Tefera Agizew

Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral therapy: a Botswana Experience, 2004-2006.

Objectives:To describe reasons for exclusion from isoniazid tuberculosis preventive therapy (IPT) and outcomes of persons living with HIV (PLWH) during 6 months of IPT. Methods:In a clinical trial conducted in government clinics, first screening (screen 1) used National IPT Program guidelines and a second screening (screen 2) was trial specific. Adherence was defined as attending 6 monthly visits. Results:Between 2004 and 2006, at 4018 screening visits, 2934 (73%) PLWH met screen 1 criteria; 1995 (68%) met screen 2 criteria and were enrolled. Major reasons for exclusion were illness (66%) at screen 1 and abnormal chest radiographs (36%) at screen 2. Tuberculin skin tests were ≥5 mm in 24% of those enrolled and 31% had CD4 lymphocyte counts <200 cells/mm3. During the 6 months, 8 (0.40%) developed tuberculosis disease, 28 (1.4%) had severe adverse events (19/28 were hepatitis including one death probably isoniazid-associated), 20 others died, and 22% initiated antiretroviral therapy (ART). Although adherence was 86%, being on ART improved adherence: relative risk 1.41 (95% confidence limits 1.04-1.91). In multivariate analysis, ART was associated with a 4.38 greater odds of adherence to IPT. Conclusions:Six months of IPT was relatively safe and well-tolerated by PLWH. Adherence to IPT was significantly better among those receiving ART with IPT.

Isoniazid-associated Hepatitis and Antiretroviral Drugs during Tuberculosis Prophylaxis in HIV-infected Adults in Botswana

RATIONALE Little is known about the incidence of isoniazid-associated hepatitis in HIV-infected Africans who receive both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART). OBJECTIVES To assess the rate of and risk factors for isoniazid (INH)-associated hepatitis in persons living with HIV (PLWH) during IPT. METHODS PLWH recruited for a clinical trial received 6 months of open-label, daily, self-administered INH at public health clinics. At screening PLWH were excluded if they had any cough, weight loss, night sweats, or other illness. Alcohol abuse was defined as meeting any CAGE criterion. INH-associated hepatitis (INH-hepatitis) was defined as having either alanine or aspartate aminotransferase greater than 5.0 times the upper limit of normal regardless of symptoms when INH was not excluded as the cause. MEASUREMENTS AND MAIN RESULTS Of 1,995 PLWH enrolled between 2004 and 2006, 1,762 adhered to at least 4 months of IPT and were analyzed. Nineteen (1.1%) developed hepatitis probably or possibly associated with INH including one death at month 6; 14 of 19 (74%) occurred in months 1-3. Antiretroviral therapy (ART) was received by 480 participants but was not statistically associated with INH-hepatitis (relative risk [RR], 1.56; 95% confidence intervals [CI], 0.62-3.9); those receiving nevirapine had a higher rate (2.0%) than those receiving efavirenz (0.9%; P = 0.34). Although alcohol use did not reach significance (RR, 1.42; 95% CI, 0.57-3.51), meeting at least one CAGE criterion approached statistical significance (RR, 2.37; 95% CI, 0.96-5.84). Neither age greater than 35 years nor the presence of hepatitis B virus core antibody was associated with INH-hepatitis. CONCLUSIONS The observed rates of INH-hepatitis were similar to published data. Six months of IPT, which is recommended by the World Health Organization, was relatively safe in this, the largest cohort of African PLWH. Clinical trial registered with www.clinicaltrials.gov (NCT 00164281).

Tuberculosis incidence after 36 months’ isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis

Objective:Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit. Design:A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011. Methods:One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4+ lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4+ cell count at baseline and updated at 36 months. Results:In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17–0.75) but not TB (0.92, 95% CI 0.55–1.53) in the posttrial period. Conclusion:The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.

Isoniazid-Associated Hepatitis in Adults Infected With HIV Receiving 36 Months of Isoniazid Prophylaxis in Botswana

BACKGROUND The World Health Organization recommends 36 months of isoniazid preventive therapy (36IPT) for adults infected with HIV living in TB-endemic countries. We determined the rates and risk factors for isoniazid-associated hepatitis with the use of 36IPT. METHODS One thousand six adults infected with HIV received 36IPT during a pragmatic randomized trial set in Botswana public health clinics providing HIV care. Enrollment exclusion criteria included jaundice or elevations of serum transaminases (ESTs) > 2.5-fold the upper limit of normal (ULN). Participants with any CD4+ lymphocyte count were eligible and received antiretroviral therapy (ART) when CD4+ < 200 cells/μL. 36IPT was stopped for severe hepatitis (more than fivefold ULN EST) but not for moderate hepatitis (2.5-fold to fivefold ULN EST). RESULTS Pharmacy refill records showed 2,237 person-years of isoniazid receipt; 48% of participants initiated ART by 36 months. A total of 1.9% (19 of 1,006) of participants were diagnosed with severe hepatitis; three had jaundice and two of these developed hepatic encephalopathy. Another 3.1% (31 of 1,006) of participants experienced moderate hepatitis. Thirty-eight percent (19 of 50) of participants with moderate to severe hepatitis concomitantly received ART. Forty percent (20 of 50) of moderate to severe cases occurred within the first 2 months of IPT and during this period were not associated with receipt of ART at baseline (hazard ratio, 1.49; 95% CI, 0.20-11.1; P = .70). CONCLUSIONS Adults infected with HIV receiving 36IPT did not have an increased incidence of moderate to severe hepatitis or hepatic encephalopathy compared with published reports among people infected with HIV, people not infected with HIV in trials or public health programs. Compared with participants not receiving ART, the risk of moderate to severe hepatitis was not increased by ART. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00164281; URL: www.clinicaltrials.gov.

Peripheral clinic versus centralized laboratory-based Xpert MTB/RIF performance: Experience gained from a pragmatic, stepped-wedge trial in Botswana

Background In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert MTB/RIF (Xpert) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert scale-up. Methods Xpert was implemented from August 2012 through November 2014 with 13 GeneXpert instruments (GeneXpert) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert testing. We documented our experience with staff training and GeneXpert performance. Test results were extracted from GeneXpert software; unsuccessful tests were analysed in relation to testing sites and trends over time. Results During 276 instrument-months of operation a total of 3,630 tests were performed, of which 3,102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3,630 Xpert tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as “error”, 119 (23%) as “invalid” and 48 (9%) as “no result”. The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11–25%) and centralized laboratory-based GeneXpert instruments (14%, 95% CI: 11–17%; p = 0.140). Conclusions Xpert introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert testing staff is essential to minimize errors.

Anti-tuberculosis treatment outcomes in HIV-infected adults exposed to isoniazid preventive therapy in Botswana.

SETTING Eight public health clinics in Gaborone and Francistown, Botswana. OBJECTIVES To describe the characteristics and outcomes of incident tuberculosis (TB) cases in human immunodeficiency virus (HIV) infected adults exposed to isoniazid preventive therapy (IPT) with access to antiretroviral and anti-tuberculosis treatment. DESIGN In 1995 HIV-infected adults, TB disease was excluded before commencing IPT. During and after receipt of 6 or 36 months of IPT, symptomatic participants were evaluated using chest radiographs, sputum microscopy, cultures and drug susceptibility testing (DST). Incident TB cases received ≥6 months of anti-tuberculosis treatment. RESULTS Seventy-five incident TB cases were identified among 619 symptomatic participants. The median duration of IPT in these cases was 6 months (range 1-35), and the median time to initiation of anti-tuberculosis treatment was 12 months after IPT cessation. Antiretroviral therapy (ART) was initiated before anti-tuberculosis treatment in 37 cases. Culture was positive in 43/58 (74%) TB cultures. DST was available for 38 cases, of which six (16%) were resistant to isoniazid (INH); 67/75 (89%) cases, including four with INH-monoresistant TB, completed anti-tuberculosis treatment or were cured. CONCLUSIONS With prompt initiation of anti-tuberculosis treatment and access to ART, excellent outcomes were achieved in a public health setting in HIV-infected adults who developed TB disease.

Higher-than-expected prevalence of non-tuberculous mycobacteria in HIV setting in Botswana: Implications for diagnostic algorithms using Xpert MTB/RIF assay

Background Non-tuberculous mycobacteria (NTM) can cause pulmonary infection and disease especially among people living with HIV (PLHIV). PLHIV with NTM disease may clinically present with one of the four symptoms consistent with tuberculosis (TB). We describe the prevalence of NTM and Mycobacterium tuberculosis complex (MTBC) isolated among PLHIV who presented for HIV care and treatment. Methods All PLHIV patients presenting for HIV care and treatment services at 22 clinical sites in Botswana were offered screening for TB and were recruited. Patients who had ≥1 TB symptom were asked to submit sputa for Xpert MTB/RIF and culture. Culture growth was identified as NTM and MTBC using the SD-Bioline TB Ag MPT64 Kit and Ziehl Neelsen microscopy. NTM and MTBC isolates underwent species identification by the Hain GenoType CM and AS line probe assays. Results Among 16, 259 PLHIV enrolled 3068 screened positive for at least one TB symptom. Of these, 1940 submitted ≥1 sputum specimen, 427 (22%) patients had ≥1 positive-culture result identified phenotypically for mycobacterial growth. Of these 247 and 180 patients were identified as having isolates were NTM and MTBC, respectively. Of the 247 patients identified with isolates containing NTM; 19 were later excluded as not having NTM based on additional genotypic testing. Among the remaining 408 patients 228 (56%, 95% confidence interval, 46–66%) with NTM. M. intracellulare was the most common isolated (47.8%). Other NTMs commonly associated with pulmonary disease included M. malmoense (3.9%), M. avium (2.2%), M. abscessus (0.9%) and M. kansasii (0.4%). After excluding NTM isolates that were non-speciated and M. gordonae 154 (67.5%) of the NTM isolates were potential pathogens. Conclusions In the setting of HIV care and treatment, over-half (56%) of a positive sputum culture among PLHIV with TB symptoms was NTM. Though we were not able to distinguish in our study NTM disease and colonization, the study suggests culture and species identification for PLHIV presenting with TB symptoms remains important to facilitate NTM diagnosis and hasten time to appropriate treatment.