We describe 27 children and adolescents <18 years of age who received bedaquiline during treatment for multidrug-resistant tuberculosis. We report good treatment responses and no cessation ...attributable to adverse effects. Bedaquiline could be considered for use with this age group for multidrug-resistant tuberculosis when treatment options are limited.
Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from ...7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.
Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. ...Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.
We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.
In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.
Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.
The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment ...outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance.
We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan.
Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients.
As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.
HAART reduces tuberculosis (TB) incidence in people living with HIV/AIDS but those starting HAART may develop active TB or subclinical TB may become apparent in the immune reconstitution inflammatory ...syndrome.
To measure the incidence rate of notified TB in people receiving HAART in five HIV programmes occurring in low-resource countries with a high TB/HIV burden.
A retrospective review in five Médecins Sans Frontières programmes (Cambodia, Thailand, Kenya, Malawi and Cameroon) allowed incidence rates of notified TB to be calculated based on follow-up time after HAART initiation.
Among 3151 patients analysed, 90% had a CD4 cell count of < 200 cells/mul. Median follow-up time ranged from 3.7 months in Thailand or Kenya to 11.1 months in Cambodia. Incidence rates were 7.6, 10.4, 17.6, 14.3 and 4.8/100 person-years for pulmonary TB and 12.7, 4.3, 6.9, 2.1 and 0/100 person-years for extra-pulmonary TB in the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon, respectively. Overall, 62.3% of pulmonary TB and 54.9% of extra-pulmonary TB were diagnosed within 3 months after HAART initiation.
High incidence rates of notified TB under HAART in programmes held in poor-resource countries were observed; these were likely to include both undiagnosed prevalent TB at HAART initiation and subclinical TB developing during the immune reconstitution inflammatory syndrome. This raises operational issues concerning TB diagnosis and treatment of TB/HIV-coinfected patients and prompts for urgent TB and HIV care integration.
Prevalence of nontuberculous mycobacteria (NTM) disease is poorly documented in countries with high prevalence of tuberculosis (TB). We describe prevalence, risk factors, and TB program implications ...for NTM isolates and disease in Cambodia. A prospective cohort of 1,183 patients with presumptive TB underwent epidemiologic, clinical, radiologic, and microbiologic evaluation, including >12-months of follow-up for patients with NTM isolates. Prevalence of NTM isolates was 10.8% and of disease was 0.9%; 217 (18.3%) patients had TB. Of 197 smear-positive patients, 171 (86.8%) had TB confirmed (167 by culture and 4 by Xpert MTB/RIF assay only) and 11 (5.6%) had NTM isolates. HIV infection and past TB were independently associated with having NTM isolates. Improved detection of NTM isolates in Cambodia might require more systematic use of mycobacterial culture and the use of Xpert MTB/RIF to confirm smear-positive TB cases, especially in patients with HIV infection or a history of TB.
Phenotypic drug-susceptibility testing (pDST), which relies on growth inhibition in the drug-containing media, remains a challenge for fastidious Mycobacterium tuberculosis complex (MTBc) isolates ...due to insufficient growth on the growth controls (GC). Middlebrook 7H11 (M7H11) medium contains casein hydrolysate, which may favor the growth of such strains.
In this study, we tested whether M7H11 reduces invalid results due to insufficient growth on the GCs and the turnaround time (TAT) of pDST for MTBc compared to Middlebrook 7H10 (M7H10) without affecting the accuracy of the pDST results and how it differs between rifampicin- and isoniazid-susceptible non multi-drug resistant (non-MDR), MDR and MDR with additional resistance to fluoroquinolones (Pre-XDR) MTBc isolates. We compared the proportions of invalid pDST results due to lack of growth on the GCs, TATs of valid parallel drug-susceptibility testings as an indicator of speed of MTBc growth, and colony-forming unit (CFU) count on the most diluted GC of the parallel pDSTs after equal incubation periods as an indicator of growth abundance on M7H11 and M7H10. We also analyzed the agreement between the pDST results of the same drug or drugs in the same drug class, tested in parallel on both media.
For MDR and pre-XDR isolates, relative to M7H10, M7H11 significantly reduced the occurrence of invalid pDST results due to insufficient growth on the GCs (odds ratio OR = ∞ 95% confidence interval (CI) 1.9-∞, P = 0.004 for MDR, OR = ∞ 95% CI 3.3-∞, P = 0.0001 for pre-XDR) and the TAT of pDSTs (OR = 17 95% CI 2.6-710.4, P = 0.0001 for MDR, OR = 9.3 95% CI 4.0-26.5, P < 0.0001 for pre-XDR). The growth abundance of MTBc on M7H11 was significantly higher compared to M7H10 (17 CFU on M7H10 vs. 28 on M7H11), irrespective of drug-resistance profiles. The agreement between the pDST results between the two media was high (Cohen's k > 0.98).
Our study findings suggest that M7H11 is preferred over M7H10 for pDSTs of MTBc isolates.
Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high ...risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.
We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for nonconversion.
We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.
A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval CI, 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90;
= 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95;
= 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with conversion.
Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.
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