Alison D. Grant

Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d'Ivoire: a randomised controlled trial

BACKGROUND There is a high incidence of opportunistic infection among HIV-1-infected patients with tuberculosis in Africa and, consequently, high mortality. We assessed the safety and efficacy of trimethoprim-sulphamethoxazole 800 mg/160 mg (co-trimoxazole) prophylaxis in prevention of such infections and in decrease of morbidity and mortality. METHODS Between October, 1995, and April, 1998, we enrolled 771 HIV-1 seropositive and HIV-1 and HIV-2 dually seroreactive patients who had sputum-smear-positive pulmonary tuberculosis (median age 32 years [range 18-64], median CD4-cell count 317 cells/microL) attending Abidjans four largest outpatient tuberculosis treatment centres. Patients were randomly assigned one daily tablet of co-trimoxazole (n=386) or placebo (n=385) 1 month after the start of a standard 6-month tuberculosis regimen. We assessed adherence to study drug and tolerance monthly for 5 months and every 3 months thereafter, as well as rates of admission to hospital. FINDINGS Rates of laboratory and clinical adverse events were similar in the two groups. 51 patients in the co-trimoxazole group (13.8/100 person-years) and 86 in the placebo group (25.4/100 person-years) died (decrease In risk 46% [95% CI 23-62], p<0.001). 29 patients on co-trimoxazole (8.2/100 person-years) and 47 on placebo (15.0/100 person-years) were admitted to hospital at least once after randomisation (decrease 43% [10-64]), p=0.02). There were significantly fewer admissions for septicaemia and enteritis in the co-trimoxazole group than in the placebo group. INTERPRETATION In HIV-1-infected patients with tuberculosis, daily co-trimoxazole prophylaxis was well tolerated and significantly decreased mortality and hospital admission rates. Our findings may have important implications for improvement of clinical care for such patients in Africa.

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies.

Haileyesus Getahun and colleagues report the development of a simple, standardized tuberculosis (TB) screening rule for resource-constrained settings, to identify people living with HIV who need further investigation for TB disease.

Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa.

Objective:To assess the performance of WHO clinical and CD4 cell count criteria for antiretroviral treatment (ART) failure among HIV-infected adults in a workplace HIV care programme in South Africa. Design:Cohort study. Methods:We included initially ART-naive participants who remained on first-line therapy and had an evaluable HIV viral load result at the 12-month visit. WHO-defined clinical and CD4 cell count criteria for ART failure were compared against a gold standard of virological failure. Results:Among 324 individuals (97.5% men, median age 40.2, median starting CD4 cell count and viral load 154 cells/μl and 47 503 copies/ml, respectively), 33 (10.2%) had definite or probable virological failure at 12 months, compared with 19 (6.0%) and 40 (12.5%) with WHO-defined CD4 and clinical failure, respectively. CD4 criteria had a sensitivity of 21.2% and a specificity of 95.8% in detecting virological failure, and clinical criteria had sensitivity of 15.2% and specificity of 88.1%. The positive predictive value of CD4 and clinical criteria in detecting virological failure were 36.8 and 12.8%, respectively. Exclusion of weight loss or tuberculosis failed to improve the performance of clinical criteria. Conclusion:WHO clinical and CD4 criteria have poor sensitivity and specificity in detecting virological failure. The low specificities and positive predictive values mean that individuals with adequate virological suppression risk being incorrectly classified as having treatment failure and unnecessarily switched to second-line therapy. Virological failure should be confirmed before switching to second-line therapy.

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3–4 month isoniazid plus rifampicin; or 3–4 month rifampicin alone. Guidelines on LTBI for low TB incidence countries – essential element of the @WHO #EndTB strategy and TB elimination http://ow.ly/RW8xn

Morbidity and Mortality in South African Gold Miners: Impact of Untreated Disease Due to Human Immunodeficiency Virus

A cohort of 1792 human immunodeficiency virus (HIV)-positive and 2970 HIV-negative South African miners was observed for 12 months starting in February 1998. All-cause hospitalizations and deaths were significantly associated with HIV infection (respective unadjusted incidence rate ratios, 2.9 and 9.2; respective 95% confidence intervals, 2.5-3.4 and 5.5-16.0). Tuberculosis (TB), bacterial pneumonia, cryptococcosis, and trauma were the major causes of admission for HIV-positive patients, whereas Pneumocystis carinii pneumonia was an uncommon cause (respective admission rates, 8.5, 6.9, 2.2, 6.0, and 0.53 admissions per 100 person-years). Enteritis, bronchitis, urinary tract infections, and soft-tissue infections were also significantly associated with HIV infection. Cryptococcosis caused 44% of deaths among HIV-positive patients. Trauma was the main hazard for HIV-negative men, causing 42% of admissions and 60% of deaths. A broad range of infectious conditions is significantly associated with HIV infection in South African miners. Identification and implementation of effective prophylactic regimens are urgently needed.

Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis

Preventive therapy may increase risk for drug resistance.

That is why I stopped the ART: Patients' & providers' perspectives on barriers to and enablers of HIV treatment adherence in a South African workplace programme

BackgroundAs ART programmes in African settings expand beyond the pilot stages, adherence to treatment may become an increasing challenge. This qualitative study examines potential barriers to, and facilitators of, adherence to ART in a workplace programme in South Africa.MethodsWe conducted key informant interviews with 12 participants: six ART patients, five health service providers (HSPs) and one human resources manager.ResultsThe main reported barriers were denial of existence of HIV or of ones own positive status, use of traditional medicines, speaking a different language from the HSP, alcohol use, being away from home, perceived severity of side-effects, feeling better on treatment and long waiting times at the clinic. The key facilitators were social support, belief in the value of treatment, belief in the importance of ones own life to the survival of ones family, and the ability to fit ART into daily life schedules.ConclusionGiven the reported uncertainty about the existence of HIV disease and the use of traditional medicines while on ART, despite a programme emphasising ART counselling, there is a need to find effective ways to support adherence to ART even if the individual does not accept biomedical concepts of HIV disease or decides to use traditional medicines. Additionally, providers should identify ways to minimize barriers in communication with patients with whom they have no common language. Finally, dissatisfaction with clinical services, due to long waiting times, should be addressed.

Attitudes to HIV voluntary counselling and testing among mineworkers in South Africa: Will availability of antiretroviral therapy encourage testing?

We conducted a study to identify attitudes that influence uptake of HIV voluntary counselling and testing (VCT) amongst gold mineworkers in South Africa; 105 healthy men were interviewed. The level of basic knowledge of HIV was high, but reported awareness of the extent of HIV infection in the workforce and perceived personal risk of HIV infection was low. Health issues were considered the most important indication for HIV testing and one-third had been tested. Fear of testing positive for HIV and the potential consequences, particularly stigmatization, disease and death, were the major identified barriers to VCT. Half of the participants felt workplace education programmes needed to be improved to promote VCT access. Twenty-six per cent became more favourably inclined towards HIV testing in response to information on improvements that have been made to the confidentiality and convenience of the companys VCT service. Only 14% then indicated that they would be more likely to access VCT if antiretroviral therapy became available. A vigorous community education programme is essential if the introduction of ART is to be effective in promoting uptake of VCT.

Hepatotoxicity in an African antiretroviral therapy cohort: The effect of tuberculosis and hepatitis B

Objective:Hepatotoxicity is a significant complication of antiretroviral therapy (ART). We assessed the incidence of and risk factors for hepatotoxicity among HIV-infected individuals on ART in South Africa. Design:We conducted a retrospective cohort study in a workplace HIV care program in South Africa which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring. Methods:We included subjects with baseline and follow-up alanine transaminase and aspartate aminotransferase tests. Severe hepatotoxicity cases were identified during the first 12 months of ART. Potential risk factors, including concomitant medication use, tuberculosis, and hepatitis B and C, were determined from clinical records, database queries, and serological testing. Associations with hepatotoxicity were investigated using Cox proportional hazards modeling. Results:Of the 868 subjects (94% male, median age 41 years), the median nadir CD4 cell count was 136/μl, 25% received concomitant tuberculosis treatment during ART, and 17% of a randomly selected subset were positive for hepatitis B surface antigen (HBsAg). We identified 7.7 episodes of severe hepatotoxicity per 100 person-years. Tuberculosis treatment increased risk 8.5 fold, positive HBsAg 3.0 fold, and nadir CD4 cells count < 100/μl 1.9 fold. Importantly, the fraction of patients with severe hepatotoxicity on ART (4.6%) was similar to the fraction with liver enzyme elevations > 5 times the upper limit of normal before starting ART (4%). Conclusions:In this African ART cohort, we found a low incidence of and minimal morbidity due to hepatotoxicity. HBsAg and concomitant tuberculosis therapy significantly increased the risk of hepatotoxicity.

The natural history of HIV-1 and HIV-2 infections in adults in Africa: a literature review

About 30 million people in Africa are estimated to be living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), yet data about the natural history of infection on the continent are sparse. We reviewed the literature on the natural history of HIV-1 and HIV-2 infections among African adults. Only one study, conducted in rural Uganda, has reported on survival from the time of HIV-1 seroconversion: the median was 9.8 years, which is similar to that reported in developed countries in the early stages of the epidemic and consistent with the findings from the follow-up of individuals identified by serological testing during community-based prevalence studies from Africa. Progression to symptomatic disease was faster in Uganda than in developed countries, due largely to the high background level of morbidity. Various studies suggest that people infected with HIV-2 survive longer and the course of the disease is possibly more variable than in people infected with HIV-1. However no studies have investigated survival from time of seroconversion among people infected with HIV-2. The majority of patients in hospital in Africa with either HIV-1 or HIV-2 have the clinical features of AIDS just before they die, and many are severely immunosuppressed. This is similar to the situation in developed countries before the introduction of highly active antiretroviral therapy (HAART). Potentially preventable infections are the leading causes of death among individuals infected with HIV-1. Prophylactic regimens and better treatments could have some effect on survival, but major improvements in life expectancy will require HAART.