Caregiver willingness to give TPT to children living with drug-resistant TB patients.

BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27-48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3-11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2-23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6-12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6-12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1-14.3), and willingness to take TPT oneself (OR 35.1, 95% CI 11.0-112.8).CONCLUSIONS A high percentage of caregivers living with MDR- or rifampicin-resistant TB patients were willing to give children a hypothetical MDR TPT. These results provide important evidence for the potential uptake of effective MDR TPT when implemented.

Effectiveness of GenoType MTBDRsl in excluding TB drug resistance in a clinical trial.

OBJECTIVES: To assess the performance of the GenoType MTBDRsl v1, a line-probe assay (LPA), to exclude baseline resistance to fluoroquinolones (FQs) and second-line injectables (SLIs) in the Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB 1 (STREAM 1) trial.METHODS: Direct sputum MTBDRsl results in the site laboratories were compared to indirect phenotypic drug susceptibility testing (pDST) results in the central laboratory, with DNA sequencing as a reference standard.RESULTS: Of 413 multidrug-resistant TB (MDR-TB) patients tested using MTBDRsl and pDST, 389 (94.2%) were FQ-susceptible and 7 (1.7%) FQ-resistant, while 17 (4.1%) had an inconclusive MTBDRsl result. For SLI, 372 (90.1%) were susceptible, 5 (1.2%) resistant and 36 (8.7%) inconclusive. There were 9 (2.3%) FQ discordant pDST/MTBDRsl results, of which 3 revealed a mutation and 5 (1.3%) SLI discordant pDST/MTBDRsl results, none of which were mutants on sequencing. Among the 17 FQ- and SLI MTBDRsl-inconclusive samples, sequencing showed 1 FQ- and zero SLI-resistant results, similar to frequencies among the conclusive MTBDRsl. The majority of inconclusive MTBDRsl results were associated with low bacillary load samples (acid-fast bacilli smear-negative or scantily positive) compared to conclusive results (P < 0.001).CONCLUSION: MTBDRsl can facilitate the rapid exclusion of FQ and SLI resistances for enrolment in clinical trials.

Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial.

BACKGROUND: The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. METHODS: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. RESULTS: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. CONCLUSION: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

HIV testing uptake among the household contacts of multidrug-resistant tuberculosis index cases in eight countries.

SETTING: The household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) index cases are at high risk of tuberculous infection and disease progression, particularly if infected with the human immunodeficiency virus (HIV). HIV testing is important for risk assessment and clinical management. METHODS: This was a cross-sectional, multi-country study of adult MDR-TB index cases and HHCs. All adult and child HHCs were offered HIV testing if never tested or if HIV-negative >1 year previously when last tested. We measured HIV testing uptake and used logistic regression to evaluate predictors. RESULTS: A total of 1007 HHCs of 284 index cases were enrolled in eight countries. HIV status was known at enrolment for 226 (22%) HHCs; 39 (4%) were HIV-positive. HIV testing was offered to 769 (98%) of the 781 remaining HHCs; 544 (71%) agreed to testing. Of 535 who were actually tested, 26 (5%) were HIV-infected. HIV testing uptake varied by site (median 86%, range 0-100%; P < 0.0001), and was lower in children aged <18 years than in adults (59% vs. 78%; adjusted for site P < 0.0001). CONCLUSIONS: HIV testing of HHCs of MDR-TB index cases is feasible and high-yield, with 5% testing positive. Reasons for low test uptake among children and at specific sites-including sites with high HIV prevalence-require further study to ensure all persons at risk for HIV are aware of their status.

Persistently high early mortality despite rapid diagnostics for drug-resistant tuberculosis cases in South Africa.

OBJECTIVE: To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. DESIGN: We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. RESULTS: Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naïve patients (aHR 3.40, 95%CI 2.90-3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). CONCLUSION: In EDRweb, mortality is highest in the first few weeks after MDR/RR-TB treatment initiation.

Cutting the cost of South African antiretroviral therapy using newer, safer drugs.

Antiretrovirals are a significant cost driver for HIV programmes. Current first-line regimens have performed well in real-life programmes, but have a low barrier to virological resistance and still carry toxicity that limits adherence. New drug developments may mean that we have access to safer, more robust and cheaper regimens, but only if the appropriate clinical trials are conducted. We briefly discuss these trials, and demonstrate the large cost savings to the South African HIV programme if these are successful.

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.

Clinical access to Bedaquiline Programme 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.

Prevalence and incidence of symmetrical symptomatic peripheral neuropathy in patients with multidrug-resistant TB.

BACKGROUND: Symptomatic symmetrical peripheral neuropathy (SSPN) is common in patients with HIV infection. It is also a common adverse event associated with both tuberculosis (TB) treatment and antiretroviral therapy (ART), particularly stavudine. While tenofovir is the one of recommended first-line nucleotide reverse transcriptase inhibitors (NRTIs), there is a risk of nephrotoxicity when using tenofovir together with the aminoglycosides needed to treat multidrug-resistant (MDR) TB. Thus, stavudine is often chosen as a treatment option for the HIV-infected MDR TB patient. OBJECTIVE: To assess whether use of stavudine both before and during treatment for MDR TB increased the prevalence and incidence of SSPN. METHOD: MDR TB patients at Sizwe Tropical Disease Hospital were examined for signs of prevalent SSPN. Age, gender, HIV status, alcohol use, TB and HIV treatment regimens both prior to admission and current, and concomitant medications were recorded. RESULTS: In this cohort of 246 patients, we found that 24.4% of patients with MDR TB had SSPN at time of admission for treatment of MDR TB. They were more likely to be HIV-infected (odds ratio (OR) 3.21; 95% CI 1.25 - 8.21) and tended to have longer (>7 months) exposure to stavudine (OR 1.81; 95% CI 0.90 - 3.63). Incident SSPN occurred in 17% of patients and was associated with older age (hazard ratio (HR) 3.00; 95% CI 1.30 - 6.89) and exposure to terizidone (HR 2.98; 95% CI 0.94 to 4.61) or, to a lesser extent, with stavudine (crude HR 1.62; 95% CI 0.65 - 4.01) in the first 6 months of MDR TB treatment. This common adverse event emphasises the need for the development of less toxic drugs for the treatment of MDR TB.

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women.

OBJECTIVE: There are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. METHODS: In this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/100 mg (n=20) or 400/100 mg (n=21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C(max) ), trough observed plasma concentration 24 hour post dose (C(min) ) and area under concentration-time curve in one dosing interval (AUC(τ) )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n=23). RESULTS: At or before delivery, all mothers achieved HIV RNA <50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC(τ) for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C(min) values were comparable. The C(min) value for atazanavir/RTV 400/100 mg was 39% higher than the C(min) for atazanavir/RTV 300/100 mg in historical controls, but the AUC(τ) values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (>2.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. CONCLUSIONS: In this study, use of atazanavir/RTV 300/100 mg qd produced C(min) comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.

Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227.

OBJECTIVES: TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients. METHODS: Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs). RESULTS: In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events. CONCLUSIONS: In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.

The epidemiology and clinical features of paraffin (kerosene) poisoning in rural African children.

One hundred and eleven children under 5 years of age admitted with a diagnosis of paraffin ingestion, constituting 9.1% of total ward admissions in this age group, were studied prospectively. The majority were between 13 and 36 months old. One-fifth of the children were in the care of another child at the same time of ingestion. Fourteen families had a past history of paraffin ingestion. Only 22% of households normally stored in paraffin above ground level and in only 15% of cases was paraffin stored in a container specified for that purpose. Emesis was attempted using home remedies in 72% of cases and was associated with a significant increase in vomiting. Vomiting had an impact on the exacerbation of the clinical features of paraffin poisoning, particularly fever. Clinical criteria laid down for suspected superadded bacterial lung infection resulted in half of the study group having blood cultures performed on day 1 and another 17 on day 4. Only two yielded isolates which possibly could have been indicative of bacteremia secondary to infective pneumonia. No child in the suspected group was treated with antibiotics and all recovered uneventfully. Admission chest X-rays contributed little to the management of the illness. Paraffin ingestion remains a serious contributor to child morbidity in rural South Africa and there appears to be room for further preventive education at community level. Specific measures could include storage of paraffin in designated containers above ground level and emphasis on adult supervision of children. Superadded bacterial pneumonia is uncommon and antibiotics in the management of suspected cases are not routinely indicated.