Treatment outcomes and costs of a simplified antiviral treatment strategy for hepatitis C among monoinfected and HIV and/or hepatitis B virus‐co‐infected patients in Myanmar

Abstract Access to hepatitis C virus (HCV) testing and treatment is limited in Myanmar. We assessed an integrated HIV and viral hepatitis testing and HCV treatment strategy. Sofosbuvir/velpatasvir (SOF/VEL) ± weight‐based ribavirin for 12 weeks was provided at three treatment sites in Myanmar and sustained virologic response (SVR) assessed at 12 weeks after treatment. Participants co‐infected with HBV were treated concurrently with tenofovir. Cost estimates in 2018 USD were made at Yangon and Mandalay using standard micro‐costing methods. 803 participants initiated SOF/VEL; 4.8% were lost to follow‐up. SVR was achieved in 680/803 (84.6%) by intention‐to‐treat analysis. SVR amongst people who inject drugs (PWID) was 79.7% (381/497), but 92.5% among PWID on opioid substitution therapy (OST) (74/80), and 97.4% among non‐PWID (298/306). Utilizing data from 492 participants, of whom 93% achieved SVR, the estimated average cost of treatment per patient initiated was $1030 (of which 54% were medication costs), with a production cost per successful outcome (SVR) of $1109 and real‐world estimate of $1250. High SVR rates were achieved for non‐PWID and PWID on OST. However, the estimated average cost of the intervention (under the assumption of no genotype testing and reduced real‐world effectiveness) of $1250/patient is unaffordable for a national elimination strategy. Reductions in the cost of antivirals and linkage to social and behavioural health services including substance use disorder treatment to increase retention and adherence to treatment are critical to HCV elimination in this population.


| INTRODUC TI ON
Hepatitis C virus (HCV) infection is a deadly but curable disease that disproportionately affects people in low-and middle-income countries (LMICs). [1][2][3] It is common among people who inject drugs (PWID) and even in otherwise low prevalence settings. 2,4 Chronic HCV infection is expected in 55% to 85% of untreated cases and is associated with liver cirrhosis, liver failure, hepatocellular carcinoma and death. Despite the development of highly effective direct-acting antiviral (DAA) treatment, which can cure HCV infection with 8-12 weeks of therapy, HCV remains a leading cause of mortality worldwide, causing more than 350,000 deaths each year. 3,5 The WHO's Global Health Sector Strategy sets goals of a 90% reduction in new HCV infections and a 65% reduction in HCV-related mortality by 2030. 6 Strategies for achieving these targets include scaling up access to affordable testing and treatment. 7 Progress in HCV treatment scale-up is encouraging, with more than 3 million treated globally with DAAs since 2015 but testing coverage and diagnosis rates are still less than 10% in LMICs. 3 In Myanmar, the prevalence of HCV infection is estimated at 2.7%, 8 HCV antibody positivity among PWID at 48.1%, and treatment access in the region under 1%. 9 HCV infection is estimated to account for 25% of hepatocellular carcinoma. 4 Myanmar's HIV epidemic ranks among the most serious in Asia and is concentrated among men who have sex with men (MSM), PWID and female sex workers (FSW). 5,10,11 HCV/HIV co-infection rates vary, with estimates ranging from 5% to 22.8% and high risk among PWID. 10,[12][13][14] Mynamar has a national treatment and testing strategy for the elimination of HCV. Availability and access to HCV testing and treatment, fear of prosecution for drug use, and high stigma for key populations, results in most presenting for HCV and HIV treatment are already well advanced in their illness. EQUIP launched a single arm demonstration project to evaluate an integrated, simplified protocol for testing and treating HCV and HIV among key populations in Myanmar. We describe the treatment outcomes and estimated costs for simplified HCV testing and DAA treatment with SOF/VEL with or without RBV for patients with and without HIV co-infection.

| Selection criteria
Eligible participants were HCV viremic, HCV treatment naïve or experienced (prior pegylated interferon [PegIFN] and RBV only), and 18 years or older, with HCV genotype 1, 2, 3, 4, 5 or 6, with or without HIV-1 co-infection. Patients with compensated cirrhosis (Child-Pugh Class A) and HBV infection were eligible; those with decompensated cirrhosis (Child-Pugh Class B or C) or prior treatment with HCV DAAs were not eligible. Patients who were ineligible for 803 participants initiated SOF/VEL; 4.8% were lost to follow-up. SVR was achieved in 680/803 (84.6%) by intention-to-treat analysis. SVR amongst people who inject drugs (PWID) was 79.7% (381/497), but 92.5% among PWID on opioid substitution therapy (OST) (74/80), and 97.4% among non-PWID (298/306). Utilizing data from 492 participants, of whom 93% achieved SVR, the estimated average cost of treatment per patient initiated was $1030 (of which 54% were medication costs), with a production cost per successful outcome (SVR) of $1109 and real-world estimate of $1250. High SVR rates were achieved for non-PWID and PWID on OST. However, the estimated average cost of the intervention (under the assumption of no genotype testing and reduced real-world effectiveness) of $1250/patient is unaffordable for a national elimination strategy. Reductions in the cost of antivirals and linkage to social and behavioural health services including substance use disorder treatment to increase retention and adherence to treatment are critical to HCV elimination in this population.

K E Y W O R D S
HBV, HCV, HIV, people who inject drugs, sustained virologic response HCV treatment were referred to other treatment centres. All participants provided written informed consent.

| Intervention description
The intervention combined HCV and HIV testing, simplified HCV treatment, and HIV treatment initiation for those with HIV co-in- fection not yet on antiretroviral therapy (ART). HCV treatment was with fixed-dose combination sofosbuvir 400 mg/velpatasvir 100 mg (SOF/VEL) ± weight-based ribavirin for 12 weeks. Ribavirin was initially included in the regimen for genotype 3 participants who were cirrhotic or who had previously failed an interferon-based treatment regimen. In April 2018, 5 months into enrolment, based on more recent findings on treatment response rates with SOF/VEL without ribavirin for genotype 3 infection, including amongst PWID and in resource-limited settings in Asia, [15][16][17][18] the protocol was revised to treat all participants with SOF/VEL alone, for 12 weeks, regardless of genotype. As such, genotyping was not required prior to treatment initiation. This allowed the inclusion of the third site in rural Kachin called Waimaw, which faced barriers to laboratory testing and had limited resources to monitor for ribavirin-associated and other toxicities.

| Laboratory evaluations
The screening laboratory evaluations included serum HCV antibody if not already available in the medical record, haemoglobin, platelets, AST, ALT, total bilirubin, albumin, creatinine, blood urea nitrogen,   DeepChek-HCV. A consensus sequence was generated for each sample and compared with the HCV genomic Basic Local Alignment Search Tool (BLAST) bank for determination of the HCV genotype and subtype. A threshold for similarity of minimum 85% was used to consider the genotype or subtype. 19,20

| Outcomes
The two primary outcomes of the analysis were sustained virologic response (SVR) at 12 weeks after the end of treatment and cost per patient with SVR. Other outcomes included safety (adverse events) during the treatment period. For the cost analysis, we assigned each patient one of four outcomes at 24 weeks after treatment initiation: (a) treatment success (SVR 12 weeks after therapy completion); (b) treatment failure (HCV viraemia greater than the lower limit of detection 12 weeks after therapy completion); (c) loss to follow-up (did not return to clinic for 24-week evaluation); or (d) death (died within the 24-week study period).

| Outcomes
Baseline sociodemographic, clinical and laboratory characteristics of the screened participants were calculated using proportions or means (standard deviations) or medians (interquartile ranges) for continuous data. The proportion with SVR was calculated for each clinical site and overall, by intention-to-treat (ITT). Differences between those successfully treated SVR achieved compared to those who failed treatment were assessed by t test or chi-square test as appropriate, and by multi-

Costs
Cost estimates were made at two sites, Yangon and Mandalay, using data from the first 492 patients from these sites. Costs were estimated from the provider perspective from initial screening date until assessment of outcome using standard economic methods described previously. 21,22 We determined variable patient resource utilization from study case reporting forms and estimated resource utilization from average clinic site capacity and total annual visits. We then multiplied the quantity of each resource used by each patient by the associated unit cost to determine a total cost per patient.
Resources incurring costs included events, laboratory assessments, HCV and HBV medications, clinic staff, indirect costs, education and outreach during the 24-week follow-up period. Events included physical examinations (physician visit), counselling visits and Fibroscans (supplies only). Laboratory assessments included HCV RNA, HCV genotyping, HIV and HBV testing, pregnancy testing, PT/ INR, and blood counts and chemistries. Indirect costs included support staff/personnel, building costs, equipment and office supplies.
HIV medications were utilized but were paid for separately by the government HIV programme and are excluded from the cost analysis. Equipment and technicians' time for Fibroscan ® testing were donated and are also excluded. Costs attributable to the research study but unlikely to be incurred in routine implementation (research staff, education and outreach activities, tariffs and shipping charges for supplies) were included only in Scenario 2.      (Table 1).

| Enrolment and patient characteristics
Six-hundred and eighty participants had HCV genotyping results available at the time of this analysis. Of these, the most common genotypes were 3 (48.8%) and 6 (41.4%). The subtypes were mostly 3b (36%) followed by 6n (19%) and many new genotype 6 subtypes were found in Myanmar.

| Treatment outcomes
Treatment outcomes by site are reported in

| Predictors of SVR
In

| Cost per patient treated and per outcome achieved
Resource utilization for the first 492 participants enrolled at the Yangon and Mandalay study sites and locally collected unit costs is presented in Table 4. Table 5 reports the cost per patient treated and per successful outcome produced for the four scenarios modelled.
A detailed breakdown by cost component and outcome for scenarios 1 and 2 is provided in Table 6. In Scenario 1, which reflects observed costs minus expenses related to research and represents the likely 'real-world' scenario for the protocol intervention, the treatment cost was an average of $930 per patient; the cost to produce a successful patient, taking into account the cost of unsuccessful outcomes, was $1109. These costs increased to $1129 and $1,216, respectively, when research expenses were included in Scenario 2 ( Several major barriers to universal treatment and elimination of HCV in Myanmar were identified, including proximity to clinics, the cost of DAAs, the cost and feasibility of HCV RNA testing, and significant virologic failure among PWID not on OST. Identification of HCV viremic patients may be improved, with a point of care assay to detect HCV viraemia or antigenemia. Increased access to substance use treatment and harm reduction services is further necessary to improve SVR rates among PWID.
It is critical to appreciate that markers of marginalization such as enforcement-oriented drug policies, poor patient-provider relationships, institutionalized stigma within health care systems and social exclusion of PWID are key drivers of challenged treatment compliance and adherence, which impact health seeking behaviour and the ability to access and complete HCV treatment. 25 PWIDs can achieve adherence to and successful outcomes from HCV treatment comparable to other populations, with low re-infection rates. 26,27 A multidisciplinary approach to HCV treatment where treatment and counselling services are offered in a 'one stop shop' has been shown to improve treatment uptake and adherence to therapy 28 . This study has shown that given enough governmental and non-governmental capacity to enrol and treat patients at accessible TA B L E 6 Cost/patient by outcome in Scenario 1 in USD, for n = 492 included in cost analysis