P14-07. Offering new prevention modalities in HIV vaccine trials: experience with male circumcision in the Phambili trial

Background: New prevention options will be added to the 'standard of prevention' offered in HIV vaccine efficacy trials as new methods prove effective. The HVTN503/Phambili trial was initiated in January 2007, shortly after results from 3 randomized controlled trials of male circumcision (MC) demonstrated that MC reduces the risk of HIV acquisition. Thus, HVTN503 investigators made plans to offer MC at no cost to enrolled male participants. Methods: All participants were informed of the benefits of MC as a component of HIV risk reduction counseling, including how and where MC could be accessed. One site offered on-site MC and the others provided referral to local services for men who requested MC. We present data on uptake of MC post-enrollment. Results: Prior to discontinuation of enrolment, 441 men joined the trial, of whom 312 (70.7%) were uncircumcised. Of these, 82 (26.3% of uncircumcised men) requested MC after enrolment. Uptake varied by site, being lower (70%) at the eThekwini site, the site with lowest baseline MC prevalence. Among 3 sites with intermediate baseline MC prevalence, uptake varied from 3.3 to 37.6%, being highest at the site providing MC on site. Uptake was similar in vaccine and placebo arms of the trial [42 (26.1%) vs. 40 (26.5%)]. There was no significant difference by arm in the timing of circumcision relative to randomization assignment being provided to participants following release of the STEP trial results [post-unblinding, vaccine 18 (42.9%) vs. placebo 13 (32.5%), p = 0.37]. Conclusion: MC, a new prevention modality, was offered as part of HIV prevention services in HVTN503. Uptake varied by provision of care model and inversely with baseline MC prevalence, but did not differ between treatment arms, and remained similar even after provision of treatment

P15-13. HVTN 503(Phambili) trial discontinuation of enrolment/vaccination: the impact on trial participant attitudes to vaccine trials and scientific research

Background: The HVTN 503/Phambili trial, a phase IIB study of the Merck Ad-5 HIV vaccine, suspended enrollment and vaccinations following results of the HVTN502/STEP study. Participants were notified of their treatment allocation and continue to be followed. We investigated the impact of the suspension on trial participants' attitudes towards HIV vaccine trials and scientific research. Methods: A self-administered questionnaire investigating knowledge and attitudes utilising a five-point likert scale, was administered 12–18 months post suspension at the 4 Phambili trial sites implementing the latest protocol. Results: Of 544 participants enrolled at 4 sites, 490 completed the questionnaire. 51% understood that vaccination, and 31% that enrolment had been permanently discontinued. Although 85% knew Phambili DSMB recommendations were based on results of the STEP study, only 51% knew that the results showed more infections in the vaccine arm. Although 90% knew they should continue protecting themselves against HIV, only 33% acknowledged trialists' concerns that the vaccine may make them more susceptible to HIV. Knowledge was similar across sites. 12% had tested for HIV antibodies outside of the trial before unblinding to establish their treatment allocation. 46% felt disappointed, angry or afraid, primarily because the vaccine would not prevent HIV in their community. 79% said they would engage in less risk behaviour. 94% thought the study team had made the correct decision by unblinding them and 96% thought site-participant communication was appropriate. 91% felt they made the right decision to enrol in Phambili and 91% planned to continue attending scheduled visits. 86% support scientific research and 80% would want to participate in future HIV vaccine. Conclusion: Despite site communications, knowledge levels were low. Importantly, most knew they should continue to protect themselves against HIV. Although almost half of participants reported negative feelings, most attitudes towards trial sites, scientific research and HIV vaccine trials were positive

No Evidence of Association between HIV-1 and Malaria in Populations with Low HIV-1 Prevalence

The geographic overlap between HIV-1 and malaria has generated much interest in their potential interactions. A variety of studies have evidenced a complex HIV-malaria interaction within individuals and populations that may have dramatic effects, but the causes and implications of this co-infection at the population level are still unclear. In a previous publication, we showed that the prevalence of malaria caused by the parasite Plasmodium falciparum is associated with HIV infection in eastern sub-Saharan Africa. To complement our knowledge of the HIV-malaria co-infection, the objective of this work was to assess the relationship between malaria and HIV prevalence in the western region of sub-Saharan Africa.Population-based cross-sectional data were obtained from the HIV/AIDS Demographic and Health Surveys conducted in Burkina Faso, Ghana, Guinea, Mali, Liberia and Cameroon, and the malaria atlas project. Using generalized linear mixed models, we assessed the relationship between HIV-1 and Plasmodium falciparum parasite rate (PfPR) adjusting for important socio-economic and biological cofactors. We found no evidence that individuals living in areas with stable malaria transmission (PfPR>0.46) have higher odds of being HIV-positive than individuals who live in areas with PfPR≤0.46 in western sub-Saharan Africa (estimated odds ratio 1.14, 95% confidence interval 0.86-1.50). In contrast, the results suggested that PfPR was associated with being infected with HIV in Cameroon (estimated odds ratio 1.56, 95% confidence interval 1.23-2.00).Contrary to our previous research on eastern sub-Saharan Africa, this study did not identify an association between PfPR and infection with HIV in western sub-Saharan Africa, which suggests that malaria might not play an important role in the spread of HIV in populations where the HIV prevalence is low. Our work highlights the importance of understanding the epidemiologic effect of co-infection and the relevant factors involved in this relationship for the implementation of effective control strategies

Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré

BACKGROUND: In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT), many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS)/sulphadoxine-pyrimethamine (SP) had been used in refugee camps for two years. METHODS: In Dabola (central Guinea), 220 children aged 6-59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ) or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea), where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 436, 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively. RESULTS: In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR)-adjusted failure rates were 1.0% (95%CI 0-5.3) for AS/AQ and 1.0% (95%CI 0-5.5) for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2-90.7) patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2-15.9). CONCLUSION: Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of implementing ACTs, but cannot predict how long their therapeutic life will be, especially in countries which have chosen drugs also available as monotherapies

Molecular epidemiology of drug-resistant malaria in western Kenya highlands

<p>Abstract</p> <p>Background</p> <p>Since the late 1980s a series of malaria epidemics has occurred in western Kenya highlands. Among the possible factors that may contribute to the highland malaria epidemics, parasite resistance to antimalarials has not been well investigated.</p> <p>Methods</p> <p>Using parasites from highland and lowland areas of western Kenya, we examined key mutations associated with <it>Plasmodium falciparum </it>resistance to sulfadoxine – pyrimethamine and chloroquine, including dihydrofolate reductase (<it>pfdhfr</it>) and dihydropteroate synthetase (<it>pfdhps</it>), chloroquine resistance transporter gene (<it>pfcrt</it>), and multi-drug resistance gene 1 (<it>pfmdr1</it>).</p> <p>Results</p> <p>We found that >70% of samples harbored 76T <it>pfcrt </it>mutations and over 80% of samples harbored quintuple mutations (51I/59R/108N <it>pfdhfr </it>and 437G/540E <it>pfdhps</it>) in both highland and lowland samples. Further, we did not detect significant difference in the frequencies of these mutations between symptomatic and asymptomatic malaria volunteers, and between highland and lowland samples.</p> <p>Conclusion</p> <p>These findings suggest that drug resistance of malaria parasites in the highlands could be contributed by the mutations and their high frequencies as found in the lowland. The results are discussed in terms of the role of drug resistance as a driving force for malaria outbreaks in the highlands.</p