Using verbal autopsy to assess the prevalence of HIV infection among deaths in the ART period in rural Uganda: a prospective cohort study, 2006-2008

<p>Abstract</p> <p>Background</p> <p>Verbal autopsy is important for detecting causes of death including HIV in areas with inadequate vital registration systems. Before antiretroviral therapy (ART) introduction, a verbal autopsy study in rural Uganda found that half of adult deaths assessed were in HIV-positive individuals. We used verbal autopsy to compare the proportion of HIV-positive adult deaths in the periods before and after ART introduction.</p> <p>Methods</p> <p>Between 2006 and 2008, all adult (≥ 13 years) deaths in a prospective population-based cohort study were identified by monthly death registration, and HIV serostatus was determined through annual serosurveys. A clinical officer interviewed a relative of the deceased using a verbal autopsy questionnaire. Two clinicians independently reviewed the questionnaires and classified the deaths as HIV-positive or not. A third clinician was the tie-breaker in case of nonagreement. The performance of the verbal autopsy tool was assessed using HIV serostatus as the gold standard of comparison. We compared the proportions of HIV-positive deaths as assessed by verbal autopsy in the early 1990s and the 2006-2008 periods.</p> <p>Results</p> <p>Of 333 deaths among 12,641 adults of known HIV serostatus, 264 (79.3%) were assessed by verbal autopsy, of whom 59 (22.3%) were HIV-seropositive and 68 (25.8%) were classified as HIV-positive by verbal autopsy. Verbal autopsy had a specificity of 90.2% and positive predictive value of 70.6% for identifying deaths among HIV-infected individuals, with substantial interobserver agreement (80.3%; kappa statistic = 0.69). The HIV-attributable mortality fraction estimated by verbal autopsy decreased from 47.0% (pre-ART period) to 25.8% (ART period), p < 0.001.</p> <p>Conclusions</p> <p>In resource-limited settings, verbal autopsy can provide a good estimate of the prevalence of HIV infection among adult deaths. In this rural population, the proportion of deaths identified by verbal autopsy as HIV-positive declined between the early 1990s and the 2006-2008 period. Verbal autopsy findings can inform policy on HIV health care needs.</p

Effect of HIV-1 subtypes on disease progression in rural Uganda: a prospective clinical cohort study.

OBJECTIVE: We examined the association of HIV-1 subtypes with disease progression based on three viral gene regions. DESIGN: A prospective HIV-1 clinical cohort study in rural Uganda. METHODS: Partial gag, env and pol genes were sequenced. Cox proportional hazard regression modelling was used to estimate adjusted hazard ratios (aHRs) of progression to: CD4≤250, AIDS onset and death, adjusted for sex, age and CD4 count at enrolment. RESULTS: Between 1990 and 2010, 292 incident cases were subtyped: 25% had subtype A, 45% had D, 26% had A/D recombinants, 1% had C and 4% were other recombinant forms. Of the 278 incident cases included in the disease progression analysis, 62% progressed to CD4≤250, 32% to AIDS, and 34% died with a higher proportion being among subtype D cases. The proportions of individuals progressing to the three endpoints were significantly higher among individuals infected with subtype D. Throughout the study period, individuals infected with subtype D progressed faster to CD4≤250, adjusted HR (aHR), (95% CI) = 1.72 (1.16-2.54), but this was mainly due to events in the period before antiretroviral therapy (ART) introduction, when individuals infected with subtype D significantly progressed faster to CD4≤250 than subtype A cases; aHR (95% CI) = 1.78 (1.01-3.14). CONCLUSIONS: In this population, HIV-1 subtype D was the most prevalent and was associated with faster HIV-1 disease progression than subtype A. Further studies are needed to examine the effect of HIV-1 subtypes on disease progression in the ART period and their effect on the virological and immunological ART outcomes

HIV-1 seroprevalence and risk factors for HIV infection among first-time psychiatric admissions in Uganda.

This study investigated HIV seroprevalence and it's correlates among patients with first-time psychiatric admissions to two national referral hospitals in urban Kampala, Uganda. A structured standardised evaluation was used to assess patients for: Diagnostic and Statistical Manual IV psychiatric diagnosis, socio-demographics, sexual behaviour and HIV status (for those HIV-positive, CDC classification and CD4 cell counts). The HIV-1 seroprevalence was 18.4% (95% CI, 13.8-23.0%). Factors that were independently associated with HIV-1 seropositivity were female gender and older age (41+years) and after adjusting for sex and age group, the nature of the current episode (highest among those with first episode of mental illness) and psychiatric diagnoses (highest in the organic affective disorders and delirium, lowest in those with bipolar affective disorder and psychotic syndromes). These results demonstrate that the prevalence of HIV is high among patients with severe mental illness in Africa and that HIV/AIDS adds to the burden of mental illness in high HIV prevalence countries in sub-Saharan Africa. Both HIV care programmes and psychiatric care clinics should be made aware of the frequent association of HIV infection and mental illness, and adopt important diagnostic and care elements of these complementary disciplines in the training and the day-to-day work of clinicians, nurses and counsellors

Effect of pregnancy on HIV disease progression and survival among women in rural Uganda.

OBJECTIVE: To investigate the effect of pregnancy on HIV disease progression and survival among HIV-infected women in rural Uganda, prior to the introduction of anti-retroviral therapy (ART). METHODS: From a clinical cohort established in 1990, we selected records from HIV-infected women of reproductive age. We conducted two analyses: (1) all HIV-infected cases contributing to analysis of CD4 decline, using a linear regression model with random intercepts and slopes; (b) incident cases with known date of seroconversion contributed to analyses of median time to CD4 <200 cells/microl, AIDS and death. RESULTS: A total of 139 women were included in the analysis of CD4 decline. Women who subsequently became pregnant had higher CD4 counts at enrolment and had a slower CD4 decline than those who did not become pregnant. In women who became pregnant, CD4 decline was faster after pregnancy than before (P < 0.0001). The survival analyses showed no significant differences between women who became pregnant and those who did not with respect to median time to CD4 count <200, AIDS or death. CONCLUSIONS: The initial comparative immunological advantage possessed by fertile women before they become pregnant is subsequently lost as a result of their pregnancy. Women should be informed about the potential negative effect of pregnancy on their immunological status and should be offered contraception. In resource-limited settings, women determined to become pregnant should be given priority for ART if eligible

HIV-1 disease progression and fertility: the incidence of recognized pregnancy and pregnancy outcome in Uganda.

OBJECTIVES: To estimate the association between HIV disease progression and the incidence of recognized pregnancy; to estimate the risk of subsequent fetal loss. METHODS: A total of 191 women (92 HIV seropositive and 99 HIV seronegative at enrolment) aged 15-49 years in an HIV clinical cohort were invited to attend routine clinic visits every 3 months. Information on HIV progression collected at the visit was related to whether there was a pregnancy beginning in the following 3 months. Visits were excluded where the woman was already pregnant, lactating, using modern contraceptives or if there was inadequate follow-up. RESULTS: There were 2524 eligible visits and 216 recognized pregnancies. The reported frequency of sexual intercourse diminished with advancing HIV disease. The adjusted odds ratio (OR) for pregnancy when the woman was in WHO stage 1 compared with HIV seronegatives was 0.58 [95% confidence interval (CI), 0.36-0.93]; stage 2, 0.47 (95% CI, 0.25-0.91); stage 3, 0.43 (95% CI, 0.25-0.74); and stage 4, (AIDS) 0.14 (95% CI, 0.02-1.09). The findings were similar for CD4 cell count, time from seroconversion and time before AIDS. There was an increase in fetal loss from the early stages of HIV infection (adjusted OR for stage 1, 5.38; 95% CI, 1.57-18.44), there were very few recognized pregnancies in the advanced stages. CONCLUSIONS: Fertility is reduced from the earliest asymptomatic stage of HIV infection resulting from both a reduced incidence of recognized pregnancy and increased fetal loss. The greatest reduction in fertility was observed following progression to AIDS when there was a very low incidence of recognized pregnancies

Genotypic variation in the pol gene of HIV type 1 in an antiretroviral treatment-naive population in rural southwestern Uganda.

The majority of studies of HIV-1 drug resistance have involved subtype B viruses. Here we have characterized subtype distribution and determined the levels of polymorphism at protease (PR) and reverse transcriptase (RT) drug resistance positions, in antiretroviral treatment-naive HIV-positive Ugandan patients. We have also investigated codon usage variability at these positions and assessed intersubtype recombination within the pol gene. The study population consisted of 187 patients, from a cohort established by the UK Medical Research Council Programme on AIDS in Uganda in 1990. Results indicate that 28.3% of patients were infected with subtype A (n = 53), 64.2% subtype D (n = 120), 6.4% A/D recombinant (n = 12), and 1.1% subtype C (n = 2). Variation in amino acid usage at drug resistance-associated positions was minimal between the two main subtypes (A and D) in RT, but there was appreciable variation in PR. Codon usage, however, was considerably more variable between subtypes A and D in both PR and RT. Thus, while no natural high-level resistance to antiretroviral therapy was detected in this cohort, subtypes A and D may possess different genetic barriers to be overcome in order to achieve resistance. With the increasing introduction of antiretroviral therapy into Africa, such information will be vital in our understanding and evaluation of the development of drug resistance as it occurs, and how to interpret resistance data the type of which has rarely previously been seen. This analysis also significantly increases the number of Ugandan PR and RT sequences characterized to date

Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A and D infected Ugandans.

BACKGROUND: The use of cellular coreceptors and modulation of cytokine concentrations by HIV to establish a productive infection is well documented. However, it is unknown whether the expression of these proteins affects the course of HIV clade A and D disease, reported to have different progression rates. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether the number of CD4(+) T-cells expressing CCR5 or CXCR4, the density of these coreceptors and concentrations of specific immune proteins linked to HIV pathogenesis vary between individuals infected with HIV clade A or D. We undertook additional analyses stratifying participants by early (CD4>500 cells/µl) or late (CD4<200 cells/µl) disease stage. Whole blood samples were taken from 50 HIV-1 infected individuals drawn from cohorts in rural south-west Uganda. Late stage participants had less than half the number of CD4(+)/CCR5(+) T-cells (p = 0.0113) and 5.6 times fewer CD4(+)/CXCR4(+) cells (p<0.0001) than early stage participants. There was also a statistically significant difference in the density of CXCR4 on CD4(+) cells between clade A and D infected early stage participants (142 [A] vs 84 [D]; p = 0.0146). Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001). Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants. MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed. CONCLUSIONS/SIGNIFICANCE: We observed specific alterations in the abundance of CD4(+)/CCR5(+) and CD4(+)/CXCR4(+) T-cells, and concentrations of immune proteins across different HIV clades and as infection progresses. Our results suggest that these changes are unlikely to explain the observed differences in disease progression between subtype A and D infections. However, our observations further the understanding of the natural progression of non-clade B HIV infection and how the virus adapts to exploit the host environment

HIV-1 disease progression and mortality before the introduction of highly active antiretroviral therapy in rural Uganda.

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