Green Light Committee for the WHO European Region

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1 Green Light Committee for the WHO European Region Country support mission report Ukraine September 2018 Country: Ukraine Dates: September 2018 Consultants: Content editors: Language editor: Dr. Kai Blondal, WHO consultant, pulmonologist, international tuberculosis consultant, Head of Department, Division of Communicable Disease Control, Reykjavik Health Care Services, Iceland MD, PhD, Professor Sven Hoffner. MD, MPH, Dr Elmira Gurbanova, WHO Consultant Mr Owen Elias (ENG) Peer review coordination Clearance of the report Dr Ogtay Gozalov, rglc/europe Secretariat, Joint Tuberculosis, HIV/AIDS and Hepatitis Program (JTH), WHO Regional Office for Europe This report has been fully cleared by the National Tuberculosis Program, Ukraine, for unrestricted publication and circulation. 1

2 Contents Acknowledgements... 3 Abbreviations... 3 Executive summary Site visit to Kherson Site visit to Sumy Annex 1. Terms of reference Annex 2. Follow-up on previous mission recommendations Annex 3. Selected data in support of the mission report

3 Acknowledgements The author would like to express her appreciation to the Ministry of Health of Ukraine, for the progress made in tuberculosis control. The author is grateful to the doctors and nurses at the sites visited for their good collaboration. Thanks also go to the WHO Country Office in Ukraine and the WHO Regional Office for Europe for facilitating the visit. The mission was prepared and organized with financial support of The Global Fund to Fight AIDS, Tuberculosis and Malaria ( under Memorandum of Understanding between WHO and TGF on Regional GLC and Secretariats (April 2017) Abbreviations AMS ARV Bdq Cfz CHA Cm Cs CVKK Dlm DOT DR-TB DST E FLD H Imp-cil Km Lfx LJ LPA Lzd MDR-TB Mfx MGIT MoD MoH MoJ Mpn National Academy of Medical Sciences antiretroviral bedaquiline clofazimine Public Health Institute capreomycin cycloserine Central Medical Coordination Committee delamanid directly observed treatment drug-resistant tuberculosis drug susceptibility testing ethambutol first-line drug isoniazid imipenem-cilastatin kanamycin levofloxacin Löwenstein Jensen (medium) line probe assay linezolid multidrug-resistant tuberculosis moxifloxacin mycobacteria growth indicator tube Ministry of Defence Ministry of Health Ministry of Justice meropenem 3

4 MTB M/XDR-TB NGO NRL NSP NTP Ofx PAS PDR-TB PHC Pto R rglc RR-TB S SLD SLI SRL STR TB TSH VDOT XDR-TB Z Mycobacterium tuberculosis multidrug- and extensively drug-resistant tuberculosis nongovernmental organization National Reference Laboratory National Strategic Plan National Tuberculosis Programme ofloxacin para-aminosalicylic acid polydrug-resistant tuberculosis primary health care prothionamide rifampicin regional Green Light Committee rifampicin-resistant tuberculosis streptomycin second-line drug second-line injectable Supranational Reference Laboratory shorter MDR-TB treatment regimen tuberculosis thyroid-stimulating hormone video directly observed treatment extensively drug-resistant tuberculosis pyrazinamide 4

5 Executive summary The regional Green Light Committee (rglc) for the WHO European Region supports the scaling up of the tuberculosis (TB) response plan in Ukraine. In this context, the National Tuberculosis Programme (NTP) requested a short training on the use of new and reprogrammed anti-tb drugs in Kherson and Sumy oblasts, so as to support their effort to launch treatment with bedaquiline (Bdq) at the end of In both oblasts, the visit comprised a one-day assessment of the oblast TB dispensary, followed by a one-day training. The short assessment was conducted to gauge the training needs of clinicians, so as to better focus the following training. The training consisted of presentations, followed by review of patient case histories. The aim was to train TB doctors to use new and reprogrammed drugs, including Bdq. The summary of findings for Kherson and Sumy oblasts can be found in sections 1 and 2 of this report. A follow-up on the recommendations from the previous visit in February 2018 was conducted and a summary of the findings can be found in Annex 2. The standard data on TB control requested by the rglc from the NTP are presented in Annex 3. During the course of the mission the following observations were made: The definition of failure used in recording treatment outcome among drug-sensitive TB patients differs from the 2013 WHO definition. According to WHO, a TB patient whose sputum smear or culture is positive at month five or later should be declared to have failed the treatment. According to the Ukrainian definition, a TB patient whose sputum smear is positive at month three should be declared to have failed the treatment. As a result, the proportion of cases classified as failures is relatively higher in Ukraine. For example, during six months of 2017, a total of 25 new patients were notified as failed in Sumy Oblast and a second treatment course with isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) was started. Of these patients, 21 (84%) finished the second course of treatment successfully. This suggests that the difference in the definition was the reason for the high proportion of failures among drugsensitive TB patients. The current definitions used in Ukraine urgently need to be reviewed and brought in-line with the ones used internationally. External quality assurance of the drug susceptibility testing (DST) of the National Reference Laboratory (NRL) was last conducted in Proficiency testing of the NRL urgently needs to be carried out. The NRL has contacted the Supranational Reference Laboratory (SRL) in Latvia to ensure that proficiency testing is done as soon as possible. Within the ongoing health-care reform, the accreditation of laboratories, including TB laboratories, is planned, to meet International Organization for Standardization/International Electrotechnical Commission (ISO/IEC) requirements. In general, the accreditation of a laboratory is the responsibility of the facility that is housing the laboratory; however, it is unlikely that any of the TB laboratories in their current condition will meet the requirements. Meanwhile, the availability of TB tests, including DST, is essential for diagnosis and treatment of patients. The requirements of accreditation need to be explored, so as to advise the TB laboratories of the next steps to be taken in order to pass the accreditation. In 2018, the NRL and oblast reference laboratories launched DST to linezolid (Lzd), which is very helpful, particularly when designing treatment regimens for retreatment of multidrug- and extensively drug-resistant TB (M/XDR-TB) cases. The NRL should also explore the possibility of performing DST to Bdq and delamanid (Dlm). The February 2018 rglc mission recommended the consolidation of national resources for joint centralized (intersectoral) procurement of TB medicines, to meet the needs of Ukraine s Ministry of Health (MoH), Ministry of Justice (MoJ), Ministry of Defence (MoD), and the TB services of the National Academy of Medical Sciences (AMS). Joint centralized procurement would ensure an 5

6 uninterrupted supply of high-quality (WHO-prequalified) medicines at the lowest price. The NTP has explored the legal issues related to the possible joint centralized intersectoral procurement of TB medicines. Current ministerial cabinet decree needs to be changed in order to allow the organization of such a joint intersectoral procurement of medicines and laboratory supplies. At present, this is beyond the remit of the NTP. The February 2018 rglc mission recommended the finalization of the National Strategic Plan (NSP) The National Social Programme against TB , which is the equivalent of the NSP will be approved without a budget by the Cabinet of Ministers at the end of The respective budget with the gap analyses was calculated and presented to the Country Coordinating Mechanism in 2017 as part of the grant application to the Global Fund to Fight AIDS, Tuberculosis and Malaria. The February 2018 rglc mission recommended the finalization of the national TB guidelines and TB protocols. It has been decided by the national authorities (MoH) that the national TB guidelines and TB protocols will not be developed further. The country will use the international guidelines. The MoH has issued a list of guidelines that could be used to guide health-care professionals in their work. The previous rglc mission was a combined visit of the representative of the WHO Regional Office for Europe, the representative of the WHO Country Office in Ukraine, the representative of the Global Fund and the rglc consultant. Table 1. Key recommendations Recommendations Responsible body Timeframe Ensure proficiency testing of the NRL for DST of first-line drugs (FLDs) and second-line drugs (SLDs) as soon as possible. Consider exploring what technical requirements have to be met by TB laboratories, so as to receive accreditation as outlined in ISO/IEC General requirements for the competence of testing and calibration laboratories. The MoH has planned to request that all laboratories in the country meet the requirement of ISO in the future. NRL, NTP, SRL, partners 2018 (and annually) MoH, NTP, NRL Launch DST to Bdq and Dlm, in collaboration with the SRL. NRL, SRL, NTP 2019 Ensure that tests all necessary tests to diagnose and manage adverse events are available at TB treatment sites. Ensure that the WHO 2013 definitions for recording and reporting of TB cases are adopted countrywide. Ensure training of the people involved in recording and reporting if necessary. Ensure that the basic bio-safety standards are met in TB laboratories countrywide Consider abolishing solid media-based DST and use liquid media-based DST instead MoH, Oblast administration 2019 MoH, NTP Q MoH, NRL, oblast administration MoH, NRL 2019 Continuous 6

7 1. Site visit to Kherson General information Kherson Oblast is situated in southern Ukraine, north of Crimea. Its population was estimated to be in About 61.5% ( ) of the population live in urban areas of the oblast and 38.5% ( ) in villages. Men make up 46.7% ( ) and pensioners 26.2% ( ) of population of the oblast. 1 Kherson Oblast is administratively subdivided into 18 rayons and three municipalities Kherson (administrative centre of the oblast), Nova Kakhovka and Kakhovka. Kherson is known for its agricultural production. Kherson City is the administrative centre of the oblast and is an important port on the Black Sea and Dnieper River, and is home to a major ship-building industry. In 2015, its population was Kherson oblast TB services The consultant visited the Kherson Oblast TB Dispensary, including the Oblast Reference Laboratory, and the department for patients with multidrug-resistant TB (MDR-TB). The structure of the TB services is as follows: Three oblast-level facilities that are planned to be united into one administrative entity: Oblast TB Dispensary (320 beds) Oblast Children s TB Hospital (60 beds) Oblast TB Hospital in Novozburjevski (50 beds, 35 of which are for TB). This hospital might be restructured to become a facility for palliative TB care. Novotroitskoya TB Hospital (80 beds, 40 of them for MDR-TB patients and 15 for XDR-TB patients). This hospital is situated 220 km from Kherson and is planned to become an inter-rayon hospital. Kherson City TB Policlinic. 18 TB units in the rayons and one in Nova Kakhovka town. TB sanatoria for children younger than 10 years of age (60 beds). Children with active TB disease are not treated there. Laboratory services The Oblast TB Dispensary has an adjoining laboratory with separate biochemical, bacteriology and TB sections. The TB laboratory is situated on the second floor and has no clear separation between lab areas used for handling M tuberculosis and other areas.the laboratory has no ventilation system. It has four biosafety cabinets (Class II) but none of the HEPA filters have been changed during the last 3 5 years. In 2017, the Oblast TB Dispensary unsuccessfully applied to the oblast administration for additional funding for HEPA filters. Ultraviolet lights have been installed and are maintained. M3 1 Wikipedia [website]. Wikipedia; 2018 ( accessed 14 September 2018). 7

8 respirators are available and are used. Fit-testing of the respirators is done annually for all staff of the Oblast TB Dispensary. The laboratory performs smear microscopy on concentrated smears. The laboratory is equipped with Xpert MTB/RIF. Culture is performed on solid Löwenstein Jensen (LJ) and FINN mediums as well as liquid media using BACTEC 960. After identification of species, DST to FLDs and SLDs is done on LJ and mycobacteria growth indicator tube (MGIT). Two sputum samples are collected for diagnosis of TB: From one sample, smear microscopy, Xpert MTB/RIF test, and culture on LJ and MGIT are performed. From the second sample, culture on LJ and FINN are performed. The DST panel is set up on MGIT: H, R, E, Z; and in case Xpert MTB/RIF shows resistance to rifampicin, then at the same time the DST is performed to amikacin (Am), capreomycin (Cm), levofloxacin (Lfx), moxifloxacin (Mfx) and linezolid (Lzd). The LJ cultures are used for monitoring of treatment effectiveness. DST on LJ is done mostly in case DST on MGIT fails, or the DST is done during treatment, not for diagnosis. DST on LJ is done to H, R, E, Cm, streptomycin (S), kanamycin (Km) and ofloxacin (Ofx). The LJ cultures are used for monitoring of treatment effectiveness. In 2017, the contamination rate on LJ was on average 3 5% and on MGIT 6 7%, which is acceptable. DST to Lzd was launched in During the period 3 May 2018 to 18 September 2018, a total of 50 DST test results to Lzd became available and 1 (2.0%) showed resistance. It seems that the method is working, although there is no quality assurance for DST to Lzd. The external quality assurance of the DST is done by the NRL annually and the 2017 results were acceptable (tables 2 3). One has to remember that the proficiency testing of the NRL by the SRL was last done in The workload of the Kherson Oblast Reference Laboratory is presented in Table 4. The only Xpert MTB/RIF equipment is situated in the Oblast Reference Laboratory (installed in 2012). In 2018, three additional Xpert MTB/RIF machines will be installed in the oblast in the Novozburjevski Dispensary, Novotroitskoya Dispensary and in the Kherson City TB Dispensary. The Xpert MTB/RIF machines have been procured by the Global Fund. The Xpert MTB/RIF consumables for TB services, as well as consumables for MGIT and Hain (GenoType MTBDR plus), are procured by the government. The consumables for Xpert MTB/RIF that are used for the tests in the primary health care (PHC) services are procured by the Global Fund. The consultant was informed that Xpert MTB/RIF tests are normally performed for all patients at the start of treatment. The sputum smear positive patients are sent to the Oblast TB Dispensary for hospitalization and get their tests done there. The sputum samples of the sputum smear negative patients are referred to the Oblast Reference Laboratory for Xpert MTB/RIF tests and culture. The oblast has a regular transportation system for samples. The rayon central health facility ensures transportation of the samples to the Oblast Reference Laboratory at least weekly. The oblast has two level 2 laboratories performing spear microscopy and cultures on LJ and FINN media: the Novotroitskoya and Novozburjevski TB dispensaries; the latter is planned to be closed. Neither of the facilities were visited. Table 2. External quality assurance of the Kherson Oblast Reference Laboratory, liquid media Drug S H R E Mxf Lfx Km Cm Concordance

9 (%) Source: National Reference Laboratory. Table 3. External quality assurance of the Kherson Oblast Reference Laboratory, solid media Drug S H R E Ofx Km Cm Concordance (%) Source: National Reference Laboratory. Table 4. Workload in the Kherson Oblast Reference Laboratory (27 December June 2018) Tests Number Culture on liquid media 979 Smear microscopy 979 DST on liquid media: DST to FLDs 307 DST to SLDs 185 Culture on solid media Smear microscopy DST to FLDs and SLDs on solid media 240 Xpert MTB/RIF: Total tests 720 Errors 30 Rifampicin resistant 84 Rifampicin sensitive 191 Indeterminate 2 M. tuberculosis not found 413 Source: Kherson Oblast Reference Laboratory. Treatment The treatment of MDR-TB and rifampicin-resistant TB (RR-TB) patients is commonly started in hospital, although clinicians reported that up to 40% of TB and MDR-TB patients start treatment in ambulatory TB services. This mission had no time to collect data on the hospitalization of TB patients in the oblast. For treatment of drug-resistant TB (DR-TB) the oblast uses Km, Cm, Lfx, Mfx, Lzd, E, Z, clofazimine (Cfz), prothionamide (Pto), cycloserine (Cs) and para-aminosalicylic acid (PAS). The common standardized treatment regimen for RR-TB and MDR-TB patients consists of Km or Cm, Lfx or Mfx, Pto, Cs and Z. E is added if there is sensitivity to it. In cases of XDR-TB or pre-xdr-tb the treatment regimen includes 5 6 anti-tb drugs deemed to be effective. Lzd has been available for 3 4 years and Cfz has been available for approximately one year. Two patients have bought Bdq and meropenem (Mpn) themselves for a few months. It is planned that the oblast will get Bdq, Dlm, imipenem-cilastatin (Imp-cil) or Mpn and amoxicillinclavulanate (Amx-clv) from the next centralized procurement made through the Global Fund grant. It is estimated that Bdq and Dlm will arrive in the oblast in November The oblast has ordered 155 treatment courses of Bdq and has planned to use 78 treatment courses in 2018 and 77 in If the new WHO 2018 recommendations on the use of Bdq are adopted in 2019 the amount of Bdq will not be sufficient for all in need. 9

10 The oblast has launched WHO recommended shorter MDR-TB regimens (STR) for never previously treated patients, comprising Km/Cm-Lfx/Mfx-Pto-Cfz-Z-E-H high-dose followed by Lfx/Mfx-Cfz-Z-E. Although the oblast does not have Hain equipment, Xpert MTB/RIF and BACTEC are used for all TB patients at the start of treatment (except for those patients whose sputum is referred to the Novotroitskoya and Novozburjevski culture labs). The information on sensitivity to FLDs and SLDs is available within a month, making STR an option for suitable patients. DST is available for the following drugs from the STR: Km, Cm, Lfx, Mfx, Z, H and E. The treatment regimens for patients with DR-TB are determined by the Central Medical Coordination Committee (CVKK). The committee reviews the cases for treatment progress every 3 4 months. The clinical management of patients with DR-TB is good, given the current availability of DST and SLDs. Directly observed treatment (DOT) is conducted by outpatient TB services or within PHC services, depending which is closer to the patient s home, with the support of nongovernmental organizations (NGOs). The patients receive social support to increase treatment adherence during outpatient treatment. Funding of the social support is budgeted under the Global Fund grant and channelled in the form of small grants to NGOs. The largest such NGOs in Ukraine are the Alliance for Public Health (Alliance), the All-Ukrainian Network of People Living with HIV/AIDS (Network) and PATH. Patients with drug-sensitive TB receive two food packages during outpatient treatment and M/XDR-TB patients receive monthly packages. Several modalities of social support that promote treatment adherence have been piloted in the country, to allow for the adoption of the most cost-effective version in the future. It is planned that the government will take over the funding of social support provided to TB patients during the next two years ( ), with a gradual increase in government funding. Video directly observed treatment (VDOT) was launched in Sumy Oblast in 2017 and Kherson Oblast is ready to launch this activity. The country has a functioning pharmacovigilance system and the oblast TB clinicians are reporting all adverse events to the pharmacovigilance centre. Furthermore, all adverse events are recorded in the TB register and estimation of auxiliary drug needs is made based on analyses of data available in the register. The problem with the estimates of need for auxiliary drugs is that not all tests are available for patients free of charge, and therefore clinicians underdiagnose adverse events. For example, the oblast TB dispensaries do not have funding to do baseline and follow-up tests for electrolytes and thyroid-stimulating hormone (TSH), thus no abnormalities or adverse events are reported. The paper-based forms for monitoring and reporting of adverse events were completed as they should be and available in all patient files. The medicines for management of adverse events and comorbidities are procured by the Oblast TB Dispensary (limited funding) and by the Global Fund. In 2018, there were 149 patients with TB/HIV coinfection in Kherson Oblast. Of them, 135 (90.6%) were on antiretroviral therapy (ART) and 143 (96%) were receiving cotrimoxazole. The supply of antiretroviral (ARV) drugs was limited in 2017, but from 2018 no gap in the supply of ARVs is expected. The Oblast TB Dispensary has a TB doctor who follows up on the treatment of TB/HIV coinfected patients. Rapid HIV tests are available in the PHC services. Blood samples are collected for CD4 cell count and viral load and sent to the HIV Centre. Treatment with ARVs starts on average in 2 weeks from the day of TB diagnosis when the CD4 cell count is under 50, and within 8 weeks when the CD4 count is higher. Table 5. Recommendations for Kherson Oblast Recommendations Responsible body Timeframe 10

11 Consider stopping DST to Ofx on solid media because the country has stopped using this drug for treatment of TB. Consider stopping the use of FINN media for cultures because it is an unnecessary additional workload for the laboratory. Find resources to improve infection control in the Kherson Oblast Reference Laboratory: Install proper separation between lab areas used for handling M tuberculosis and other areas Consider installing ventilation recommended for the TB laboratory performing culture and DST. Ensure that maintenance of the biosafety cabinets is conducted in good time (change of HEPA filters, routine check-up). Adopt standard operational procedures for the Oblast Reference Laboratory after they are developed by the NRL. NRL, NTP 2019 NRL, NTP 2019 Kherson Oblast administration NRL, NTP, Kherson Oblast Reference Laboratory As soon as possible Site visit to Sumy General information Sumy Oblast is situated in the north-eastern part of Ukraine, with a population of in The administrative centre of the oblast is the city of Sumy, with population of Other important cities within the oblast include Konotop, Okhtyrka, Romny and Shostka. Seven main rivers flow through the oblast, with the Desna River the largest. The oblast is comprised of 19 rayons. Sumy Oblast TB services The consultant visited the Sumy Oblast TB Dispensary including the Oblast Reference Laboratory and the department for patients with M/XDR-TB. The structure of the oblast TB services is as follows: Inpatients facilities (total 280 beds): Oblast TB Dispensary (195 beds). Shostkinskii Inter-rayon TB Hospital (60 beds). It is planned to close this hospital in the future. Department for Paediatric TB in Sumy City Central Hospital (25 beds). 18 outpatient TB units in the rayons (commonly the units are part of the outpatient policlinics) and 3 outpatient units in Sumy City. TB sanatoria for children (110 beds). Children with active TB disease are not treated there. 2 Estimate from Sumy Oblast TB Dispensary. 11

12 The Oblast TB Dispensary has two locations: the inpatient facility is situated 17 km from Sumy City and the outpatient facility is located in the city. At the time of the mission, there were 72 patients in the Oblast TB Dispensary, although its capacity is 195 beds. The inpatient section is divided into the following departments: department for drug-sensitive TB (45 beds) department for mono- and polyresistant TB (30 beds) department for extrapulmonary TB (20 beds) department for M/XDR-TB (50 beds) department for thoracic surgery (30 beds) department for palliative TB care (30 beds). Sumy Oblast has a total of 85 TB doctors filling in positions. The Oblast TB Dispensary has 30 TB doctors and 50 staff positions. However, the head of Oblast TB Dispensary pointed out that the current number of doctors was sufficient for the number of patients they have. Patients with sputum-smear negative TB or MDR-TB are generally not hospitalized for treatment. In 2017, the oblast had a total of 581 drug-sensitive TB patients, 238 of whom were hospitalized for the start of treatment (41.0%). The same year, the oblast had 167 M/XDR-TB patients, 123 of whom were hospitalized (73.6%).This is a good achievement compared to the policy five years ago, when all TB patients were hospitalized. In 2017, the oblast had 62 patients with TB/HIV coinfection. Laboratory services The Oblast Reference Laboratory is situated in a separate building on the campus of the Oblast TB Dispensary. The building is dilapidated beyond repair. The clean and dirty areas are not separated and the Laboratory has no ventilation system. The laboratory has one biosafety cabinet (Class II) installed in 2006; since then the HEPA filter has been changed only once. A company comes to repair equipment if something is broken, but none is available to carry out regular maintenance of laboratory equipment. Ultraviolet lights are installed and maintained. M3 respirators are available and are used. The laboratory has two doctors, five laboratory technicians and one assistant. The laboratory performs smear microscopy on concentrated smear for TB diagnosis and follow up of treatment. The laboratory is equipped with Xpert MTB/RIF, the only such equipment in the oblast. Culture is performed on solid media (LJ) as well as liquid media using BACTEC 960 (installed in 2009). After identification of species DST to FLDs and SLDs is done on LJ and MGIT. Two sputum samples are collected for diagnosis of TB: From one sample, smear microscopy, Xpert MTB/RIF test, and culture on LJ and BACTEC are performed. From the second sample, smear microscopy and culture on LJ are performed. For new patients, DST is performed on liquid and solid media. For previously treated patients, DST is usually done on solid media only. DST to Lfx and Mfx, Cm and Z is not available, which makes it difficult to design a treatment regimen for M/XDR-TB. Usually, DST to the following drugs is set up on MGIT: H, R, E, Z and S. If Xpert MTB/RIF shows resistance to R, then DST to FLDs and SLDs is performed simultaneously and DST to Lzd is done instead of DST to S. The panel for DST to SLDs consists of: Am, Cm, Lfx, Mfx and Lzd. 12

13 DST on LJ is done to ethionamide, Km, Cs, PAS and Ofx. It was recommended that DST to Ofx be discontinued, as it is not used any longer for treatment of TB. It was also recommended that DST to Bdq and Dlm be performed in collaboration with the NRL. The LJ cultures are used for monitoring of treatment effectiveness. DST is repeated in cases where the patient remains culture positive, but not more frequently than every three months. In 2017, the contamination rate on LJ was 3.5% and on MGIT 8.1%, which is acceptable. DST to Lzd was started in Between 9 February 2018 and 20 August 2018 a total of 86 DST tests to Lzd were conducted and 2 (2.3%) of them showed resistance. It seems that the method is working, although no external quality assurance is carried out for the DST to Lzd. External quality assurance of the DST to FLDs and SLDs is done by the NRL. The 2017 results of the external quality assurance were acceptable (Table 6). The Xpert MTB/RIF equipment (four modules) was installed in the Oblast Reference Laboratory in 2013 and it is the only such equipment in the oblast. Calibration is done annually, with the support of the NTP central level. The oblast has a regular transportation system for biological material. The material is sent weekly to the Reference Laboratory from the rayons. The coverage with Xpert MTB/RIF tests at the start of treatment was reported to be more than 90%. Usually, smear microscopy is conducted in the rayon TB unit and if the patient is found to be smear negative then a sputum sample is collected and sent to the Oblast TB Dispensary for Xpert MTB/RIF test, smear microscopy and culture. If the smear microscopy result is positive in the rayon, the patient is sent to the Oblast TB Dispensary for further investigations and hospitalization. The laboratory network is comprised of the Oblast Reference Laboratory, three laboratories performing smear microscopy and cultures on LJ, and 27 smear microscopy laboratories. There is a plan to close culture laboratories and transport all samples to the Oblast Reference Laboratory. Currently, the culture laboratories are mainly performing LJ cultures for follow-up of treatment. The NRL sends panels for annual external quality assurance of DST to the Oblast Reference Laboratory. The 2017 results were good (Table 7). However, one has to remember that proficiency testing of the NRL was last conducted in External quality assurance of the smear microscopy laboratories in the oblast is conducted quarterly by the Oblast Reference Laboratory using: (1) blind re-reading of 5% of the slides by the Reference Laboratory and (2) sending 5 10 slides to the smear laboratories for reading. The workload of the Reference Laboratory is presented in Table 8. The Reference Laboratory s Xpert MTB/RIF test results for eight months of 2018 are presented in Table 9. Table 6. External quality assurance of DST on liquid media in Sumy Oblast Reference Laboratory, 2017 Drug S H R E Mxf Lfx Km Cm Concordance (%) Source: National Reference Laboratory. Table 7. External quality assurance of DST on solid media in Sumy Oblast Reference Laboratory, 2017 Drug S H R E Ofx Km Cm Concordance (%) Source: National Reference Laboratory. 13

14 Table 8. Workload of Sumy Oblast Reference Laboratory, 6 months of 2018 Tests Number Culture on liquid media 806 Smear microscopy DST on liquid media: DST to FLDs 269 DST to SLDs 141 Culture on solid media DST to FLDs on solid media 102 DST to SLDs on solid media 201 Identification of species 155 Xpert MTB/RIF 729 Source: Oblast Reference Laboratory. Table 9. Xpert MTB/RIF test results, 8 months of 2018 Tests Number Total tests 957 Errors NA Rifampicin resistant 107 Rifampicin sensitive 245 Undetermined NA No M. tuberculosis found NA NA = information not available. Source: Oblast Reference Laboratory. Treatment For treatment of DR-TB the oblast has Km, Cm, Lfx, Mfx, Lzd, Cfz, Pto, Cs, PAS, Z and E. The common standardized treatment regimen for RR-TB and MDR-TB patients consists of Km or Cm, Lfx or Mfx, Pto, Cs and Z. E is added if there is still sensitivity to it. In cases of XDR-TB or pre-xdr-tb the treatment regimen includes 5 6 anti-tb drugs deemed to be effective. Lzd has been available for 3 4 years and Cfz has been available for approximately one year. It is planned that the oblast will get Bdq, Dlm, Imp-cil or Amx-clv from the next centralized procurement conducted through the Global Fund grant. It is estimated that these drugs will arrive in the country by November Sumy Oblast has ordered 134 courses of Bdq. In 2017, a total of 167 M/XDR-TB patients were diagnosed. Thus, the number of Bdq treatment courses to be made available in 2019 should cover the needs of the oblast to start with. The oblast has not launched WHO recommended STRs. Treatment regimens for patients with DR-TB are determined by the CVKK. The committee reviews the cases for treatment progress every two months. The clinical management of patients with DR-TB is good, given the current availability of DST and SLDs. However, the management of patients in 14

15 outpatient facilities was not assessed during the mission. The TB doctors in the outpatient services are expected to consult the CVKK on any changes in the TB treatment of patients. This means that clinicians have a tendency to rely heavily on the CVKK and lose their independent thinking. As elsewhere in the country, DOT is conducted by outpatient TB services and at PHC points, depending on which is closer to the patient s home, with the support of NGOs. Patients receive social support to increase treatment adherence during outpatient treatment. The funding of social support is budgeted under the Global Fund grant and channelled through the Public Health Department of the oblast. The Public Health Department has contracts with NGOs for follow-up with the patients. Patients with drug-sensitive TB receive two food packages during outpatient treatment and M/XDR- TB patients receive monthly packages. Sumy Oblast was the first to launch VDOT. The distance from the Sumy City to the borders of the oblast is between 60 km and 300 km, which makes it difficult to implement DOT. Thus, VDOT has been very helpful. At the time of the mission, 23 patients were on VDOT in the oblast. The country has a functioning pharmacovigilance system and the oblast TB clinicians are reporting all adverse events to the pharmacovigilance centre. Furthermore, all adverse events are recorded in the TB register and estimation of auxiliary drugs needs is made based on analysis of the data available in the register. The paper-based forms for monitoring and reporting of adverse events were completed as they should be and are available in all patient files. The medicines for management of adverse events and comorbidities are procured by the Oblast TB Dispensary (limited funding) and by the Global Fund. The Oblast TB Dispensary was not able to perform biochemistry tests at the time of the mission because the equipment was broken. The administration of the Dispensary was optimistic that the new analyser will be bought before the end of the year. Testing for TSH is not done in the Dispensary, but can be done elsewhere in the town if needed. The Dispensary has electrocardiogram (ECG) equipment with automatic reading of the QTc. All clinicians were able to read the ECG. However, the ECG is sent to a cardiologist in town, who provides an official interpretation of the ECG. Recording and reporting In 2016, 8% (45/565) of new and relapsed cases with drug-sensitive TB failed treatment. During 6 months of 2017, a total of 25 new patients were notified as failed and a second treatment course with H+R+E+Z (HREZ) was started. Of these, 21 (84%) finished the second course of treatment successfully. The reason for the high proportion of failures among drug-sensitive TB patients seems to be the use of definitions that differ from the one recommended by WHO in According to the 2006 national policy in Ukraine, a patient with drug-sensitive TB who is sputum smear positive after 90 days of treatment should be recorded as failed, and is reregistered as after failure and starts a second treatment course with HREZ. The definitions used in Ukraine urgently need to be reviewed and brought in-line with the ones used internationally. Table 10. Recommendations for Sumy Oblast Recommendations Responsible body Timeframe Consider stopping DST to Ofx on solid media because the country has stopped using the drug for treatment of TB. NRL, NTP

16 Explore the possibility of moving the Oblast Reference Laboratory to a new refurbished location or building a new one. The building housing the Oblast Reference Laboratory is dilapidated beyond repair. Install proper separation between the dirty and clean zones in the Oblast Reference Laboratory. Ensure regular maintenance of the biosafety cabinet (change of HEPA filters, routine check-up). Adopt standard operating procedures for Sumy Oblast Reference Laboratory after they are developed by the NRL. Explore the possibility of separating MDR-TB and XDR-TB patients in Sumy Oblast TB Dispensary. Ensure that all tests for monitoring of adverse events are available for patients with DR-TB throughout the treatment (during in- and outpatient treatment). Consider performing DST on liquid media for all patients at the start of treatment. Sumy Oblast administration Sumy Oblast TB Dispensary, Sumy Oblast administration Sumy Oblast TB Dispensary, Sumy Oblast administration Sumy Oblast Reference Laboratory, NRL Sumy Oblast TB Dispensary Sumy Oblast TB Dispensary Sumy Oblast TB Dispensary 2019 As soon as possible Q Q4 16

17 Annex 1. Terms of reference The aim of the proposed mission is to support the lead clinical consultant to: assess progress made and readiness for effective introduction of new drugs, specifically bedaquiline (Bdq), by the National Tuberculosis Programme (NTP) in Kherson and Sumy oblasts; carry out mini-training of tuberculosis (TB) clinicians on the use of new and reprogrammed drugs for treatment of multidrug- and extensively drug-resistant TB (M/XDR-TB) patients. 17

18 Annex 2. Follow-up on previous mission recommendations This annex contains details of a brief follow-up on the recommendations from the previous visit in February Recommendation Finalize and approve the National Strategic Plan (NSP) Finalize and approve the national tuberculosis (TB) guidelines (nastanova) and the subsequent national TB protocols. Proceed with the plan to establish, within the ongoing health-care reform, an effective funding system for TB services, covering both inpatient and outpatient facilities. Consolidate national resources for a joint centralized (intersectoral) procurement of TB medicines, to meet the needs of Ukraine s MoH, Ministry of Justice (MoJ), Ministry of Defence (MoD), and the TB services of the National Academy of Medical Sciences (AMS). Joint centralized procurement would ensure an uninterrupted supply of high-quality (WHOprequalified) medicines at the lowest price. Consolidate national resources for joint centralized (intersectoral) procurement of laboratory supplies for the MoH, MoJ, MoD and the TB services of the AMS. Consider signing a cooperation agreement between the MoH, MoJ and MoD to facilitate implementation of TB control activities between sectors under the coordination of the MoH. Timeframe The National Social Programme against TB will be approved without a budget by the Cabinet of Ministers at the end of The respective budget with the gap analyses was calculated and presented to the Country Coordinating Mechanism (CCM) as part of the grant application to the Global Fund to Fight AIDS, Tuberculosis and Malaria in It has been decided by the national authorities (the Ministry of Health, MoH) that the national TB guidelines and TB protocols will not be developed any longer. The country will use the international guidelines. The MoH has issued a list of the guidelines that could be used as a reference for health-care professionals in their work In progress within the ongoing health-care reform. The National TB Programme (NTP) has explored the legal issues related to the possible joint intersectoral procurement of TB medicines. The ministerial cabinet decree needs to be changed in order allow the organization such a joint intersectoral procurement of medicines and laboratory supplies. The respective ministries have signed the document. However, the operational procedures, following the cooperation agreement, have to be signed by the heads of involved organizations, which has not been done due to the rapid changes in the structure of the organizations. 18

19 Finalize and approve the National New Drugs and Shorter MDR-TB Treatment Regimen Implementation Plan, with a stepwise expansion plan; proceed with ordering of bedaquiline (Bdq) and delamanid (Dlm). Consider developing oblast-specific new drugs and shorter multidrug-resistant TB (MDR-TB) treatment regimen implementation plans, following approval of the national document. Develop a concept/plan for national reference laboratories (NRLs), including TB; ensure that government funding is available to enable NRLs to carry out their reference function. Ensure that TB drugs procured by the government are prequalified by WHO and meet standards of good manufacturing practice. Support the penitentiary system in developing a prison-specific plan for future introduction of new TB medicines and shorter MDR-TB treatment regimens (STRs). Treatment strategies and administration Ensure that cases that are resistant to fluoroquinolones but sensitive to second-line injectables (SLIs) have the option to continue with SLIs throughout the treatment regimen in case the new and reprogrammed drugs are not available (option to use SLIs three times a week after the initial 3 6 months of treatment, or as determined by possible adverse events). Decrease hospitalization of TB patients; as a rule, patients with sputum smear-negative TB or drugresistant TB should not be hospitalized. TB laboratory services Ensure proficiency testing of the NRL for drug susceptibility testing for first-line and second-line drugs as soon as possible. Ensure that transportation of biological material to level 3 laboratories is prioritized at all sites where material is collected for TB diagnosis Q3 The National New Drugs and Shorter MDR-TB Treatment Regimen Implementation Plan has been signed by the Programme Committee under the National Advisory Committee for TB In progress There has been no change in terms of development of a concept for NRLs, including TB. The NTP or MoH have difficulties in requesting the prequalification of drugs by WHO as it is not under their area of governance Rapid structural and staff changes have taken place in the prison administration and the development of the plan has been delayed. The NTP/MoH has advised the specialists to use the international guidelines in their diagnostic and treatment decisions and there is a sufficient amount of injectables, thus it is no longer a problem. Furthermore, the 2018 WHO rapid communication recommends against the wider use of injectables in general. Very good progress at the sites visited. For example, in Sumy only 41.0% of drug-sensitive TB patients and 73.6% of multidrug- and extensively drug-resistant TB (M/XDR-TB) patients were hospitalized in Proficiency testing was not done in 2015, 2016, 2017 or and continuous The transportation of sputum samples to the oblast level was regular and timely in Kherson and Sumy. 19

20 Consider preparing and approving a national strategic plan to optimize the laboratory network. Consider applying for technical assistance to the Supranational Reference Laboratory (SRL) and partners. Consider further decreasing the number of level 2 and sputum smear laboratories (continuous plan) The MoH and the Public Health Institute (CHA) envision preparation of the national strategic plan for TB laboratories to be part of the general plan for health-care reform; therefore no separate plan will be produced for (TB) laboratories. Good progress: in 2017 Ukraine had 62 level 2 culture laboratories and in 2018 had 59. The plan is to further decrease the number of laboratories. Review the need for various techniques in laboratories at all levels, taking into account workload, the prospect of an improved transportation system, administrative and geographical particularities, expansion of rapid diagnostic techniques, the prospect of an optimized TB facility network, and ongoing primary health care reform. The assessment of needs is being done annually but the NTP and MoH are not in a position to implement any major changes as this depends on the decision of the local administration, ongoing health-care reform, licencing and accreditation of facilities, and available funding. Develop standard operating procedures for the NRL (TB) and other TB laboratories. Consider establishing a working group for development of standard operating procedures that is composed of the representatives of the NRL and level 3 laboratories. Consider providing more training to staff performing Hain tests in the oblasts. Find ways to ensure that maintenance of equipment and ventilation systems in level 3 (and level 2) laboratories can be sustained after support from the Global Fund (and other partners) comes to an end The NTP has hired a consultant (funded by the Global Fund) to carry out the initial assessment of the requirements that the (TB) laboratories have to meet in order to pass International Organization for Standardization (ISO) accreditation In July 2018, PATH supported the training of laboratory specialists on performing Hain tests (with a trainer from Gauting SRL). The specialists were from Lvov, Kharkov, Nikolajev and the NRL. There is also a plan to send a team of laboratory staff from the NRL to Gauting in Q and beyond The NTP and MoH are working on solutions as part of the health-care reform. 20

21 Information system and data management Consider simplifying the TB reporting system by decreasing the number of reporting forms. As the electronic TB register is updated daily, quarterly and annually, reports can be generated electronically and do not need to be filled out by hand and signed. Provided that they are properly filled in, paper-based rayon/district TB registers and patient files are sufficient for purposes of validating data. Infection control Ensure that TB infection control forms part of the revised national infection control guidelines. Intensify cooperation with national authorities responsible for monitoring TB infection control in order to provide further on-the-job training (joint monitoring) for staff and to ensure that they can assume responsibility for monitoring and evaluation of TB infection control countrywide The newly established Monitoring and Evaluation Department of the CHA has finalized the list of forms that could be digitalized. The next step is to implement changes in the TB register software, which will allow a decrease in the number of reporting forms (such as forms 11 and 7) The new infection control standards, including TB infection control standards, have been developed and will be opened for public discussion in a few weeks. The CHA has established a department for infection control which will take on this task. The supervision checklists used for monitoring TB infection control have been provided to the infection control department by the NTP. Ensure that infection control measures are implemented in all level 3 and level 2 laboratories, including in the penitentiary system: ensure sufficient ventilation; HEPA filters in safety hoods are changed as necessary; dirty and clean zones are separated; etc. TB drug supply Consider increasing the order of new TB drugs for pre-xdr and XDR-TB patients so as to ensure universal access to all patients in need by Ethics Develop and implement a framework for TB palliative care, which also covers the penitentiary system. National guidelines on palliative care have been developed and approved by the MoH. Recommendations to WHO 2018 and beyond No progress A large order was placed in 2018 for 3268 treatment courses of Bdq. The first shipment will arrive in November 2018 and 10 oblasts will start treatment using Bdq. The same order contains 50 treatment courses of Dlm The NTP has conducted an assessment of needs for palliative TB care in oblasts and forwarded it to the MoH in order to prepare a general plan for palliative care. 21

22 Consider advocating that WHO publications are added to the list of references used by the MoH for their guidelines and guides. Consider providing technical assistance to the MoH/NTP in finalizing the national TB guidelines The MoH is preparing to update the list of references to be used countrywide and WHO publications will be part of the list The national TB guidelines will not be developed; international guidelines will be used instead. 22

23 Annex 3. Selected data in support of the mission report The following tables present data requested from the National Tuberculosis Register in support of this mission report. Table A3.1a. TB case notifications, Kherson, New cases Previously treated cases All TB cases a New cases per All TB cases per b Incident (new and relapse) cases in children (0 14 years) TB = tuberculosis a Only new and relapses. b Only relapses Table A3.1b. TB case notifications, Sumy, New cases Previously treated cases All TB cases a New cases per All TB cases per b Incident (new and relapse) cases in children (0 14 years) a Only new and relapses. b Only relapses Table A3.1c. TB case notifications, Ukraine, New cases Previously treated cases All TB cases a New cases per All TB cases per b Incident (new and relapse) cases in children (0 14 years a Only new and relapses. b Only relapses. Table A3.2a. TB case notifications by category, Kherson,