Estimates of the impact of HIV infection on fertility in a rural Ugandan population cohort

Fertility rates in a population-based cohort of over 3500 women aged 15-49 years living in rural southwest Uganda are described and examined in relation to infection with HIV. Over a six-year follow-up period (1989/90 to 1995/6) the average general fertility rate was estimated as 199 births per thousand woman-years of observation (95 % confidence interval 191 to 207) with a total fertility rate of 6.2 births per woman. The overall prevalence of infection with HIV was 12 per cent and remained relatively stable during follow-up. With the exception of women aged 15-19 years, women who were not infected with HIV had higher fertility than HIV-infected women. The overall age-adjusted fertility rate in HIV-infected women was 0.74 of that of uninfected women (95% confidence interval 0.63 to 0.87, P<0.001) and this result was unaffected by additional adjustment for marital status. When combined with an overall HIV prevalence rate of 12 per cent, this corresponds to a three per cent reduction in fertility rates in the whole population. The lower fertility in HIV-positive women is unlikely to be explained by increased use of contraception, as use of modern contraceptive methods in rural Uganda is low and fewer than ten per cent of women are aware of their HIV-serostatus. More likely explanations are reduced sexual activity due to clinical symptoms associated with HIV infection or lower fertility associated with coexisting infections with other sexually transmitted diseases, such as syphilis. A reduction in fertility caused by HIV infection itself cannot be excluded. The implications of these findings for the use of antenatal clinic data to provide population estimates of HIV prevalence are discussed

The general population cohort in rural south-western Uganda: a platform for communicable and non-communicable disease studies.

The General Population Cohort (GPC) was set up in 1989 to examine trends in HIV prevalence and incidence, and their determinants in rural south-western Uganda. Recently, the research questions have included the epidemiology and genetics of communicable and non-communicable diseases (NCDs) to address the limited data on the burden and risk factors for NCDs in sub-Saharan Africa. The cohort comprises all residents (52% aged ≥13years, men and women in equal proportions) within one-half of a rural sub-county, residing in scattered houses, and largely farmers of three major ethnic groups. Data collected through annual surveys include; mapping for spatial analysis and participant location; census for individual socio-demographic and household socioeconomic status assessment; and a medical survey for health, lifestyle and biophysical and blood measurements to ascertain disease outcomes and risk factors for selected participants. This cohort offers a rich platform to investigate the interplay between communicable diseases and NCDs. There is robust infrastructure for data management, sample processing and storage, and diverse expertise in epidemiology, social and basic sciences. For any data access enquiries you may contact the director, MRC/UVRI, Uganda Research Unit on AIDS by email to [email protected] or the corresponding author

How have ART treatment programmes changed the patterns of excess mortality in people living with HIV? Estimates from four countries in East and Southern Africa

Background: Substantial falls in the mortality of people living with HIV (PLWH) have been observed since the introduction of antiretroviral therapy (ART) in sub-Saharan Africa. However, access and uptake of ART have been variable in many countries. We report the excess deaths observed in PLWH before and after the introduction of ART. We use data from five longitudinal studies in Malawi, South Africa, Tanzania, and Uganda, members of the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA). Methods: Individual data from five demographic surveillance sites that conduct HIV testing were used to estimate mortality attributable to HIV, calculated as the difference between the mortality rates in PLWH and HIV-negative people. Excess deaths in PLWH were standardized for age and sex differences and summarized over periods before and after ART became generally available. An exponential regression model was used to explore differences in the impact of ART over the different sites. Results: 127,585 adults across the five sites contributed a total of 487,242 person years. Before the introduction of ART, HIV-attributable mortality ranged from 45 to 88 deaths per 1,000 person years. Following ART availability, this reduced to 14–46 deaths per 1,000 person years. Exponential regression modeling showed a reduction of more than 50% (HR =0.43, 95% CI: 0.32–0.58), compared to the period before ART was available, in mortality at ages 15–54 across all five sites. Discussion: Excess mortality in adults living with HIV has reduced by over 50% in five communities in sub-Saharan Africa since the advent of ART. However, mortality rates in adults living with HIV are still 10 times higher than in HIV-negative people, indicating that substantial improvements can be made to reduce mortality further. This analysis shows differences in the impact across the sites, and contrasts with developed countries where mortality among PLWH on ART can be similar to that of the general population. Further research is urgently needed to establish why the different impacts on mortality were observed and how the care and treatment programmes in these countries can be more effective in reducing mortality further

Child survival in relation to mother's HIV infection and survival: evidence from a Ugandan cohort study.

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

Associations between helminth infection and CD4+ T cell count, viral load and cytokine responses in HIV-1-infected Ugandan adults.

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

A polymorphism that reduces RANTES expression is associated with protection from death in HIV-seropositive Ugandans with advanced disease.

We investigated the effect of RANTES polymorphisms on human immunodeficiency virus type 1 (HIV-1) disease progression in an urban population of Uganda. HIV-positive individuals homozygous for the INT1.1C polymorphism, which had been associated previously with low RANTES expression, were less likely to die than were those with other genotypes (hazard ratio, 0.53 [95% confidence interval, 0.33-0.83]; P=.007). This report of a non-human leukocyte antigen genetic association with HIV-1 and/or acquired immunodeficiency syndrome disease progression in an African population reveals a genetic effect different from that reported elsewhere for African Americans and may impact therapeutic strategies targeting the RANTES pathway in HIV infection

Cytokine responses and progression to active tuberculosis in HIV-1-infected Ugandans: a prospective study.

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

A randomized, double-blind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis.

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