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Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Funder: National Health Service, Funder: European Research Council (Advanced Researcher Award) Cancer Research UK Cambridge Cancer Centre Medical Research Council (Infrastructure Award) National Health Service, Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother-son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.

Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2), the translocation breakpoint disrupted two genes: the known renal tumor suppressor gene (TSG) FLCN (and clinical features of Birt‐Hogg‐Dubé syndrome were detected) and RASGEF1A. In four cases, the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement, the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly, NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC‐associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC‐associated t(3;8)(p14.2;q24.1). These findings (a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, (b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, (c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation‐associated RCC, and (d) demonstrate the utility of GS for investigating such cases.

OBJECTIVES To investigate the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a vulnerable population of children and their household contacts. METHODS SARS-CoV-2 reverse transcription polymerase chain reaction assays and coronavirus disease 2019 (COVID-19) immunoglobulin G serology tests were performed in children and their household contacts after enrollment during primary health care clinic visits. Participants were followed prospectively with subsequent specimens collected through household visits in Manguinhos, an impoverished urban slum (a favela) in Rio de Janeiro at 1, 2, and 4 weeks and quarterly post study enrollment. RESULTS Six hundred sixty-seven participants from 259 households were enrolled from May to September 2020. This included 323 children (0–13 years), 54 adolescents (14–19 years), and 290 adults. Forty-five (13.9%) children had positive test results for SARS-CoV-2 polymerase chain reaction. SARS-CoV-2 infection was most frequent in children aged CONCLUSIONS In our setting, children do not seem to be the source of SARS-CoV-2 infection and most frequently acquire the virus from adults. Our findings suggest that, in settings such as ours, schools and child care potentially may be reopened safely if adequate COVID-19 mitigation measures are in place and staff are appropriately immunized.

Background Chikungunya is an arbovirus, transmitted by Aedes mosquitoes, which emerged in the Americas in 2013 and spread rapidly to almost every country on this continent. In Brazil, where the first cases were detected in 2014, it currently has reached all regions of this country and more than 900,000 cases were reported. The clinical spectrum of chikungunya ranges from an acute self-limiting form to disabling chronic forms. The purpose of this study was to estimate the seroprevalence of chikungunya infection in a large Brazilian city and investigate the association between viral circulation and living condition. Methodology/principal findings We conducted a population-based ecological study in selected Sentinel Areas (SA) through household interviews and a serologic survey in 2016/2017. The sample was of 1,981 individuals randomly selected. The CHIKV seroprevalence was 22.1% (17.1 IgG, 2.3 IgM, and 1.4 IgG and IgM) and varied between SA from 2.0% to 70.5%. The seroprevalence was significantly lower in SA with high living conditions compared to SA with low living condition. There was a positive association between CHIKV seroprevalence and population density (r = 0.2389; p = 0.02033). Conclusions/significance The seroprevalence in this city was 2.6 times lower than the 57% observed in a study conducted in the epicentre of the CHIKV epidemic of this same urban centre. So, the herd immunity in this general population, after four years of circulation of this agent is relatively low. It indicates that CHIKV transmission may persist in that city, either in endemic form or in the form of a new epidemic, because the vector infestation is persistent. Besides, the significantly lower seroprevalences in SA of higher Living Condition suggest that beyond the surveillance of the disease, vector control and specific actions of basic sanitation, the reduction of the incidence of this infection also depends on the improvement of the general living conditions of the population., Author summary Chikungunya is a disease caused by viruses transmitted by Aedes mosquitoes. It stands out because it can produce chronic cases and disabling forms. This survey was conducted in a large city in Brazil, involving 1,981 people living in different living conditions/LC, distributed in 30 urban areas. Interviews and blood collection were performed to know the seroprevalence of chikungunya virus (CHIKV). The global seroprevalence was 22.1%, ranged from 2.0 to 70.5%. The areas where the highest and lowest seroprevalence were of low LC, but population density was different among them, which was related to seroprevalence. The mosquito index was not associated with the seroprevalence. Our results showed that lower seroprevalence than another survey conducted in the epicentre of the epidemic of this same city. So, a considerable proportion of the population of Feira de Santana is susceptible to the CHIKV. Possibly the virus will continue to circulate and manifest itself as endemic or epidemic, as long as LC remain favourable to the reproduction of the transmitting vector of CHIKV.

Background Undifferentiated febrile illness (UFI) is one of the most common reasons for people seeking healthcare in low-income countries. While illness and death due to specific infections such as malaria are often well-quantified, others are frequently uncounted and their impact underappreciated. A number of high consequence infectious diseases, including Ebola virus, are endemic or epidemic in the Federal Republic of Sudan which has experienced at least 12 UFI outbreaks, frequently associated with haemorrhage and high case fatality rates (CFR), since 2012. One of these occurred in Darfur in 2015/2016 with 594 cases and 108 deaths (CFR 18.2%). The aetiology of these outbreaks remains unknown. Methodology/Principal findings We report a retrospective cohort study of the 2015/2016 Darfur outbreak, using a subset of 65 of 263 outbreak samples received by the National Public Health Laboratory which met selection criteria of sufficient sample volume and epidemiological data. Clinical features included fever (95.8%), bleeding (95.7%), headache (51.6%) and arthralgia (42.2%). No epidemiological patterns indicative of person-to-person transmission or health-worker cases were reported. Samples were tested at the Public Health England Rare and Imported Pathogens Laboratory using a bespoke panel of likely pathogens including haemorrhagic fever viruses, arboviruses and Rickettsia, Leptospira and Borrelia spp. Seven (11%) were positive for Crimean-Congo haemorrhagic fever virus (CCHFV) by real-time reverse transcription PCR. The remaining samples tested negative on all assays. Conclusions/Significance CCHFV is an important cause of fever and haemorrhage in Darfur, but not the sole major source of UFI outbreaks in Sudan. Prospective studies are needed to explore other aetiologies, including novel pathogens. The presence of CCHFV has critical infection, prevention and control as well as clinical implications for future response. Our study reinforces the need to boost surveillance, lab and investigative capacity to underpin effective response, and for local and international health security., Author summary The Federal Republic of Sudan has had at least 12 outbreaks of febrile illness of unknown cause associated with symptoms of haemorrhage and high case fatality rates since 2012. Outbreaks without clear diagnosis are concerning, particularly in countries such as Sudan where a range of high consequence diseases, including viral haemorrhagic fevers, are endemic or epidemic, and local laboratory capacity is limited. We transferred historical samples stored in the National Public Health Authority from one of these outbreaks that occurred in Darfur 2015–2016 to the Public Health England Laboratory at Porton, UK, and tested them against a wide range of infectious diseases to try to identify the cause, and to help the Sudanese Federal Ministry of Health to develop and target their limited laboratory capacity. We found that Crimean-Congo Haemorrhagic Fever was an important cause but not the only source of cases in this outbreak. This has implications for prevention and control as well as for treating cases. Our study also highlighted the need for future studies to explore other possible causes, including new pathogens, and reinforced the need to boost surveillance, lab and investigative capacity for more timely and complete outbreak response.

OBJECTIVE: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. DESIGN: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. METHODS: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. RESULTS: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. CONCLUSIONS: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.

Identifying correlates of immunity or susceptibility to disease promotes understanding of pathogenesis and development of diagnostic tools, treatments, and vaccines. There is evidence that type 1 cytokine responses are associated with protection against tuberculosis, and suppression of type 1, or switching to type 2 responses, with susceptibility, but this has not been studied prospectively. We studied a cohort of 631 HIV-1-infected Ugandan adults. At enrollment we performed whole blood cultures for type 1 (interferon [IFN]-gamma, interleukin [IL]-2) and type 2/immunosuppressive (IL-5, IL-10) responses to mycobacterial antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). The incidence of tuberculosis was not associated with IFN-gamma responses, but was higher among participants with IL-2 responses (adjusted rate ratios [RR]: PPD 3.48; CFP 3.99; P < 0.001). For tuberculin skin test-positive participants, high incidence was also associated with an IL-10 response to PPD (adjusted RR 6.24, P = 0.03); for those with a BCG scar, high incidence was associated with positive IL-5 responses (adjusted RRs: PPD 3.64, P = 0.006; CFP 3.44, P = 0.04). The association with IL-2 production may reflect a response to tuberculous infection or to activating disease; the associations with IL-10 and IL-5 are in keeping with the expected role of immunosuppressive or type 2 cytokines.

BACKGROUND: An association between HIV-1 and malaria is expected in theory, but has not been convincingly shown in practice. We studied the effects of HIV-1 infection and advancing immunosuppression on falciparum parasitaemia and clinical malaria. METHODS: HIV-1-positive and HIV-1-negative adults selected from a population-based cohort in rural Uganda were invited to attend a clinic every 3 months (routine visits) and whenever they were sick (interim visits). At each visit, information was collected on recent fever, body temperature, and malaria parasites. Participants were assigned a clinical stage at each routine visit and had regular CD4-cell measurements. FINDINGS: 484 participants made 7220 routine clinic visits between 1990 and 1998. Parasitaemia was more common at visits by HIV-1-positive individuals (328 of 2788 [11.8%] vs 231 of 3688 [6.3%], p

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Abnormal CD45 splicing has been recognized in humans, caused by a C77G transversion in the gene encoding CD45 (PTPRC). Recently the C77G polymorphism has been associated with multiple sclerosis and increased susceptibility to HIV-1 infection. These studies suggest that the regulation of CD45 splicing may be critical for the proper function of the immune system. Because of these data we examined the frequency of the C77G allele in African and Asian populations from countries with high or low prevalence of HIV infection. Here we report that the variant CD45 C77G allele is absent in African populations. We further show that populations living in the Pamir mountains of Central Asia have a very high prevalence of the C77G variant.

Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes.

Objective: To describe sexual behaviour trends in a rural Ugandan cohort in the context of an evolving HIV epidemic, 1993–2006. Methods: Sexual behaviour data were collected annually from a population cohort in which HIV serological surveys were also conducted. Behaviour trends were determined using survival analysis and logistic regression. Trends are reported based on the years in which the respective indicators were collected. Results: Between 1993 and 2006, median age at first sex increased from 16.7 years to 18.2 years among 17–20-year-old girls and from 18.5 years to 19.9 years among boys. Both sexes reported a dip in age at sexual debut between 1998 and 2001. One or more casual partners in the past 12 months among men rose from 11.6% in 1997 to 12.7% in 2004 and then declined to 10.2% in 2006. Among women it increased from 1.4% in 1997 to 3.7% in 2004 and then reduced to 1.4% in 2006. The rise in casual partners between 1997 and 2004 was driven mainly by older age groups. Trends in condom use with casual partners varied by age, increasing among those aged 35+ years, declining in the middle age groups and presenting a dip and then a rise in the youngest aged group (13–19 years). Conclusion: Among youth, risky behaviour declined but increased in the late 1990s/early 2000s. Among those aged 35+ years, condom use rose but casual partners also rose. Several indicators portrayed a temporary increase in risk taking behaviour from 1998 to 2002.

Two significant challenges face researchers tracking HIV-related socio-economic and demographic change over time in large cohort studies. Firstly, data collected in cohort studies established to describe the dynamics of HIV infection may contain no systematic data on household consumption expenditures which is an established measure of current and long-run household welfare. The second challenge is the choice of the unit of analysis in order to recognise and record impact; this is because most cohorts use the household as that unit. This means that the influence of factors outside that unit cannot easily be tracked. In this paper we show how a detailed understanding of the impact of HIV and AIDS on wider families and social networks, obtained through in-depth longitudinal research with a small number of households, can shed light on the findings from quantitative analysis from a larger cohort in the same population in rural Uganda. The findings of large-scale survey data from more than 2000 households over a 12-year period showed a lack of a strong association between poverty, HIV status and/or death of the household head. In-depth ethnographic research with 26 households in 1991/2 and a restudy of the same households in 2006/7 provide insights into the reasons for this finding: the choice of socio-economic indicators and support from other family and community members play a part in affecting survey findings on the impact of HIV at household level. One other factor is important in explaining the findings. HIV-infected family members from outside the household may drain resources from the household, so looking at the impact of HIV and AIDS on people's wider families provides pointers to why those who have not had an AIDS-related death in their own household may have failed to prosper. Our qualitative findings show that AIDS may well throw households into disarray and poverty, but more often reduces development and hinders families from getting out of poverty. Used strategically, small longitudinal studies can provide important information with which to explain patterns observed in large-scale quantitative datasets.

Throughout the 1990s, HIV-1 prevalence and incidence were falling in Uganda. Recently, some researchers have noticed that HIV-1 prevalence is levelling off. We examine prevalence, incidence, and sexual behaviour trends in a rural population cohort in Uganda over 16 years.We report prevalence by survey round and incidence by calendar year from a prospective general population cohort study. Using logistic regression Wald tests, we examined casual partners, condom use, and pregnancies. We examined age at sexual debut by means of life tables.HIV-1 prevalence declined from 8.5% in 1990/1991 to 6.2% in 1999/2000, and thereafter rose to 7.7% in 2004/2005. Incidence (per 1000 person-years at risk) fell from 7.5 in 1990 to 4.1 in 1998, and thereafter increased to 5.0 by 2004. The 2005 incidence estimate reached an all-time low of 2.5, but the preliminary 2006 estimate shows a rise again. Incidence trends varied by age and sex. Some sexual behaviour indicators showed more risky behaviour in recent years compared with the 1990s, whereas others indicated that the reduction in risky behaviour that began in the 1990s continues.HIV-1 prevalence is rising in this cohort. Incidence is stabilizing, and shows signs of increasing among some subgroups. The extent to which changing sexual behaviour has played a role in these epidemiological trends is unclear, but it is likely to have contributed. To solidify the success that Uganda had throughout the 1990s in controlling the HIV epidemic, the efforts in HIV prevention need to be re-strengthened, using all strategies known.

Limited research has been conducted outside Western settings on how HIV-positive parents decide to test and disclose their own HIV status to children. We conducted a qualitative study in 2001 and 2005 to assess parent attitudes and current counselling policy and practice regarding child testing and parental disclosure in Uganda prior to the roll-out of antiretroviral therapy. Parent perspectives were obtained through extended in-depth interviews with 10 HIV-positive parents recruited from The AIDS Support Organization (TASO) Entebbe branch. Counselling policy and practice were explored through key informant interviews with directors and two counsellors from each of five Ugandan counselling institutions with national or regional coverage. Respondents had 51 children ranging from 4 to 36 years with a median age of 13. Five of 10 parents had disclosed their status to their children usually to all and four of these had tested one child for HIV. All those who tested any child had also disclosed their status to some or all of their children. Parents regularly worried that their children may be infected but all preferred to wait for emergence of symptoms before considering HIV tests citing fear of childrens emotional reaction and lack of perceived benefits from knowing status. Counselling policy directors confirmed the absence of policy and training guidelines on the subject of parent-child disclosure. Counsellors reported improvising and giving inconsistent advice on this common concern of clients. Concerns over disclosure to children of parents HIV status and testing children for HIV represent a major psychological burden for HIV-positive parents. Further research is needed but current counselling practice could be improved now by adapting lessons learned from existing research. (authors)

OBJECTIVE: To provide estimates of survival and progression to different HIV disease endpoints after HIV infection among adults in a rural Ugandan setting. DESIGN: A prospective population-based cohort study. METHODS: Eligible individuals at least 15 years of age with documented HIV seroconversion were recruited from a general population cohort in rural Uganda, along with a randomly selected proportion of HIV-prevalent and HIV-negative individuals. All participants were followed up every 3 months, and CD4 cell counts taken every 6 months in HIV-positive participants. Life tables and Kaplan-Meier functions were used to estimate survival patterns for all endpoints [death, time to World Health Organization (WHO) stage 2, 3, AIDS and CD4 cell count < 200 cells/mul]. Analysis of follow-up time was truncated when antiretroviral therapy (ART) became available in the area in January 2004. RESULTS: We recruited 240 HIV incident cases, 108 prevalent cases and 257 HIV-negative controls. Crude mortality rates were 70.0 per 1000 person-years in HIV-positive, and 12.1 per 1000 person-years in HIV-negative individuals. The median time from seroconversion to death was 9.0 years (N = 240) and 6.2 years to a CD4 cell count less than 200 cells/mul or WHO stage 4 (N = 229). The median time from ART eligibility (CD4 cell count < 200 cells/mul, < 350 cells/mul and WHO stage 3, or WHO stage 4) to death was 34.7 months. Older age at seroconversion was a risk factor for faster progression to death and ART eligibility. CONCLUSION: HIV progression in this African cohort is similar to that reported in industrialized countries before the widespread introduction of ART.

Onchocerca volvulus nodules were removed from 77 fully compliant patients in a longitudinal study of ivermectin treatment in Sierra Leone. The patients had participated in a randomized controlled trial and received either 4 annual doses of ivermectin or 10 6-monthly doses over 6 years. Worms were examined 9 months after the last treatment for evidence of changes in morphology, viability and reproductivity. The findings were compared with results for the 2 groups obtained at earlier surveys of the same study population. Repeated treatment at 6 and 12-month intervals has resulted in a marked ageing of the male worm population profile and a significant reduction in the proportion of live female worms found in the nodules. In addition, there has been a reduction in reproductivity of 90% or more. However, most of the worms found were still alive and potentially fertile, underlining the need for the continuation of regular ivermectin treatment to maintain the benefits achieved.

Studies report substantial sexual behaviour change in Africa in response to HIV/AIDS. Generally there seems to be an increase in condom use and a reduction in partners, with men reporting more change than women. However, it is not only important to know whether people are changing their sexual behaviour but also their reasons for changing and the consistency and extent of change. Between 1996 and 2000 a study involving 196 respondents was carried out in rural southwest Uganda to investigate the exact nature of behaviour change and the reasons for change or lack of change since people became aware of HIV/AIDS. Data were collected from three rounds of questionnaire surveys, four rounds of open in-depth interviews, six rounds of semi-structured interviews and from informal conversations and participant observation. In order to obtain a comprehensive assessment of behaviour change the data for each participant from all sources were compared and discrepancies were then followed up by re-interviewing participants. After triangulation between all sources of data, 48% of respondents had ever used a condom. Condom use in 76% of all cases was at least partly AIDS related, while 19% was exclusively for protection against HIV. Condom use tended to be sporadic: only 13% of condom users currently used a condom regularly and most of this use was for family planning. After triangulation, 45% had reduced the number of sexual partners. Of all partner reductions, 93% was at least partly AIDS related; 29% was exclusively to avoid HIV. Half of those who had reduced the number of partners either stuck to one partner or abstained. Men reported more change than women. Of those who reported no partner reduction, 89% could not reduce the number of partners because they already had only few or a single partner or abstained; most of these were women. Most of those who could change their sexual behaviour had already changed, though the degree of change (particularly condom use) was often minimal. Not only behaviour change, but also the maintenance of safe behaviour is important. Also, understanding reasons for change and extent and consistency of change are important when planning and evaluating interventions.

BACKGROUND Previous studies have found that in Africa, a greater risk of HIV infection is often found in groups with higher educational attainment. However, some serial cross-sectional studies have found greater reductions in HIV prevalence among more educated groups, especially in cohorts of young adults. More recent studies have found some instances where higher schooling levels are associated with lower HIV prevalence. METHODS We describe changes in the association between schooling levels, HIV prevalence and condom use in a rural population-based cohort between 1989/1990 and 1999/2000, in Masaka District, Uganda. RESULTS In 1989-1990, higher educational attainment was associated with higher risk of HIV-1 infection, especially among males, but once odds ratios are adjusted for age, no significant relation between schooling and HIV infection remains. In 1999-2000, there is, for females aged 18-29 years, a significant relationship between higher educational attainment and lower HIV prevalence, even after adjustment for age, gender, marital status and wealth (P for trend 0.01). Tests for interaction, significant for males and both genders combined, show that more schooling has been shifting towards an association with less HIV infection between 1989-1990 and 1999-2000, especially for young individuals. Condom use increased during the study period and this increase has been concentrated among more educated individuals. CONCLUSIONS These findings suggest that over a decade more educated young adults, especially females, have become more likely to respond to HIV/AIDS information and prevention campaigns by effectively reducing their sexual risk behaviour.

Summary Objectives To investigate the effects of malaria parasitaemia and clinical malaria on mortality in HIV seropositive and seronegative adults. Methods A cohort of adults in rural Uganda were followed from 1990 to 1998. Participants attended routine clinic visits every 3 months and also when sick (interim visits). Information was collected on HIV serostatus, history of fever, current fever and malaria parasite levels. Malaria was categorized as any parasitaemia, significant parasitaemia (≥1.25 × 106 parasites/ml at routine or ≥50 parasites per 200 white blood cells at interim visits) or clinical malaria. The effect of malaria on all-cause mortality was assessed using Cox models. Results The 222 HIV seropositive participants made 2762 routine visits and 1522 interim visits. During follow-up, of the 211 participants with full records, 69% had at least one episode of parasitaemia, 51% experienced significant parasitaemia and 28% had clinical malaria. There were 90 deaths in 922 person-years of observation. There were no significant associations between numbers of visits with any parasitaemia, significant parasitaemia or clinical malaria on mortality rates. The highest mortality rates were observed in those making four or more routine visits with significant parasitaemia [adjusted mortality rate ratio (RR) 3.27 compared with those making 0 such visits; P = 0.078] and those making two or more visits with clinical malaria (adjusted RR 2.23; P = 0.093). There was no significant interaction between any malaria category and HIV serostatus. Conclusion We found no evidence of a strong detrimental effect of malaria on all-cause mortality in HIV seropositive adults in this setting.

BACKGROUND: Studies showing that helminths stimulate type 2 cytokine responses and influence responses to unrelated antigens suggest that helminths may accelerate human immunodeficiency virus type 1 (HIV-1) disease progression in coinfected individuals and that antihelminthic therapy may be beneficial. By the same logic, however, the increase in type 2 cytokines occurring immediately after antischistosomal treatment might increase viral replication and be detrimental. METHODS: To assess the effect of antischistosomal therapy on immune responses and HIV-1 replication, a cohort of 163 Ugandans coinfected with Schistosoma mansoni and HIV-1 was treated with praziquantel. CD4(+) T lymphocyte counts, eosinophil counts, and plasma HIV-1 RNA concentrations were measured before treatment and 1 month and 5 months after treatment. Schistosoma mansoni- and Mycobacterium tuberculosis-specific cytokine responses and serum interleukin (IL)-10 concentrations were analyzed. RESULTS: Transient increases in viral load and sustained decreases in CD4(+) T lymphocyte count were observed, especially in subjects with higher-intensity infections. Despite enhanced posttreatment S. mansoni-specific type 2 responses, no increase in eosinophils or in M. tuberculosis-specific type 2 responses nor any decline in M. tuberculosis-specific interferon (IFN)-gamma responses were seen. A significant decline in circulating IL-10 concentrations was observed. CONCLUSION: Although the mechanisms underlying the increase in viral load after treatment with praziquantel are unclear, these results do not support the hypothesis that treating schistosomiasis is beneficial in the management of HIV-1 disease in Africa.

Objective: The objective of this study was to investigate the management of sexually transmitted diseases (STDs) in the Ugandan private sector clinics and drug shops. Study: Men with urethral discharge who had consulted clinics (264) or drug shops (141) for treatment in 5 districts were interviewed using a precoded questionnaire 1 to 3 weeks after initiation of treatment. Results: Seventy-seven percent of patients sought treatment within 1 week of onset of symptoms but only 7% were properly managed (treated according to National Guidelines, told to use a condom or abstain, and to refer their partner). The reported cure rate was 47% and only 9% were treated according to National Guidelines. Eighteen percent of patients used condoms during treatment, 36% persuaded their partner to go for treatment, and 87% completed the recommended treatment course. Of patients not reporting cure, 56% would still recommend the treatment to a friend. Conclusion: Quality of STD management by private providers is poor. Improvement should occur concurrently at public and private facilities. Possible strategies include training and social marketing of prepackaged treatment for STDs.

Background. Active tuberculosis may accelerate progression of human immunodeficiency virus (HIV) infection by promoting viral replication in activated lymphocytes. Glucocorticoids are used in pleural tuberculosis to reduce inflammation-induced pathology, and their use also might reduce progression of HIV by suppressing immune activation. We examined the effect that prednisolone has on survival in HIV-1-associated pleural tuberculosis. Methods. We conducted a randomized, double-blind, placebo-controlled trial of prednisolone as an adjunct to tuberculosis treatment, in adults with HIV-1-associated pleural tuberculosis. The primary outcome was death. Analysis was by intention to treat. Results. Of 197 participants, 99 were assigned to the prednisolone group and 98 to the placebo group. The mortality rate was 21 deaths/100 person-years (pyr) in the prednisolone group and 25 deaths/100 pyr in the placebo group (age-, sex-, and initial CD4 + T cell count-adjusted mortality rate ratio, 0.99 [95% confidence interval, 0.62-1.56] [P = .95]). Resolution of tuberculosis was faster in the prednisolone group, but recurrence rates were slightly (though not significantly) higher, and use of prednisolone was associated with a significantly higher incidence of Kaposi sarcoma (4.2 cases/100 pyr, compared with 0 cases/100 pyr [P = .02]). Conclusions. In view of the lack of survival benefit and the increased risk of Kaposi sarcoma, the use of prednisolone in HIV-associated tuberculous pleurisy is not recommended.

Antigenic properties of the V3 region are reflected by HIV-1 serotypes. These may represent biological properties of the virus. We serotyped HIV-1 in 142 serum samples from participants in a rural Uganda cohort who seroconverted between August 1991 and December 2001. Clinical progression was assessed using Cox proportional hazards and Kaplan-Meier methods. Of 112 (79%) samples successfully serotyped, 36% were serotype A, 17% serotype B, 18% serotype C, and 29% serotype D. Median follow-up time, age at enrollment, and first CD4 count were similar in each serotype group. Clinical progression was faster for serotype D than other serotypes to AIDS or death, death, and CD4 count

We show that Ugandan adults coinfected with Schistosoma mansoni and human immunodeficiency virus type 1 (HIV-1) are able to mount S. mansoni-specific immune responses but that few such responses increase after treatment with praziquantel (PZQ). Levels of soluble worm antigen (SWA)-specific immunoglobulin (Ig) G1, IgG2, IgG3, IgG4, interleukin (IL)-4, and IL-5 increased significantly in HIV-negative participants after treatment with PZQ, whereas most soluble egg antigen-specific antibody responses and levels of interferon- gamma were unaltered. Only levels of SWA-specific IL-5 increased in HIV-1-coinfected participants after treatment. These deficiencies in immune responses may account for the previously reported increased susceptibility to infection and reinfection with S. mansoni in individuals coinfected with HIV-1.

CD4(+) T cell help is important for the functionality of CD8(+) cytotoxic T-lymphocytes (CTLs) in limiting viral replication and may contribute to mediation of apparent resistance to HIV-1 infection in exposed seronegative (ESN) individuals. Using five HIV-1 antigens in an intracellular cytokine assay, the presence of specific antigen-responsive interferon- gamma-positive (IFN-gamma(+)) CD69(+) CD4(+) T-lymphocytes was evaluated in ESNs, their seropositive partners, and unexposed seronegative controls. Ten ESNs (five females, five uncircumcised males) were identified from 10 HIV-1 serodiscordant couples with a history of frequent unprotected sexual intercourse. All ESNs and controls were negative on two EIAs and for HIV-1 proviral DNA. The frequency of ESNs with antigen-responsive IFN-gamma(+) CD69(+) CD4(+) T-lymphocytes ranged from three to five of eight for the different HIV-1 antigens. Six of eight ESNs tested had a positive response to at least one of the five antigens. Responses were on average 3.5 times higher among seropositives compared to ESNs and absent in the five unexposed controls. A negative correlation was noted between responses in ESNs and the plasma viral load of their seropositive spouse. Clade-specific and cross-clade reactivity were noted in both ESNs and seropositive partners tested. The findings confirm that ESNs are in a state of HIV-1-specific immune activation and suggest that HIV-1-specific IFN-gamma(+) CD69(+) CD4(+) T-lymphocytes in addition to HIV-1-specific CD8(+) CTLs already described by others are potential immunological correlates of protection from persistent HIV-1 infection.

Objective: To analyse the contribution of maternal survival and HIV status to child (under-5 years) mortality in a rural population cohort in South-west Uganda. Methods: Approximately 10 000 people residing in 15 neighbouring villages were followed between 1989 and 2000 using annual censuses and serological surveys to collect data on births deaths and adult HIV serostatus. Mother–child records were linked child mortality risks (per 1000 births) and hazard ratios (HRs) for child mortality according to maternal HIV serostatus were computed allowing for time-varying covariates. Results: A total of 3727 children were born of whom 415 died during 14 110 child years of follow-up. Mother’s HIV status at birth was ascertained unambiguously for 3004 children of whom 218 were born to HIV-positive mothers. Infant mortality risk was higher for HIV seropositive than seronegative mothers (225 versus 53) as was child mortality risk (313 versus 114). Child mortality risk was also higher for mothers who died (571) than for surviving mothers (128). After controlling for child’s age and sex independent predictors of mortality in children were: mother’s terminal illness or death (HR = 3.8); mother being HIV positive (HR = 3.2); child being a twin (HR = 2.0); teenage motherhood (HR = 1.7) and maternal absence (HR = 1.7). Conclusion: Maternal survival and HIV status are strong predictors of child survival. The higher mortality in HIV-infected women compounds mortality risks for their children regardless of children’s HIV status. Programmes aimed at the welfare of children should take into account the independent effect of mothers’ HIV and vital status. (authors)

Surveys have been conducted to measure prevalence of eye disease in Africa, but not of incidence, which is needed to forecast trends. The incidence of visual loss is reported in southwest Uganda.A rural population residing in 15 neighbouring villages was followed between 1994-5 (R1) and 1997-8 (R2). Survey staff screened adult residents (13 years or older) for visual acuity using laminated Snellen's E optotype cards at each survey. Those who failed (VA6/18) were evaluated by an ophthalmic clinical officer and an ophthalmologist. Incidence of visual loss (per 1000 person years (PY)) was calculated among those who had normal vision at R1.2124 people were studied at both survey rounds (60.9% of those screened at R1); 48% were male. Participants in R1 were older (34.7 versus 31.5 years at R2, p0.001). Visual loss in R2 occurred in 56 (2.8%) of 1997, yielding a crude incidence rate of 9.9, and an age standardised incidence rate of 13.2, per 1000 PY. Incidence of visual loss increased with age from 1.21 per 1000 PY among people aged 13-34 to 64.2 per 1000 PY in those aged 65 years or older (p for trend0.001). The six commonest causes of visual loss were: cataract, refractive error, macular degeneration, chorioretinitis, glaucoma, and corneal opacity. If similar rates are assumed for the whole of Uganda, it is estimated that 30 348 people would develop bilateral blindness or bilateral visual impairment, per year.Cataract and refractive error were the major causes of incident visual loss in south west Uganda. These data are valuable for forecasting and planning eye services.

Senga (father's sister) is a traditional channel of communication about sexual behaviour for adolescent females in rural Uganda. We evaluated a modification of this approach as an intervention for HIV and STDs in a pilot study in two intervention villages and one control village over 12 months. Eleven adult women and three adolescent girls were chosen and trained to become sengas. Adolescent girls were encouraged to visit the sengas for sexual health information. Adult sengas saw an average of 21 clients; adolescent sengas saw five. Adolescent girls made 45% of visits. The expected reasons for attending the sengas accounted for 51% of visits. Knowledge about HIV/AIDS, sexual communication skills, consistent condom use and family planning service use increased in the intervention group of girls over the study period and compared to control girls. Symptomatic STDs decreased in the intervention group. This intervention was readily accepted by the community; members of all ages and both sexes attended for a wider variety of reasons than anticipated. Adolescent girls in the intervention group showed improved knowledge, attitudes and practices related to HIV and STDs. This promising intervention warrants further testing in larger studies and other settings.

We implemented social marketing of pre-packaged treatment for men with urethral discharge ( Clear Seven) in Uganda, and studied its feasibility, acceptability and effectiveness as a possible means to treat STDs and thereby prevent HIV. Clear Seven was distributed at private health care outlets in three rural districts and two divisions of the capital. Comparisons were made with a pre-intervention period in the same sites plus one additional rural district. There were almost universally positive attitudes to Clear Seven. Cure rate (84% versus 47%), treatment compliance (93% versus 87%), and condom use during treatment (36% versus 18%) were significantly higher among Clear Seven users ( n=422) than controls ( n=405). Partner referral was similar but fewer Clear Seven partners were symptomatic when seeking treatment. Distribution of socially marketed pre-packaged treatment for male urethritis should be expanded in sub-Saharan Africa. Consideration should be given to developing similar kits for women.

It has been proposed that helminth infection may exacerbate HIV progression by promoting activation of 'type 2' immune responses. To examine this hypothesis, we investigated helminth infection in a cohort of HIV-1-seropositive adults in Entebbe, Uganda, during November 1999 to January 2000. Individuals with helminths were treated. At enroLlment, after 5 weeks and after 4 months, CD4+ and CD8+ T cell counts and viral load were measured. Cytokine responses (interferon [IFN]-gamma, interleukin [IL]-2, IL-4 and IL-5) to Schistosoma mansoni adult worm antigen (SWA), Mycobacterium tuberculosis culture filtrate proteins (CFPs) and phytohaemagglutinin (PHA) were measured in a whole blood assay. At baseline, CD4+ T cell counts and CD4+: CD8+ ratios were higher in individuals with helminths than in those without (median CD4+ T cell counts 467/microL and 268/microL, respectively, P = 0.005). Viral load was lower among those with helminths but this was not statistically significant. During follow-up, CD4+ T cell counts and cytokine responses to PHA fell among individuals without helminths. Among those treated for helminths, CD4+ counts remained stable. Viral loads showed a transient increase at 5 weeks, which was more marked among those treated for helminths, but the levels at 4 months were similar to baseline in both groups. Among those with schistosomiasis, IFN-gamma and IL-2 responses to CFP, and IL-2 and IL-4 responses to PHA declined but there was a sustained increase in cytokine responses to SWA following treatment. These data do not support the hypothesis that helminth infection exacerbates HIV infection. The possibility that chronic helminth infection may suppress HIV replication and that effects on HIV replication may vary during helminth infection and treatment should be considered.

The objective of this study was to examine the epidemic trends of HIV-1 infection in a rural population cohort in Uganda followed for 10 years. The methods used were to assess incidence and prevalence trends in adults in this longitudinal cohort study. The results showed that incidence of infection has fallen significantly in all adults, and separately in males, females, young adults and older adults over the course of the study period. There was also a reduction in prevalence, especially in young men and women. There was some evidence of a cohort effect in women. The conclusions are that this study provides the first evidence of a falling incidence in a rural general population in Africa. This was an observational cohort exposed to national health education messages, giving hope that similar campaigns elsewhere in Africa could be used effectively in efforts to control the HIV epidemic.

To examine relationships between diarrhoea, CD4 cell counts and stool pathogens in a community-based cohort of HIV-infected adults in Uganda.Stool specimens, obtained between October 1995 and December 1997, were linked to patients' symptoms and laboratory results. The relationship between CD4 counts and symptoms was tested using the Wilcoxon rank-sum test and those between organisms and diarrhoea using first a univariate Mantel-Haenszel analysis and then a logistic regression model adjusted for CD4 count and multiple organisms.1,213 HIV-infected individuals (70% women, median CD4 cell count at enrollment 215 cells/microl) were followed for 1,224 person years of observation (pyo). 484 stool samples were examined, 357 from patients with diarrhoea. The rate of diarrhoea was 661 episodes per 1,000 pyo. CD4 counts were significantly lower in individuals with diarrhoea than those without (P0.001, Wilcoxon rank-sum test). Forty-nine percent of diarrhoeal stools and 39% of stools from asymptomatic patients contained enteric pathogens. The most frequent isolates were helminths (29.5% of all stools), followed by bacteria (19.2%) and then protozoa (8.9%). Rates of isolation of diarrhoea-associated pathogens were 29% from diarrhoeal stools and 17% from asymptomatic stools (P = 0.01, chi(2) test). The association between diarrhoea and infection with bacteria or protozoa was weak and there was no association with helminths. Cryptosporidium parvum infection alone was associated with low CD4 counts.Diarrhoea was common and most strongly associated with low CD4 counts. Bacteria were frequently found, even in stools from asymptomatic individuals. Over two-thirds of diarrhoeal episodes were undiagnosed, suggesting that unidentified agents or primary HIV enteropathy are important causes of diarrhoea in this population.

Summary Background In Uganda, there have been encouraging reports of reductions in HIV-1 prevalence but not in incidence, which is the most reliable measure of epidemic trends. We describe HIV-1 incidence and prevalence trends in a rural population-based cohort between 1989 and 1999. Methods We surveyed the adult population of 15 neighbouring villages for HIV-1 infection using annual censuses, questionnaires, and serological surveys. We report crude annual incidence rates by calendar year and prevalence by survey round. Findings 6566 HIV-1 seronegative adults were bled two or more times between January, 1990, and December, 1999, contributing 31 984 person years at risk (PYAR) and 190 seroconversions. HIV-1 incidence fell from 8·0 to 5·2 per 1000 PYAR between 1990 and 1999 (p=0·002, X 2 for trend). Significant sex-specific and age-group-specific reductions in incidence were evident. Incidence was 37% lower for 1995–99 than for 1990–94 (p=0·002, t -test). On average, 4642 adult residents had a definite HIV-1 serostatus at each yearly survey round. HIV-1 prevalence fell significantly between the first and tenth annual survey rounds (p=0·03, X 2 for trend), especially among men aged 20–24 years (6·5% to 2·2%) and 25–29 years (15·2% to 10·9%) and women aged 13–19 years (2·8% to 0·9%) and 20–24 years (19·3% to 10·1%) (all p 2 for trend). Interpretation Our findings of a significant drop in adult HIV-1 incidence in rural Ugandans give hope to AIDS control programmes elsewhere in sub-Saharan Africa where rates of HIV-1 infection remain high.

The effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression was investigated in 1045 adults in Uganda. At enrollment and every 6 months, a clinical history, examination, and laboratory investigations that included CD4 cell counts were done. HIV-1 envelope subtype was assessed mainly by peptide serology supplemented by heteroduplex mobility assay and DNA sequencing. A multivariate analysis of survival was performed to assess the prognostic value of HIV-1 subtype on death. A marginal general linear model also determined the effect of subtype on CD4 cell count during follow-up. Subtype D was associated with faster progression to death (relative risk, 1.29; 95% confidence interval, 1.07-1.56; P=.009) and with a lower CD4 cell count during follow-up (P=.001), compared with subtype A, after adjusting for CD4 cell count at enrollment. In Africa, envelope subtype D is associated with faster disease progression, compared with subtype A.

Despite the recognition of Cryptococcus neoformans as a major cause of meningitis in HIV-infected adults in sub-Saharan Africa, little is known about the relative importance of this potentially preventable infection as a cause of mortality and suffering in HIV-infected adults in this region.A cohort study of 1372 HIV-1-infected adults, enrolled and followed up between October 1995 and January 1999 at two community clinics in Entebbe, Uganda.Systematic and standardized assessment of illness episodes to describe cryptococcal disease and death rates.Cryptococcal disease was diagnosed in 77 individuals (rate 40.4/1000 person-years) and was associated with 17% of all deaths (77 out of 444) in the cohort. Risk of infection was strongly associated with CD4 T cell counts200 x 10(6) cells/l(75 patients) and World Health Organization (WHO) clinical stage 3 and 4 (68 patients). Meningism was present infrequently on presentation (18%). Clinical findings had limited discriminatory diagnostic value. Serum cryptococcal antigen testing was the most sensitive and robust diagnostic test. Cryptococcal antigenaemia preceded symptoms by a median of 22 days (100 days in 11% of patients). Survival following diagnosis was poor (median survival 26 days; range 0-138).Cryptococcal infection is an important contributor to mortality and suffering in HIV-infected Ugandans. Improvements in access to effective therapy of established disease are necessary. In addition, prevention strategies, in particular chemoprophylaxis, should be evaluated while awaiting the outcome of initiatives to make antiretroviral therapy more widely available.

This paper describes the implementation of a large community-based HIV/AIDS behavioural intervention in rural Uganda and presents 4 years' worth of quantitative process data. The intervention involved 560 field-based workers (57% male, 76% subsistence farmers, mean age 35 years), supervised by six central staff. Intervention channels included drama and video shows, Community Educators (CEs), as well as leaflet and condom distribution. Activities focused on one or more of 16 key topics. In total, 392 000 attendances (51% female) were recorded--a mean of over 6 for each of the 64 000 target adults--at 81 000 activities, with CEs attracting 71% of the total attendance; 164 000 leaflets and 242 000 condoms were also distributed. The annual cost of the intervention per target individual was approximately US$1.76. Our voluntary workforce experienced an annual attrition rate of 11%, with 'stable' workers more likely to be older, married or opinion leaders in their community than those who dropped out. We calculate that even a significant increase in the proportion of female field workers would have made little difference either to the sex ratio of attendees or to overall attendance. In spite of some initial resistance to the intervention, particularly in relation to condoms, we have demonstrated that people in rural Africa can accept and actively participate in the dissemination of HIV/AIDS prevention messages throughout their own communities.

Objectives: To describe the progression times of HIV-1 infection from seroconversion to AIDS and to death and time from first developing AIDS to death in rural Uganda. Also to describe the proportion of individuals within the cohort dying with AIDS and the CD4 lymphocyte count before death. Design: A prospective longitudinal population-based cohort. Methods: Since 1990 107 HIV-prevalent cases 168 incident cases and 235 HIV seronegative controls have been recruited into a cohort in rural Uganda. Participants are recruited from the general population and they are reviewed routinely every 3 months and at other times when ill. Results: The median time from seroconversion to death was 9.8 years. Age over 40 years at seroconversion was associated with more rapid progression (P

BACKGROUND: Falciparum malaria and HIV-1 infection are two of the most important health problems facing sub-Saharan Africa. No convincing evidence of an association between symptomatic malaria and HIV-1 infection has been found. OBJECTIVE: To investigate the effect of HIV-associated immunosuppression on malarial fever rates. DESIGN: An observational cohort study in HIV-specific, primary healthcare clinics in Entebbe, Uganda, on 1371 HIV-1-infected adults participating in a randomized trial of 23-valent pneumococcal vaccine. METHODS: Cohort members underwent routine 6 monthly surveillance and had open clinic access when sick. Episodes of fever were assessed according to standardized protocols. Rates of malaria are described according to HIV immune status determined by CD4 T cell counts. RESULTS: Incidence rates of Plasmodium falciparum malarial fever showed a marked inverse relationship with CD4 T cell count; 140, 93 and 57 cases per 1000 pyo for CD4 T cell groups 500 respectively, P < 0.001. Malarial fever definitions incorporating parasite density criteria (derived from asymptomatic surveillance) to correct for chance findings of fever and P. falciparum parasitaemia, did not affect the association of incidence rates with immunosuppression. CONCLUSION: These data support an interaction between symptomatic P. falciparum and HIV. Emphasis on mosquito avoidance measures should be an important component of education and counselling of HIV/AIDS patients in malaria-endemic areas, and suggests an additional HIV-related public health problem in Africa.

We compared HIV-1 RNA levels using the nucleic acid sequenced based amplification (NASBA) test kit in 2 samples taken one year apart from participants infected with env subtype A or D in a population-based cohort in Uganda. Fifty participants were infected with subtype A and 70 with subtype D. HIV-1 RNA levels were significantly higher in subtype D unadjusted ( P = 0.001), and after adjusting for age, gender, and CD4 count ( P < 0.001). Eighty-six participants had HIV-1 RNA measurements in both years and 67 (78%) were within one log10 of their result a year before. There was no relationship between the difference in log viral load and proportion of CD4 change. Individuals infected with subtype D had a higher average increase in viral load and this was statistically significant if adjusted for baseline levels and CD4 count ( P = 0.015).

The aim was to investigate the association between alcohol consumption and HIV seropositivity in a rural Ugandan population. The adult population residing in a cluster of 15 neighboring villages has been kept under epidemiological surveillance for HIV infection using annual censuses and serosurveys since 1989. At the eighth annual survey all respondents were asked about their history of alcohol consumption the sale of alcohol in their household and other sociodemographic information. After informed consent blood was drawn for HIV serology. Of the total adult population 3279 (60%) were interviewed; 48% were males; 905 (27%) had not started sexual activity and were excluded from further analysis. Of the remaining 2374 8% were HIV infected 57% had ever drunk alcohol and 4% lived in households where alcohol was sold. Living in a household where alcohol was sold was associated with a history of having ever drunk alcohol (odds ratio [OR] 2.9 95% confidence interval [CI]: 1.7-4.8). HIV prevalence among adults living in households selling alcohol was 15% compared with 8% among those living in households not selling alcohol (OR 2.0 95% CI: 1.1-3.6). Individuals who had ever drunk alcohol experienced an HIV prevalence twice that of those who had never drunk 10% vs. 5% (OR 2.0 95% CI: 1.5-2.8). This association remained after adjusting for potential confounders including sale of alcohol in the household and Muslim religion (OR 1.8 95% CI: 1.2-2.7). Only age marital status and having ever drunk alcohol independently predicted HIV seropositivity in a logistic regression model. The authors have demonstrated an association between a history of alcohol consumption and being HIV seropositive. This unexplored factor may explain in part the observed lower prevalence of HIV infection among Muslims. Public health campaigns need to stress the relationship between HIV and alcohol. (authors)

We aimed to assess the acceptability of a variety of formulations of female-controlled methods of protection against HIV and STDs among men and women in south-western Uganda. Pilot interviews were carried out with 50 men and 55 women and 25 focus group discussions (FGDs) were held with 138 women and 42 men. The female condom, foaming tablets, sponge, foam, gel and film were demonstrated to 146 women and 35 of their male partners, who then tried out 2 of the products. They were interviewed 7 times during the course of 5 months. At the end experiences were evaluated during a second series of FGDs. Sixty-five (45%) women completed the trial. The main reasons for non-completion were related to geographical mobility. Product preference after the initial demonstration was similar to that at the end of the trial. The most popular formulations were the sponge (25% of the women), foaming tablets (23%), and the female condom (19%). The foam was of medium popularity (16%). The gel (9%) and film (7%) were least popular. Ten per cent of the women and 14% of the men reported products interfering with sexual enjoyment; 24% of the women and 67% of the men said products increased enjoyment. 'Dry sex' is not popular in this area and increased lubrication was an important determinant of acceptability. Age, level of education and location did have some effect on preference. Although secrecy was a dominant theme in the FGDs, 87% of the women had informed their partners by the end of the trial. The products were generally well received. Female control was an important issue for both sexes. Male attitudes were ambivalent because female ownership of products increased women's control. Although they have clear preferences, women appear to accept the products generally and might use a single available product just as readily if choice was limited, as long as it conforms to general cultural preferences, such as those relating to wet/dry sex.

The objective was to assess whether the WHO staging classification for HIV provides prognostically valuable and applicable information in rural Uganda. Data were obtained from a population-based cohort of 232 HIV-infected individuals. Clinical information was obtained using a detailed questionnaire and ascertained by physical examination. Participants were seen routinely every 3 months and when they were sick. A computer algorithm based on clinical history examination and laboratory findings was used to stage HIV-positive participants at each routine visit. Kaplan-Meier survival estimates and the Cox proportional hazard model were used to assess the prognostic strength of the clinical and laboratory categories of the system. An attendance rate of 81% and 799 person-years of follow-up were achieved. Survival probability estimates at 6 years from being seen in clinical stages 1 2 3 and 4 were 63% 46% 24% and 6% respectively. When staging was revised to incorporate lymphocyte categories the survival probabilities were 73% 62% 39% and 6% respectively. Unexplained prolonged fever and severe bacterial infection had survival probabilities closer to stage 2 conditions mucocutaneous herpes simplex virus infection for more than 1 month and cryptosporidiosis with diarrhea for more than 1 month closer to stage 3 and oral candidiasis closer to stage 4 conditions. Even without the laboratory markers the clinical category of the WHO staging system is useful for predicting survival in individuals with HIV disease. This is important for areas with limited access to laboratory markers. A simple rearrangement of a few clinical conditions could improve the prognostic significance of the WHO system. (authors)

Objective: Few studies have described levels and determinants of perceived risk of HIV-1 among African adults for whom the sero-status is known. This study describes HIV risk perception obtained from a large rural population in south-west Uganda which also underwent serological testing for HIV. Design: Cross-sectional survey. Methods: Information on risk perception and sexual behaviour was collected by interview. Sera were obtained from all consenting adults (13 years and above) in order to assess HIV-1 prevalence. Results: Of 14 818 adults with a definitive sero-status, 9.7% were HIV-1 positive and 51% considered themselves to be at risk of infection. Risk perception showed similar patterns as age- and sex-specific sero-prevalence and there was correspondence between risk factors for perceived risk and known HIV risk factors. Partner's sexual behaviour was the commonest reason for risk perception in women whereas men cited their own sexual behaviour. Abstinence from sex was much more commonly mentioned as a protective practice than condom use in men and women. Conclusion: Half of the adults we have studied already see infection with HIV as a real possibility in their lives and are aware of HIV risk behaviours. More efforts should be made to implement sustainable control measures rather than simply raising awareness. In addition to recommending abstinence, these include mutual faithfulness, condom use and better treatment for STDs.

The objective was to estimate the likely percentage of HIV infections that may be attributable to one-off partnerships (such as those between female sex workers and their clients) and longer-term partnerships in rural Uganda. This was addressed by the application of a microsimulation model (SimulAIDS) of the transmission dynamics of HIV infection, drawing on data from a population cohort of 10,000 in rural Uganda. For a scenario reproducing documented characteristics of the study population in 1990, when adult HIV prevalence was 9%, and during subsequent follow up (1990-1994), when adult HIV incidence was 8 per 1000 person-years, the percentage of HIV infections in men (women) attributed to one-off partnerships decreased from 96% (26%) during 1980 to 67% (8%) in 1989 and 22% (5%) in 1994. Reducing HIV transmission between one-off partners early in an HIV epidemic may substantially limit the potential for the spread of HIV infection. At a later phase, prevention must also focus on control of transmission between longer-term HIV-discordant partners.This paper presents results of a study using a simulation model in estimating the likely percentage of HIV infections that may be attributable to one-off partnerships (e.g., female sex workers and their clients) and longer-term partnerships among the rural population of Uganda. The study adopted SimulAIDS, an age-structured microsimulation model of the HIV infection dynamics along with ulcerative and non-ulcerative sexually transmitted diseases. Data obtained from the 10,000 cohort population reflected a decline in the incidence of HIV in adults between 1990 and 1994, a result which could be attributed to one-off sexual partnerships in 1980, 1984, 1989, 1994, and 1999. The study supports that minimizing transmission of HIV from short-term sexual partnerships during early stage of the disease could have a strong impact on the reduction in the spread of HIV infection.

While human immunodeficiency virus (HIV)-related causes of death have been well documented in developed countries, in Africa data are scanty and mainly based on autopsy studies from city hospitals which are highly selective and may not represent causes of HIV-associated deaths in the general population. This study, from a rural population, describes the causes of death in HIV-positive people and their HIV-negative controls.A natural history cohort comprising HIV-1 infected participants and HIV-negative controls was established in rural Uganda in 1990. Causes of death were determined by reviewing the premorbid clinical and laboratory findings and from information obtained from relatives. Blindness to the deceased's HIV serostatus was maintained throughout.In all, 78 deaths occurred over a 6-year period: 63 deaths occurred in the HIV-positive cases (53 prevalent and 10 incident cases) and 15 deaths in the HIV-negative controls. Of the prevalent cases, 56%, and 9% the incident cases enrolled died, compared with 7% of the HIV-negative controls. Of the 55 HIV-positive cases with sufficient data to establish cause of death, 52 (95%) were assessed as having HIV-associated deaths and 48 (87%) died in WHO stage 4 (AIDS). The main causes of death were wasting syndrome (31%), chronic diarrhoea (22%), cryptococcal meningitis (13%) and chest infection (11%).Our results represent an unbiased selection of deaths in a rural area. The HIV-positive cases have high death rates and die of HIV-related pathologies. The main causes of death reflect the WHO clinical case definition of AIDS. Cryptococcal meningitis is also a common cause of death in this population.A natural history cohort (NHC) of HIV-1-infected subjects and HIV-negative controls was established in rural Uganda in 1990. By the end of 1996, 440 participants had enrolled in the cohort: 107 prevalent cases, 108 incident cases, and 225 HIV-negative controls. The authors report the causes of death among HIV-infected cohort members over the 6-year period ending December 1996. Causes of death were determined by reviewing the premorbid clinical and laboratory findings, as well as from information obtained from relatives. All study clinic staff are blind to the HIV serostatus of participants in the NHC. 78 deaths occurred over the 6-year study period: 63 deaths among HIV-positive cases (53 prevalent and 10 incident cases) and 15 deaths among HIV-negative controls. 56% of prevalent cases, 9% of incident cases and 7% of controls died. Of the 55 HIV-positive cases with enough data to establish cause of death, 52 were determined to have HIV-associated deaths, of whom 48 died in World Health Organization stage 4 illness. Main causes of death were wasting syndrome (31%), chronic diarrhea (22%), cryptococcal meningitis (13%), and chest infection (11%).

To describe the early manifestations of HIV-1 infection before the development of AIDS, in a rural Ugandan population.Three monthly follow-up of HIV-1-infected and uninfected participants in an HIV-1 natural history cohort from the start of the cohort in 1990 to the end of 1996.A total of 107 persons with prevalent infection and 104 persons with incident infection were enrolled. Eighty (75%) prevalent and 89 (86%) incident individuals were asymptomatic on enrollment. Of the 91 persons with incident infection seen within 2 years of their estimated date of seroconversion, 51% [95% confidence interval (CI), 40-61] were still asymptomatic 2 years after seroconversion. At 4 and 5 years after seroconversion, only 26% (95% CI, 17-36) and 11% (95% CI, 4-22), respectively, remained asymptomatic. A total of 89 participants entered World Health Organization (WHO) stage 2, and their main stage-defining conditions were weight loss10% (and5%) and minor mucocutaneous manifestations. The median CD4 lymphocyte count for participants entering WHO stage 2 was 516 x 10(6) cells/l (interquartile range, 360-884 x 10(6)/l). A total of 94 participants entered WHO stage 3 and the main reasons were weight loss10%, unexplained chronic diarrhoea, fever for more than 1 month, and severe bacterial infection. The median CD4 lymphocyte count for participants entering WHO stage 3 was 428 x 10(6) cells/l (interquartile range, 276-736 x 10(6)/l). The rates of all conditions reported under the WHO staging system were significantly more frequent in HIV-positive persons than HIV-negative controls with the exception of fever for more than 1 month and oral hairy leukoplakia (which was seen in only three individuals).These are the first data from a non-selected African population describing the early manifestations of HIV infection. The main early manifestations were weight loss, minor mucocutaneous features, chronic diarrhoea, chronic fever and severe bacterial infections. The apparent rapid development of HIV-related signs and symptoms is probably indicative of the high background level of these conditions in our study area, as reflected by the rates of these conditions in the HIV-negative controls.

The study was based in south-west Uganda where significant differences in HIV prevalence have been found between urban and rural areas. Longitudinal data collected in a diary format was used to determine the extent to which high-risk men and women living in a truck stop/trading town had sexual contact with people from surrounding rural areas and a nearby fishing village. Study participants were 143 men, 75 of whom were resident in the town, 40 in a fishing village and 28 in rural areas, and 81 women, of whom 47 were resident in the town, 25 in the fishing village and 9 in a rural area. During 1687 man weeks the 143 men made 3149 trips and had 5189 sexual contacts. Ninety-two per cent of these sexual contacts occurred in the man's current place of residence and 21% were with a new partner. The 81 women participated for 1280 women weeks during which they recorded 6378 sexual contacts. Women who lived in the fishing village and the rural area had around 90% of their contacts with local men while those who lived in the town fell into 3 categories: women who charged a relatively high price for commercial sex had only 11% of contacts with men living in the town, while those who charged a tenth of the price had 71% of contacts with town men. The small number of women who fell into an intermediate category, in terms of price, had sexual contact with a wide variety of men. These findings show that there is little scope for HIV infection to spread between different residential or occupational groups. This may help to explain how large differences in HIV seropositivity between neighbouring localities can be maintained for long periods, despite considerable social and economic mixing between groups and high levels of sexual partner change within groups.In southwest Uganda, there is concern that sexual mixing between rural areas with low HIV prevalence and urban areas with high HIV prevalence will produce uniformly high rates of HIV. To determine the extent of such mixing, a prospective study was conducted in a trading town on the trans-African highway with a steady flow of male truckers, an agricultural hinterland to the west, and a fishing village to the east. A total of 143 men recruited largely from bars and 81 women reported to be sexually promiscuous kept records of their sexual contacts over a 6-month period. During 1687 man-weeks of observation, the men made 3149 road trips and had 5189 sexual contacts; 92% of these contacts occurred in the men's place of residence and 21% involved a new partner. 59% of town men's sexual contacts, 61% reported by men in the fishing village, and 52% of those in rural areas involved casual partners. An additional 6378 sexual encounters were recorded during 1280 woman-weeks. Close to 90% of women's sexual contacts in the 2 rural areas involved local men. Among the highest-paid town commercial sex workers, only 11% of sexual contacts involved men from the town; in contrast, 71% of sexual encounters among town women who charged only 10% the price of their more expensive counterparts were with local men. Serologic testing of a subset of 75 men and 52 women yielded HIV prevalences of 28% and 52%, respectively. The distinct sexual networks identified in this study suggest it is unlikely that rates of HIV infection in the rural areas will reach those in nearby trading towns.

The majority of people infected with HIV-1 live in Africa, yet little is known about the natural history of the disease in that continent. We studied survival times, disease progression, and AIDS-defining disorders, according to the proposed WHO staging system, in a population-based, rural cohort in Uganda.In 1990 we recruited a random sample of people already infected with HIV-1 (as prevalent cases) detected during the initial survey round of a general-population study to form a natural-history cohort. Individuals from the general-population cohort who seroconverted between 1990 and 1995 (incident cases) were also invited to enroll. Participants were seen routinely every 3 months and when they were III.By the end of 1995, 93 prevalent cases and 86 incident cases had been enrolled. Four patients in the prevalent group were in stage 4 (AIDS) at the initial visit. During the next 5 years, 37 prevalent cases progressed to AIDS. Seven incident cases progressed to AIDS and the cumulative progression to AIDS at 1, 3, and 5 years after seroconversion was 2%, 6%, and 22%, respectively. The cumulative probability of AIDS at 4 years from entering stages 1, 2, and 3 was 11%, 33%, and 58%, respectively. There were 47 deaths among prevalent cases and seven among incident cases during follow-up. The cumulative mortality 4 years after patients entered stages 1, 2, 3, and 4 was 9%, 33%, 56%, and 86%, respectively. The median survival after the onset of AIDS was 9.3 months.Our results are important for the setting of priorities and rationalisation of treatment availability in countries with poor resources. We found that progression rates to AIDS are similar to those in developed countries for homosexual cohorts and greater than for cohorts infected by other modes of transmission. However, we have found that the rates of all-cause mortality are much higher and the progression times to death are shorter than in developed countries.The authors studied AIDS-defining disorders, disease progression, and survival times in cohorts of HIV-infected people in a rural region of Uganda. A random sample of people already infected with HIV-1 was recruited in 1990. The subjects had been detected during the initial survey round of a general-population study to form a natural-history cohort. Individuals from the general-population cohort who seroconverted between 1990 and 1995 were also invited to enroll in the study. Participants were seen routinely every 3 months and when they were ill. By the end of 1995, 93 prevalent cases and 86 incident cases had been enrolled. Four patients in the prevalent group were in World Health Organization-defined stage 4 HIV disease, AIDS, at the initial visit. Over the next 5 years, 37 prevalent cases progressed to AIDS. Seven incident cases progressed to AIDS and the cumulative progression to AIDS at 1, 3, and 5 years after seroconversion was 2%, 6%, and 22%, respectively. The cumulative probability of AIDS at 4 years from entering stages 1, 2, and 3 was 11%, 33%, and 58%, respectively. There were 47 deaths among prevalent cases and seven among incident cases during follow-up. The cumulative mortality 4 years after patients entered stages 1, 2, 3, and 4 was 9%, 33%, 56%, and 86%, respectively. The median survival duration after the onset of AIDS was 9.3 months.

BACKGROUND: Early initiation of antiretroviral therapy reduces risk of transmission to the uninfected partner in HIV discordant couples, but there are relatively little observational data on HIV transmission within couples from non-trial settings. The aims of this paper are to estimate HIV incidence among HIV discordant couples using longstanding observational data from a rural Ugandan population and to identify factors associated with HIV transmission within couples, including the role of HSV-2 infection. METHODS: Using existing data collected at population-wide annual serological and behavioural surveys in a rural district in southwest Uganda between 1989 and 2007, HIV discordant partners were identified. Stored serum samples were tested for HSV-2 serostatus using the Kalon ELISA test. HIV seroconversion rates and factors association with HIV seroconversion were analysed using Poisson regression. RESULTS: HIV status of both partners was known in 2465 couples and of these 259 (10.5%) were HIV serodiscordant. At enrollment, HSV-2 prevalence was 87.3% in HIV positive partners and 71.5% in HIV negative partners. Of the 259 discordant couples, 62 converted to HIV (seroconversion rate 7.11/100 PYAR, 95%CI; 5.54, 9.11) with the rate decreasing from 10.89 in 1990-1994 to 4.32 in 2005-2007. Factors independently associated with HIV seroconversion were female sex, non-Muslim religion, greater age difference (man older than woman by more than 15 years), higher viral load in the positive partner and earlier calendar period. HSV-2 was not independently associated with HIV acquisition (HR 1.62, 95%CI; 0.57, 4.55) or transmission (HR 0.61, 95%CI; 0.24, 1.57). No transmissions occurred in the 29 couples where the index partner was on ART during follow up (872 person-years on ART). DISCUSSION: HIV negative partners in serodiscordant couples have a high incidence of HIV if the index partner is not on antiretroviral therapy and should be provided with interventions such as couple counselling, condoms and antiretroviral treatment.

Human isotype specific antibody responses to a recombinant pi-class glutathione S-transferase (Ov24) from Onchocerca volvulus were assessed by ELISA, using a large and well-characterized bank sera (n = 238) from an hyper-endemic area of moderate intensity from Sierra Leone. IgG1, IgG4 and IgA responses, but neither IgG2 nor IgE response, to Ov24 were detected in infected subjects. The relationships between Ov24 antibody levels and skin microfilarial density, number of nodules, age, sex, eosinophil counts and clinical sign of reactive and chronic pathology were analysed using Pearson's correlation coefficient. Significant correlations between both IgA and IgG3 antibody levels and age were found (P < 0.01). Although no firm conclusions could be drawn from this study sample regarding the relationships between antibody levels and parasite load or clinical status, a negative correlation (P = 0.06) between Ov24 IgG3 antibody levels and microfilarodermia was found.