EECA Regional SORT IT People Who Inject Drugs and have tuberculosis: Opioid Substitution Therapy improves treatment outcomes in Ukraine

Introduction: Opioid substitution therapy is one of the pillars of harm reduction strategies for People Who Inject Drugs (PWID). OST should be an integral part of tuberculosis (TB) care to increase the uptake, compliance and effectiveness of treatment and also curtail risk behaviours. We aimed to compare TB treatment outcomes in relation to OST among PWID in six regions of Ukraine. Methodology: A retrospective cohort study using routine programmatic data from centres offering integrated TB and OST (December 2016 – May 2020). OST involved use of methadone or buprenorphine. TB treatment outcomes were standardized. Results: Of 228 PWID (85% male) diagnosed with TB, 104 (46%) had drug sensitive and 124 (64%) drug-resistant TB. The majority had pulmonary TB (95%), 64 (28%) were HCV-positive and 179 (78%) were HIV-positive, 91% of the latter were also on ART. There were 114 (50%) PWID with TB on OST. For drug-sensitive TB (n-104), treatment success was significantly higher (61%) in those on adjunctive OST than those not on OST (42%, p < 0.001). Similarly, for drug resistant TB (N -124) treatment success was also significantly higher when individuals were on OST (43%) compared to when not on OST (26%, p < 0.001). Conclusions: This operational research study shows that OST is associated with significantly improved treatment success in PWID and can contribute to achieving Universal Health Coverage and the WHO Flagship Initiative “Find. Treat. All. #End TB”. We advocate for the scale up of this intervention in Ukraine.


Introduction
Opioid substitution therapy (OST -using methadone or buprenorphine) is one of the pillars of harm reduction strategies for People Who Inject Drugs (PWID). OST should be an integral part of tuberculosis (TB) care so as to increase the uptake, compliance and effectiveness of treatment and at the same time, curtail risk behaviours [1][2][3][4][5][6]. PWID are considered a "key population" group who are often socially marginalized and have limited access to health services [7]. They are at a 20 to 50 times higher risk of contracting HIV infection than the general population and contribute to about 10% of all new HIV infections globally [8].
Outbreaks of drug-susceptible and multi-drug resistant TB (MDR-TB) are also common in this group [9]. Finding ways of improving the detection of TB among PWID is important and aligns well with the Sustainable Development Goal (SDG) of achieving Universal Health Coverage for TB and also the WHO Flagship Initiative "Find. Treat. All. #End TB" [10]. Two of the three targets in the WHO and Stop TB Partnership Plan to end TB involve key populations such as PWID. One of these targets aims to ensure that TB diagnostic and treatment services reach at least 90% of all key population groups, while the other aims to achieve a minimum of 90% treatment success [11]. The International Charitable Foundation "Alliance for Public Health" (the Alliance), a Non-Governmental Organization (NGO) in Ukraine, coordinates HIV and TB prevention and care services working with PWID in Ukraine. A unique aspect of their work is the integrated delivery model of "OST with TB care" offered at the same health facility. This overcomes the barrier or vertical and disconnected delivery of such services, which is common in countries of the former Soviet Union [12]. A PubMed search revealed no studies that 52S have described TB treatment outcomes from NGO health facilities that have integrated OST and TB care among PWID in East Europe and Central Asia. There is very limited research on TB/OST programs implementation available from Ukraine. The study conducted in Kyiv oblast regarding predictors of poor TB treatment outcomes revealed that the country is experiencing and urgent need in programmatic interventions, especially aimed at patients with the highest risk of poor outcomes such as PWID [13]. Another study showed that methadone treatment improves TB treatment among hospitalized opioid dependent patients in Ukraine [14]. Those PWID on OST might have better compliance with TB treatment [15]. On the other hand, there are known drug-drug interactions between methadone and rifampicin and OST is known to reduce cell mediated immunity, all of which might influence TB treatment outcomes [16,17]. The subject of OST for PWID with TB is a recognized research priority in Ukraine and the wider European region. Our experience may thus guide operational strategies to improve integrated TB care for PWID in Ukraine and beyond. Taking into account very limited research on the topic, the authors believe that this paper will play a very important role in provision and scaling up both TB treatment and OST services for PWID. This study aims to compare TB treatment outcomes in relation to being on OST among PWID in six regions of Ukraine. Among PWID, the specific objectives were to determine the a) socio-demographic and clinical characteristics of TB patients who were and were not on OST, and b) TB treatment outcomes in relation to OST.

Methodology
This was a retrospective cohort study using routine programmatic data managed by the Public Health Center of the Ministry of Health of Ukraine.

Study population and study period
The study population included PWID diagnosed with TB and who started TB treatment in six regions of Ukraine. The inclusion criteria were: (a) age 18 and older; (b) having a history of injecting drug use (IDU). The study period was December 2016 to May 2020.

General setting
Ukraine is the largest country in Eastern Europe with a population of 42 million, and an HIV prevalence of 0.9% [18]. There are an estimated 324,300 PWID in the country: HIV prevalence is 22.6% in this sub-group and 63.9% have concomitant Hepatitis C [19]. The TB incidence rate in PWID is 80 (52-115) per 100,000 population [20]. In Ukraine only 4.25% of the total estimated number of PWID receive OST [12].
The Alliance oversees, supervises and monitors all activities including TB care and harm reduction activities, of non-governmental organizations (NGOs) who work with PWID. Within the Global Fund and PEPFAR grants, the Alliance is the principal recipient and provides sub-grants and ensures regular reporting to donors. There are formal agreements between the Alliance and Ministry of Health of Ukraine. Alliance is a principal recipient of the Global Fund for supervision and implementation of activities conducted by over 100 NGOs involving with PWID in Ukraine. Alliance collaborates closely with the Government and links up closely with existing health facilities.

Specific setting and study sites
The study sites included six TB centres offering integrated TB and OST in six regions (Chernihiv, Dnipro, Donetsk, Kherson, Kyiv, Zhytomyr) of Ukraine. The most frequently used injectable drugs include in graded order are: opium, street methadone, amphetamine type stimulants, hypno-sedatives and hallucinogens. Injection may be through intravenous, intramuscular and subcutaneous routes. Drugs are procured through peers and drug dealers. Self-made concoctions are also common. All NGOs offer a package of health interventions according to WHO guidelines [21], including the provision of sterile injecting equipment through needle and syringe exchange programs.

Management of tuberculosis
The management of TB is according to National and World Health Organisation (WHO) guidelines [22]. Both drug-sensitive and drug-resistant TB are managed at TB clinics by dedicated TB doctors. The Alliance provides integrated services of OST at the selected six TB sites. However, HIV/AIDS management is only available in separate HIV/AIDS clinics. As of now, HCV treatment is not available within the national public health programmes. TB treatment outcomes are standardised and categorized into favourable outcomes (cured + treatment completed) and unfavourable outcomes (lost to follow up, died, failed, not evaluated and not recorded) [22].

Opioid Substitution Therapy
Opioid Substitution Therapy (OST) is also known as "agonist replacement therapy" or "opioid agonist therapy". OST is defined as the administration under 53S medical supervision of a prescribed psychoactive substance, pharmacologically related to the one producing dependence. Agents suitable for substitution therapy are those with some opioid properties so that they have the capacity to prevent the emergence of withdrawal symptoms and reduce craving. The available agents for OST include methadone and buprenorphine which are administered orally. The objectives of OST are broad and include: reduction of dependence on illicit drugs; a decrease in morbidity and mortality caused by illicit opioids; reduction in the risk of infectious diseases; improvement of physical and mental health; reduction in criminal behaviour; facilitation of the reintegration of PWID into the workforce and education system and a general improvement in social functioning as a whole [1]. All PWID with active TB are first offered inpatient TB treatment and counselled for OST. The patient can start OST only after discharge from inpatient TB care when he/she is registered with the Narcology service and subsequently the patient can receive OST drugs in the TB facility. When the patient is receiving inpatient TB treatment and OST, the psycho-social support and counselling is provided by NGOs working within the TB clinics under the supervision of the Alliance. TB treatment regimens remain unchanged with OST.

Data management, analysis and statistics
The data were collected from two sources -a national register of TB patients managed by the Public Health Center of the Ministry of Health of Ukraine and a national OST patient register managed by the

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Alliance. The variables collected included sociodemographic variables, clinical data on TB, HIV and HCV status, OST related data and TB treatment outcomes. These data were double-entered and analyzed using SAS statistical software (Cary, North Carolina, USA). We summarized the results using descriptive statistics (numbers, proportions). Differences between groups were assessed using the chi-square test with 95% confidence intervals. Levels of statistical significance were set at p ≤ 0.05.

Ethical considerations
Permission to use the data was obtained from the Alliance and the National TB Control programme of Ukraine. Ethical approval was received from the Institutional Review Board of the Alliance (Kyiv, Ukraine) followed by the Union Ethics Advisory Group of the International Union against the TB and Lung disease (Paris, France). As we used secondary data, the issue of informed consent did not apply.
A total of 114 (50%) studied TB patients were on OST. The characteristics of those who were, and were not, on OST are shown in Table 1. Between those on OST and those not on OST, females, employment status and ART showed significant differences. The HIV prevalence among OST patients was 76% while among non-OST this was 81% and 97% of those on OST were on ART while this was 86% for those not on OST (P-0.03). The prevalence of HCV in the cohort was 28%.

Drug-sensitive TB
Of the 228 PWID with TB, 104 (46%) had drug sensitive TB. Standardized TB treatment outcomes for drug sensitive TB are shown in Table 2a. Overall treatment success was 52%. Treatment success was significantly higher (61%) in those on adjunctive OST than those not on OST (42%, p < 0.001).

Drug-resistant TB
There were 124 (54%) PWID with drug resistant TB (96 XDR-TB, 13 MDR-TB and 15 with mono/poly resistance, Table 1). The overall treatment success for drug resistant TB was at a low 34% (Table 2b), but significantly higher when individuals were on OST (43%) compared to when not on OST (26%).

Discussion
To our knowledge, this is the first study from an NGO setting in Eastern Europe that has assessed TB treatment outcomes in relation to OST among PWID with a high HIV and HCV prevalence. Half of all PWID were placed on OST and in this group, TB treatment outcomes were significantly better for both drugsensitive and drug resistant TB (Figure 1). Moreover, to our knowledge this is the first study conducted in Ukraine to compare the TB treatment outcomes among PWID on and not on OST, and our findings are compliant with the results of very limited previously conducted in Ukraine research on the topic [14]. Our results are also in line with similar studies conducted worldwide [23,24]. This study is an important step towards achieving the STOP-TB target of ensuring that TB diagnostic and treatment services reach at least 90% of key populations. Reaching out to those left out of the health system is also pivotal for achieving equity and Universal Health Coverage under the WHO flagship initiative "Find.Treat.All" #End TB" [10]. This study also addresses a recognized national and global health research priority. The study strengths are that we covered six regions (including rural settings) of Ukraine, and the findings are likely to mirror the operational reality on the field. All consecutive PWID with TB were included and there was no missing data on TB treatment outcomes. The Alliance also has a dedicated monitoring and evaluation unit that ensures data quality and we thus believe our data is robust. To improve reporting quality, we also adhered to STROBE guidelines [25].
The findings from this study have some important policy and practice implications. First, in both drugsensitive and drug-resistant TB, OST made a significant difference to treatment outcomes. This is supportive evidence for further integration and scale up of OST as a basic package of care for PWID in Ukraine. The fact that considerable proportions of PWID in our cohort were also HIV and HCV positive brings to imagination, the clinical and programmatic complexity of managing these individuals. That not-withstanding, collaborative linkages were successfully established with all involved programs, all patients were followed up and monitored and 91% of the cohort were also placed on ART. This demonstrates that in terms of joint collaboration "it can be done". The role of an NGO in bridging services and fostering a patient-centered approach involving "many diseases, one patient" merits recognition. Second, although OST improved TB treatment outcomes, the treatment success levels remain far from the desired 90% mark. An added consideration is that 96 (77%) of the 124 individuals with drug-resistant TB had extensively drug-resistant TB (XDR-TB). Global data involving 9528 patients with XDR-TB from 57 countries revealed a treatment success of 39% [20]. Despite being focused on a much more difficult cohort of PWID, our results compares well with this figure. A way forward to improve the lot of MDR-TB patients is to embark on the use of more effective shorter-term MDR-TB regimens designed on the basis of the latest evidence coupled with more patient-centered models [26][27][28][29]. Shorter MDR-TB regimens will facilitate TB management both from the health system and patient perspectives. Third, we need to make efforts to increase the number of OST patients among PWID. We believe there are several structural and patient-related factors that hamper further gains. For example: to access OST, all PWID need to be formally registered as "drug addicts" which curbs social liberties such as freedom to drive a car or be employed in certain livelihoods. This is likely to be perceived as a punitive measure and will only serve as a disincentive to those who desire to benefit from OST. There are also established quotas for OST which limits the overall number that can benefit. Further qualitative research into the structural and patient centered barriers to OST would be very useful for informed-decision making and re-orienting policy and practice. OST services also need to be provided in an integrated package of TB-HIV-HCV and OST in a "One-Stop-Shop" approach. The "how to" of this approach would benefit from operational research. Another limitation is that several variables had small sample sizes which did not allow performing adjusted ORs to verify if OST is independently associated with treatment success. Finally, despite being screened for HCV, none of the PWID had access to treatment. The 56S once-daily pill, which is a combination of the already approved drug sofosbuvir and a new drug called ledipasvir can cure HCV [30]. The cost of one tablet of sofosbuvir is $1,000 (many times the value of its weight in gold!). A full 12-week course of treatment with this drug costs $84,000 and with the current state of affairs, this practically remains unavailable in Ukraine. We strongly advocate for wider access to generic treatment. Differential access for PWID who are at highest risk of acquisition and transmission of HCV and who at the same time, are the most vulnerable is merited. The main study limitation is that due to sample size limitations, we were unable to perform a sub-analysis of the HCV cohort. This merits specific research.

Conclusions
This study is an excellent example of relevant operational research conducted close to the supply and demand of health services and which can contribute to achieving Universal Health Coverage for TB in Ukraine and beyond. Our results show that access to OST significantly improves TB treatment outcomes in PWID as well as the effectiveness of treatment of MDR-TB in PWID, THUS we are advocating for the scale up of both interventions in Ukraine. coordinated by TDR (the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases). The specific SORT IT programme that led to these publications included a partnership between TDR and the European Tuberculosis Research Initiative (ERI-TB) at the WHO Regional Office for Europe, and was implemented by: the Tuberculosis Research and Prevention Center, Armenia; The Alliance for Public Health, Ukraine; The Centre for Operational Research, The Union, France; the Operational Research Unit (LuxOR), Médecins Sans Frontières, Brussels Operational Centre, Luxembourg; Sustainable Health Systems Sierra Leone; and TDR. The authors also thank Yana Sazonova for provision of technical assistance thoughout the whole process.

Funding
TDR and partners are able to conduct their work thanks to the commitment and support of a variety of funders. These include long-term core contributors from national governments and international institutions, as well as designated funding for specific projects within current priorities. A full list of TDR donors is available on our website at: https://www.who.int/tdr/about/funding/en/. This SORT IT programme was funded by the United States Agency for International Development (USAID) and supported by implementing partners. Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.