Search

Objective: To investigate the role of HIV-1 envelope subtypes on disease progression in a rural cohort of Ugandan adults where two major HIV-1 subtypes (A and D) exist., Methods: Participants of a clinical cohort seen between December 1995 and December 1998 had blood collected for HIV-1 subtyping. These included prevalent cases (people already infected with HIV at the start of the study in 1990) and incident cases (those who seroconverted between 1990 and December 1998). HIV-1 subtyping was carried out by heteroduplex mobility assay and DNA sequencing in the V3 env region. Disease progression was measured by the rate of CD4 lymphocyte count decline, clinical progression for the incident cases as time from seroconversion to AIDS or death, to first CD4 lymphocyte count < 200 x 10(6)/l and to the World Health Organization clinical stage 3. All analyses were adjusted for age and sex., Results: One hundred and sixty-four individuals, including 47 prevalent and 117 incident cases, had V3 env subtype data of which 65 (40%) were subtyped as A and 99 as D. In the incident cases, 44 (38%) were subtyped as A and 73 as D. There was a suggestion that for most end-points A had a slower progression than D. The cumulative probability of remaining free from AIDS or death at 6 years post-seroconversion was 0.72 [95% confidence interval (CI), 0.50 to 0.85] for A and 0.58 (95% CI, 0.42 to 0.71) for D, and the adjusted hazard ratio of subtype D compared to A was estimated to be 1.39 (95% CI, 0.66 to 2.94; P = 0.39). The estimated difference in rates of decline in square root CD4 lymphocyte counts was -0.41 per year (95% CI, -0.98 to 0.15; P = 0.15)., Conclusion: This study suggests that although subtype A may have a slower progression than D, HIV-1 envelope subtype is not a major factor in determining the progression of HIV-1 disease in a rural population in Uganda.

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).

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<0.0001). At HIV-1-positive visits, lower CD4-cell counts were associated with higher parasite densities, compared with HIV-1-negative visits (p=0.0076). Clinical malaria was significantly more common at HIV-1-positive visits (55 of 2788 [2.0%] vs 26 of 3688 [0.7%], p=0.0003) and the odds of having clinical malaria increased with falling CD4-cell count (p=0.0002) and advancing clinical stage (p=0.0024). Participants made 3377 interim visits. The risk of clinical malaria was significantly higher at visits by HIV-1-positive individuals than HIV-1-negative individuals (4.0% vs 1.9%, p=0.009). The risk of clinical malaria tended to increase with falling CD4-cell counts (p=0.052)., Interpretation: HIV-1 infection is associated with an increased frequency of clinical malaria and parasitaemia. This association tends to become more pronounced with advancing immunosuppression, and could have important public-health implications for sub-Saharan Africa.

The molecular epidemiology of a population-based cohort in a cluster of 15 villages in southwestern Uganda was investigated by sequencing part of the p24 gag gene and performing heteroduplex mobility assays (HMAs) of the V3 region of the env gene. Sequence and HMA data, obtained for 69 and 88 proviruses, respectively, showed that the clade A and D viruses were present at a ratio of about 0.67:1. No other clades were detected. Thirteen (22%) of 59 proviruses for which both gag and env data were obtained appeared to be recombinants. Although both clade A and D viruses were present in 13 of the villages, their distribution was unequal: for example, from env data 59% of clade A viruses were found in the eastern villages, compared with only 27% of clade D viruses. Phylogenetic (maximum likelihood) analysis of the p24 gag sequences showed a total of five clusters supported by bootstrap resampling values above or close to 75%. Four clusters were sexual partners, but there was no known sexual contact between the persons in the other cluster. The DNA sequences showed between 0.5 and 8.3% divergence from the cohort clade A or D consensus sequences. The sequences were not closely related to those published for other clade A or D proviruses.

Background: HIV-1 infection is associated with lower fertility among women in sub-Saharan Africa and this association is not explained by the frequency of sexual intercourse, illness, knowledge of HIV status or infection with other sexually transmitted diseases. Women with fertility problems are at increased risk of marital instability and, therefore, HIV infection; consequently, pre-existing subfertility among HIV-infected women may contribute to the association., Objective: This study examines the relationship between HIV-1 infection and the incidence of recognised pregnancy and the role of low gravidity prior to seroconversion in rural Uganda., Methods: A group of 176 women (80 HIV infected and 96 uninfected) were enrolled into an HIV-1 natural history cohort and invited to attend 3-monthly clinic appointments. Data from clinic visits were analysed to assess the independent effects of HIV infection and age, lactation, illness, reported frequency of sexual intercourse and sexually transmitted diseases (STD) on the risk of pregnancy in the following 3 months. The number of previous pregnancies was recorded at enrolment, and the effect of gravidity was examined for the subgroup of women who were uninfected at enrolment or who enrolled within 2 years of their estimated seroconversion date., Results: During follow-up, 124 pregnancies were observed in 83 women beginning in the 3 months following 47 (7.0%) of 669 visits made by HIV-infected women and 77 (9.5%) of 812 visits by HIV-negative women (P = 0.12). Adjusting for age, lactation, illness, STD and the reported frequency of sexual intercourse, the estimated reduction in the risk of pregnancy associated with HIV infection was 47% [95% confidence interval (CI) 18-66]. Pre-existing low gravidity was strongly associated with a reduced incidence of pregnancy (odds ratio 0.39; CI 0.19-0.81). Additionally, adjusting for low gravidity reduced the estimate of the effect of HIV infection by almost a half, to 25% (95% CI-57-29)., Conclusion: Low gravidity prior to seroconversion accounts for almost 50% of the observed association between HIV infection and lowered incidence of pregnancy, after adjusting for age, lactation, illness, STD and the frequency of sexual intercourse.

Apart from a small number of reports from people who are based in hospitals, data on viral load in HIV-infected people in sub-Saharan Africa, where most infections occur, are lacking. We report serum HIV-1 RNA levels in a population-based cohort in rural Uganda using the nucleic acid sequence-based amplification procedure (NASBA) test kit and describe their relation to CD4 counts and World Health Organization (WHO) clinical staging. The median (interquartile range [IQR]) viral loads were 87,000 copies/ml (37,500-295,000 copies/ml) in 40 prevalent cases infected for >6 years, and 31,000 copies/ml (7800-174,000 copies/ml) in 65 incident cases with seroconversion dates within the previous 6 years. Although we found a correlation between viral load and absolute CD4 count (p < .0001), there was no evidence for an association with CD4 decline (p = .1). Overall, there was a significant trend of increasing viral load with worsening clinical stage from a median viral load of 15,000 for those in WHO stage 1 (asymptomatic) to 150,600 copies/ml for those in stage 4 (AIDS; p < .001). However, the association was seen only in incident cases. Thus, we found that the NASBA test on serum was a useful indicator of disease stage especially in persons known to be infected for <6 years. Such baseline data are important for vaccine research, and if antiretroviral drugs become available to more than a few people in Africa, it will be important that accurate viral load estimations are available at least in a proportion of people to monitor the effectiveness of treatment, and measure the compliance and emerging resistance to these drugs.

Background: 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., Methods: 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., Results: 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%)., Conclusions: 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.

Objectives: To describe the early manifestations of HIV-1 infection before the development of AIDS, in a rural Ugandan population., Methods: 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., Results: 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 loss <10% (and > 5%) 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 loss >10%, 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)., Conclusion: 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.

Purpose: To report the ocular findings in HIV-1 seropositive individuals and HIV-negative controls in a population-based cohort in rural Uganda., Methods: Participants were examined by an ophthalmologist, who was unaware of their HIV-status., Results: 238 participants were examined, 43 were HIV-1 prevalent cases (infected prior to 1990); 62 were HIV-1 incident cases and 133 were HIV-negative controls. Eleven of the HIV-positive participants had AIDS, and a further 8 had a CD4 count of less than 200 cells/mm3. Bilateral low vision was recorded in 9 participants and cataracts were the main cause of bilateral low vision. The mean intra-ocular pressure (IOP) was 12.6 mm Hg, and no association was found between IOP and CD4 lymphocyte count. Although significantly more HIV positives had some sign of intraocular inflammation compared to the negatives (p = 0.02) there was no significant linear trend in the HIV positives with decreasing CD4 count. Overall, 11 (26%) prevalent, 6 (10%) incident cases and 8 (6%) HIV-negatives controls had some evidence of intraocular inflammation, however, only one person had reduced visual acuity attributable to these lesions. Punctate epithelial erosions and keratic precipitates in the anterior chamber were seen significantly more frequently in HIV-positives compared to the HIV-negative controls. Cotton wool spots were not seen., Conclusions: A substantial proportion of HIV-infected persons had ocular findings which may have been attributable to their infection, however in only one case did this result in reduced visual acuity. Although the ocular complications of AIDS seem to comprise a large extra element in the work load of tertiary care hospitals dealing with eye problems, on a population basis such cases are infrequent.

Background: 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., Methods: 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., Findings: 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., Interpretation: 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.

Objective: To describe a population-based rural cohort of HIV-1-seropositive and seronegative individuals established in 1990 in south-west Uganda, and determine survival times in the cohort., Design: Prospective cohort study., Methods: Participants were recruited from a large population study, and invited to attend a clinic every 3 months. They were seen by clinicians who administered detailed medical questionnaires and undertook a physical examination., Results: By the end of 1995, 390 (79%) of the 491 people asked to enrol in the natural history cohort (NHC) had done so. Ninety-three were prevalent cases of HIV infection detected during the initial survey round of the general population cohort in 1989/1990, 66 were subsequent incident cases, 177 were age-matched HIV-negative controls and 54 were HIV-negative spouses of HIV-positive individuals. Twenty participants seroconverted in the NHC. The age-standardized mortality rates per 1000 person-years for the prevalent, incident, and negative cases were 156.5 [95% confidence interval (CI), 115.8-211.4], 35.0 (95% CI, 16.4 75.0) and 13.5 (95% CI, 7.3-25.1), respectively. The median survival time from enrolment to death for the prevalent cases was 4.5 years (95% CI, 3.5- > 5.2); > 5.4 years from seroconversion for the incident cases; and > 5.2 years from enrolment for the HIV-negative cases. The 5-year cumulative survival for prevalents, incidents and HIV-negative participants was 46%, 83% and 94%, respectively., Conclusions: We have described an NHC of HIV-positive and HIV-negative participants which is representative of the general population. The NHC was established over 5 years ago; it is continuing and we are maintaining good compliance rates. Survival probabilities in the cohort were lower than most other reported studies.