Jennifer Hughes

Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis.

BACKGROUND South Africa has a large burden of extensively drug-resistant tuberculosis (XDR-TB); only 15% of XDR-TB patients have successful outcomes. OBJECTIVE To describe the safety and effectiveness of bedaquiline (BDQ) in the South African BDQ Clinical Access Programme. DESIGN An interim cohort analysis. RESULTS Of the first 91 patients enrolled between March 2013 and July 2014 (with follow-up until August 2014), 54 (59%) were human immunodeficiency virus (HIV) infected. The median CD4 count was 239 cells/μl, and all patients were on antiretroviral therapy (ART) at initiation of BDQ; 33 had XDR-TB, 41 were pre-XDR-TB with fluoroquinolone resistance and 17 were pre-XDR-TB with resistance to an injectable. Of the 91 patients, 58 (64%) had completed 24 weeks of BDQ, 28 were still on BDQ, 3 were lost to follow-up, 1 had died and 1 had BDQ withdrawn following atrial fibrillation. Of the 63 patients with 6 months follow-up, 48 (76%) had either culture-converted or remained culture-negative after initiation of BDQ. QTcF was monitored monthly and exceeded 500 ms in three participants; this resolved in all three. CONCLUSION Interim safety and culture conversion outcomes for patients accessing BDQ in South Africa, including HIV-infected patients on ART and patients with pre-XDR- and XDR-TB, suggest that BDQ may be both efficacious and safe.

Impact of Decentralized Care and the Xpert MTB/RIF Test on Rifampicin-Resistant Tuberculosis Treatment Initiation in Khayelitsha, South Africa

Decentralization of treatment for rifampicin-resistant tuberculosis was associated with high treatment initiation and resulted in reduced time to treatment initiation. Xpert for TB diagnosis resulted in a significant further reduction in time to treatment.

Drug–drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB

OBJECTIVES Bedaquiline is a new anti-TB drug, which is metabolized by cytochrome P450 (CYP) 3A4. Concomitant ART is important for all HIV-infected patients treated for TB, but several antiretrovirals inhibit or induce CYP3A4. Single-dose drug-drug interaction studies found no significant interactions with nevirapine or lopinavir/ritonavir, but these findings could be misleading, especially because of bedaquilines long terminal t1/2. We evaluated the effect of nevirapine and lopinavir/ritonavir on bedaquiline exposure. METHODS We conducted a parallel-group pharmacokinetic study of three groups of participants who were on bedaquiline as part of therapy for drug-resistant TB: no ART (HIV seronegative); nevirapine-based ART; and lopinavir/ritonavir-based ART. Non-compartmental analyses were done and exposure of bedaquiline and its M2 metabolite compared between the no-ART group and the two ART groups. RESULTS We enrolled 48 participants: 17 in the no-ART group, 17 in the nevirapine group and 14 in the lopinavir/ritonavir group. The following median bedaquiline pharmacokinetic parameters were significantly higher in the lopinavir/ritonavir group than in the no-ART group: AUC(0-48) (67 002 versus 34 730 ng · h/mL; P = 0.003); Tmax (6 versus 4 h; P = 0.003); and t1/2 (55 versus 31 h; P = 0.004). On multivariate analysis, bedaquiline exposure was increased by lopinavir/ritonavir, male sex and time on bedaquiline. Bedaquiline exposure was not significantly different between the nevirapine group and the no-ART group. M2 metabolite exposure was not significantly different in either of the antiretroviral groups compared with the no-ART group. CONCLUSIONS Lopinavir/ritonavir significantly increased bedaquiline exposure. The clinical significance of this interaction remains to be determined.

New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations

&NA; It is estimated that 33,000 children develop multidrug‐resistant tuberculosis (MDR‐TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR‐TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR‐TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR‐TB literature by providing practice‐based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR‐TB drugs and the new shorter MDR‐TB regimen in children and adolescents.

Programmatic treatment outcomes in HIV-infected and uninfected drug-resistant TB patients in Khayelitsha, South Africa

BACKGROUND South Africa has high burdens of HIV, TB and drug-resistant TB (DR-TB, rifampicin-resistance). Treatment outcome data for HIV-infected versus uninfected patients is limited. We assessed the impact of HIV and other factors on DR-TB treatment success, time to culture conversion, loss-from-treatment and overall mortality after second-line treatment initiation. METHODS A retrospective cohort analysis was conducted for patients initiated on DR-TB treatment from 2008 to 2012, within a community-based, decentralised programme in Khayelitsha, South Africa. RESULTS Among 853 confirmed DR-TB patients initiating second-line treatment, 605 (70.9%) were HIV infected. HIV status did not impact on time to sputum culture conversion nor did it impact treatment success; 48.1% (259/539) and 45.9% (100/218), respectively (p=0.59). In a multivariate model, HIV was not associated with treatment success. Death during treatment was higher among HIV-infected patients, but overall mortality was not significantly higher. HIV-infected patients with CD4 <=100 cells/ml were significantly more likely to die after starting treatment. CONCLUSIONS Response to DR-TB treatment did not differ with HIV infection in a programmatic setting with access to antiretroviral treatment (ART). Earlier ART initiation at a primary care level could reduce mortality among HIV-infected patients presenting with low CD4 counts.

Loss from Treatment for Drug Resistant Tuberculosis: Risk Factors and Patient Outcomes in a Community-Based Program in Khayelitsha, South Africa

Background A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting. Methodology LFT, defined as interruption of treatment for ≥2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013. Results Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two-year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment. Conclusion LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs.

Linezolid for multidrug-resistant tuberculosis in HIV-infected and -uninfected patients

Two recent systematic reviews found that treatment outcomes with regimens containing linezolid for complicated cases of multidrug-resistant (MDR) tuberculosis (TB) are equal to or better than those reported for uncomplicated MDR-TB [1, 2] and better than those reported among patients treated for extensively drug-resistant (XDR)-TB [3–6]. Existing data on treatment outcomes with linezolid for MDR-TB are predominantly among HIV-uninfected patients; <10% of patients were HIV co-infected in the reviews [1, 2]. There is concern over the safety of using linezolid within MDR-TB regimens for HIV-infected patients due to underlying HIV-related neuropathy and bone marrow dysfunction as well as a potentially higher incidence of adverse events in patients on antiretroviral therapy (ART), notably anaemia with zidovudine and peripheral neuropathy with stavudine [7]. Given the high rate of HIV/TB co-infection in many settings, we report here our clinical experience with the use of linezolid for treatment of XDR-TB and complicated MDR-TB among HIV-infected and -uninfected patients in community-based programmes supported by Médecins Sans Frontières (MSF) in two high-burden settings in Khayelitsha, South Africa [8], and Mumbai, India [7]. We carried out a retrospective analysis of routinely collected data. Programmes at both sites were approved by either MSF or local university ethics review boards. Due to restricted access to linezolid in South Africa as well as limited capacity for operational research in both programmes, the numbers are small, and data were collected and analysed over a limited time period only. Linezolid is an effective treatment option for MDR/XDR-TB, including among HIV-co-infected patients on ART http://ow.ly/JoPzO

Examples of Bedaquiline Introduction for the Management of Multidrug-Resistant Tuberculosis in Five Countries

BACKGROUND For the first time in almost 50 years, there are new drugs available for the treatment of tuberculosis (TB), including bedaquiline (BDQ) and delamanid (DLM). The rate of introduction, however, has not kept pace with patient needs. It is estimated that as many as 23% of multidrug-resistant TB (MDR-TB) patients have an indication for receiving BDQ. As this is the first time the MDR-TB community is introducing new medications, it is important to understand how implementation can be developed in a variety of settings. METHODS A qualitative assessment of country TB programs in which more than 5% of MDR-TB patients were started on BDQ under program conditions. RESULTS National TB programs in Belarus, France, Georgia, South Africa, and Swaziland all started sizeable cohorts of patients on BDQ in 2015. Common factors observed in these programs included experience with compassionate use/expanded access, support from implementing partners, and adequate national or donor-supported budgets. Barriers to introduction included restriction of BDQ to the in-patient setting, lack of access to companion drugs, and the development of systems for pharmacovigilance. CONCLUSION The five countries in this paper are examples of the introduction of new therapeutic options for the treatment of TB.

Clinical Access Program for Bedaquiline for the treatment of drug-resistant tuberculosis

While clinical disease caused by drug-sensitive Mycobacterium tuberculosis (MTB) can usually be treated successfully, clinical disease caused by drug-insensitive MTB is associated with a poorer prognosis. In December 2012, a new drug, bedaquiline, was approved by the US Food and Drug Administration. This article documents the process whereby the National Department of Health, Right to Care and Médecins Sans Frontières obtained access to this medication for South Africans who might benefit from subsequent implementation of the Clinical Access to Bedaquiline Programme.

Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study

BACKGROUND Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa. METHODS We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment. FINDINGS Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment. INTERPRETATION Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials. FUNDING Médecins Sans Frontières (MSF).