Maria A. Quigley

Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study.

BACKGROUNDnAn 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.nnnMETHODSnHIV-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.nnnFINDINGSn484 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).nnnINTERPRETATIONnHIV-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.

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

BACKGROUNDnTreatment 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.nnnMETHODSnWe 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.nnnFINDINGSnCompared 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).nnnINTERPRETATIONnThe 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.

Twice weekly tuberculosis preventive therapy in HIV infection in Zambia.

Background:A randomized double-blind placebo-controlled trial was conducted to estimate the efficacy of preventive therapy for tuberculosis (TB) in HIV-infected adults in Lusaka, Zambia. The main outcome measures were the incidence of TB, mortality and adverse drug reactions. Methods:During a 2 year period, 1053 HIV-positive individuals without evidence of clinical TB were randomly assigned to receive 6 months of isoniazid twice a week (H), or 3 months of rifampicin twice a week (R) plus pyrazinamide (Z), or a placebo. Therapy was taken twice a week and was self administered. Subjects presenting with symptoms during the follow-up period were investigated for TB. Results:The 1053 subjects in the study were followed up for a total of 1631 person-years (median = 1.8 years). Twenty-nine subjects were taken off treatment as a result of adverse drug reactions. A total of 96 cases of TB/probable TB (59 TB and 37 probable TB) were diagnosed during the study period and 185 deaths were reported. One hundred and fifteen subjects (11%) did not return to the study clinic at any time after enrolment. The incidence of TB was lower in those subjects on preventive therapy (H and RZ groups combined) compared with those on placebo (rate ratio = 0.60, 95% CI: 0.36–1.01, P = 0.057), as was the incidence of TB/probable TB (rate ratio = 0.60, 95% CI: 0.40–0.89, P = 0.013). The effect of preventive therapy was greater in those with a tuberculin skin test (TST) of 5 mm or greater, in those with a lymphocyte count of 2 × 109/l or higher, and in those with haemoglobin of 10 g/dl or higher. There was no difference in mortality rates between the preventive therapy and placebo groups. The effect of preventive therapy declined after the first year of the study so that by 18 months the rates of TB in the treated groups were similar to that in the placebo group. Conclusion:This study has demonstrated that preventive therapy with either twice weekly isoniazid for 6 months or a combination of rifampicin and pyrazinamide for 3 months reduced the incidence of TB in HIV-infected persons in Zambia. No effect was observed on mortality. The effect was greatest in persons who had a positive TST or a lymphocyte count of 2 × 109/l or greater, indicating that preventive therapy may be more effective in people with less advanced immunosuppression. The limited duration of the protective effect reported in this study raises the question of the need for lifelong preventive therapy or re-prophylaxis.

Helminth Infection Is Not Associated with Faster Progression of HIV Disease in Coinfected Adults in Uganda

BACKGROUNDnWe studied a cohort of human immunodeficiency virus (HIV)-infected adults in Uganda who were not receiving antiretroviral therapy, to explore the impact of helminths on HIV progression in areas where antiretrovirals are not available.nnnMETHODSnA total of 663 patients were screened for helminths, treated presumptively with albendazole and selectively with praziquantel, and monitored for 6 months. Blood samples were analyzed for CD4+ cell count and HIV-1 RNA.nnnRESULTSnSchistosoma mansoni, hookworm, Strongyloides stercoralis, and Mansonella perstans were the most prevalent helminths. Helminth infection was not associated with higher viral load, lower CD4+ cell count, or faster decrease in CD4+ cell count preceding antihelminthic therapy. The effect of coinfection on HIV disease progression varied with species. CD4+ cell counts were highest in subjects with hookworm and Mansonella perstans infection. For most helminths, effective treatment was associated with greater decrease in CD4+ cell count than in those in whom infection was still present at follow-up. A highly significant decrease in viral load at 6 months was seen in patients with persistent Mansonella perstans infection at follow-up. Mortality was lower in subjects with hookworm infection at enrollment.nnnCONCLUSIONnHelminth infection was not associated with more-advanced HIV disease or faster disease progression. Antihelminthic therapy may not be beneficial in slowing HIV progression in coinfected adults.

A Randomized, Double-Blind, Placebo-Controlled Trial of the Use of Prednisolone as an Adjunct to Treatment in HIV-1—Associated Pleural Tuberculosis

BACKGROUNDnActive 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.nnnMETHODSnWe 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.nnnRESULTSnOf 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]).nnnCONCLUSIONSnIn 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.

The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447]

Background Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects “spill-over”, altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life. Purpose To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood. Methods The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 × 2(×2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed. Conclusion This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy.

The risk of enteric infections associated with wastewater reuse: the effect of season and degree of storage of wastewater.

The effect of season and wastewater storage on the risk of Ascaris lumbricoides infection and diarrhoeal disease associated with wastewater reuse was studied in Mexico in 1991. Data were collected from 10,489 individuals during a dry-season survey. Exposure was to untreated wastewater, or effluent from 1 reservoir (< or = 1 nematode egg/L), or no wastewater irrigation (control group). The results were compared with a previous rainy-season survey which included effluent from 2 reservoirs in series. Direct exposure to untreated wastewater was associated with an excess risk of A. lumbricoides infection in children aged < 5 years (OR = 18.0) and persons aged > 5 years (OR = 13.5) and an increased risk of diarrhoea, particularly to children aged < 5 years (OR = 1.75); effects were stronger in the dry than in the rainy season. There was also an excess risk associated with the 1-reservoir group for A. lumbricoides infection (OR = 21.2 and 9.4) and for diarrhoeal disease (OR = 1.1 and 1.5) but little excess associated with the 2-reservoirs group. Therefore, wastewater retention in 1 reservoir (quality 10(5) faecal coliforms/100 mL, < or = 1 egg/L) does not significantly reduce risks of Ascaris infection and diarrhoeal disease whereas retention in 2 reservoirs in series (quality 10(3) faecal coliforms/100 mL, no detectable eggs/L) does.

Validity of data-derived algorithms for ascertaining causes of adult death in two African sites using verbal autopsy.

Summary backgroundu2002u2002Verbal autopsy (VA) is used to ascertain causes of death using information obtained from bereaved relatives. Causes of death can be ascertained from VA questionnaires by a panel of physicians or from predefined algorithms. In a previous study, we developed data‐derived algorithms using VA data from 796 adult deaths in hospitals in Tanzania, Ethiopia, and Ghana (primary sites). These computerized algorithms accurately estimated the cause‐specific mortality fractions (CSMFs) for deaths due to injuries, meningitis, TB/AIDS and diarrhoeal diseases in the primary sites. Since the same data were used to generate and to validate the algorithms, the accuracy of our algorithms may have been overestimated. We report here on the validity of the algorithms when they were applied to VA data from two secondary sites in Ghana and Tanzania. Here, ‘validity’ is taken to mean the degree to which the algorithms replicated the physician‐generated CSMF for major causes of death, when applied to the same VA data.

Association between HIV and subpreputial penile wetness in uncircumcised men in South Africa.

Objectives: To describe the prevalence and characteristics of subpreputial penile wetness and to investigate the association between current levels of penile wetness and HIV infection. Methods: Male attenders at a sexually transmitted infections clinic in Durban, South Africa were enrolled and treated for their presenting sexually transmitted infection complaint. They were asked to return after 14 days when a structured questionnaire was administered, and the degree of wetness of the glans penis and coronal sulcus was assessed clinically. Results: Six hundred and fifty men were enrolled, and 488 (75%) returned. Three hundred eighty-six uncircumcised men were included for statistical analysis of whom 215 (56%) were HIV positive. One hundred ninety-six (50.8%) had no penile wetness, and 190 (49.2%) had penile wetness. In the adjusted analysis, penile wetness was associated with younger age, low level of attained education, low income, higher lifetime numbers of sexual partners, and not washing after sex. The prevalence of HIV was greater in those with penile wetness 126 of 190 (66.3%) compared with 90 of 196 (45.9%) with no penile wetness, crude prevalence odds ratio 2.32 (95% confidence interval [CI], 1.54-3.50, P = < 0.001), crude prevalence relative risk 1.44 (95% CI, 1.23-1.63, P = < 0.001), and adjusted for predictors of HIV, confounders and herpes type 2 antibodies, odds ratio 2.38 (95% CI, 1.42-3.97, P = < 0.001), and relative risk 1.46 (95% CI, 1.19-1.68, P = < 0.001). Conclusions: This is the first study to show an association between subpreputial penile wetness and HIV. Consideration should be given to providing advice about improving penile hygiene in uncircumcised men in areas where HIV is a significant problem. Good penile hygiene should also be promoted at the community level to become a desirable social norm.

Patterns of sexual behaviour in a rural population in north-western Tanzania

The HIV epidemic in sub-Saharan Africa has been characterised by the predominance of heterosexual transmission. Patterns of sexual behaviour have been implicated in the spread of the epidemic, but few quantitative data are available on sexual behaviour in rural populations in Africa. This paper reports data from a survey of 1117 adults aged 15-54 years selected randomly from twelve rural communities in Mwanza Region, Tanzania. Sexual debut occurred early, 50% of women and 46% of men reporting first sex before age 16. On average, women married 1.8 years and men 6.1 years after their sexual debut. In women, age at sexual debut appears to have increased over time, in parallel with an increase in age at first marriage. Men were generally married later, to women around five to ten years younger than themselves. Marital dissolution and remarriage were common in both sexes. Reported numbers of sexual partners were compared with those recorded in a population survey in Britain. More men reported 10 or more lifetime partners, or three or more partners in the past year, in rural Mwanza (48% and 29%) than in Britain (24% and 6%). Women reported fewer partners, and results were broadly similar to British data. Casual sex during the past year was reported by 53% of the men and 15% of the women, but only 2% of men reported sexual contact with bar girls or commercial sex workers. Only 20% of men and 3% of women had ever used a condom. Interventions are needed to reduce the high levels of sexual partner change and casual sex, and low levels of condom use, recorded in this rural population. Targeting of interventions to traditional core groups may be of limited value in rural areas, and additional strategies are needed, focusing particularly on teenagers who are at high risk of HIV and other sexually transmitted diseases.