APRIL 2018 NEWSLETTER

1. MDR-TB patients in KwaZulu-Natal, South Africa: Cost-effectiveness of 5 models of care.

PLoS One. 2018 Apr 18;13(4):e0196003. doi: 10.1371/journal.pone.0196003. eCollection 2018.

Loveday M(1)(2), Wallengren K(3), Reddy T(4), Besada D(1), Brust JCM(5), Voce A(6), Desai H(7), Ngozo J(8), Radebe Z(8), Master I(9), Padayatchi N(2), Daviaud E(1).

BACKGROUND: South Africa has a high burden of MDR-TB, and to provide accessible treatment the government has introduced different models of care. We report the most cost-effective model after comparing cost per patient successfully treated across 5 models of care: centralized hospital, district hospitals (2), and community-based care through clinics or mobile injection teams.

METHODS: In an observational study five cohorts were followed prospectively. The cost analysis adopted a provider perspective and economic cost per patient successfully treated was calculated based on country protocols and length of treatment per patient per model of care. Logistic regression was used to calculate propensity score weights, to compare pairs of treatment groups, whilst adjusting for baseline imbalances between groups. Propensity score weighted costs and treatment success rates were used in the ICER analysis. Sensitivity analysis

focused on varying treatment success and length of hospitalization within each model.

RESULTS: In 1,038 MDR-TB patients 75% were HIV-infected and 56% were successfully treated. The cost per successfully treated patient was 3 to 4.5 times lower in the community-based models with no hospitalization. Overall, the Mobile model was the most cost-effective.

CONCLUSION: Reducing the length of hospitalization and following community-based models of care improves the affordability of MDR-TB treatment without compromising its effectiveness.

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2. Early experience with delamanid-containing regimens in the treatment of complicated multidrug-resistant tuberculosis in Hong Kong.

Eur Respir J. 2018 Apr 12. pii: 1800159. doi: 10.1183/13993003.00159-2018. [Epub  ahead of print]

Chang KC(1), Chung-Ching Leung E(2), Law WS(2), Leung WM(2), Tai LB(2), Lee SN(2), Lam FM(3), Chau CH(3), Yun-Wing Mok T(4), Yew WW(5), Leung CC(2).

EXTRACT: Hong Kong is a tuberculosis (TB) intermediate-burden region with a disease notification rate of 60.5 per 100 000 population in 2015. With the use of supervised treatment since 1970s, and the use of drug susceptibility testing (DST) for guiding use of TB drugs for several decades, TB drug resistance rates in Hong Kong have declined and the multidrug-resistant (MDR) TB rate has been kept at around 1%. Successful control of MDR-TB was partly attributable to judicious use of ofloxacin and later levofloxacin in the 1990s, the introduction of linezolid in 2000s among patients with fluoroquinolone (FQ)-resistant MDR-TB or extensively drug-resistant (XDR) TB, with intermittent dosing to enable its prolonged use, and selective use of delamanid among patients with complicated MDR-TB since 2012. To echo our support for using delamanid in the treatment of MDR-TB, we would like to report our early experience in Hong Kong regarding the use of delamanid-containing regimens among patients with pre-XDR-TB (MDR-TB with bacillary resistance to either FQ or second-line injectable agents) or XDR-TB.

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3. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2018 Apr;6(4):265-275. doi: 10.1016/S2213-2600(18)30078-X.

Fregonese F(1), Ahuja SD(2), Akkerman OW(3), Arakaki-Sanchez D(4), Ayakaka I(5), Baghaei P(6), Bang D(7), Bastos M(8), Benedetti A(9), Bonnet M(10), Cattamanchi A(11), Cegielski P(12), Chien JY(13), Cox H(14), Dedicoat M(15), Erkens C(16), Escalante P(17), Falzon D(18), Garcia-Prats AJ(19), Gegia M(18), Gillespie SH(20), Glynn JR(21), Goldberg S(22), Griffith D(23), Jacobson KR(24), Johnston JC(25), Jones-López EC(24), Khan A(22), Koh WJ(26), Kritski A(27), Lan ZY(9), Lee JH(28), Li PZ(1), Maciel EL(29), Galliez RM(30), Merle CSC(31), Munang M(15), Narendran G(32), Nguyen VN(33), Nunn A(21), Ohkado A(34), Park JS(28), Phillips PPJ(35), Ponnuraja C(36), Reves R(37), Romanowski K(38), Seung K(39), Schaaf HS(19), Skrahina A(40), Soolingen DV(41), Tabarsi P(6), Trajman A(42), Trieu L(2), Banurekha VV(32), Viiklepp P(43), Wang JY(13), Yoshiyama T(44), Menzies D(45).

BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months  or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology.

FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95%  CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates.

INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen  for this important and common form of drug-resistant tuberculosis.

FUNDING: World Health Organization and Canadian Institutes of Health Research.

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lobal programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):407-412. doi: 10.5588/ijtld.17.0706.

Cox V(1), Brigden G(2), Crespo RH(3), Lessem E(4), Lynch S(5), Rich ML(6), Waning B(3), Furin J(7).

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis  (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.

RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.

CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

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5. Treatment responses in multidrug-resistant tuberculosis in Germany.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):399-406. doi: 10.5588/ijtld.17.0741.

Heyckendorf J(1), van Leth F(2), Avsar K(3), Glattki G(4), Günther G(5), Kalsdorf B(1), Müller M(6), Olaru ID(7), Rolling T(8), Salzer HJF(1), Schuhmann M(9), Terhalle E(1), Lange C(10).

BACKGROUND: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available.

OBJECTIVE: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB.

METHOD: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment.

RESULTS: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%;  culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment.

CONCLUSION: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

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