HIV-1 remains a major global health problem, with 2.5 million new infections in 2011, of which 70% were in sub-Saharan Africa. In countries with mature generalised epidemics, including Uganda, there are groups that are more disproportionately affected (Most-At-Risk Populations [MARPs]) such as fishing communities, with high HIV infection, and extensive sexual networks bridging into the general population. Proven HIV prevention strategies are often not readily available to MARPs. Recent data from fishing communities in Uganda indicate that HIV infection rates in these communities are up to 5 times higher than the national average. In Uganda, approximately 10% of the population are engaged in fishing-related activities, but this group could be contributing a substantial proportion of HIV infections. Proven HIV interventions are only partially effective, and need to be combined for effective HIV control. Combination prevention programmes are rights-based, evidence-informed and community-owned programmes that incorporate a mix of effective behavioural, biomedical and structural interventions, prioritised to meet the HIV prevention needs of individuals and communities, to have the greatest sustained impact on reducing new infections. We propose a trial on the effectiveness of implementing combination prevention in fishing communities in Uganda, to generate data that will complement that from other ongoing trials taking place elsewhere in Africa in general populations. The social context of MARPs is different from general populations and designing and evaluating an appropriate combination HIV prevention package in these core groups is critical to reduce HIV rates not only in these populations but also in the wider general population. The trial will use a stepped-wedge cluster randomised design, in which each cluster (community) will receive the intervention in a phased manner during follow-up. This ensures that all communities will receive the intervention during the trial, whilst minimising logistical difficulties in implementing the intervention in several clusters simultaneously. Twelve fishing communities will be randomised into 4 equally-sized groups, and the time at which each group first receives the intervention is randomised. The study will take 60 months, with the first 3 communities receiving the intervention from month 18 onwards, and the last 3 communities receiving the intervention from month 42 onwards. During the baseline phase before the intervention is introduced, a census will be undertaken in each community from which a simple random sample of 240 adults (aged 18 years or old) will be recruited in each community and their HIV status determined. The incidence of HIV among participants who were HIV seronegative during the baseline survey will be determined during follow-up surveys. This is the primary outcome. Secondary outcomes include the impact on community viral load, behaviour changes, the level of uptake of the intervention, and the cost and cost-effectiveness of the intervention. Given the burden of HIV, the "standard of care" package consisting of condom distribution, HIV risk counselling and testing (through routine government health units), and selected structural interventions targeting stigma and discrimination, harmful cultural norms and practices will be provided to all communities throughout the trial. We will select the most effective interventions, which, applied together, are most likely to have synergy and impact highly on HIV transmission. We will consider only "real life" evidence-based interventions that are affordable and scale-able within African prevention, care and support programmes. The trial results will increase understanding of the implementation, uptake and impact of combination HIV prevention on HIV incidence among MARPS, and will aid policy makers in deciding on practical measures to scale up these interventions in similar populations in developing countries.

The clinical course of HIV infection seems to some extent to be different between industrialised and developing countries. Clinical data on HIV infection in Africa have mostly become available from research conducted at urban hospitals. Few clinical data are available from rural parts of Africa. Data on the natural course of the infection from its onset are even scarcer. Research is required to understand the natural course of the disease in the context of rural Africa, and in particular the nature of opportunistic infections and other disorders that define AIDS in this environment. Such data are needed to optimise treatment guidelines and to plan health interventions. Data on survival after the time of infection are also of interest for epidemiology and for epidemiological modelling. Since 1990, MRC has been following a clinical cohort of HIV infected patients that reside in an area where the MRC keeps a population of 25 rural communities under surveillance (as described in another abstract). Patients are regularly examined, and observations are recorded. An HIV-negative control group is also included, in order to provide information on background disease patterns and mortality. All study participants are treated whenever ill. This Rural Clinical Cohort (RCC) has provided very detailed insights in the natural course of HIV infection and its disease manifestation. In recent years, more effective drugs have become available to treat HIV infection. Such antiretroviral therapy (ART) can drastically reduce HIV in the blood and the tissue, and reinstall the competence of the bodys immune response to other infections and to HIV associated cancers. In industrialised countries, ART has been shown to have a strong positive impact on the survival and the general health of HIV infected patients. It has initially been unclear whether in the African environment (that is characterised by a great variety of additional health problems), and in particular in rural Africa where the majority of Africans live, similar successes may be possible. Another concern is what effect successful ART provision may have on sexual risk taking. It is also not clear to what extent the required adherence to ART will be possible in areas in which it is not easy for the population to attend regular clinical appointments. Such appointments are required to re-supply drugs and to check patients for side effects. Research is needed to establish whether ART can be effective in areas with limited infrastructure. ART has been introduced in the RCC in January 2004, and has since been provided to all study participants who are in need of it, both from the RCC and from the wider study population within which the RCC resides. The opportunity is used to investigate the research questions discussed above, and in particular to explore the effects of ART on the course of HIV infection and mortality, to identify problems with the provision and follow-up of ART, and to develop practical solutions. The RCC also provides an opportunity to contribute to the basic science research of the MRC in Uganda, for example in investigating which different types of HIV strains are circulating in the population, what their relationship is to HIV disease progression, and whether and how resistance to the drugs used for ART develops.

"Vaccines are a key weapon against infectious diseases which continue to have major detrimental impacts on health and development in in low-income countries (LICs). However, the effectiveness of some vaccines is reduced in tropical LICs and in rural vs urban settings. For example, the TB vaccine, BCG, provides 80% protection in some temperate countries, but 0% in some tropical settings. A potential explanation for this phenomena includes exposure to parasites so to further understanding we will compare the vaccine responses for Ugandan adolescents among three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort who have low parasite exposure; (2) island communities where over 80% have schistosomiasis (a parasitic worm infection); (3) rural communities with high malaria exposure, where over 50% of school-children unknowingly have malaria. We will also look at how parasitic infections interact with other viral or bacterial infections (“transkingdom” effects) and how these indirect effects impact the immune system. Finally, we will use statistical approaches to explore how the urban-rural environment, parasites, ""transkingdom"" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in tropical LIC settings and inform public health policy to improve effectiveness of vaccine programmes."

Collating information on human health and disease, and understanding the biological processes that may cause disease can help identify ways to develop new treatments for these diseases. The use of complex statistics, computational resources and genetic information has greatly facilitated our understanding of human disease. For Africa to fully benefit from the technological advances in computing and ways to store and manage "big scientific data", we will need to ensure that African researchers have access to such resources locally. As part of an international collaboration, we aim to build a computational network and resource in Uganda, and train the next generation of African computer scientists as part of this initiative. This project will help facilitate our understanding on diseases in Africa and also provide a way to assess changes in the prevalence of these diseases, including HIV and other chronic diseases such as diabetes.

A group of about 700 patients was recruited who have been on ART for up to 7 years. This unusual follow-up group provides an opportunity to address questions about the long term effects of ART with respect to HIV disease and treatment side effects. Such effects may differ from those seen in the North because of genetic characteristics, type of ART regimen received, differences in treatment adherence, or due to other diseases typical for Africa. We will also make use of this group for a trial to investigate the safety of stopping cotrimoxazole prophylaxis in patients doing well on ART (this is a drug that prevents bacterial infections in patients with weak immune system and may no longer be needed in patients who regained their immunity due to ART). We will also explore whether nurses (rather than doctors) can provide routine follow up care for ART patients (which would be important for areas where there is no doctor), or whether larger intervals between drug refills (e.g. 3 months versus 1 month) are safe in managing patients. - We also keep regular contact with patients who have been HIV infected for a long time, but who are still well and do not need ART yet. This group is important for research on the immunological factors that may protect individuals from becoming HIV infected at all or infected individuals from experiencing fast diseases progression. Such knowledge may be helpful for the design of an effective vaccine against HIV infection.