The potential use of rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis.

Background: Use of the Xpert MTB/RIF assay has increased the number of people diagnosed with rifampicin-resistant tuberculosis (RR-TB), especially in South Africa where Xpert is now the initial diagnostic for individuals with TB symptoms. We hypothesized that a proportion of RR-TB patients determined by Xpert can be treated with a rifabutin-containing regimen. Methods: Rifabutin susceptibility by rpoB mutation was assessed in 349 individuals from South Africa and 172 from Belgium. rpoB polymorphisms were identified by Sanger sequencing. Rifampicin and rifabutin susceptibility was assessed phenotypically. A systematic review was performed to comprehensively collate information on rifabutin susceptibility by rpoB polymorphism. Rifabutin susceptibility was assigned to rpoB polymorphisms based on their positive likelihood ratios and ORs. Results: One hundred and twelve rpoB polymorphisms (67.9% from literature) were identified from all 2045 RR-TB patients, of which 17 polymorphisms could be classified as susceptible/resistant to rifabutin. Eleven polymorphisms were associated with rifabutin susceptibility. The 516GTC mutation was the most common, representing 70% (South Africa) and 76% (Belgium) of all rifabutin-susceptible isolates. At a population level, the 11 polymorphisms associated with rifabutin susceptibility occurred in 33.2% and 16.6% of all South African and Belgian patients diagnosed with RR-TB, respectively. Conclusions: Identification of the exact rpoB polymorphism leading to the diagnosis of RR-TB has the potential to allow inclusion of rifabutin in the treatment regimen of a substantial proportion of RR-TB patients. A randomized controlled trial evaluating the efficacy of a rifabutin-containing TB treatment regimen in these selected patients is needed to provide the evidence required for a change in policy.

Low Frequency of Acquired Isoniazid and Rifampicin Resistance in Rifampicin-Susceptible Pulmonary Tuberculosis in a Setting of High HIV-1 Infection and Tuberculosis Coprevalence.

Background: We estimated the incidence of acquired isoniazid and rifampicin resistance in rifampicin-susceptible tuberculosis in a setting of high human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis coprevalence. Methods: GeneXpert MTB/RIF-confirmed patients with rifampicin-susceptible tuberculosis were recruited at antituberculosis treatment initiation in Khayelitsha, South Africa. Liquid culture and adherence assessment were performed at 2 and 5-6 months. MTBDRplus was performed on mycobacteria-positive cultures to ascertain acquired drug resistance (ADR). Spoligotyping and whole-genome sequencing were performed to ascertain homogeneity between baseline isolates and isolates with ADR. Baseline isolates were retrospectively tested for isoniazid monoresistance. An electronic database review was performed to ascertain tuberculosis recurrences. Results: A total of 306 participants (62% with HIV-1 coinfection, of whom 71% received antiretroviral therapy) were recruited. Ascertainment of outcomes was complete for 284 participants. Five acquired a resistant Mycobacterium tuberculosis strain during or subsequent to treatment. One strain was confirmed to have ADR, 2 were confirmed as causing exogenous reinfection, and 2 were unrecoverable for genotyping. Incident ADR was estimated to have ranged from 0.3% (95% confidence interval [CI], .1%-1.9%; 1 of 284 participants) to 1% (95% CI, .2%-3%; 3 of 284 participants). Seventeen of 279 baseline isolates (6.1%; 95% CI, 3.6%-9.6%) had isoniazid monoresistance (13 of 17 had an inhA promoter mutation), but 0 of 17 had amplified resistance. Conclusions: Treatment with standardized antituberculosis regimens dosed daily throughout, high uptake of antiretroviral therapy, and low prevalence of isoniazid monoresistance were associated with a low frequency of ADR.

Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis.

Pyrazinamide resistance is largely unknown in the spectrum of drug resistant phenotypes. We summarize data on PZA resistance in clinical isolates from South Africa. PZA DST should be performed when considering its inclusion in treatment of patients with rifampicin-resistant TB or MDR-TB.

High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South African patients with extensively drug-resistant tuberculosis.

BACKGROUND: There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. METHODS: We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. RESULTS: Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin. CONCLUSION: In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.

Implementation of genotype MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa.

BACKGROUND: Diagnosis of drug resistance and timely initiation of multidrug-resistant (MDR) tuberculosis therapy are essential to reduce transmission and improve patient outcomes. We sought to determine whether implementation of the rapid MTBDRplus diagnostic shortened the time from specimen collection to patient MDR tuberculosis therapy initiation. METHODS: We conducted a retrospective cohort analysis of 197 MDR tuberculosis patients treated at Brewelskloof, a rural tuberculosis hospital in Western Cape Province, South Africa, between 2007 and 2011. RESULTS: Eighty-nine patients (45%) were tested using conventional liquid culture and drug susceptibility testing (DST) on solid medium and 108 (55%) were tested using the MTBDRplus assay after positive acid-fast bacilli or culture. Median time from sample taken to therapy initiation was reduced from 80 days (interquartile range [IQR] 62-100) for conventional DST to 55 days (IQR 37.5-78) with the MTBDRplus. Although the laboratory processing time declined significantly, operational delays persisted both in the laboratory and the clinical infrastructure for getting patients started on treatment. In multivariate analysis, patients tested using the MTBDRplus test had a reduced risk of starting treatment 60 days or more after sputum collection of 0.52 (P < .0001) compared with patients tested with culture-based DST, after adjustment for smear status and site of disease. CONCLUSIONS: Use of MTBDRplus significantly reduced time to MDR tuberculosis treatment initiation. However, DST reporting to clinics was delayed by more than 1 week due, in part, to laboratory operational delays, including dependence on smear and culture positivity prior to MTBDRplus performance. In addition, once MDR tuberculosis was reported, delays in contacting patients and initiating therapy require improvements in clinical infrastructure.

Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study.

BACKGROUND: Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes. METHODS: In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion. FINDINGS: 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment. INTERPRETATION: In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity. FUNDING: South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership.