Hepatitis C continuum of care: Experience of integrative hepatitis C treatment within a human immunodeficiency virus clinic in Indonesia.

INTRODUCTION: Direct-acting antiviral drugs (DAAs) have changed the paradigm of hepatitis C therapy for both HCV/HIV co-infected and HCV mono-infected patients. We aimed to describe the HCV continuum of care of HIV-infected patients treated in an HIV clinic after a free DAA program in Indonesia and identify factors correlated with sofosbuvir-daclatasvir (SOF-DCV) treatment failure.
METHODS: We did a retrospective cohort study of adult HIV/HCV co-infected patients under routine HIV-care from November 2019 to April 2020 in the HIV integrated clinic of Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We evaluated some factors correlated with sofosbuvir-daclatasvir treatment failure: gender, diabetes mellitus, previous IFN failure, cirrhosis, concomitant ribavirin use, high baseline HCV-RNA, and low CD4 cell count. RESULTS AND DISCUSSION: Overall, 640 anti-HCV positive patients were included in the study. Most of them were male (88.3%) and former intravenous drug users (76.6%) with a mean age of 40.95 (SD 4.60) years old. Numbers and percentages for the stages of the HCV continuum of care were as follows: HCV-RNA tested (411; 64.2%), pre-therapeutic evaluation done (271; 42.3%), HCV treatment initiated (210; 32.8%), HCV treatment completed (207; 32.2%), but only 178 of these patients had follow-up HCV-RNA tests to allow SVR assessment; and finally SVR12 achieved (178; 27.8%). For the 184 who completed SOF-DCV treatment, SVR12 was achieved by 95.7%. In multivariate analysis, diabetes mellitus remained a significant factor correlated with SOF-DCV treatment failure (adjusted RR 17.0, 95%CI: 3.28-88.23, p = 0.001).
CONCLUSIONS: This study found that in the HCV continuum of care for HIV/HCV co-infected patients, gaps still exist at all stages. As the most commonly used DAA combination, sofosbuvir daclatasvir treatment proved to be effective and well-tolerated in HIV/HCV co-infected patients. Diabetes mellitus was significant factor correlated with not achieving SVR12 in this population.

Introduction

Co-infection of the human immunodeficiency virus (HIV) with hepatitis C virus (HCV) is still one of the world’s significant health problems. After successful antiretroviral therapy (ART), chronic viral hepatitis still accounts for about 10% of mortality among HIV-infected patients [1]. In the Southeast Asian population, the prevalence of hepatitis C co-infection in HIV patients is 4.1%, while the prevalence of HIV/HCV co-infection in Indonesia is 17.9% [2].

Before the direct-acting antiviral (DAA) therapy era, HCV cure rates were significantly lower in HIV/HCV co-infected patients than in HCV mono-infected patients [3]. Nowadays, sustained virological response (SVR) rates in HIV-infected people match those in HIV-negative people [4]. DAA treatment has been recommended in many guidelines due to its oral administration, fewer and less severe side effects, and higher SVR rate compared to interferon (IFN) treatment [5-7]. However, several barriers to DAA therapy persist in lower-middle-income countries, including Indonesia. These barriers include limited case findings, high diagnostic and drug pricing, difficulties in defining the liver fibrosis phase, high patient lost to follow up, weak data systems, and insufficient finances. There is limited access to and choice of DAAs for HIV-infected patients [7-9].

The World Health Organization (WHO) aims to eliminate HCV as a public health threat by 2030, with the goal of reducing incidence by 80% and HCV-related mortality by 65% from 2015 numbers [10]. To achieve this, WHO recommends a continuum of care (CoC), which is a framework that describes the successive steps in health care required for individuals to achieve optimal health outcomes. CoC is an essential framework to predict, monitor, and evaluate progress in achieving these targets and allows country or population comparison [11].

Several reports have demonstrated attempts to achieve HCV micro-elimination in HIV/HCV co-infected patients within HIV clinics [12-14]. Compared to HCV mono-infected patients, HIV/HCV co-infected patients are more likely to be in care and have better access to HCV treatment [14].

The Indonesian government launched a free DAA program in seven demonstration provinces in 2017, using mainly a combination of sofosbuvir (SOF) and daclatasvir (DCV) [7.8]. Our hospital was one of the first sites of this program. This study was carried out in HIV integrative clinic of a university hospital in Jakarta. The main goal was to describe the HCV continuum of care among HIV-infected patients after the introduction of the free DAA program. An additional goal was to identify factors correlated with not achieving SVR at week 12 (SVR12) of SOF-DCV, the most common drug combination used in Indonesia.

Methods

Study population

We conducted a retrospective cohort study of HIV/HCV co-infected patients in the HIV integrated clinic of Cipto Mangunkusumo Hospital. This clinic provides comprehensive HIV care, including opportunistic infection, mental health, and hepatitis care. Hepatologists have been providing DAA treatment once a week since the free DAA program started. The multidisciplinary team was formed in response to the initiation of the DAA program in 2017 included HIV physicians, counselors, nurses, pharmacy, and data support staff. The available drugs are sofosbuvir, daclatasvir, simeprevir (SMV), ribavirin (RBV, and elbatasvir-grazoprevir (EBR-GZR). Elbatasvir-grazoprevir is provided for dialysis patients. HCV genotyping test is not a requirement of starting DAA treatment. All HCV/HIV co-infected patients are eligible for DAA treatment regardless of their fibrosis status. For those with severe opportunistic infections or those using rifampicin for tuberculosis treatment, treatment is delayed until the condition is resolved or antituberculosis is stopped.

All HIV-infected patients, aged 18 years and older, and known to be anti-HCV positive, who were following routine HIV-care from November 2019 to April 2020, were included in the cascade of care evaluation. Patients who started taking sofosbuvir and daclatasvir in 2017–2019 were included for the analysis of to evaluate factors correlated with treatment failure. This additional analysis excluded pregnant women and hepatocellular carcinoma patients.

Data collection

Data was primary derived from medical records, included demographics, transmission risk, and antiretroviral therapy. Three core indicators were used to monitor and evaluate the global health sector strategy on viral hepatitis B and C based on WHO recommendations. These included: (1) testing, (2) treatment, and (3) cure. They were modified and studied as HCV continuum of care as follows. The entry port into the cohort was HCV antibody positivity, and then several steps in the continuum of care were assessed: Step 1: HCV-RNA testing; Step 2: complete pre-therapeutic eligibility evaluation, including liver fibrosis assessment; Step 3: treatment initiation; Step 4: treatment completion; Step 5: sustained virological response at week 12 [12].

The potential factors correlated with SOF-DCV treatment failure, evaluated based on various DAAs studies, were gender, diabetes mellitus, previous IFN failure, cirrhosis, concomitant use of ribavirin (RBV), high baseline HCV-RNA (more than 800,000 IU/mL, 800,000 IU/mL or below), and low CD4 cell count (below 200 cells/mm3, a minimum of 200 cells/mm3) [15-20]. With this combination, non-cirrhotic patients got 12 weeks of treatment, and cirrhotic patients got 24 weeks. The daclatasvir dose was 90 mg in those using efavirenz or nevirapine-based ART and 60 mg in those using other regimens. Detectable HCV-RNA 12 weeks after treatment completion was defined as not achieving sustained virologic response (SVR12) or treatment failure. Ethical approval was provided by the Ethics Committee of the Faculty of Medicine Universitas Indonesia for the use of routinely collected anonymous data with a waiver for informed consent.

Statistical analysis

Results are presented as proportions. The proportion (%) of patients involved in each step of the care cascade was calculated by comparing it to the starting population. Bivariate analysis using the Chi-squared test was used to identify factors associated with not achieving SVR12.

Independent factors correlated with SOF-DCV treatment failure were assessed using a multivariate logistic regression, which included gender, CD4 cell count, diabetes mellitus, history of IFN failure, baseline HCV-RNA, cirrhosis, and ribavirin combination. A backwards stepwise selection process was used to include factors with the significance level of P < 0.25 for the final model. The level of significance was set at 5%, and the risk ratio (RR) with 95% CI was calculated to determine the association. A p-value of less than 0.05 was considered statistically significant.

Results and discussion

Patients

During the study period, a total of 2094 HIV-infected patients were in routine care. Of these patients, 664 were HIV/HCV co-infected (31.8%), all of which used antiretroviral therapy. Twenty-four patients (3.6%) had successfully been treated with an IFN-based regimen before the availability of DAA, leaving 640 patients for further analysis. Most of them were male (565 patients; 88.3%), with a mean age of 40.95 (SD 4.60) years old. HIV and HCV transmission routes were as follows: 490 (76.6%) former intravenous drug users, 98 (15.3%) heterosexual contact, 8 (1.3%) homosexual contact, 3 (0.3%) other routes, and for 41 (6.4%) unknown transmission route.

HCV treatment cascade

Fig 1 shows the diagnosis-based HCV care cascade since the initiation of the free DAA program in July 2017. In total, 411 of 640 (64.2%) anti-HCV-positive patients underwent HCV-RNA testing, of whom 359 patients were HCV-RNA positive (87.3%). Access to affordable HCV-RNA tests was identified as a major pitfall to start the treatment process as HCV-RNA quantification is still considered an expensive test for most of these patients. The same gaps in the proportion of patients who screened as anti-HCV antibody positive but did not get a confirmatory viral load test were also reported in some countries [7]. The usual cost for the HCV-RNA test in Indonesia is USD 139 [21]. When the government launched the free DAA program, HCV-RNA reagent was included in the coverage. However, supply did not match the number of anti-HCV-positive patients. Therefore, clinicians might have prioritized HCV-RNA tests for patients who were considered ready for DAA treatment. Some of these patients still had severe opportunistic infections or were using rifampicin for tuberculosis treatment which is known to interact with most available DAA drugs.

Fig 1

HCV care cascade for HCV diagnosed HIV-infected patients in care.

Arrows represent the proportion of patients in the previous stage of the cascade that progressed to the next stage of care. Note: SVR = sustained virological response.

Of the 359 HCV-RNA positive patients, 271 patients (75.5%) started their pre-treatment evaluation to define the level of fibrosis, and 210 patients started DAA treatment (58.5%). One possible reason for not doing the pre-treatment evaluation is the cost of the diagnostic procedure before starting DAA. Transient elastography (TE) still carries a high cost, thus often causing a delay in treatment initiation. In the previous report, we proposed an APRI score ≥ 1 or a FIB-4 score ≥ 1.66 as an alternative to TE for defining cirrhosis in HIV/HCV co-infected patients before starting DAA [9].

Due to the free DAA program’s interruption, the remaining 61 patients who had pre-treatment evaluation could not start treatment in 2020. While waiting for the availability of the drugs, four of the patients passed away. The free program started again in January 2021, and it is very likely that some of these patients will initiate DAA treatment soon.

Patients were treated with the following DAA combination: SOF-DCV (98.5%), SOF-DCV-RBV (0.5%), SOF-SMV (0.5%), and EBR-GZR (0.5%). Almost all patients (98.6%) who started DAA completed their treatment, in either a 12 or 24-weeks duration. Three patients did not complete the treatment course: two patients passed away and one stopped treatment due to side effects.

Of the 207 patients who completed the treatment, 178 achieved SVR12 (86.0%), and eight failed to do so. Eight percent of these patients (21 patients) did not have HCV-RNA test 12 weeks after treatment completion. The disruption of the program, including disruption to the supply of free HCV-RNA reagent, was one of the reasons. This point of cascade constitutes the biggest gap in several countries. A study describing the cascade of care of all HCV-infected patients in Cambodia, India, Vietnam, Rwanda, Myanmar, Nigeria, and Indonesia has shown a gap of 55% between initiation of treatment and SVR12 HCV-RNA conducted [7]. However, this study presents better SVR12 documentation as the gap between treatment initiation and SVR12 documentation was only 10%.

To the authors’ knowledge, this is the first study to provide an assessment of cascade of care for HCV among HIV-infected patients in Indonesia after the introduction of the free DAA program. Compared to the Indonesian cascade of care for all HCV-infected patients, the cohort described in this study exhibited a different pattern. Both have shown similar treatment initiation rates: 32.8% of 640 HCV antibody positive patients in this study started DAA treatment while 31.8% of 17200 HCV antibody positive patients in the Indonesian report started DAA. The SVR12 rate in our HCV care cascades was 27.8% (178 of 640 HIV/HCV co-infected patients), higher than the SVR12 rate documented in national HCV care cascades (9.5%: 1635 of 17200 all HCV-infected patients) [7]. Our DAA SVR12 treatment rate was considered lower than studies reported in other countries [12, 13, 22–24].

Regarding safety and tolerability, the main adverse effects recorded during and after 12 weeks of treatment cessation were headache (20%), fatigue (18.6%), nausea (7.6%), itchiness (4.8%), gastrointestinal trouble (3.3%), muscle pain (1.9%), sleep disturbance (1.4%), and fever (1.4%). Only one person stopped treatment due to headaches. Others only experienced mild and well-tolerated effects.

This study shown that integrating HCV services within an HIV clinic has overcome several barriers to HCV treatment care, such as referral systems and treatment adherence. The multidisciplinary team that communicated regularly had promoted better engagement in the HCV treatment care, although there was an interruption of drug supply later on. The SVR12 rate in HIV/HCV-coinfected patients in this clinic exceeds the rated reported in national data and shows the effectiveness of this model [7]. Several studies have shown similar efforts to eliminate HCV infection within HIV clinics. Rizk, et al described a co-located HCV clinic within a hospital-based HIV clinic in Connecticut. Of 173 patients, 70.5% initiated DAA treatment resulting in 56.1% SVR12. Most of these patients, however, had mental health issues, abused alcohol, and were active drug users [12]. Though 76.6% of patients in this study were previously intravenous drug users, we did not have data on currently active drug users. Other studies have also shown successful efforts toward HCV micro elimination in HIV care after universal access to DAAs [12, 13, 25–27].

Factors correlated with SOF-DCV treatment failure

Overall, 184 HIV/HCV co-infected patients completed SOF-DCV treatment and underwent HCV-RNA quantification. These patients had already been using antiretroviral treatment for a median of 9 (5–12) years, mainly NVP-based therapy (43.5%) and EFV-based therapy (41.8%), as seen in Table 1. Most of the patients had an absolute CD4 cell count of more than 200 cells/mm3.

Table 1

Characteristics of patients completed sofosbuvir-daclatasvir treatment cascade (n = 184).

Characteristics
Male, n (%)	165 (89.7%)
Age in years, mean (SD)	38.1 (4.2)
HIV/HCV risk factor, n (%)
History of IVDU	166 (90.2%)
Heterosexual transmission	15 (8.2%)
Homosexual transmission	3 (1.6%)
Diabetes mellitus, n (%)	9 (4.9%)
Cirrhosis, n (%)	38 (20.7%)
Previous IFN treatment failure, n (%)	15 (8.2%)
HCV treatment regimen, n (%)
SOF + DCV (90)	147 (79.9%)
SOF + DCV (60)	36 (19.6%)
SOF + DCV (90) + RBV	1 (0.5%)
SOF-DCV duration, n (%)
12 weeks	143 (77.7%)
24 weeks	41 (22.3%)
Baseline HCV-RNA, n (%)
≥ 800.000 IU/mL	140 (76.1%)
< 800.000 IU/mL	44 (23.9%)
ART duration in years, median (IQR)	9 (5–12)
ART used, n (%)
NVP-based	80 (43.5%)
EFV-based	77 (41.8%)
LPV/r based	25 (13.6%)
Other	2 (1.1%)
Recent absolute CD4 cell, n (%)
<200 cells/mm3	26 (14.1%)
≥200 cells/mm3	158 (85.9%)

SD: Standard deviation; IVDU: Intravenous drug user; IFN: Interferon; SOF: Sofosbuvir; DCV: Daclatasvir; RBV: Ribavirin; ART: Antiretroviral therapy; IQR: Interquartile range; NVP: Nevirapine; EFV: Efavirenz; LPV/r: Lopinavir/ritonavir.

SVR12 for patients using SOF-DCV regimen was achieved by 176 of 184 patients (95.7%). This SVR rate was comparable with rates reported in phase III studies [28], and other real-life situations in HIV/HCV co-infection [15, 16, 29, 30], even though HCV genotyping was not a requirement of starting this treatment program. A recent meta-analysis has shown that the SVR12 rate of SOF-DCV±RBV among HIV/HCV co-infected patients in clinical-trials was 97% (95% CI 93–99%), and in real-world studies 94.1% (95% CI 91.2–96.4%) [4].

Eight patients (4.3%) failed to achieve SVR12 and needed further treatment. Treatment failure was not defined by their gender, recent CD4, previous IFN treatment failure, RBV combination, nor higher baseline HCV-RNA before starting SOF-DCV treatment, as seen in Table 2. In multivariate analysis, the presence of cirrhosis could not predict treatment failure, although it was significant in univariate analysis. In this study, nine patients had been diagnosed with diabetes mellitus before starting SOF-DCV treatment. One-third of these 9 patients did not achieve SVR12, showing that. patients with diabetes mellitus had a 17 times higher treatment failure rate (95% CI 3.28–88.23). A study by Patel, et al supported this finding. In that study, diabetes mellitus was negatively associated with achieving SVR12 (OR 0.68, 95% CI 0.13–0.94) [15]. A prior study from Spain of 1059 HCV mono-infected patients in the interferon era showed that insulin resistance, the driving factor that leads to type 2 diabetes, was a negative predictor for achieving SVR12 (OR 0.44, 95% CI 0.20–0.97) [31].

Table 2

Results from univariable and multivariable logistic regression models to identify independent factors correlated with sofosbuvir and daclatasvir treatment failure (n = 184).

Factors	Non-SVR12	SVR12	RR (95%CI)	p	Adjusted RR (95% CI)	p
	N (%)	N (%)
Gender
Male	8 (4.8%)	157 (95.2%)	-	1.000
Female	0 (0%)	19 (100%)
CD4
<200 cells/mm3	2 (7.7%)	24 (92.3%)	2.03 (0.43–9.50)	0.315
≥ 200 cells/mm3	6 (3.8%)	152 (96.2%)
Diabetes mellitus
Yes	3 (33.3%)	6 (66.7%)	11.67 (3.29–41.33)	0.004	17 (3.28–88.23)	0.001
No	5 (2.9%)	170 (97.1%)
History of IFN failure
Yes	0 (0%)	15 (100%)	-	1.000
No	8 (4.7%)	161 (95.3%)
Baseline HCV-RNA
≥ 800.000 IU/mL	7 (5.0%)	133 (95.0%)	2.20 (0.28–17.40)	0.682
< 800.000 IU/mL	1 (2.3%)	43 (97.7%)
Cirrhosis
Yes	4 (10.5%)	34 (89.5%)	3.84 (1.01–14.66)	0.058	1.95 (0.34–11.04)	0.451
No	4 (2.7%)	142 (97.3%)
Ribavirin combination
No	8 (4.4%)	175 (95.6%)	-	1.000
Yes	0 (0%)	1 (100%)

SVR: Sustained virologic response; IFN = interferon

For those who did not achieve SVR12, testing for HCV genotype might be needed for future treatment options. In the original phase III ALLY-3 study, a much lower SVR12 rate was observed in genotype 3-infected patients with cirrhosis treated with SOF-DCV for 12 weeks [28]. The addition of RBV to SOF-DCV was recommended to improve the SVR12 response in genotype 3 infected patients with cirrhosis [32, 33]. Our previous study in 2014 showed that genotype 3 is the second most common HCV (21.9%) genotype in HIV/HCV co-infected patients after genotype 1 (68.6%) [34].

This study has several limitations. First, not all treated patients have HCV-genotyping data. Though genotype 3 was the second most prevalent in this population, the percentage of cure for those who completed treatment was more than 90%. Second, the study included a relatively small number of patients with HCV-RNA evaluation after treatment completion, thus limiting the number of variables analysed by multivariate analysis to find factors correlated with treatment failure. This number has been an obstacle to making a firm conclusion. Furthermore, HCV reinfections after DAA treatment and cures after retreatment were not evaluated in this study. Finally, as this is a single tertiary center experience with a selected population of young age, mostly previous IVDU, low cirrhotic proportion, and mostly interferon treatment-naive, these results may not be generalized to other health care systems in different regions.

Conclusions

Establishing HCV treatment within a HIV clinic facilitated a better HCV care cascade of HIV/HCV co-infected patients. We found sofosbuvir-daclatasvir treatment to be an effective treatment in HIV/HCV co-infected patients, which resembled other real-world studies, and supports the use of DAA to achieve HCV elimination in 2030. Diabetes mellitus was significant factor correlated with not achieving SVR12 in this population.

19 May 2021

PONE-D-21-12487

Hepatitis C Continuum of Care: an Experience of Integrative Hepatitis C Treatment within Human Immunodeficiency Virus Clinic in Indonesia

PLOS ONE

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Reviewer #1: 1. The paper provides a good account of a Hepatitis C treatment program in Indonesia. The data presented is good. The authors will however need to revise their manuscript with the help of an editor or a native English speaker to improve the grammar and sentence structure to bring the manuscript up to the standards required for publication.

2. In the second paragraph of the introduction the authors mention barriers to DAA still being present in Indonesia. They however failed to state clearly what specific barriers were referring to. The authors will need to clearly state what types of access barriers exist in Indonesia and other lower- and middle-income countries.

3. In the methods section under “Data Collection” the authors list potential predictors of treatment failure without stating how these were determined. If this was based on prior studies this must be stated and appropriately referenced.

4. It is interesting that the study population has 76.6% previous injection drug users with no mention made of current drug users. Did the researchers review the charts for subsequent drug screens in this population to make that determination? Most studies in substance abusing populations suggest that addition is a chronic disease and relapse rates are usually high. If the determination of current drug use was not done in this population the more appropriate description will be individuals with history of IV drug use.

5. The authors failed to state if there were any clinical or other criteria for determining which HCV positive clients were evaluated for HCV treatment. Per the information from the introduction pregnant women and those with Hepatocellular Carcinoma (HCC) were excluded but since pregnancy is not a persistent problem the drop from 64.2% to 42.3% is too great to be due to pregnancy and HCC alone. If other criteria were used to determine who to treat other than HCC and pregnancy such as ongoing drug use, alcohol use etc, this must be included in the manuscript.

6. The authors used the period for designating decimals in most parts of the manuscript but chose to use commas in the data on tolerability of the treatment agents and side effects reported. I suggest they maintain the standard of using a period to designate a decimal here and in all parts of the manuscript.

7. The statement in the results section stating that the observed SVR rate of 27.8% being better than the national rate of 31.3% in coinfected patients is false. Unless I am reading the sentence wrong. The authors must look closely at their SVR numbers and correct their statement appropriately.

8. The authors in their methods and introduction mention performing a logistic regression model to determine predictors of SVR outcomes with DAA treatment. It is however not clear what methods they used to determine the fitness of their model to the data. The criteria used to determine which variables were maintained or excluded from the optimum chosen model was not mentioned. To ensure appropriate reproducibility of the study all these statistical methods will have to be documented.

9. For a predominantly male HIV/HCV coinfected population it is interesting to note a very small proportion of reported same sex HIV/HCV sexual transmission. Is it possible that there are social and cultural factors impacting accurate self-reported HIV risk behaviors?

10. Though the authors did mention some of the possible reasons for the low SVR rate for the cascade mostly at the level of the treatment initiation to SVR that is the stage with the greatest drop. For the most impact on public health and to provide good data for programs seeking to improve the HCV the authors need to focus on each part of the cascade providing possible reasons why individuals failed to transition across the cascade. If those impacted by the program ending are included in the cascade.

11. The authors state as one of the primary objectives determining predictors of HCV treatment outcome with DAA yet this is not mentioned in their conclusion. The authors will need to state in their conclusion which predictors they found to be significant as well as any key covariates determined to have no predictive value.

Reviewer #2: Improving HCV cascade of care is vital to achieve HCV elimination. Even with high rates of SVR, it is important to find predictors of DAAs failure. Authors evaluated these issues in a selected population.

I have some comments:

Why wasn’t the 36% of the population tested for HCV RNA?

You lost many patients in the track: why was that? Can you comment a little more on the causes of failing evaluating fibrosis and initiating treatment? Was the interruption of the program the only motive for not initiating treatment?

In line 149 you wrote: “…but higher SVR12 rate (27.8% vs. 9.5%).” Can you clarify these percentages?

In Predictors of SOF/DCV failure section you are repeating previously presented results. Please correct this.

DBT2 effect might be overestimated due to the small number of patients. The 95%CI is huge (3.2-88.2).

As you mentioned your study has many major limitations:

- Absence of genotyping is a major flaw, specially if GT3 is the second most prevalent in your population since it has a reduce SVR rate to DCV/SOF.

- The small number of patients avoids taking firm conclusions. When analyzing all variables these numbers reduce more.

- This is a very selected population: young age, mostly IVDU, low proportion of cirrhotics, los proportion of previously IFN treated. You must add a comment in the discussion section.

The idea is interesting, especially the analysis of the cascade of care. This can be improved.

You will have to increase the number of patients to take solid conclusion about predictors of failure.

There are some grammatical mistakes. Please, review the text with a professional writer.

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1 Jul 2021

July, 1st, 2021

Dear Editor of Plos One,

Thank you for the opportunity to revise our manuscript entitled “Hepatitis C Continuum of Care: An Experience of Integrative Hepatitis C Treatment within Human Immunodeficiency Virus Clinic in Indonesia”. The constructive comments from reviewers really helped us to improve content of this manuscript. We sincerely hope that we have addressed the arguments presented and revised the manuscript satisfactorily.

Reviewer 1 gave a profound evaluation to our manuscript and has brought about important views as well as incisive counterpoints, which we highly appreciate. We also appreciate the detailed correction on the Result Tables and have revised section accordingly. Reviewer 2 provided a brief and comprehensive summary to our research, and we thank the reviewer for the positive response. We have also thoroughly added the study drawbacks in limitation.

One of the authors dr Rahmat Hariyanto passed away due to malignant melanoma at May, 8th 2021. We have added † symbol in author information and a sentence in the acknowledgement.

We have no conflicting interest in writing this manuscript and no financial disclosure need to be done since this study was not received any grant.

We hope that you may find the article in this revised state as satisfactory. We look forward to further feedback or editorial guidance as necessary.

Kind regards,

Evy Yunihastuti

Reviewer #1:

1. The paper provides a good account of a Hepatitis C treatment program in Indonesia. The data presented is good. The authors will however need to revise their manuscript with the help of an editor or a native English speaker to improve the grammar and sentence structure to bring the manuscript up to the standards required for publication.

Thank you for the positive evaluation of our manuscript. We have corrected this new version with the help of professional writer.

2. In the second paragraph of the introduction the authors mention barriers to DAA still being present in Indonesia. They however failed to state clearly what specific barriers were referring to. The authors will need to clearly state what types of access barriers exist in Indonesia and other lower- and middle-income countries.

We sincerely appreciate your suggestion. Several barriers to DAA did persist in lower-middle-income countries, including Indonesia. These barriers include limited case findings, high diagnostic and drug pricing, difficulties in defining the liver fibrosis phase, high patient lost to follow up, weak data systems, and insufficient finances. We stated this description in line 43-45.

3. In the methods section under “Data Collection” the authors list potential predictors of treatment failure without stating how these were determined. If this was based on prior studies this must be stated and appropriately referenced.

Thank you for the detailed correction. We defined the potential predictors based on previous DAAs studies and we have added the references accordingly (line 96).

4. It is interesting that the study population has 76.6% previous injection drug users with no mention made of current drug users. Did the researchers review the charts for subsequent drug screens in this population to make that determination? Most studies in substance abusing populations suggest that addition is a chronic disease and relapse rates are usually high. If the determination of current drug use was not done in this population the more appropriate description will be individuals with history of IV drug use.

Thank you for bringing this issue. The determination of current drug use was not part of standard evaluation before starting DAA at our clinic. Because this study was a retrospective study, we did not have the data. You were right, they are individuals with history of IV drug use (former intravenous drug users). We made changed in Table 1 and add this information in the discussion (line 203-205).

5. The authors failed to state if there were any clinical or other criteria for determining which HCV positive clients were evaluated for HCV treatment. Per the information from the introduction pregnant women and those with Hepatocellular Carcinoma (HCC) were excluded but since pregnancy is not a persistent problem the drop from 64.2% to 42.3% is too great to be due to pregnancy and HCC alone. If other criteria were used to determine who to treat other than HCC and pregnancy such as ongoing drug use, alcohol use etc, this must be included in the manuscript.

Thank you for pointing this out. Pregnant women and hepatocellular carcinoma patients were excluded in the analysis of SOF-DCV treatment failure, not in the continuum of care data. In determining who to threat, for those with severe opportunistic infections or those using rifampicin for tuberculosis treatment, treatment is delayed until the condition is resolved or antituberculosis is stopped. Ongoing drug use and alcohol use were not considered as exclusion criteria to start DAA. We moved these exclusion criteria to line 87-88 and delete the exclusion criteria in the abstract (line 9-10) to avoid confusion.

6. The authors used the period for designating decimals in most parts of the manuscript but chose to use commas in the data on tolerability of the treatment agents and side effects reported. I suggest they maintain the standard of using a period to designate a decimal here and in all parts of the manuscript.

Thank you for reminding us about maintaining the standard format in the whole manuscript. We have changed all the commas to periods in line 126 and 189-190.

7. The statement in the results section stating that the observed SVR rate of 27.8% being better than the national rate of 31.3% in coinfected patients is false. Unless I am reading the sentence wrong. The authors must look closely at their SVR numbers and correct their statement appropriately.

Thank you for your detailed observation. We humbly apologize for the error in statement 31.3% was the national number of HCV patients who conducted SVR12 evaluation of all patients started treatment, while the number of our study was 88.6%. To avoid the confusion, we changed the paragraph below, comparing DAA initiation and SVR rate only, not comparing SVR VL testing.

Both have shown similar treatment initiation rates: 32.8% of 640 HCV antibody positive patients in this study started DAA treatment while 31.8% of 17200 HCV antibody positive patients in the Indonesian repor started DAA. The SVR12 rate in our study was 27.8%, higher than the SVR12 rate documented in national HCV care cascades (9.5%) (line 182-186).

8. The authors in their methods and introduction mention performing a logistic regression model to determine predictors of SVR outcomes with DAA treatment. It is however not clear what methods they used to determine the fitness of their model to the data. The criteria used to determine which variables were maintained or excluded from the optimum chosen model was not mentioned. To ensure appropriate reproducibility of the study all these statistical methods will have to be documented.

Thank you for detailed observation. We use a backwards stepwise selection process to determine the predictors in multivariate logistic regression. We have added the detailed in line 119-120.

9. For a predominantly male HIV/HCV coinfected population it is interesting to note a very small proportion of reported same sex HIV/HCV sexual transmission. Is it possible that there are social and cultural factors impacting accurate self-reported HIV risk behaviors?

Thank you for bringing this problem. Our clinic was one of the first MSM-friendly clinic in Indonesia. We started with MSM sensitivity training back in 2011, then conducted the training to other HIV centers in Indonesia. Our counselors evaluated all patients risk behaviors before starting antiretroviral therapy. Though it is still possible that the patients did not report accurate HIV risk behavior, we believe the number might be minimal.

10. Though the authors did mention some of the possible reasons for the low SVR rate for the cascade mostly at the level of the treatment initiation to SVR that is the stage with the greatest drop. For the most impact on public health and to provide good data for programs seeking to improve the HCV the authors need to focus on each part of the cascade providing possible reasons why individuals failed to transition across the cascade. If those impacted by the program ending are included in the cascade.

Thank you for the insightful suggestion. We rewrote most of paragraphs in HCV treatment cascade section, trying to explain each part of the cascade and providing possible reasons why individuals failed to transition across the cascade (line 136-147, 150-154, 172-178).

11. The authors state as one of the primary objectives determining predictors of HCV treatment outcome with DAA yet this is not mentioned in their conclusion. The authors will need to state in their conclusion which predictors they found to be significant as well as any key covariates determined to have no predictive value.

Thank you for the suggestion. We have added in the conclusion and abstract that diabetes mellitus was significant predictor of not achieving SVR12 (line 26-27, 273-274).

Reviewer #2: Improving HCV cascade of care is vital to achieve HCV elimination. Even with high rates of SVR, it is important to find predictors of DAAs failure. Authors evaluated these issues in a selected population.

Thank you for kindly emphasizing the important of the article and the positive overall feedback on the manuscript.

1. Why wasn’t the 36% of the population tested for HCV RNA?

The usual cost for the HCV-RNA test in Indonesia is USD 139 (Trickey, 2019) which is considered too high cost for our patients who mostly come from low-middle-income family. When the government launched the free DAA program, HCV-RNA reagent was included in the coverage. However, supply did not matched the number of anti-HCV-positive patients. Therefore, clinicians might have prioritized HCV-RNA tests for patients who were considered ready for DAA treatment. Some of these patients still had severe opportunistic infections or were using rifampicin for tuberculosis treatment which is known to interact with all available DAA drugs. We have added this discussion in line 141-147.

2. You lost many patients in the track: why was that? Can you comment a little more on the causes of failing evaluating fibrosis and initiating treatment? Was the interruption of the program the only motive for not initiating treatment?

One possible reason for not doing the pre-treatment evaluation is the cost of the diagnostic procedure before starting DAA. Transient elastography (TE) still carries a high-cost, thus often causing a delay in treatment initiation. We have added this information in line 150-152. For those who had pre-treatment evaluation, the interruption of the program was solely the reason not to start treatment.

3. In line 149 you wrote: “…but higher SVR12 rate (27.8% vs. 9.5%).” Can you clarify these percentages?

In our study, 27.8% (178 of 640 anti-HCV positive HIV co-infected patients) achieved SVR12 while in national data 9.5% (1635 of 17200 all HCV-infected patients) achieved SVR12 (Boeke, 2020).

4. In Predictors of SOF/DCV failure section you are repeating previously presented results. Please correct this.

Thank you for the detailed correction. We humbly apologize for this error. We have deleted the repeating results in predictors of SOF-DCV treatment failure section.

5. DBT2 effect might be overestimated due to the small number of patients. The 95%CI is huge (3.2-88.2).

The small number of data did limit our ability to analyze the true association to DBT2 with SOF-DCV treatment failure as the 95% CI was huge. Patel, et al and Romero-Gomez, et al also shown an association of diabetes and insulin resistance to SVR12 achievement. We have added this limitation in line 260-263.

6. As you mentioned your study has many major limitations:

- Absence of genotyping is a major flaw, specially if GT3 is the second most prevalent in your population since it has a reduce SVR rate to DCV/SOF.

- The small number of patients avoids taking firm conclusions. When analyzing all variables these numbers reduce more.

- This is a very selected population: young age, mostly IVDU, low proportion of cirrhotics, los proportion of previously IFN treated. You must add a comment in the discussion section.

Thank you very much for the insightful critique. We have added these limitation details in the discussion (line 259-267).

7. The idea is interesting, especially the analysis of the cascade of care. This can be improved.

Thank you for the crucial suggestion. We rewrote most of paragraphs in HCV treatment cascade section, trying to explain each part of the cascade and providing possible reasons why individuals failed to transition across the cascade (line 136-147, 150-154, 172-178).

8. You will have to increase the number of patients to take solid conclusion about predictors of failure.

Thank you for bringing this important point. It is absolutely the right thing to do when we have more patients. Other studies reporting higher number of patients, but with various DAA regimen, while this study only for sofosbuvir and daclatasvir combination.

9. There are some grammatical mistakes. Please, review the text with a professional writer.

Thank you for the suggestion. We have made some corrections according to professional writer’s suggestion.

13 Jul 2021

PONE-D-21-12487R1

Hepatitis C Continuum of Care: An Experience of Integrative Hepatitis C Treatment within Human Immunodeficiency Virus Clinic in Indonesia

PLOS ONE

Dear Dr. Yunihastuti,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Your modified manuscript was reviewed by two original reviewers. Although one reviewer was satisfied with modifications, the other still identified several important problems and made valuable suggestions to improve your paper. Please carefully review the attached comments and provide point-by-point responses.

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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Reviewer #1: No

Reviewer #2: Partly

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. The Title could be modified to read “Hepatitis C Continuum of Care: Experience of Integrative Hepatitis C Treatment within a Human Immunodeficiency Virus Clinic in Indonesia”, this reads better with same number of words.

2. The sentence on page 15 line 53 “This study was carried out in a specific clinical care of HCV treatment within an integrated HIV clinic in a university hospital in Jakarta” is not clear enough. It is difficult to tell what the authors are attempting to convey with that sentence. This sentence will need to be revise to improve clarity.

3. I suggest the authors rather than use predictors of treatment failure consider the term correlates of treatment failure. The term predictors may suggest some causality, this study is however only able to determine associations and not causality. Correlate is thus a more accurate term for the identified variables in such an analysis.

4. On page 8 and 9 line 127 – 129, I suggest the authors change that sentence suggesting interaction with all available, HCV drugs. This statement is based on mechanism of action some of these interactions have not been formally studied. A more accurate phrase will be “………. most available DAA drugs”.

5. In the manuscript the authors quote a SVR12 rate of 27.8% for their analysis and a 9.5% rate for Indonesia. This numbers appear to be the successful treatment rate from the cascade. Using the term SVR12 which must only be used to describe successful treatment in those who received HCV antivirals is incorrect. The effective SVR12 rate is 84.7%. This is repeated in many parts of the paper the authors need to make sure they correct that error.

6. The reported SVR12 of 95.7% is higher than what I calculated of 84.7% based on all patients who initiated treatment. That is the method used in most analysis, I would suggest the authors clearly define SVR in their analysis since it appears to be different from standard practice. Also, since this calculation is different from other studies comparing with phase III studies and other reports is really not a fair and accurate statement. The authors could do multiple analysis for SVR, but it needs to be clear what the denominator is for each calculation.

7. The manuscript authors will require to work closely with an English language editor to ensure the message provided in this manuscript is accurate to avoid errors in messaging due to difficulties with English.

Reviewer #2: Authors accomplished all suggestions made by the reviewers.

There are still some limitations, but these cannot be corrected (as suggested in the Discussion).

Thanks for your effort and your time.

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22 Jul 2021

July 22nd, 2021

Dear Plos One Editor,

Thank you for the opportunity to revise our manuscript entitled “Hepatitis C Continuum of Care: Experience of Integrative Hepatitis C Treatment within a Human Immunodeficiency Virus Clinic in Indonesia”. The constructive comments from reviewers really helped us to improve content of this manuscript.

We have no conflicting interest in writing this manuscript and no financial disclosure need to be done since this study was not received any grant.

We hope that you may find the article in this revised state as satisfactory. We look forward to further feedback or editorial guidance as necessary.

Kind regards,

Evy Yunihastuti

Reviewer #1:

1. The Title could be modified to read “Hepatitis C Continuum of Care: Experience of Integrative Hepatitis C Treatment within a Human Immunodeficiency Virus Clinic in Indonesia”, this reads better with same number of words.

We really appreciate your valuable suggestion. We have changed the title according to your suggestion.

2. The sentence on page 15 line 53 “This study was carried out in a specific clinical care of HCV treatment within an integrated HIV clinic in a university hospital in Jakarta” is not clear enough. It is difficult to tell what the authors are attempting to convey with that sentence. This sentence will need to be revise to improve clarity.

Thank you for pointing this out. We changed this sentence to improve clarity. This study was carried out in HIV integrative clinic of a university hospital in Jakarta. (page 5 line 54)

3. I suggest the authors rather than use predictors of treatment failure consider the term correlates of treatment failure. The term predictors may suggest some causality, this study is however only able to determine associations and not causality. Correlate is thus a more accurate term for the identified variables in such an analysis.

Thank you very much for the insightful critique. We understand that this study was unable to determine causality. Therefore, we have changed the term predictor to factor correlated with treatment failure in the whole manuscript.

4. On page 8 and 9 line 127 – 129, I suggest the authors change that sentence suggesting interaction with all available, HCV drugs. This statement is based on mechanism of action some of these interactions have not been formally studied. A more accurate phrase will be “………. most available DAA drugs”.

Thank you for your detailed observation. We have changed the sentence according to your suggestion. Rifampicin is known to interact with most available DAA drugs. (page 8 line 127-129)

5. In the manuscript the authors quote a SVR12 rate of 27.8% for their analysis and a 9.5% rate for Indonesia. This numbers appear to be the successful treatment rate from the cascade. Using the term SVR12 which must only be used to describe successful treatment in those who received HCV antivirals is incorrect. The effective SVR12 rate is 84.7%. This is repeated in many parts of the paper the authors need to make sure they correct that error.

Thank you for your bringing this point. Studies evaluating HCV continuum of care calculated SVR12 rate in various ways: Boerekamps, et al calculated SVR12 based on patients retained in care; Rizk, et al calculated based on all HCV patients; Saris, et al and Boeke, et al used number of patients with available treatment outcome as denominator; Adekunle, et al used number of patients initiate HCV treatment as denominator of SVR12 rate. We used SVR12 definition the same way as Rizk, et al to define SVR12 rate for the cascade, which was 27.8% (178 of 640 all HIV/HCV co-infected patients). We manually calculated the SVR12 rate for Indonesia in the same way (9.5%: 1635 of 17200 all HCV-infected patients).

When evaluating predictor or SOF-DCV treatment failure, the denominator was all patients using SOF-DCV regimen who had treatment outcome data (176 of 184 patients; 95.7%). Two other patients with available treatment outcome were using SOF-SMV and EBR-GZR regimen, not SOF-DCV.

We have changed the method section (line 79-96) and added the denominator for each calculation of SVR12 as your suggestion (line. 164-166 and 198)

6. The reported SVR12 of 95.7% is higher than what I calculated of 84.7% based on all patients who initiated treatment. That is the method used in most analysis, I would suggest the authors clearly define SVR in their analysis since it appears to be different from standard practice. Also, since this calculation is different from other studies comparing with phase III studies and other reports is really not a fair and accurate statement. The authors could do multiple analysis for SVR, but it needs to be clear what the denominator is for each calculation.

Thank you for the insightful suggestion. We have added the denominator for each calculation of SVR12 according to your suggestion (line 164-166 and 198). We did two different analysis for SVR12. First, SVR12 rate as part of HCV continuum of care cascade, which used HCV antibody positivity as denominator. Second, when evaluating predictor or SOF-DCV treatment failure, the denominator was all patients using SOF-DCV regimen who had treatment outcome data (176 of 184 patients; 95.7%). This was considered the effective SVR12 of SOF-DCV that can be compared with the results of phase III studies and other reports.

7. The manuscript authors will require to work closely with an English language editor to ensure the message provided in this manuscript is accurate to avoid errors in messaging due to difficulties with English.

Thank you for your suggestion. We have worked closely with English editor and native speaker for this correction.

Reviewer #2:

Authors accomplished all suggestions made by the reviewers. There are still some limitations, but these cannot be corrected (as suggested in the Discussion). Thanks for your effort and your time.

We appreciate the reviewer for the positive response and all suggestions for our manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

2 Aug 2021

Hepatitis C Continuum of Care: Experience of Integrative Hepatitis C Treatment within a Human Immunodeficiency Virus Clinic in Indonesia

PONE-D-21-12487R2

Dear Dr. Yunihastuti,

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Yury E Khudyakov, PhD

Academic Editor

PLOS ONE

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4 Aug 2021

PONE-D-21-12487R2

Hepatitis C Continuum of Care: Experience of Integrative Hepatitis C Treatment within a Human Immunodeficiency Virus Clinic in Indonesia

Dear Dr. Yunihastuti:

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