalence survey (N = 9,750 individuals; N = 354 communities) was carried out in 2007 across the regions of Bangladesh known to be endemic for malaria. Data were corrected to a standard age range of 2 to less than 10 years. Bayesian geostatistical logistic regression models with environmental covariates were used to predict P. falciparum prevalence for 2- to 10-year-old children (PfPR(2-10)) across the endemic areas of Bangladesh. The predictions were combined with gridded population data to estimate the number of individuals living in different endemicity classes. Across the endemic areas, the average PfPR(2-10) was 3.8%. Environmental variables selected for prediction were vegetation cover, minimum temperature, and elevation. Model validation statistics revealed that the final Bayesian geostatistical model had good predictive ability. Risk maps generated from the model showed a heterogeneous distribution of PfPR(2-10) ranging from 0.5% to 50%; 3.1 million people were estimated to be living in areas with a PfPR(2-10) greater than 1%. Contemporary GIS and model-based geostatistics can be used to interpolate malaria risk in Bangladesh. Importantly, malaria risk was found to be highly varied across the endemic regions, necessitating the targeting of resources to reduce the burden in these areas.

The benefits of participatory methodologies to develop effective community dialogue in the context of a microbicide trial feasibility study in Mwanza, Tanzania.

BackgroundDuring a microbicide trial feasibility study among women at high-risk of HIV and sexually transmitted infections in Mwanza, northern Tanzania we used participatory research tools to facilitate open dialogue and partnership between researchers and study participants.MethodsA community-based sexual and reproductive health service was established in ten city wards. Wards were divided into seventy-eight geographical clusters, representatives at cluster and ward level elected and a city-level Community Advisory Committee (CAC) with representatives from each ward established. Workshops and community meetings at ward and city-level were conducted to explore project-related concerns using tools adapted from participatory learning and action techniques such as listing, scoring, ranking, chapatti diagrams and pair-wise matrices.ResultsKey issues identified included beliefs that blood specimens were being sold for witchcraft purposes; worries about specula not being clean; inadequacy of transport allowances; and delays in reporting laboratory test results to participants. To date, the project has responded by inviting members of the CAC to visit the laboratory to observe how blood and genital specimens are prepared; demonstrated the use of the autoclave to community representatives; raised reimbursement levels; introduced HIV rapid testing in the clinic; and streamlined laboratory reporting procedures.ConclusionParticipatory techniques were instrumental in promoting meaningful dialogue between the research team, study participants and community representatives in Mwanza, allowing researchers and community representatives to gain a shared understanding of project-related priority areas for intervention.

How informed is consent in vulnerable populations? Experience using a continuous consent process during the MDP301 vaginal microbicide trial in Mwanza, Tanzania

BackgroundHIV prevention trials conducted among disadvantaged vulnerable at-risk populations in developing countries present unique ethical dilemmas. A key concern in bioethics is the validity of informed consent for trial participation obtained from research subjects in such settings. The purpose of this study was to investigate the effectiveness of a continuous informed consent process adopted during the MDP301 phase III vaginal microbicide trial in Mwanza, Tanzania.MethodsA total of 1146 women at increased risk of HIV acquisition working as alcohol and food vendors or in bars, restaurants, hotels and guesthouses have been recruited into the MDP301 phase III efficacy and safety trial in Mwanza. During preparations for the trial, participatory community research methods were used to develop a locally-appropriate pictorial flipchart in order to convey key messages about the trial to potential participants. Pre-recorded audio tapes were also developed to facilitate understanding and compliance with gel-use instructions. A comprehension checklist is administered by clinical staff to all participants at screening, enrolment, 12, 24, 40 and 50 week follow-up visits during the trial. To investigate womens perceptions and experiences of the trial, including how well participants internalize and retain key messages provided through a continuous informed consent process, a random sub-sample of 102 women were invited to participate in in-depth interviews (IDIs) conducted immediately after their 4, 24 and 52 week follow-up visits.Results99 women completed interviews at 4-weeks, 83 at 24-weeks, and 74 at 52 weeks (a total of 256 interviews). In all interviews there was evidence of good comprehension and retention of key trial messages including that the gel is not currently know to be effective against HIV; that this is the key reason for conducting the trial; and that women should stop using gel in the event of pregnancy.ConclusionsProviding information to trial participants in a focussed, locally-appropriate manner, using methods developed in consultation with the community, and within a continuous informed-consent framework resulted in high levels of comprehension and message retention in this setting. This approach may represent a model for researchers conducting HIV prevention trials among other vulnerable populations in resource-poor settings.Trial registrationCurrent Controlled Trials ISRCTN64716212