March 2019 Newsletter

NEWS ANNOUNCEMENTS

 

WHO consolidated guidelines on drug-resistant tuberculosis treatment
These Consolidated guidelines include a comprehensive set of WHO recommendations for the treatment and care of DR-TB, derived from these WHO guidelines documents. The consolidated guidelines include policy recommendations on treatment regimens for isoniazid-resistant TB (Hr-TB) and MDR/RR-TB, including longer and shorter regimens, culture monitoring of patients on treatment, the timing of antiretroviral therapy (ART) in MDR/RR-TB patients infected with the human immunodeficiency virus (HIV), use of surgery for patients receiving MDR-TB treatment, and optimal models of patient support and care.
Access the full guidelines and WHO report here.
Download the guidelines directly here.

Upcoming RESIST-TB Webinar
On Friday, April 12th from 08:30 to 9:30 EST (14:30-15:30 CEST and SAST), RESIST-TB will be hosting a webinar on two presentations from the 2019 Conference on Retroviruses and Opportunistic Infections (CROI):
THE INHindsight Trial
(Early bactericidal activity of high-dose isonizaid against multidrug-resistant TB)
by Kelly E. DooleyThe DELIBERATE Trial
(QT effects of bedaquiline, delamanid or both in MDR-TB patients)
by Gary Maartens*An announcement will sent out soon with details on how to join the webinar.

PUBLICATIONS

1. Treatment outcomes of patients switching from an injectable drug to bedaquiline during short standardized MDR-TB treatment in Mozambique
Clin Infect Dis. 2019 Mar 11. pii: ciz196. doi: 10.1093/cid/ciz196.
Bastard M, Molfino L, Mutaquiha C, Galindo MA, Zindoga P, Vaz D, Mahinça I, du Cros P, Rusch B, Telnov A

ABSTRACT: Bedaquiline was recommended by WHO as the preferred option in treatment of MDR-TB patients with long regimen. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched injectable dug to bedaquiline suggest that bedaquiline based short regimen is effective and safe.

This article is unavailable via open access.

2. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.
N Engl J Med. 2019 Mar 13. doi: 10.1056/NEJMoa1811867.
Nunn AJ, Phillips PPJ, Meredith SK, et. al.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.
METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive
a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.
RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group – a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia’s formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.
CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.

Read the full article here.

3. Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with
Tuberculosis.

Antimicrob Agents Chemother. 2019 Mar 11. pii: AAC.00055-19. doi: 10.1128/AAC.00055-19.
Alghamdi WA, Alsultan A, Al-Shaer MH, An G, Ahmed S, Alkabab Y, Banu S, Barbakadze K, Houpt E, Kipiani M, Mikiashvili L, Schmidt S, Heysell SK, Kempker RR, Cegielski JP, Peloquin CA.

BACKGROUND: Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on
cycloserine in tuberculosis (TB) patients. We pooled several studies into a large
PK dataset to estimate the population PK parameters for cycloserine in TB
patients. We also performed simulations to provide insight into optimizing the
dosing of cycloserine.
METHODS: TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA.
RESULTS: Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA was achieved as the total daily dose was increased. The
highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/L. For MICs >16 mg/L, doses of at least 500 mg three times daily or 750 mg twice daily were needed.
CONCLUSIONS: The current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs >16mg/L. Further studies are needed regarding the efficacy and tolerability of daily doses >1000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimized exposure, which can potentially reduce the drug adverse effects.

Read the full article here.

4. Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.
Lancet HIV. 2019 Mar;6(3):e201-e204. doi: 10.1016/S2352-3018(19)30035-9.
O’Donnell MR, Padayatchi N, Daftary A, Orrell C, Dooley KE, Rivet Amico K, Friedland G.

ABSTRACT: Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa
and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.

Read the full article here (will require a free Lancet account).

 

5. Health care gaps in the global burden of drug-resistant tuberculosis.                                                                                                  Int J Tuberc Lung Dis. 2019 Feb 1;23(2):125-135. doi: 10.5588/ijtld.18.0866.                                                                                                               Cox V, Cox H, Pai M, Stillo J, Citro B, Brigden G.

ABSTRACT: The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

Revamped WHO Civil Society Task Force

The World Health Organization has revamped its Civil Society Task Force on TB to strengthen collaboration for accelerating progress towards ending TB. As countries are beginning to ramp up efforts to end TB following commitments made by Heads of State at the first-ever UN High-Level Meeting on TB (UN HLM) in September 2018, the role of civil society in driving action and accountability is more important than ever.

Find the full article here.

The Combined Use of Delamanid and Bedaquiline for MDR-TB: Current Evidence and Practices

On April 5th, Dr. Cathy Hewison and Dr. Lorenzo Guglielmetti presented a webinar covering the current clinical practice and results of use of MDR-TBregimens containing the delamanid and bedaquiline combination from endTB, MSF and Europe, as well an overview of the latest publications and the ongoing studies and trials.

Two new drugs for tuberculosis, delamanid and bedaquiline, have shown to be effective and safe for the treatment of MDR-TB. Today, more and more clinicians around the world are experienced in using these drugs as part of a longer conventional MDR-TB regimen with good results. However, there is less experience in using delamanid and bedaquiline together in the same MDR-TB treatment regimen due to concerns about the common effects on the QT interval. Whilst there are studies ongoing to document the effect on the QT interval of these drugs in combination as well as clinical trials testing the safety and effectiveness of regimens including the combination, these results will not be available for the next 3-5 years. In the meantime, clinicians have used their best clinical judgement and have prescribed the combination of delamanid and bedaquiline as part of a longer conventional MDR-TB regimen, for individual patients in need.

Presentation slides will be available shortly.

UN Zero Draft Political Declaration calls for Joint Action on TB and AIDS

This April the co-facilitators leading negotiations for the 2016 United Nations High-Level Meeting on Ending AIDS, the UN Permanent Representatives of Switzerland and Zambia, released the Zero Draft Political Declaration. The Zero Draft contains commitments which aim to end AIDS and TB epidemics by 2030, and will be negotiated and finalized by governments leading up to the High-Level Meeting in New York on June 8-10th.  Included in the proposed commitments are the reductions of TB-related deaths among people living with HIV by 75% by 2020, development of new service delivery models to ensure delivery of more integrated services for HIV and TB, and recognition that TB remains the leading cause of death among people living with HIV. To read more about the Zero Draft, visit TB Online here or the UNAIDS website here.

Delamanid to be added to the Global Drug Facility

The Stop TB partnership and Otsuka Pharmaceutical have arranged for the inclusion of delamanid in the Global Drug Facility (GDF). This inclusion will allow the drug to be available at a cost of US$1,700 per six-month treatment. Delamanid has been tested in children as young as six, may be able to be administered in pregnant women (based on physician discretion), and pending the results of a phase III clinical trial, recommendations for its use may be broadened. Unfortunately, the drug has yet to reach many patients outside of clinical trials, as the drug is currently only registered in areas where there are relatively few MDR-TB patients. To read the full press release, visit the Treatment Action Group website here. To read more, visit the Médecins Sans Frontières website here, or view a press release from Treatment Action Group here and Otsuka here.

NEXT Trial Approved by MCC in South Africa

The NEXT trial, an open-label RCT to evaluate a new treatment regimen for patients with MDR-TB, has been approved in South Africa by the Medicine Controls Council. The NEXT trial aims to evaluate the impact of a new injection-free six-to-nine month treatment regimen of linezolid, bedaquiline, levofloxacin, pyrazinamide and ethionamide/high dose isoniazid compared to the conventional empiric injection-based regimen of 21-24 months treatment. The secondary aim is to determine if other treatment-related outcomes including adverse events, adherence to treatment, culture conversion, and cure/completion are significantly different in the intervention and conventional arms. To read more about the NEXT trial, visit the ClinicalTrials.gov listing here.

Nix-TB Trial for XDR-TB Launched

TB Alliance has announced the start of the Nix-TB trial, aimed at  testing all-oral drug regimen, that has the potential to shorten, simplify, and improve treatment for XDR-TB. Nix-TB will study a three-drug regimen of bedaquiline, pretonamid, and linezolid. To read more on the launch of the trial, visit the TB Alliance website here, and the trial factsheet here.

TB activist Phumeza Tisile receives cochlear implant

Phumeza Tisile, an XDR-TB survivor and activist, lost her hearing due to side effects from drugs to treat XDR-TB. Last month, Phumeza received a cochlear implant and was able to hear for the first time in almost five years. Read her post here to hear more about this experience or visit her blog at the MSF website here to learn more about her story.

Bedaquiline donation program started April 1st

On April 1st, the bedaquiline donation program was opened, allowing countries to request bedaquiline. This program is in response to the agreement between The United States Agency for International Development (USAID) and Janssen Therapeutics, to provide the drug free to 30,000 MDR-TB patients in over 100 low- and middle-income countries over a four year period. For more information and a step-by-step guide to navigating the bedaquiline donation program, visit the TB Online website here.

September eNewsletter

Drug-resistant tuberculosis control in South Africa: scientific advances and health system strengthening are complementary.

Padayatchi N, Loveday M, Naidu N.

Expert Opin Pharmacother. 2014 Oct;15(15):2113-6.

Abstract We examine some aspects of the South African health system that have contributed to the current multi- and extensively drug-resistant tuberculosis(M(X)DR-TB) epidemic and identify opportunities for change and improvement. Implementation of several recent major scientific advances have the potential to accelerate the control of M(X)DR-TB, but health systems strengthening will be essential.

View the abstract here

 

A Field Evaluation of the Hardy TB MODS Kit™ for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis.

Martin L, Coronel J, Faulx D, Valdez M, Metzler M, Crudder C, Castillo E, Caviedes L, Grandjean L, Rodriguez M, Friedland JS, Gilman RH, Moore DA.

PLoS One. 2014 Sep 16;9(9):e107258.

Abstract BACKGROUND: Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory. METHODS & FINDINGS: 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples). CONCLUSIONS: MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.

View the full text here

 

Drug-resistant tuberculosis in Israel: risk factors and treatment outcomes.

Mor Z, Goldblatt D, Kaidar-Shwartz H, Cedar N, Rorman E, Chemtob D.

Int J Tuberc Lung Dis. 2014 Oct;18(10):1195-201.

Abstract SETTING: All culture-positive tuberculosis (TB) isolates in Israel. OBJECTIVES: To outline the magnitude of drug-resistant TB in Israel, describe treatment outcomes and identify risk factors. DESIGN: Retrospective study of laboratory data of all strains of adult TB patients tested for resistance to first- and second-line anti-tuberculosis drugs between 1999 and 2010. RESULTS: Of 4652 reported TB cases, 3552 (76.3%) underwent culture (annual range 73-81%); 445 (12.5%) were resistant to one or more first-line drugs, while 207 (5.8%) had multidrug-resistant TB (MDR-TB). Risk factors for MDR-TB included being male, age 30-59 years, migrants (mainly from the former Soviet Union [FSU]) who had stayed in Israel >2 years, and having pulmonary TB, human immunodeficiency virus (HIV) infection and sputum smear positivity. Of all MDR-TB patients, 71.0% achieved treatment success, while 19.8% died. Twelve Israeli citizens had extensively drug-resistant TB (5.8% of MDR-TB cases). All had emigrated from the FSU and had pulmonary TB; 1 was HIV-infected. Seven (58.4%) achieved treatment success and 5 (41.6%) died. CONCLUSIONS: Drug-resistant TB in Israel is influenced by migration, especially from the FSU, where the patients were probably infected. Rapid sputum sampling performed in the early stages of the disease, patient isolation and drug susceptibility testing should be the standard of care to avoid further transmission and improve TB control.

View the abstract here

 

Successful ‘9-month Bangladesh regimen’ for multidrug-resistant tuberculosis among over 500 consecutive patients.

Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL.

Int J Tuberc Lung Dis. 2014 Oct;18(10):1180-7.

Abstract SETTING: Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh. OBJECTIVE: To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a standardized regimen consisting of a minimum 9 months. DESIGN: This was a prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS: Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION: The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance.

View the abstract here

 

Short-course Bangladesh regimen for multidrug-resistant tuberculosis: a step in the right direction?

Lalloo UG.

Int J Tuberc Lung Dis. 2014 Oct;18(10):1137-8.

No abstract available. View the article in Pubmed here. 

 

HIV, multidrug-resistant TB and depressive symptoms: when three conditions collide.

Das M, Isaakidis P, Van den Bergh R, Kumar AM, Nagaraja SB, Valikayath A, Jha S, Jadhav B, Ladomirska J.

Glob Health Action. 2014 Sep 9;7:24912.

Abstract BACKGROUND: Management of multidrug-resistant TB (MDR-TB) patients co-infected with human immunodeficiency virus (HIV) is highly challenging. Such patients are subject to long and potentially toxic treatments and may develop a number of different psychiatric illnesses such as anxiety and depressive disorders. A mental health assessment before MDR-TB treatment initiation may assist in early diagnosis and better management of psychiatric illnesses in patients already having two stigmatising and debilitating diseases.  OBJECTIVE: To address limited evidence on the baseline psychiatric conditions of HIV-infected MDR-TB patients, we aimed to document the levels of depressive symptoms at baseline, and any alteration following individualized clinical and psychological support during MDR-TB therapy, using the Patient Health Questionnaire-9 (PHQ-9) tool, among HIV-infected patients. DESIGN: This was a retrospective review of the medical records of an adult (aged >15 years) HIV/MDR-TB cohort registered for care during the period of August 2012 through to March 2014. RESULTS: A total of 45 HIV/MDR-TB patients underwent baseline assessment using the PHQ-9 tool, and seven (16%) were found to have depressive symptoms. Of these, four patients had moderate to severe depressive symptoms. Individualized psychological and clinical support was administered to these patients. Reassessments were carried out for all patients after 3 months of follow-up, except one, who died during the period. Among these 44 patients, three with baseline depressive symptoms still had depressive symptoms. However, improvements were observed in all but one after 3 months of follow-up. CONCLUSION: Psychiatric illnesses, including depressive symptoms, during MDR-TB treatment demand attention. Routine administration of baseline mental health assessments by trained staff has the potential to assist in determining appropriate measures for the management of depressive symptoms during MDR-TB treatment, and help in improving overall treatment outcomes. We recommend regular monitoring of mental health status by trained counsellors or clinical staff, using simple, validated and cost-effective tools.

View the full text here

 

Delamanid: A new armor in combating drug-resistant tuberculosis.

Xavier AS, Lakshmanan M.

J Pharmacol Pharmacother. 2014 Jul;5(3):222-4.

Abstract Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA) for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability.

View the full text here

 

A targets framework: Dismantling the invisibility trap for children with drug-resistant tuberculosis.

Becerra MC, Swaminathan S.

J Public Health Policy. 2014 Sep 11. doi: 10.1057/jphp.2014.35.

Abstract Tuberculosis (TB) is an airborne infectious disease that is both preventable and curable, yet it kills more than a million people every year. Children are highly vulnerable, but often invisible casualties. Drug-resistant forms of TB are on the rise globally, and children are as vulnerable as adults but less likely to be counted as cases of drug-resistant disease if they become sick. Four factors make children with drug-resistant TB ‘invisible’: first, the nature of the disease in children; second, deficiencies in existing diagnostic tools; third, overreliance on these tools; and fourth, our collective failure to deploy one effective tool for finding and treating children – contact investigation. We describe a nascent science-advocacy network – the Sentinel Project on Pediatric Drug-Resistant Tuberculosis – whose goal is to end child deaths from this disease. Provisional annual targets, focused on children exposed at home to multidrug-resistant TB, to be updated every year, constitute a framework to focus attention and collective actions at the community, national, and global levels. The targets in two age groups, under 5 and 5-14 years old, tell us the number of: (i) children who require complete evaluation for TB disease and infection; (ii) children who require treatment for TB disease; and (iii) children who would benefit from preventive therapy.Journal of Public Health Policy advance online publication, 11 September 2014; doi:10.1057/jphp.2014.35.

View the abstract here

 

Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug-Resistant Tuberculosis.

Worley MV, Estrada SJ.

Pharmacotherapy. 2014 Sep 9. doi: 10.1002/phar.1482.

Abstract Bedaquiline is a diarylquinoline antitubercular drug with a novel mechanism of action against Mycobacterium tuberculosis. Bedaquiline works by inhibiting bacterial adenosine triphosphate (ATP) synthase and represents the first novel class of antituberculosis agents in more than 40 years. Bedaquiline is indicated for the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with at least three other antitubercular drugs when no other effective regimen is available. The recommended bedaquiline dosage is 400 mg orally once/day for 2 weeks followed by 200 mg orally 3 times/week for 22 weeks. Bedaquiline should be administered with food, which increases the bioavailability 2-fold. Bedaquiline is metabolized by cytochrome P450 isoenzyme 3A4 and is impacted by both inducers and inhibitors of this isoenzyme. Concentration-dependent bactericidal activity was observed in laboratory and murine studies. Accelerated approval was granted in the United States and European Union based on the results of two phase IIb clinical studies that used sputum culture clearance as a surrogate end point for clinical efficacy. These studies showed greater sputum culture clearance up to week 24 for the bedaquiline group compared with placebo. Common adverse events in clinical trials included nausea, arthralgia, and headache. Serious adverse events included elevated serum transaminase levels and rate-corrected QT-interval prolongation. Unexplained higher mortality was seen in patients receiving bedaquiline versus those receiving placebo. Bedaquiline is a novel agent with a unique mechanism of action and has the potential to meet a great need in patients with MDR TB who have no other treatment options. Due to safety concerns and limited clinical information, phase III trials are needed to fully determine its place in therapy.

View the abstract here

 

Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial.

Nunn AJ, Rusen I, Van Deun A, Torrea G, Phillips PP, Chiang CY, Squire SB, Madan J, Meredith SK.

Trials. 2014 Sep 9;15(1):353. doi: 10.1186/1745-6215-15-353.

Abstract BACKGROUND: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection. METHODS/DESIGN: STREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites. DISCUSSION: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB.

View the full text here. 

 

Second-line drug susceptibilities of multidrug-resistant tuberculosis strains isolated in Thailand: an update.

Chaiprasert A, Srimuang S, Tingtoy N, Makhao N, Sirirudeeporn P, Tomnongdee N, Theankeaw O, Charoensook S, Leechawengwongs M,Prammananan T.

Int J Tuberc Lung Dis. 2014 Aug;18(8):961-3. doi: 10.5588/ijtld.13.0197.

Abstract The increasing incidence of multidrug-resistant tuberculosis (MDR-TB) and the emergence of extensively drug-resistant tuberculosis (XDR-TB) globally hamper the successful treatment and effective control of TB. Information on second-line drug susceptibility, which is of utmost importance for patient care, is still limited. This study demonstrates the susceptibilities of 1447 strains of MDR-TB, including 58 XDR-TB strains, isolated from Siriraj Hospital, Bangkok, Thailand, to aminoglycosides, fluoroquinolones, ethionamide (ETH), para-aminosalicylic acid (PAS) and linezolid. Results revealed that 93-94% of the MDR-TB strains were susceptible to aminoglycosides, 85-98% to fluoroquinolones, 78% to ETH, 85% to PAS and 99% to linezolid

View the abstract here. 

 

A new paradigm for multidrug-resistant tuberculosis?

Reichman LB, Schaaf HS, Pontali E, Migliori GB.

Int J Tuberc Lung Dis. 2014 Aug;18(8):884. doi: 10.5588/ijtld.14.0347.

No abstract available. View the article in Pubmed here. 

 

Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009-2012.

Bamrah S1, Brostrom R1, Dorina F2, Setik L2, Song R1, Kawamura LM3, Heetderks A1, Mase S1.

Int J Tuberc Lung Dis. 2014 Aug;18(8):961-3. doi: 10.5588/ijtld.13.0197.

Abstract SETTING: Few studies have shown the operational feasibility, safety, tolerability, or outcomes of multidrug-resistant latent tuberculous infection (MDR LTBI) treatment. After two simultaneous multidrug-resistant tuberculosis (MDR-TB) outbreaks in Chuuk, Federated States of Micronesia, infected contacts were offered a 12-month fluoroquinolone (FQ) based MDR LTBI treatment regimen. DESIGN: Between January 2009 and February 2012, 119 contacts of MDR-TB patients were followed using a prospective observational study design. After MDR-TB disease was excluded, 12 months of daily FQ-based preventive treatment of MDR LTBI was provided by directly observed therapy. RESULTS: Among the 119 infected contacts, 15 refused, while 104 began treatment for MDR LTBI. Of the 104 who initiated treatment, 93 (89%) completed treatment, while 4 contacts discontinued due to adverse effects. None of the 104 contacts who undertook MDR LTBI treatment of any duration developed MDR-TB disease; however, 3 of 15 contacts who refused and 15 unidentified contacts developed MDR-TB disease. CONCLUSION: Providing treatment for MDR LTBI can be accomplished in a resource-limited setting, and contributed to preventing MDR-TB disease. The Chuuk TB program implemented treatment of MDR LTBI with an 89% completion rate. The MDR LTBI regimens were safe and well tolerated, and no TB cases occurred among persons treated for MDR LTBI.

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Shifting gears to control drug-resistant tuberculosis.

Berkelman RL, Cassell GH, Whitney EA, Keshavjee S.

Clin Infect Dis. 2014 Sep 15;59(6):908-10. doi: 10.1093/cid/ciu479. Epub 2014 Jun 18.

No abstract available. View this article in Pubmed here. 

 

Rapid molecular screening for multidrug-resistant tuberculosis in a resource-limited region of China.

Zhang D, Liu B, Wang Y, Pang Y.

Trop Med Int Health. 2014 Oct;19(10):1259-66. doi: 10.1111/tmi.12359. Epub 2014 Jul 17.

Abstract OBJECTIVE: To investigate the molecular characteristics of MDR and XDR strains circulating in Chongqing, China. METHODS: The drug target genes conferring for rifampicin (RIF), isoniazid (INH), ethambutol (EMB), ofloxacin (OFLX) and kanamycin (KAN) resistance were screened by DNA sequencing to determine the mutation frequencies in this area. RESULTS: Drug susceptibility of 208 MDR isolates revealed that 132 (63.46%) were resistant to streptomycin (SM), 96 (46.15%) to ethambutol (EMB), 51 (24.52%) to ofloxacin (OFLX), and 26 (12.50%) to kanamycin (KAN); six (2.88%) isolates had XDR profiles. In comparison with the drug susceptibility phenotype, the sensitivity of drug resistance by DNA sequencing was 91.83% for RIF, 87.50% for INH, 66.67% for EMB, 74.51% for OFLX and 53.85% for KAN resistance. 12.50% of EMB- and 1.27% of OFLX-susceptible isolates were harboured genetic mutations in embB and gyrA, respectively. CONCLUSION: Our findings demonstrate that the hot-spot regions localised in rpoB, katG and inhA genes serve as excellent markers for the corresponding drug resistance, while EMB, OFLX or KAN drug-resistant TB cases may not be identifiable by scanning embB, gyrA, rrs and eis promoter in Chongqing, indicating that further studies on the drug resistance mechanisms of EMB, OFLX and KAN are urgently needed to elucidate the low sensitivity between genomic substitutions and drug-resistant phenotype.

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Microscopic observation drug susceptibility assay for the diagnosis of TB and MDR-TB in HIV-infected patients: a systematic review and meta-analysis.

Wikman-Jorgensen P1, Llenas-García J2, Hobbins M3, Ehmer J3, Abellana R4, Queiroga Gonçalves A4, Pérez-Porcuna TM5, Ascaso C4.

Eur Respir J. 2014 Sep 3. pii: erj00796-2014.

Abstract The objective of the present study was to assess the diagnostic accuracy of the microscopic observation drug susceptibility (MODS) assay for tuberculosis (TB) diagnosis in HIV-infected patients. MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials, African Index Medicus, ResearchGate, SciELO, and the abstracts of the main conferences on infectious diseases and tropical medicine were searched, and other sources investigated. Only studies including HIV-infected patients evaluating MODS for the diagnosis of TB and using culture-based diagnostic tests as a gold standard were analysed. Summary sensitivity and specificity were calculated with a bivariate model. 3259 citations were found, 29 were selected for full-text review and 10 studies including 3075 samples were finally analysed. Overall diagnostic accuracy of MODS for the diagnosis of TB was a sensitivity of 88.3% (95% CI 86.18-90.2%) and specificity 98.2% (95% CI 97.75-98.55%). For multidrug-resistant (MDR)-TB, sensitivity was 89% (95% CI 66.07-97%) and specificity was 100% (95 CI 94.81-100%). For smear-negative pulmonary TB, a sensitivity of 88.2% (95% CI 86.1-89.9%) and specificity of 98.2% (95% CI 96.8-98.9%) were found. Costs varied between USD 0.72 and 7.31 per sample. Mean time to positivity was 8.24 days. MODS was found to have a good accuracy for the diagnosis of TB and MDR-TB in HIV-infected patients with low cost and fast results.

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Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis.

Dharmadhikari AS, Mphahlele M, Venter K, Stoltz A, Mathebula R, Masotla T, van der Walt M, Pagano M, Jensen P, Nardell E.

Int J Tuberc Lung Dis. 2014 Sep;18(9):1019-25. doi: 10.5588/ijtld.13.0834.

Abstract BACKGROUND: Effective treatment for drug-susceptible tuberculosis (TB) rapidly renders patients non-infectious, long before conversion of sputum acid-fast smear or culture to negative. Multidrug-resistant TB (MDR-TB) patients on treatment are currently assumed to remain infectious for months. While the resources required for prolonged hospitalization are a barrier to the scale-up of MDR-TB treatment, the safety of community treatment is clear. OBJECTIVES: To estimate the impact of treatment on infectiousness among MDR-TB patients. METHODS: A series of five human-to-guinea pig TB transmission studies was conducted to test various interventions for infection control. Guinea pigs in adjacent chambers were exposed to exhaust air from a hospital ward occupied by mostly sputum smear- and culture-positive MDR-TBpatients. The guinea pigs then underwent tuberculin skin testing for infection. Only the control groups of guinea pigs from each study (no interventions used) provide the data for this analysis. The number of guinea pigs infected in each study is reported and correlated with Mycobacterium tuberculosis drug susceptibility relative to treatment. RESULTS: Despite exposure to presumably infectious MDR-TB patients, infection percentages among guinea pigs ranged from 1% to 77% in the five experiments conducted. In one experiment in which guinea pigs were exposed to 27 MDR-TB patients newly started on effective treatment for 3 months, there was minimal transmission. In four other experiments with greater transmission, guinea pigs had been exposed to patients with unsuspected extensively drug-resistant tuberculosis who were not on effective treatment. CONCLUSIONS: In this model, effective treatment appears to render MDR-TB patients rapidly non-infectious. Further prospective studies on this subject are needed.

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Increase in anti-tuberculosis drug resistance in Botswana: results from the fourth National Drug Resistance Survey.

Menzies HJ, Moalosi G, Anisimova V, Gammino V, Sentle C, Bachhuber MA, Bile E, Radisowa K, Kachuwaire O, Basotli J, Maribe T, Makombe R,Shepherd J, Kim B, Samandari T, El-Halabi S, Chirenda J, Cain KP.

Int J Tuberc Lung Dis. 2014 Sep;18(9):1026-33.

Abstract SETTING: Although approximately 0.5 million cases of multidrug-resistant tuberculosis (MDR-TB) occur globally each year, surveillance data are limited. Botswana is one of the few high TB burden countries to have carried out multiple anti-tuberculosis drug resistance surveys (in 1995-1996, 1999 and 2002). OBJECTIVE: In 2007-2008, we conducted the fourth national survey of anti-tuberculosis drug resistance in Botswana to assess anti-tuberculosis drug resistance, including trends over time. In the previous survey, 0.8% (95%CI 0.4-1.5) of new patients and 10.4% (95%CI 5.6-17.3) of previously treated patients had MDR-TB. DESIGN: During the survey period, eligible specimens from all new sputum-smear positive TB patients and from all TB patients with history of previous anti-tuberculosis treatment underwent mycobacterial culture and anti-tuberculosis drug susceptibility testing (DST). RESULTS: Of 924 new TB patients and 137 with previous anti-tuberculosis treatment with DST results, respectively 23 (2.5%, 95%CI 1.6-3.7) and 9 (6.6%, 95%CI 3.3-11.7) had MDR-TB. The proportion of new TB patients with MDR-TB has tripled in Botswana since the previous survey. CONCLUSION: Combatting drug-resistant TB will require the scale-up of MDR-TB diagnosis and treatment to prevent the transmission of MDR-TBand strengthening of general TB control to prevent the emergence of resistance.

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Rapid impact of effective chemotherapy on transmission of drug-resistant tuberculosis: pity the guinea pig.

Farmer PE, Raviglione MC.

Int J Tuberc Lung Dis. 2014 Sep;18(9):1009-11. doi: 10.5588/ijtld.14.0538.

No abstract available. View this article in Pubmed here.