6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. METHODS: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per µL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. FINDINGS: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups. INTERPRETATION: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. FUNDING: US Centers for Disease Control and Prevention and US Agency for International Development.

Influences on place of death in Botswana.

OBJECTIVE: There is an emerging body of research aimed at understanding the determinants of place of death, as where people die may influence the quality of their death. However, little is known about place of death for people of Southern Africa. This study describes place of death (home or hospital) and potential influencing factors (cause of death, age, gender, occupation, and district of residence). METHOD: We collected the death records for years 2005 and 2006 for all adult non-traumatic deaths that occurred in Botswana, described them, and looked for associations using bivariate and multivariate analyses. RESULTS: The evaluable sample consisted of 18,869 death records. Home deaths accounted for 36% of all deaths, and were predominantly listed with "unknown" cause (82.3%). Causes of death for hospital deaths were HIV/AIDS (49.7%), cardiovascular disease (13.8%), and cancer (6.6%). The mean age at the time of all deaths was 53.2 years (SD = 20.9); with 61 years (SD = 22.5) for home deaths and 48.8 years (SD = 18.6) for hospital deaths (p < .001). Logistic regression analysis revealed the following independent predictors of dying at home: unknown cause of death; female gender; >80 years of age; and residing in a city or rural area (p < .05). SIGNIFICANCE OF RESULTS: A major limitation of this study was documentation of cause of death; the majority of people who died at home were listed with an unknown cause of death. This finding impeded the ability of the study to determine whether cause of death influenced dying at home. Future study is needed to determine whether verbal autopsies would increase death-certificate listings of causes of home deaths. These data would help direct end-of-life care for patients in the home.

Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4(+) cell counts in Gaborone, Botswana.

BACKGROUND: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy. METHODS: From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana. RESULTS: We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4(+) cell counts, of whom 62 (16%) had a CD4(+) cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy. CONCLUSIONS: We observed low rates of CD4(+) cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4(+) cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.

Two and a half years of routine HIV testing in Botswana.

BACKGROUND: Botswana was the first African country to introduce routine HIV testing (RHT). OBJECTIVE: To report program data for the first 2.5 years of RHT. METHODS: RHT was introduced in 2004. Rapid HIV tests were introduced later the same year and are widely available. The main criteria for RHT are symptoms of HIV/AIDS, pregnancy, sexually transmitted infection, and attendance for medical examination. Testing may also be self-initiated. FINDINGS: There has been a rapid scale-up of RHT. A total of 60,846 persons were tested through RHT in 2004 versus 157,894 in 2005 and 88,218 in the first half of 2006. Testing rates in the population through RHT were 40 per 1000 persons, 93 per 1000 persons, and 104 per 1000 persons, respectively. In 2005, 89% of those offered testing accepted, with 69% of those tested being female and 31% male. The proportion of men who tested HIV-positive was 34% versus 30% for women. The main reasons for testing in 2005 were patient's wish (50%), pregnancy (25%), medical examination (7%), clinical suspicion (6%), and sexually transmitted infection (2%). Attendance at voluntary counseling and testing centers has increased parallel to the scale-up of RHT. CONCLUSIONS: RHT has been widely accepted by the population, and no adverse effects or instances have been reported. It has provided increased access to preventive services and earlier assessment for antiretroviral treatment. We believe the benefits of RHT clearly outweigh the risks.

Changes in the etiology of sexually transmitted diseases in Botswana between 1993 and 2002: implications for the clinical management of genital ulcer disease.

BACKGROUND: In recent years, increasing evidence has accumulated that suggests the majority of cases of genital ulcer disease in sub-Saharan Africa are due to viral and not bacterial infections. Although many cross-sectional studies support such a trend, few serial cross-sectional data are available to show the evolution of genital ulcer disease over time. METHODS: We surveyed the prevalence of sexually transmitted diseases (STDs) among patients with STD symptoms and women recruited from family planning clinics in 3 cities in Botswana in 2002 and compared our findings with those from a survey of a similar population conducted in 1993. RESULTS: The observed proportion of cases of genital ulcer disease due to chancroid decreased from 25% in 1993 to 1% in 2002, whereas the proportion of ulcers due to herpes simplex virus increased from 23% in 1993 to 58% in 2002. Although the proportion of ulcers due to syphilis was similar for both surveys, the rate of positive serologic test results for syphilis among patients with genital ulcer disease decreased from 52% in 1993 to 5% in 2002. During this period, decreases in the prevalence of gonorrhea, syphilis-reactive serologic findings, chlamydial infection, and trichomoniasis were also detected among patients with STDs and women from family planning clinics. These changes remained significant after estimates were adjusted for the sensitivity and specificity of diagnostic tests. CONCLUSIONS: Our findings suggest a decrease in the prevalence of bacterial STDs and trichomoniasis, a reduction in the proportion of ulcers due to bacterial causes, and an increase in the proportion of ulcers due to herpes simplex virus during the period 1993-2002. These changes should be taken into consideration when defining new guidelines for the syndromic management of genital ulcer disease.

Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana.

BACKGROUND: We conducted a pharmacokinetic study of antimycobacterial drugs involving a cohort of patients with pulmonary tuberculosis (TB) in Gaborone, Botswana, to assess the prevalence of and risk factors for low drug concentrations in serum. METHODS: Adults participated if they had a history of cough > or =2 weeks, had abnormal chest radiograph findings, consented to testing for human immunodeficiency virus (HIV), had sputum cultures positive for Mycobacterium tuberculosis, and were receiving antituberculous therapy for >7 days. Observed maximum serum concentrations were compared with published normal ranges. RESULTS. Of 91 patients enrolled, 89 (98%) were outpatients, and 59 (68%) of 87 patients tested had HIV infection. The following numbers of patients had low serum concentrations of the following drugs: isoniazid, 27 (30%) of 90; rifampin, 71 (78%) of 91; ethambutol, 37 (41%) of 91; and pyrazinamide, 1 (1%) of 91. Low serum concentrations of both isoniazid and rifampin occurred in 23 (26%) of 90 patients. Low serum concentrations of rifampin were found in both HIV-infected and non-HIV-infected patients, and such patients were less likely to have >4 weeks of symptoms, more likely to have lymphadenopathy, and more likely to have low serum albumin levels (P<.05 for all). The associations with noncavitary pulmonary disease (P=.12) and HIV infection (P=.07) did not reach statistical significance. Delayed absorption was most common with ethambutol, followed by rifampin. CONCLUSIONS: These data, predominantly from HIV-infected patients with TB, suggest that low isoniazid, rifampin, and ethambutol concentrations are common in Botswana. In contrast, pyrazinamide usually is well absorbed.

Tuberculosis serodiagnosis in a predominantly HIV-infected population of hospitalized patients with cough, Botswana, 2002.

A sensitive and accurate tuberculosis (TB) serodiagnostic test would aid in the control of TB, but results of current tests are relatively unreliable for persons infected with human immunodeficiency virus (HIV). We evaluated a new prototype immunochromatographic strip test and 5 commercially available serodiagnostic TB tests in a prospective study comprised of 465 consecutively enrolled patients with suspected TB from 2 hospitals in Botswana. Consenting adults underwent HIV testing, >/=2 sputum smears and cultures, and mycobacterial blood culture. Patients were defined as having TB on the basis of any positive smear or culture. Between January and September 2002, 465 of 498 consecutive patients consented to enrollment. A total of 384 patients (83%) were infected with HIV, and 175 (38%) had TB; the mycobacterial blood culture was the sole source of diagnosis for 26 patients (15%) with TB. Among the tests evaluated, the sensitivity was 0%-63%, the specificity was 39%-99%, the positive predictive value was 0%-39%, and the negative predictive value was 63%-65%. We conclude that the serodiagnostic tests evaluated in this study lacked sufficient sensitivity as sole tests for TB in this population.