InterVA-4 as a public health tool for measuring HIV/AIDS mortality: a validation study from five African countries.

BACKGROUND: Reliable population-based data on HIV infection and AIDS mortality in sub-Saharan Africa are scanty, even though that is the region where most of the world's AIDS deaths occur. There is therefore a great need for reliable and valid public health tools for assessing AIDS mortality. OBJECTIVE: The aim of this article is to validate the InterVA-4 verbal autopsy (VA) interpretative model within African populations where HIV sero-status is recorded on a prospective basis, and examine the distribution of cause-specific mortality among HIV-positive and HIV-negative people. DESIGN: Data from six sites of the Alpha Network, including HIV sero-status and VA interviews, were pooled. VA data according to the 2012 WHO format were extracted, and processed using the InterVA-4 model into likely causes of death. The model was blinded to the sero-status data. Cases with known pre-mortem HIV infection status were used to determine the specificity with which InterVA-4 could attribute HIV/AIDS as a cause of death. Cause-specific mortality fractions by HIV infection status were calculated, and a person-time model was built to analyse adjusted cause-specific mortality rate ratios. RESULTS: The InterVA-4 model identified HIV/AIDS-related deaths with a specificity of 90.1% (95% CI 88.7-91.4%). Overall sensitivity could not be calculated, because HIV-positive people die from a range of causes. In a person-time model including 1,739 deaths in 1,161,688 HIV-negative person-years observed and 2,890 deaths in 75,110 HIV-positive person-years observed, the mortality ratio HIV-positive:negative was 29.0 (95% CI 27.1-31.0), after adjustment for age, sex, and study site. Cause-specific HIV-positive:negative mortality ratios for acute respiratory infections, HIV/AIDS-related deaths, meningitis, tuberculosis, and malnutrition were higher than the all-cause ratio; all causes had HIV-positive:negative mortality ratios significantly higher than unity. CONCLUSIONS: These results were generally consistent with relatively small post-mortem and hospital-based diagnosis studies in the literature. The high specificity in cause of death attribution achieved in relation to HIV status, and large differences between specific causes by HIV status, show that InterVA-4 is an effective and valid tool for assessing HIV-related mortality.

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.

HIV and mortality of mothers and children: evidence from cohort studies in Uganda, Tanzania, and Malawi.

BACKGROUND: The steady decline in child mortality observed in most African countries through the 1960s, 1970s, and 1980s has stalled in many countries in the 1990s because of the AIDS epidemic. However, the census and household survey data that generally are used to produce estimates of child mortality do not permit precise measures of the adverse effect of HIV on child mortality. METHODS: To calculate excess risks of child mortality as the result of maternal HIV status, we used pooled data from 3 longitudinal community-based studies that classified births by the mother's HIV status. We also estimated excess risks of child death caused by increased mortality among mothers. The joint effects of maternal HIV status and maternal survival were quantified using multivariate techniques in a survival analysis. RESULTS: Our analysis shows that the excess risk of death associated with having an HIV-positive mother is 2.9 (95% confidence interval = 2.3-3.6), and this effect lasts throughout childhood. The excess risk associated with a maternal death is 3.9 (2.8-5.5) in the 2-year period centered on the mother's death, with children of both infected and uninfected mothers experiencing higher mortality risks at this time. CONCLUSION: HIV impacts on child mortality directly through transmission of the virus to newborns by infected mothers and indirectly through higher child mortality rates associated with a maternal death.

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.

23-Valent pneumococcal polysaccharide vaccine in HIV-infected Ugandan adults: 6-year follow-up of a clinical trial cohort.

23-Valent pneumococcal polysaccharide vaccine was previously reported to be ineffective in HIV-infected Ugandan adults. Prolonged follow-up of trial participants confirmed persistent excess of all-cause pneumonia in vaccine recipients [hazard ratio (HR) 1.6; 95% confidence interval (CI) 1.0-2.4], but surprisingly a survival advantage favouring vaccination (HR 0.84; CI 0.7-1.0). An explanation for the improvement in survival in the face of excess morbid events is lacking; a role for vaccine in HIV care in Africa remains unlikely.

The effects of alternative study designs on the power of community randomized trials: evidence from three studies of human immunodeficiency virus prevention in East Africa.

BACKGROUND: Randomized intervention trials in which the community is the unit of randomization are increasingly being used to evaluate the impact of public health interventions. In the design of community randomized trials (CRT), the power of the study is likely to be affected by two issues: the matching or stratification of communities, and the number and size of the communities to be randomized. METHODS: Data from three East African community intervention trials, designed to evaluate the impact of interventions to reduce human immunodeficiency virus (HIV) incidence, are used to compare the efficiency of different trial designs. RESULTS: Compared with an unmatched design, stratification reduced the between-community variation in the Mwanza trial (from 0.51 to 0.24) and in the Masaka trial (from 0.38 to 0.28). The reduction was smaller in the Rakai trial where the selected communities were more homogeneous (from 0.15 to 0.11). For all trials, individual matching of communities produced estimates of between-community variation similar to those from the stratified designs. The linear association between HIV prevalence and incidence was strong in the Mwanza trial (correlation coefficient R = 0.83) and the Masaka trial (R = 0.83), but weak in the Rakai trial (R = 0.28). Unmatched study designs that use smaller communities tend to increase between-community variation, but reduce the design effect and improve study power. CONCLUSIONS: These empirical data suggest that selection of homogeneous communities, or stratification of communities prior to randomization, may improve the power of CRT.

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.

Screening for intestinal helminth infestation in a semi-urban cohort of HIV-infected people in Uganda: a combination of techniques may enhance diagnostic yield in the absence of multiple stool samples.

Intestinal helminth prevalence is best determined by using multiple stool samples from each subject, but this may be difficult in the clinic or hospital setting. We used a range of well-established parasitological techniques in a study of interactions between helminth infestation and HIV in a cohort of 412 HIV-infected people in Entebbe, Uganda. Analysis of a single stool sample underestimated helminth prevalence, especially of low-intensity infections, but a combination of Kato-Katz smear, formol-ether concentration (FEC), charcoal culture for Strongyloides and a serum enzyme-linked immunosorbent assay for Schistosoma mansoni antigen (CAA) increased diagnostic yield. Helminths were diagnosed in 23% patients by FEC alone, 35% by FEC and Kato-Katz, 39% by FEC, Kato-Katz and charcoal culture and 49% by a combination of all three tests plus CAA. Performing a range of techniques on a single sample may enhance the detection of parasites. Techniques vary in their sensitivity for different helminths so the appropriate choice of techniques depends on which parasite species are being sought.

Eosinophilia and progression to active tuberculosis in HIV-1-infected Ugandans.

It has been suggested that type 1 immune responses protect against tuberculosis (TB), while type 2 responses, such as those induced by helminths, may suppress protective responses and increase susceptibility to TB. Factors associated with progression to active TB were investigated in a cohort of HIV-1-infected Ugandan adults, a group at high risk of TB. High rates of subsequent progression to active TB were associated with eosinophil counts > or = 0.4 x 10(9)/L at enrolment. Eosinophilia at enrolment was associated with male gender, low socio-economic status, high CD4+ T cell counts, and schistosomiasis, but adjusting for these factors did not explain the association of eosinophilia with progression to active TB (adjusted rate ratio = 2.76, P = 0.004). Eosinophilia is most likely to be indicative of a type 2 immune response induced by helminth infection in this Ugandan cohort, but the mechanism of the observed association between eosinophilia and risk of TB remains to be determined.

Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda.

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.

Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults.

OBJECTIVE: 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. DESIGN: 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. METHODS: Systematic and standardized assessment of illness episodes to describe cryptococcal disease and death rates. RESULTS: 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 counts < 200 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). CONCLUSIONS: 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.

Independent effects of reported sexually transmitted infections and sexual behavior on HIV-1 prevalence among adult women, men, and teenagers in rural Uganda.

OBJECTIVE: To assess whether sexually transmitted infections (STIs) and sexual behavior are independently associated with HIV-1 among adult women, men, and teenagers in rural Uganda. DESIGN: Cross-sectional survey. METHODS: All adults (13 years and older) residing in 18 communities were invited to participate. HIV status was determined from serum samples and data collected during confidential interview. Independent effects of risk factors for HIV were estimated using adjusted odds ratios (ORs) with 95% confidence intervals (CIs) from logistic regression. RESULTS: Women reporting genital ulcers in the last 12 months were over twice as likely to be HIV positive after adjustment for sociodemographic factors and number of lifetime sexual partners (OR, 2.5; 95% CI, 1.9-3.4). Equivalent associations were stronger for men (OR, 3.2; 95% CI, 2.2-4.7) but weaker for teenagers (OR, 2.0, 95% CI, 0.5-8.7). Number of lifetime sexual partners was associated ( p <.05) with HIV status for women, men, and teenagers independently of reported genital ulcers. Teenagers reporting casual partners were over four times ( p <.001), and men reporting condom use almost twice ( p <.001), as likely to be HIV positive. Neither history of genital discharge nor other measures of sexual behavior were independently related to HIV status. CONCLUSION: Reported STIs and sexual behavior are independently associated with HIV in rural Uganda. Community-based interventions to reduce HIV should target both and should include teenagers.