Ўзбекистон Республикаси
Соғлиқни сақлаш вазирлиги
Effectiveness of a simplified short regimen for
Multidrug Resistant Tuberculosis treatment in Karakalpakstan, Uzbekistan
Joint MSF - Operational Centre Amsterdam / MOH Uzbekistan Research Protocol
Research Protocol - amendment
April 2014
Philipp du Cros1
Khamraev Atadjan (deputy of Chairman of Supreme Council of Karakalpakstan)2
Tillashaikhov Mirzagalib (MoH Uzbekistan, Director of specialized medical center of TB and pulmonology) 2
Parpieva Nargiza (MoH Uzbekistan, chief TB specialist)2
Tigay Zinaida (Chief of TB2)2
Sholtaeva Marjan (Chief TB doctor of Kegeily rayon)2
Abdrasuliev Tleubergen (Chief TB doctor of Shumanay rayon)2
Marttje Betlam (Doctor Kegeily Rayon)1
Emily Wise (Doctor Shumanay)1
Teshome Ashagre (Medical Coordinator)1
Johanna Kuhlin1
Andrii Slyzkyi(laboratory manager) 1
Alia Taye Epidemiologist Uzbekistan1
Sebastian Dietrich1
Bern-Thomas Nyangwa1
Jane Greig1
Pamela Hepple1
Graham Cooke3
Krzysztof Herboczek1
Muhammad Asif1
Jay Achar1
Catherine Berry1
1 Médecins Sans Frontières, Operational Center Amsterdam
2 Ministry of Health Uzbekistan
3 Imperial College London
Main contacts
Co-Principal Investigator MSF Co-Principal Investigator MoH
Dr. Philipp du Cros Dr. Khamraev A. Karimovich
Médecins Sans Frontières–UK
67 Saffron Hill
London
e-mail:
Pilot Coordinator
Catherine Berry
Médecins Sans Frontières, Nukus
e-mail:
Phone: +998913778652
TABLE OF CONTENTS
LIST OF ABBREVIATIONS 4
SUMMARY 5
INTRODUCTION 6
Context 7
Current Standard of Care for MDR TB 8
Evidence for short course MDR TB treatment 9
HYPOTHESIS 10
RESEARCH OBJECTIVES 10
Primary objective 10
Secondary objectives 10
PATIENTS AND METHODOLOGY 11
1. Study design 11
2. Study sites 11
3. Partnership/study coordination 11
4. Study participants and sample size 12
5. Study endpoints 14
6. Case Definitions 15
7. Treatment options 16
8. Monitoring of adverse events/reactions 18
9. Assessment of treatment effectiveness 19
10. Study procedure and patient flow 22
11. Laboratory tests and electrocardiogram 24
12. Variables 25
13. Data collection 25
14. Statistical Analysis 26
ETHICAL ISSUES 26
1. Ethical Committee 26
2. Consent forms 26
3. Expected risks and advantages 27
4. Confidentiality 28
5. Community Involvement 28
BUDGET 28
TIMELINE 29
DISSEMINATION OF STUDY RESULTS 29
REFERENCES 30
LIST OF ABBREVIATIONS
ALT Alanine aminotransferase
ART Antiretroviral Therapy
BMI Body Mass Index
Cfz Clofazimine
Cm Capreomycin
DST Drug Sensitivity Test
DR TB Drug resistant tuberculosis
E Ethambutol
FLD First line drugs
Gfx Gatifloxacin
H Isoniazid
Hb Hemoglobin
HIV Human Immunodeficiency Virus
IUATLD International Union Against Tuberculosis and Lung Diseases
Km Kanamycin
Mfx Moxifloxacin
MSF Médecins Sans Frontières/Doctors without Borders
MDR TB Multidrug resistant TB
MTB Mycobacterium tuberculosis
MoH Ministry of Health
MGIT Mycobacteria Growth Indicator Tube
NRL National Reference Laboratory
OCA Operational Centre Amsterdam
Pto Prothionamide
SLD Second line drugs
TB Tuberculosis
TSH Thyroid stimulating hormone
VL Viral load
WHO World Health Organization
XDR TB Extremely drug resistant tuberculosis
Z Pyrazinamide
SUMMARY
Multidrug resistant tuberculosis (MDR TB) is a growing problem and few people have access to adequate diagnosis and treatment. The current recommended treatment regimen for MDR TB has a minimum of 20 months duration with high toxicity. Scale up of MDR TB treatment is associated with high default rates, and experience in the MSF programme in Uzbekistan shows that the current standard treatment greatly limits the ability to scale up to meet the high rates of MDR TB in the region. Evidence from Bangladesh in 2010 showed that a 9-month short-course regimen could achieve a relapse free-cure rate of 88%. Several countries in West Africa started implementing similar regimens with similar outcomes. Evidence of effectiveness of this shortened regimen amongst regions with high second line drug use and resistance is still limited. We propose an observational study under programmatic conditions to evaluate the effectiveness of a shortened course MDR TB regimen in the high MDR/XDR TB prevalence setting of Karakalpakstan.
A prospective observational study has been designed. All patients with presumptive MDR TB identified with rapid molecular testing (MTBDR plus or Xpert® MTB/RIF assay) and later on culture confirmed MDR TB without the history of the previous treatment for MDR TB for longer than one month will be included in the study. The study regimen is composed of an intensive phase of at least 4 months duration of Pyrazinamide (Z) + Ethambutol (E) + Isoniazid (H) + Moxifloxacin (Mfx) + Capreomycin (or Kanamycin/Amikacin) (Cm/Km/Am) + Prothionamide (Pto) + Clofazimine (Cfz) and a continuation phase of oral drugs Z-E-Mfx-Pto-Cfz. Patients will be followed up until the end of treatment and during 12 months after treatment completion in order to evaluate the rate of relapse.
The primary outcome measure is the success rate at the end of treatment, and relapse and re-infection rates during 12 months of follow up after completion of treatment. Secondary outcome measures include rate of adverse events, interim outcomes with sputum smear microscopy and culture conversion rates at 4 and 6 months and time to conversion.
Data will be recorded in patient’s clinical files and electronic databases and analyzed with Stata 11.0.
This study is a result of ongoing collaboration of MSF with the MoH in Uzbekistan; results will be shared with the national health authorities, World Health Organization and the rest of the scientific community and aim to influence and improve treatment and care of patients with MDR TB.
INTRODUCTION
Multidrug-resistant tuberculosis (MDR-TB) is defined as Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, the two most effective anti-tuberculosis drugs. An estimated 440,000 new cases of MDR-TB occur globally each year with an estimated 150,000 deaths (WHO 2010). The highest proportions of MDR-TB globally are in countries of Eastern Europe and Central Asia, including Uzbekistan.
MDR TB / XDR TB is an increasing problem as highlighted in the 2012 WHO global tuberculosis report. (WHO 2012) MDR-TB treatment requires complex, expensive treatment with less effective second line drugs, and is often associated with significant side effects. The minimum treatment duration is 20 months. Treatment outcomes for patients with MDR-TB are worse than for drug sensitive TB, with low success rates and high rates of treatment failure and default (WHO 2011). The implementation of MDR TB treatment worldwide is stagnating with very limited scale up predicted between 2012-2015 with current treatment, leaving a large gap between those in need of treatment and those diagnosed and commenced on treatment. (WHO 2012) In addition, a recent systematic review showed that increased cohort size is associated with increased rates of default suggesting that as programmes scale up, results worsen (Toczek 2012).
In 2010, a cohort study of MDR TB patients treated with a 9 month short course regimen achieved a relapse-free cure rate of 88% in 206 patients (Van Deun 2010). Following the publication of the Bangladesh experience, several countries in Africa are piloting implementation of similar regimens and early results show similarly impressive outcomes. The Union for tuberculosis and lung disease has included this regimen in its recently published tuberculosis programmatic guidelines (Ait-Khaled 2010). MSF is currently using the 9-month regimen in Chad, South Sudan and the Central African Republic, and will commence implementation of a prospective cohort study in Swaziland.
Children have characteristically paucibacillary tuberculosis and thus they may require shorter duration and fewer drugs than adults to treat MDR TB infection and they could benefit from this regimen; however evidence of MDR TB treatment in children is scarce. We aim to include children in this study.
Further data from the Bangladesh short course programme have consistently shown relapse free treatment success of 85.5% in 476 patients with 2 years follow up. Reported adverse events are lower than those reported with standard MDR TB treatment. However in patients with fluoroquinolone resistance the relapse free success rate was lower at 73.2%, and amongst this group those who failed had high rates of amplification of resistance (Van Deun 2012). There is still much contention about the 9 month MDR TB regimen owing to the fact that the data available is of low quality evidence from single arm cohort studies, and in the case of the Bangladesh programme there were a large number of patients eligible for enrolment who did not get included which suggests the possibility of biased selection. It is unclear what would allow this short course regimen to work, and there is no data about the impact of baseline resistance to drugs used in the regimen such as pyrazinamide, ethambutol, injectables or prothionamide. WHO has requested that countries piloting this regimen collect data under operational research conditions, and have cautioned that there is not enough data to know whether this regimen will be effective in all contexts.
We propose an observational study to evaluate the effectiveness of this short-course MDR TB regimen in the high MDR TB prevalence and high second line drug resistance setting of Karakalpakstan, Uzbekistan.
Context
Uzbekistan is included in WHO’s 27 high burden MDR-TB countries, with a recent National TB drug resistance survey reporting 23% of new TB patients and 62% of previously treated patients were infected with MDR-TB (WHO 2012). Karakalpakstan is an autonomous region of Uzbekistan, situated in the North West of the country, covering approximately one third of the country, with a population of approximately 1.2 million. The Karakalpakstan population suffers from high rates of health problems, associated with severe environmental degradation as well as economic, social and health care services deterioration (Crighton 2011). The prevalence of TB in Karakalpakstan was reported to be 464/100,000 population, considerably higher than in the rest of Uzbekistan (227/100,000) (WHO 2009, MoH Uzbekistan 2009).
Médecins Sans Frontières (MSF), together with the Ministry of Health, initiated a DOTS-plus project to treat MDR-TB in 2003 in 2 rayons (districts) in Karakalpakstan, Uzbekistan. Drug sensitivity testing (DST) was initially provided for DR-TB suspects, but was expanded to include all smear positive patients from 2006. Treatment was based on international treatment guidelines, initially with individualized treatment regimens. In 2010, the programme commenced scaling up to other districts. Simplified treatment guidelines for comprehensive TB care for diagnosis and treatment of all forms of TB were developed with standardized side effect management. Psychosocial support, health education and enablers/incentives are provided in accordance with international best practice. Initially patients were hospitalized, but in 2011 ambulatory treatment from day 1 was introduced as an option for patients who did not require hospitalization. Comprehensive TB care has now been introduced to 8 districts, and in 2013 treatment will commence in a further 2-3 districts.
Sputum smear microscopy, culture and DST are conducted according to international standards in the Nukus mycobacteriology laboratory. Smears are assessed using fluorescence microscopy. Rapid molecular tests were introduced in 2007 (Hain MTBDR plus) and Xpert MTB/RIF was introduced for 2 districts and pediatric cases in 2012. BACTEC™ MGIT™ 960 liquid culture system was introduced to the laboratory for first line drug testing in September 2007 and for second line drug testing in 2011 Quality control tests of the performance of the Nukus laboratory are evaluated by the Gauting laboratory.
By September 2012, 2670 patients with TB showing any form of drug resistance had completed treatment in Karakalpakstan. Treatment success rates are in line with experience reported internationally, with 62% success rate for all MDR-TB patients treated between 2003-2008 (Lalor 2011). Resistance rates to ofloxacin (fluoroquinolones) and capreomycin at baseline are low as <3%, while resistance rates to kanamycin have ranged between 10-20%. Resistance rates to ethambutol and pyrazinamide are >60%, and to prothionamide approximately 15% (Nukus epidemiologist personal communication).
Current Standard of Care for MDR TB
The current standard of care for MDR TB treatment involves a long duration of treatment (minimum 20 months) with at least 5 anti-TB medications including an injectable for a minimum of 8 months. The treatment recommendations are based on low quality of evidence with some recommendations being conditional, mostly from evidence from single arm retrospective cohort descriptions, expert opinion and anecdotal evidence (WHO 2011). Treatment success rates are less than ideal with systematic reviews showing success rates of 62-64% (Orenstein, 2009; Johnston, 2009), but a recent individual patient data meta-analysis of over 9000 MDR TB patients reporting success rates of only 54% (Ahuja, 2012).
Standard MDR TB treatment is associated with a high incidence of side effects. More than one third of patients will suffer from significant nausea and vomiting despite prescription of anti-emetics, and more than 10% of patients will suffer from each of the following side effects: diarrhea (21%), arthralgia (16%), dizziness/vertigo (14%), hearing disturbances (12%), headache (11%), sleep disturbances (11%), electrolyte disturbances (11%) and abdominal pain (11%). In addition, serious life threatening or life impinging side effects are reasonably frequent including: psychosis (3%), peripheral neuropathy (8%), depression (6%), allergic reaction (5%), seizures (4%), hypothyroidism (3.5%), hepatitis (2%) and renal failure (1%). (WHO 2008) One of the major issues discussed by all patients participating in online blogging about their experience with MDR TB in several countries was the major impact on their lives of the side effects of the current treatment regimen (TB and me blogs: http://blogs.msf.org/tb/).
Default rates from MDR-TB treatment are high with 23% default reported in a recent meta-analysis(Ahuja 2012). Reported factors influencing defaulting from TB treatment include lengthy treatment, side effects, high cost of treatment for patients in settings where patients must pay, indirect costs such as loss of wages, increased poverty and gender discrimination, dissatisfaction with health care worker attitudes, limited knowledge, and negative beliefs and attitudes to treatment, challenges with drug procurement and sustained supply of second-line drugs, substance abuse, and psychiatric disorders. In addition, a recent meta-analysis showed that as programme size increases default rates also increase, highlighting the difficulties of scaling up effective MDR-TB treatment with current international gold standard treatment (Toczek 2012). Patients defaulting from treatment are at higher risk of mortality and morbidity, and may contribute to further spread of MDR-TB in the community.
In summary, the current standard of care for MDR TB treatment is complex, requires a long duration, results in over 1 in 5 patients starting treatment defaulting and the majority of patients experience significant and sometimes life threatening side effects. The regimens are based on low quality scientific evidence and as experienced in the MSF/MoH programme in Uzbekistan the current regimen is not feasible to rapidly scale up in order to meet the scale of the global problem. In response to the new WHO global TB report in 2012 a recent Lancet editorial stated that “The response to the problem is woefully insufficient” and concluded that it is time to re-examine the current tuberculosis control approach as “The status quo is unacceptable” (Lancet editorial 2012).