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.

Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana.

BACKGROUND: We explored the association between antituberculosis drug pharmacokinetics and treatment outcomes among patients with pulmonary tuberculosis in Botswana. METHODS: Consenting outpatients with tuberculosis had blood samples collected 1, 2, and 6 h after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (C(max)) and areas under the serum concentration time curve were determined. Clinical status was monitored throughout treatment. RESULTS: Of the 225 participants, 36 (16%) experienced poor treatment outcome (treatment failure or death); 155 (69%) were infected with human immunodeficiency virus (HIV). Compared with published standards, low isoniazid C(max) occurred in 84 patients (37%), low rifampin C(max) in 188 (84%), low ethambutol C(max) in 87 (39%), and low pyrazinamide C(max) in 11 (5%). Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count category. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide C(max) was associated with a higher risk of documented poor treatment outcome, compared with normal C(max) (50% vs. 16%; P < .01). HIV-infected patients with a CD4 cell count <200 cells/microL had a higher risk of poor treatment outcome (27%) than did HIV-uninfected patients (11%) or HIV-infected patients with a CD4 cell count 200 cells/microL (12%; P = .01). After adjustment for HIV infection and CD4 cell count, patients with low pyrazinamide C(max) were 3 times more likely than patients with normal pyrazinamide C(max) to have poor outcomes (adjusted risk ratio, 3.38; 95% confidence interval, 1.84-6.22). CONCLUSIONS: Lower than expected antituberculosis drug C(max) occurred frequently, and low pyrazinamide C(max) was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve tuberculosis cure rates.

Community attitudes on tuberculosis in Botswana: an opportunity for improving the National Tuberculosis Programme outcomes, 2011.

OBJECTIVES: The Botswana tuberculosis HIV Knowledge Attitude and Practice study sought to assess knowledge, attitudes and practices of communities on TB and identify sources of their information on this disease and HIV. Specific objectives of the study were to: (a) collect baseline information on the knowledge, attitudes, and practices about tuberculosis treatment seeking and adherence behaviors in Botswana. (b) Identify barriers which discourage people who may have smear positive tuberculosis from testing and getting treatment (e.g. social stigma) and constraints which prevent them from initiating and completing treatment. RESULTS: Approximately 92% of respondents (n = 2029), reported that having TB was not something embarrassing, while about 97% (n = 2030) were not ashamed of having a family member with TB. Approximately 95% (n = 2030) expressed willingness to accommodate their relatives with TB at their homes or, work with TB patients (n = 2026). About 21% of the respondents however, believed in myths that TB infection is a result of either having sex with women who had miscarried (n = 2028), or food poisoning (n = 2031) while about 17% believed that TB infection is a result of sleeping with a widow or widower (n = 2031).

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

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.

HIV risk factors among patients with tuberculosis--Botswana 1999.

To identify factors associated with HIV in Botswana, a standardized questionnaire was administered to 135 tuberculosis patients with known HIV status. HIV-positive patients were more likely than HIV-negative patients to: be female (45% vs 26% (adjusted prevalence odds ratio (aPOR)=3.8, 95% confidence interval (CI)=1.1-12.7)); be 26-35 years old (50% vs 19% (aPOR=2.7, CI=0.7-10.7)); be unmarried (91% vs 71% (aPOR=13.3, CI=2.5-72.7)); have higher income (24% vs 10% (aPOR=8.2, CI=1.6-42.9)); report separation from spouse/partner for work (63% vs 52% (aPOR=1.8, CI=0.5-6.2)); have 2 sex partners other than their regular partner (82% vs 67% (aPOR=1.8, CI=0.5-7.5)); and state that they or their partner drank alcohol before sex (77% vs 55% (aPOR=6.8, CI=1.9-24.1)). Only 22% of respondents used condoms during all of their past 10 sexual encounters. These data provide information for HIV prevention strategies.

Outcomes of the Botswana national HIV/AIDS treatment programme from 2002 to 2010: a longitudinal analysis.

BACKGROUND: Short-term mortality rates among patients with HIV receiving antiretroviral therapy (ART) in sub-Saharan Africa are higher than those recorded in high-income countries, but systematic long-term comparisons have not been made because of the scarcity of available data. We analysed the effect of the implementation of Botswana's national ART programme, known as Masa, from 2002 to 2010. METHODS: The Masa programme started on Jan 21, 2002. Patients who were eligible for ART according to national guidelines had their data collected prospectively through a clinical information system developed by the Botswana Ministry of Health. A dataset of all available electronic records for adults (≥18 years) who had enrolled by April 30, 2010, was extracted and sent to the study team. All data were anonymised before analysis. The primary outcome was mortality. To assess the effect of loss to follow-up, we did a series of sensitivity analyses assuming varying proportions of the population lost to follow-up to be dead. FINDINGS: We analysed the records of 126,263 patients, of whom 102,713 had documented initiation of ART. Median follow-up time was 35 months (IQR 14-56), with a median of eight follow-up visits (4-14). 15,270 patients were deemed lost to follow-up by the end of the study. 63% (78,866) of the study population were women; median age at baseline was 34 years for women (IQR 29-41) and 38 years for men (33-45). 10,230 (8%) deaths were documented during the 9 years of the study. Mortality was highest during the first 3 months after treatment initiation at 12·8 deaths per 100 person-years (95% CI 12·4-13·2), but decreased to 1·16 deaths per 100 person-years (1·12-1·2) in the second year of treatment, and to 0·15 deaths per 100 person-years (0·09-0·25) over the next 7 years of follow-up. In each calendar year after the start of the Masa programme in 2002, average CD4 cell counts at enrolment increased (from 101 cells/µL [IQR 44-156] in 2002, to 191 cells/µL [115-239] in 2010). In each year, the proportion of the total enrolled population who died in that year decreased, from 63% (88 of 140) in 2002, to 0·8% (13 of 1599) in 2010. A sensitivity analysis assuming that 60% of the population lost to follow-up had died gave 3000 additional deaths, increasing overall mortality from 8% to 11-13%. INTERPRETATION: The Botswana national HIV/AIDS treatment programme reduced mortality among adults with HIV to levels much the same as in other low-income or middle-income countries. FUNDING: The African Comprehensive HIV/AIDS Partnerships.

The Madikwe Forum: a comprehensive partnership for supporting governance of Botswana's HIV and AIDS response.

There is a need for actors within the philanthropic sector to pursue collaborative partnerships with developing nations which could result in sustainable country-led responses to HIV and AIDS. There is also a need to evaluate the structures governing these partnerships in order to determine their effectiveness in strengthening national responses to HIV and AIDS. This article presents findings from a qualitative study of a governance structure of the African Comprehensive HIV/AIDS Partnerships (ACHAP), namely the Madikwe Forum. The investigation sought to critically reflect on the role and effectiveness of the Madikwe Forum in Botswana's response to HIV and AIDS and to consider the value of such a forum for other developing nations and partnership arrangements. The findings indicate that the Madikwe Forum has enabled considerable progress in the implementation of ACHAP-supported initiatives in Botswana. The constructive working relationship and close alignment between ACHAP and the Botswana government's objectives and priority areas were viewed as critical to this success. However, problems exist regarding the operation of the forum as well as a lack of focus on monitoring and evaluation, which requires the forum's urgent attention.

Modeling dynamic interactions between pre-exposure prophylaxis interventions & treatment programs: predicting HIV transmission & resistance.

Clinical trials have recently demonstrated the effectiveness of Pre-Exposure Prophylaxis (PrEP) in preventing HIV infection. Consequently, PrEP may soon be used for epidemic control. We model the dynamic interactions that will occur between treatment programs and potential PrEP interventions in resource-constrained countries. We determine the consequences for HIV transmission and drug resistance. We use response hypersurface modeling to predict the effect of PrEP on decreasing transmission as a function of effectiveness, adherence and coverage. We predict PrEP will increase need for second-line therapies (SLT) for treatment-naïve individuals, but could significantly decrease need for SLT for treatment-experienced individuals. If the rollout of PrEP is carefully planned it could increase the sustainability of treatment programs. If not, need for SLT could increase and the sustainability of treatment programs could be compromised. Our results show the optimal strategy for rolling out PrEP in resource-constrained countries is to begin around the "worst" treatment programs.

The cost and impact of male circumcision on HIV/AIDS in Botswana.

The HIV/AIDS epidemic continues to be a major issue facing Botswana, with overall adult HIV prevalence estimated to be 25.7 percent in 2007. This paper estimates the cost and impact of the draft Ministry of Health male circumcision strategy using the UNAIDS/WHO Decision-Makers' Programme Planning Tool (DMPPT). Demographic data and HIV prevalence estimates from the recent National AIDS Coordinating Agency estimations are used as input to the DMPPT to estimate the impact of scaling-up male circumcision on the HIV/AIDS epidemic. These data are supplemented by programmatic information from the draft Botswana National Strategy for Safe Male Circumcision, including information on unit cost and program goals. Alternative scenarios were developed in consultation with stakeholders. Results suggest that scaling-up adult and neonatal circumcision to reach 80% coverage by 2012 would result in averting almost 70,000 new HIV infections through 2025, at a total net cost of US$47 million across that same period. This results in an average cost per HIV infection averted of US$689. Changing the target year to 2015 and the scale-up pattern to a linear pattern results in a more evenly-distributed number of MCs required, and averts approximately 60,000 new HIV infections through 2025. Other scenarios explored include the effect of risk compensation and the impact of increasing coverage of general prevention interventions. Scaling-up safe male circumcision has the potential to reduce the impact of HIV/AIDS in Botswana significantly; program design elements such as feasible patterns of scale-up and inclusion of counselling are important in evaluating the overall success of the program.

Estimated HIV trends and program effects in Botswana.

BACKGROUND: This study uses surveillance, survey and program data to estimate past trends and current levels of HIV in Botswana and the effects of treatment and prevention programs. METHODS/PRINCIPAL FINDINGS: Data from sentinel surveillance at antenatal clinics and a national population survey were used to estimate the trend of adult HIV prevalence from 1980 to 2007. Using the prevalence trend we estimated the number of new adult infections, the transmission from mothers to children, the need for treatment and the effects of antiretroviral therapy (ART) and adult and child deaths. Prevalence has declined slowly in urban areas since 2000 and has remained stable in rural areas. National prevalence is estimated at 26% (25-27%) in 2007. About 330,000 (318,000-335,000) people are infected with HIV including 20,000 children. The number of new adult infections has been stable for several years at about 20,000 annually (12,000-26,000). The number of new child infections has declined from 4600 in 1999 to about 890 (810-980) today due to nearly complete coverage of an effective program to prevent mother-to-child transmission (PMTCT). The annual number of adult deaths has declined from a peak of over 15,500 in 2003 to under 7400 (5000-11,000) today due to coverage of ART that reaches over 80% in need. The need for ART will increase by 60% by 2016. CONCLUSIONS: Botswana's PMTCT and treatment programs have achieved significant results in preventing new child infections and deaths among adults and children. The number of new adult infections continues at a high level. More effective prevention efforts are urgently needed.