Jessica Nakiyingi

23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial.

BACKGROUND Infection with Streptococcus pneumoniae is a frequent and serious problem for HIV-immunosuppressed adults. Vaccination is recommended in the USA and Europe, but there are no prospective data that show vaccine efficacy. METHODS 1392 (937 female) HIV-1-infected adults in Entebbe, Uganda, were enrolled. 697 received 23-valent pneumococcal polysaccharide vaccine and 695 received placebo. The primary endpoint was first event invasive pneumococcal disease. Secondary endpoints included vaccine serogroup-specific invasive disease, all (probable and definite) pneumococcal events, all-cause pneumonia, and death. FINDINGS First invasive events occurred in 25 individuals (24 bacteraemias, one pyomyositis), 15 in the vaccine arm and ten in the placebo arm (hazard ratio [HR] 1.47; 95% CI 0.7-3.3). 22 isolates (88%) were of vaccine-specific serogroups with 15 events in the vaccine arm compared with seven in the placebo arm (HR 2.10; 0.9-5.2). All pneumococcal events had a similar distribution (20 vs 14; HR 1.41; 0.7-2.8) though all-cause pneumonia was significantly more frequent in the vaccine arm (40 vs 21; HR 1.89; 1.1-3.2). Mortality was unaffected by vaccination. INTERPRETATION 23-valent pneumococcal polysaccharide vaccination is ineffective in HIV-1-infected Ugandan adults and probably has little, or no, public health value elsewhere in sub-Saharan Africa. Increased rates of pneumococcal disease in vaccine recipients may necessitate a reappraisal of this intervention in other settings.

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 × 106 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.

Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial

BACKGROUND Treatment of sexually-transmitted infections (STIs) and behavioural interventions are the main methods to prevent HIV in developing countries. We aimed to assess the effect of these interventions on incidence of HIV-1 and other sexually-transmitted infections. METHODS We randomly allocated all adults living in 18 communities in rural Uganda to receive behavioural interventions alone (group A), behavioural and STI interventions (group B), or routine government health services and community development activities (group C). The primary outcome was HIV-1 incidence. Secondary outcomes were incidence of herpes simplex virus type 2 (HSV2) and active syphilis and prevalence of gonorrhoea, chlamydia, reported genital ulcers, reported genital discharge, and markers of behavioural change. Analysis was per protocol. FINDINGS Compared with group C, the incidence rate ratio of HIV-1 was 0.94 (0.60-1.45, p=0.72) in group A and 1.00 (0.63-1.58, p=0.98) in group B, and the prevalence ratio of use of condoms with last casual partner was 1.12 (95% CI 0.99-1.25) in group A and 1.27 (1.02-1.56) in group B. Incidence of HSV2 was lower in group A than in group C (incidence rate ratio 0.65, 0.53-0.80) and incidence of active syphilis for high rapid plasma reagent test titre and prevalence of gonorrhoea were both lower in group B than in group C (active syphilis incidence rate ratio, 0.52, 0.27-0.98; gonorrhoea prevalence ratio, 0.25, 0.10-0.64). INTERPRETATION The interventions we used were insufficient to reduce HIV-1 incidence in rural Uganda, where secular changes are occurring. More effective STI and behavioural interventions need to be developed for HIV control in mature epidemics.

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.

Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults.

BackgroundFalciparum 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. ObjectiveTo investigate the effect of HIV-associated immunosuppression on malarial fever rates. DesignAn 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. MethodsCohort 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. ResultsIncidence 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 < 200, 200–499 and > 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. ConclusionThese 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.

Declining HIV-1 incidence and associated prevalence over 10 years in a rural population in south-west Uganda: a cohort study

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 31984 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, chi(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, chi(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<0.001, chi(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.

Two-year HIV-1-associated mortality in a Ugandan rural population

The mortality in 15 villages in South-West Uganda was studied in relation to HIV infection. After a population census, serum samples were tested for antibodies to HIV-1. Deaths were ascertained over 2 years. Unequivocal HIV-1 serology results were available for 9389 individuals. The prevalence of infection was 4.8% for all ages and 8.2% for adults (aged 13 or more). 198 deaths were recorded during 15,725 person years of observation. Mortality among seronegative adults was 7.7 per 1000 and among seropositive adults 115.9 per 1000. The excess annual death rate associated with HIV-1 infection was 5.3 per 1000 and in adults 7.9 per 1000. Highest excess mortality was 16.9 per 1000 in the age group 25-34. Among adults, half of all deaths and among those aged 13-44 over 80% of deaths were attributable to HIV-1 infection. These results show the strong impact that HIV-1 infection is having on mortality in a rural area of Uganda where the overall HIV-1 adult prevalence rate is below 10%--a rate lower than in many other parts of East Africa.

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 mothers 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 mothers 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.

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.

Adjusting ante-natal clinic data for improved estimates of HIV prevalence among women in sub-Saharan Africa.

ObjectivesTo find a simple and robust method for adjusting ante-natal clinic data on HIV prevalence to represent prevalence in the general female population in the same age range, allowing for fertility differences by HIV status. BackgroundHIV prevalence comparisons for pregnant women and women in the general community show that prevalence in the latter is significantly higher than in the former. An adjustment procedure is needed that is specific for the demographic and epidemiological circumstances of a particular population, making maximum use of data that can easily be collected in ante-natal clinics or are widely available from secondary sources. MethodsBirth interval length data are used to allow for subfertility among HIV-positive women. To allow for infertility, relative HIV prevalence ratios for fertile and infertile women obtained in community surveys in populations with similar levels of contraception use are applied to demographic survey data that describe the structure of the population not at risk of child-bearing. ResultsFor populations with low contraception use, the procedure yields estimates of general female HIV prevalence of 35–65% higher than the observed ante-natal prevalence, depending on population structure. Results were verified using general population prevalence data collected in Kisesa (Tanzania) and Masaka (Uganda). For high contraception use populations, adjusted values range from 15% higher to 5% lower, but only limited verification has been possible so far. ConclusionsThe procedure is suitable for estimating general female HIV prevalence in low contraception use populations, but the high contraception variant needs further testing before it can be applied widely.