key: cord-0313736-37yb1bzh
authors: Antoniak, S.; Chasela, C.; Morgan Freiman, J.; Stopolianska, Y.; Barnard, T.; Gandhi, M.; Liulchuk, M.; Tsenilova, Z.; Dible, J.; Wose Kinge, C.; Minior, T.; Mohamed, S.; Barralon, M.; Marange, F.; Cavanaugh, C.; Ackpan, F.; van der Horst, C.; Antonyak, S.; Xulu, T.; Sigwebela, N.; Chew, K. W.; Sanne, I. M.; Rosen, S. S.
title: Treatment and Cost -outcomes of a simplified antiretroviral treatment strategy for hepatitis C among HCV and HIV co-infected patients in Ukraine
date: 2021-03-20
journal: nan
DOI: 10.1101/2021.03.19.21253780
sha: 353c31e021f7b414928f0636bfcd3af88d837024
doc_id: 313736
cord_uid: 37yb1bzh

Background: We conducted a demonstration project of an integrated HIV and viral hepatitis testing and treatment strategy using generic ledipasvir/sofosbuvir (LDV/SOF). Methods: Eligible HCV viraemic adults from two clinics in Kyiv were treated with LDV/SOF +/- weight-based ribavirin for 12 weeks. Clinical assessments were performed at screening and week 24 and as needed; treatment was dispensed every 4 weeks. The primary outcome was sustained virologic response (SVR)12 weeks after treatment. Program costs in 2018 USD were estimated per patient treated using observed resource utilization, local unit, and antiretroviral therapy (ART) costs over the 24-week period. Results: 868 participants initiated on treatment, 87% (755) were PWID and 55.5% (482) were HIV co-infected. The common genotypes were 1 (74.1%) and 3 (22%) and SVR was achieved in 831/868 (95.7%) by intention-to-treat analysis. The average cost per patient treated was $680, assuming generic LDV/SOF and ribavirin pricing and standard quantitative HCV viral load testing. Medications comprised 38% of the average cost/patient, laboratory tests 26%, events (clinic visits, counselling) 10%, and indirect costs 26%. ART accounted for 60% of all drug costs, with HCV medications just 40%. Conclusion: Generic LDV/SOF +/- ribavirin provided produced exceptionally good outcomes including amongst patients with genotype 3 HCV and PWID at an average cost of <$700/patient year, including ART for those with HIV. Under the assumptions of generic drug pricing but higher laboratory costs, an average cost of $750/patient is likely a reasonable estimate for this intervention in Ukraine, excluding costs for scaling or maintaining the treatment program.

Globally, an estimated 71 million people are living with chronic hepatitis C virus (HCV) 59 infection and are at risk for significant morbidity, including liver cirrhosis, liver failure, 60 hepatocellular carcinoma and death 1-3 . Even in low-HCV prevalence settings, HCV infection 61 remains common among people who inject drugs (PWID) and HIV-infected men who have sex 62 with men (MSM) 1, 4 . Despite the development of highly effective direct-acting antiviral (DAA) 63 treatment, which can cure HCV infection with 8-12 weeks of therapy, HCV remains a leading 64 cause of mortality worldwide, causing more than 350,000 deaths each year 5,65 . Of these, 85,000 65 are in Eastern Europe 7 , including Ukraine. The WHO's Global Health Sector Strategy sets goals 66 of a 90% reduction in new HCV infections and a 65% reduction in HCV-related mortality by 67 2030 8, 9 . Progress in HCV treatment scale-up has been encouraging, with more than 3 million 68 treated globally with direct-acting antivirals since 2015. Testing and diagnosis rates are still less 69 than 10% in LMICs, however 10 . 70 71 In Ukraine, roughly 3-5% of the population-as many as 2 million people-are estimated to 72 be HCV-infected 11 . Those most at risk are PWID, people living with HIV (PLHIV), sex workers 73 (SW), MSM, prisoners, members of the military, populations in conflict zones, and sexual 74 partners of PLHIV. A lack of adequate facilities and free-to-client services, combined with fear 75 of prosecution for drug use and stigma suffered by key populations, particularly PWID and 76 MSM,, means that most individuals who present for treatment for HCV and HIV are already well 77 advanced in their illness 12 . 78 79 Low cost, scalable, integrated HIV and HCV testing and treatment strategies offer a chance 80 to achieve WHO targets for HIV and HCV elimination in dual epidemic regions. We describe 81 the treatment outcomes and estimated costs for an integrated HIV and HCV treatment program 82 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Intervention 105

The intervention combined HCV and HIV testing, HCV treatment, simplified HCV 106 treatment monitoring, and HIV treatment initiation for those with HIV co-infection not yet on 107 antiretroviral therapy. HCV treatment was with fixed-dose combination ledipasvir/sofosbuvir/ 108 (LDV/SOF) 400 mg/90 mg +/-weight-based ribavirin (1000 mg for patients <75 kg and 1200 109 mg for those ≥ 75 kg administered orally in two divided doses) for 12 weeks and provided by the 110 project. Ribavirin was included in the regimen for treatment experienced cirrhotic genotype 1 111 and 4 participants and all participants with genotype 3 HCV. HIV treatment was per national 112 guidelines, within the National HIV treatment program 13 . Participants with HBV co-infection 113 and hepatitis B surface antigen positivity were concurrently treated with tenofovir. Participants 114 were followed for 24 weeks (through 12 weeks after treatment completion), including 115 assessments of HCV and HIV treatment outcomes and safety. Intervention steps are illustrated in 116 Figure 1 . A four-week supply of study medications was dispensed at weeks 0, 4, and 8 and 117 psychosocial and peer support were provided at entry, 4, 8, 12 and 24 weeks. Participants not 118 already on medication-assisted treatment (MAT) were referred for harm reduction, including 119 MAT programs. 120

Clinical evaluations and drug dispensing 122 A complete clinical assessment including medical history, physical exam, and review of 123 concomitant medications was performed at screening. Subsequently, clinical assessments were 124 driven by reported symptoms and required only at entry and week 24. Liver disease stage 125 (presence or absence of cirrhosis) was defined by any of the following and by the study 126 physician's judgement: cirrhosis on liver ultrasound; liver histology (liver biopsy); AST-to-127 platelet ratio index (APRI)>1.0 and FIB-4>3.25; or liver stiffness by transient elastography 128

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. were performed at the Synevo central laboratory in Kyiv for all participants. 151 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Outcomes 152

The two primary outcomes of the analysis were virologic status at week 24 and cost per 153 patient, stratified by outcome. We assigned each patient one of four virologic status outcomes at 154 24 weeks after treatment initiation: 1) treatment success, defined as sustained virologic response 155 (SVR) at 12 weeks after the end of treatment (week 24); 2) treatment failure (HCV viremia 156 greater than the lower limit of detection 12 weeks after therapy completion); 3) loss to follow up 157 (did not return to clinic for 24-week evaluation); or 4) death (died within the 24-week study 158 period). Other outcomes included safety (adverse events) during the treatment period. 159

Outcomes 161

Baseline sociodemographic, clinical, and laboratory characteristics of the participants were 162 calculated using proportions or means (standard deviations) or medians (interquartile ranges) for 163 continuous data. The proportion with SVR was calculated for each clinical site and overall, by 164 intention to treat (ITT). Differences between those successfully treated SVR achieved compared 165 to those who failed treatment were assessed by t test or chi-square test as appropriate, and by 166 multivariable logistic regression. A p-level of less than 0.2 in the bivariate analysis was used to 167 select variables for multivariable analysis. A final model was determined using stepwise 168 backward elimination method and only p-level of less than 0.05 were considered for the final 169 Costs were estimated from the provider perspective from initial screening date until 174 assessment of cure 12 weeks after HCV treatment completion (24 weeks total) using standard 175 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101/2021.03.19.21253780 doi: medRxiv preprint micro-costing methods described previously 14, 15 . Resource costs are reported in four categories: 176 1) indirect costs (support staff/personnel, building costs, equipment, and office supplies, 177 including education and outreach costs); events (physician visits, counselling visits, and 178

Fibroscans; laboratory tests (HCV viral load modeled using the centralized laboratory pricing at 179 the Synevo laboratory, HCV genotyping, HIV and HBV testing, pregnancy testing if applicable, 180 PT/INR, blood counts, chemistries, and imaging); and medications (HCV, HBV, and HIV). 181

Costs incurred solely for research purposes (e.g. obtaining informed consent, data entry, etc.) 182

were not included. 183

We determined variable patient resource utilization from a de-identified dataset compiled 185 from study participant case reporting forms and estimated resource utilization from average 186 clinic site capacity and total annual visits. We then multiplied the quantity of each resource used 187 by each patient by the associated unit cost to determine a total cost per patient. We evaluated the 188 average resource utilization per patient by cost category and the four HCV treatment outcomes 189 defined for the cost analysis and estimated 95% confidence intervals by outcome category. Cost 190 estimates utilized data from a subset of all patients enrolled in the study; the subset included 191 sequentially enrolled patients during the first six months of the enrollment period. 192 193 Study data were managed with HepatiC® (ABL SA, Luxembourg). The patient resource 194 utilization matrix for this study was generated using SAS software, Version 9.3 (SAS Institute 195

Inc., Cary, NC, USA). Estimates per patient treated and per successful outcome were made using 196 the HE 2 RO Healthcare Costs and Outcome Model (http://www.heroza.org/researchtools/the-197 healthcare-cost-and-outcomes-model-hcom) (HE 2 RO, Johannesburg, South Africa). Economic 198 models were generated with Excel 2011. 199 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (00007612) Gromashevsky. Out of the 868 who started treatment, 87% (755) were PWID, of whom 60.7% 215 (434) were on MAT; most PWID were seen at Gromashevsky. The majority of participants, 216 91.8% (797), were not cirrhotic ( Table 1 ). The mean APRI Score was 0.5 (0.3-0.8). 217

The most common HCV genotypes were 1 (74.1%) and 3 (22.0%) ( Table 1 ). The median 219 (interquartile range, IQR) HCV RNA was 6.1 (5.7-7.1) log 10 IU/m. Among those HIV infected 220 (n=482), the median CD4 count was 507 cells/mm 3 (351-704), and majority had HIV viral 221 suppression (<200 copies per millilitre of blood) at entry. 20 had detectable viral load with a 222 median (interquartile range) of 72 (52.5-267) copies per millilitre of blood; and 5 were 223 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. HCV RNA, Log 10 IU/mL (median, IQR) 6.9 (6.0-11.5) 5.9 (5.5-6.2) 6. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Following treatment initiation, 6 participants were lost to follow up (LTFU), 1 discontinued 247 treatment prematurely and 1 died due to myocardial infarction between week 12 and week 24. 248

Eight hundred and sixty were assessed for SVR at 24 weeks. By intention-to-treat analysis (ITT), 249 which defined all non-successful outcomes as failures, 37 participants failed therapy, for an 250 overall treatment success rate of 831/868 (95.7%). The SVR rates for participants with genotype 251 1 and 3 HCV were 95.5% and 96.3% respectively (Table 3) . SVR rates differed significantly by 252 site and by HIV coinfection status. The majority of treatment failures happened among the HIV-253 co-infected patients. All loss to follow up and the treatment discontinuation were from 254 Gromashevsky clinic; the treatment failures were from Kyiv City Hospital (n=29 (Table 2) (10) F4 0 (0.0) 6 (1.7) 9 (0.9) All rights reserved. No reuse allowed without permission.

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Characteristics of participants are compared between the SVR group and the non-SVR 258 group by ITT population in Table 3 . There were significant differences in the odds of achieving a 259 successful treatment response by treatment site, marriage status, and HIV co-infection status in 260 both univariate and multivariate analysis. 261

Resource utilization for the first 522 participants enrolled at the Kyiv and Gromashevsky 263 study sites and locally collected unit costs are presented in Table 4 , and a detailed breakdown by 264 cost component and outcome is provided in Table 5 . We note that the estimates in Table 5  265 assume generic pricing for LDV/ SOF of $1.06 per tablet; brand pricing for this medication is 266 estimated to cost $10.61/tablet. The results shown in Table 5 are a reasonable proxy for costs 267 under "real world" conditions, with a cost per patient of $680. 268

The study protocol included some resources that may not be regarded as essential for the 270 intervention, such as a Fibroscan, and that many patients actually received more laboratory tests 271 than were called for in the protocol. The cost of these excess resources is included in the estimate 272 in Table 5 . If the Fibroscan were removed and the quantities of liver tests, creatinine tests, and 273 INR/PT were each cut in half, the average cost per patient would be $616. 274 275 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 In a demonstration project of an integrated, simplified protocol for treating HCV and HIV 294

among key populations in Ukraine, of whom 87% (755) were PWIDS and 55.5% (482) were 295 HCV/HIV co-infected, a high SVR rate of 95.7% was achieved amongst all who initiated 296 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 treatment. Very high retention rates were observed especially in Kyiv City clinic. In our study, the estimated average cost of treatment per patient initiated on HCV therapy, 320 including the costs for both HCV and HIV treatment, was $680. The small handful of patients 321 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101/2021.03.19.21253780 doi: medRxiv preprint who did not achieve SVR or did not return for the 24-week evaluation (LTFU) cost slightly less 322 per patient, while the single patient who died cost substantially more, due largely to expensive 323 HIV drugs The cost per patient treated reported here ($680/patient) is dependent on utilizing the 324 lowest cost testing platform to confirm HCV viremia and treatment response (the status quo 325

Synevo labs) and securing generic pricing for HCV medications. Other laboratory platforms will 326 likely cause the cost/patient to go up or down depending on patient volume. Reducing the 327 frequency of laboratory tests will also reduce costs. If generic drugs cannot be obtained, the cost 328 of treatment will be substantially higher. As HCV treatment moves towards the use of pan-329 genotypic drugs, further reductions in the laboratory cost component are possible with 330 elimination of genotype testing, though the cost of the medications will likely be higher than 331 generic LDV/SOF. For program budgeting purposes, under the assumption of generic drug 332 pricing but higher laboratory costs, an average cost of $750/patient is likely a reasonable 333 estimate for this intervention. This does not include costs for scaling up or maintaining the 334 treatment program, such as procurement, training, management, and oversight. 335

In conclusion, an integrated HCV/HIV treatment program in Ukraine achieved excellent 337 outcomes with LDV/SOF+ribavirin HCV treatment in a patient population in which most 338 individuals were co-infected with HIV and were PWID, and a substantial proportion had 339 genotype 3 HCV infection. Loss to follow up was very low and cure rates very high. Adverse 340 events due to RBV were minimal. The cost per patient, while relatively high for Ukraine, was 341 modest by international standards. Going forward, a partnership among community-based 342 organisations, private laboratories, and government that can secure generic medications and 343 provide point of care testing may be an affordable strategy for making HCV treatment 344 universally available in Ukraine. 345 346 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted March 20, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Figure 2: Enrolment of participants and outcomes All rights reserved. No reuse allowed without permission.

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The global burden of viral hepatitis from 371 1990 to 2013: findings from the Global Burden of Disease Study

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