Efficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients

Background: With the availability of direct acting antiviral treatment for hepatitis C (HCV), HIV and HCV co-infected patients show comparable treatment responses to HCV-monoinfected patients. An 8-week course of sofosbuvir/ledipasvir (SOF/LDV) is highly effective for the treatment of HCV genotype 1 infection in treatment-naïve mono-infected patients with HCV viral loads <6 million IU/ml. There is limited data on the efficacy of this 8-week HCV treatment regimen in HIV-infected individuals with similar viral loads. Methods: The study was a retrospective review of HIV-infected adults coinfected with HCV genotype 1 for whom an 8-week course of SOF/LDV was prescribed by providers at two clinics in the Yale-New Haven Health system from November 1, 2014 until April 30, 2016. Treatment efficacy was assessed as the proportion of treatment initiators who achieved a sustained virologic response 12 weeks after completion of therapy (SVR 12). Results: Nineteen patients met study eligibility criteria and included 14 men (74%); and 12 African-Americans (63%). All patients were on antiretroviral therapy with fully suppressed HIV viral loads and were HCV treatment-naïve. All patients had pre-treatment HCV viral loads <6 million IU/mL. Eighteen patients (95%) completed HCV treatment. Overall, SVR 12 was 95%, with 1 treament failure occurring due to suboptimal adherence. Conclusion: Among our HIV-infected patient cohort with HCV genotype 1 infection, 95% of those treated with an 8 week course of SOF/LDV achieved SVR 12. This is comparable to the efficacy of the same treatment regimen in patients without HIV infection. This study lends proof of concept to the use of shorter course SOF/LDV treatment for HIV-HCV genotype 1 coinfected patients with viral loads <6 million IU/ml. Larger studies are indicated to validate our findings.


Introduction
HIV and hepatitis C virus (HCV) share similar epidemiologic risk factors and routes of transmission, such that among HIV infected individuals, the prevalence of HCV infection is high and estimated at 25% (https://www.cdc.gov/hepatitis/populations/hiv. htm). Among certain risk groups, such as injection drug users with HIV infection, prevalence rates as high as 90% have been reported (https://www.cdc.gov/hepatitis/populations/hiv.htm). HIV infection alters the natural history of HCV disease, such that there are higher and faster rates of progression to liver cirrhosis with its resultant complications; this negative interaction may not be impacted by the receipt of effective antiretroviral therapy (ART) 1,2 .
Since the sequencing of the HCV genome, there has been an explosion in the number of drugs approved for the treatment of HCV infection. The direct acting antiviral treatment regimens now allow for fully orally administered, well tolerated, and highly effective treatments for HCV infection. However, multiple studies have shown that of the individuals eligible for HCV treatment, few have received treatment 3,4 . A primary obstacle to the treatment of HCV infection is the exorbitant cost of the treatment regimens 5,6 . Therefore, cost saving measures including shortened duration of therapy are of interest to patients and their providers 7 . Emerging data suggests that 8-week rather than 12-week regimens may be effective for HCV treatment among selected patients 8,9 .
The United States Food and Drug Administration (FDA) approved sofosbuvir/ledipasvir (SOF/LDV) in 2014 for the treatment of chronic HCV genotype 1 infection. The ION-3 study of SOF/LDV that included treatment-naïve non-cirrhotic patients with HCV genotype 1, found that the sustained virologic response 12 weeks after end of therapy (SVR12) was comparable between the 8-week (with and without ribavirin) and 12-week treatment arms in a post hoc analysis for patients who had a pre-treatment HCV viral load (VL) <6 million IU/ml 10 . Based on this data, the American Association for the Study of Liver Diseases/ Infectious Diseases Society of America guidelines recommend that treatment-naïve, genotype 1 patients without cirrhosis, who are non-black, HIV-negative and with a pre-treatment HCV VL <6 million IU/ml (http://www.hcvguidelines.org/full-report/ hcv-testing-and-linkage-care) can be successfully treated with 8 weeks of SOF/LDV. However, the guidelines cite limited data as the reason to not recommend an 8-week SOF/LDV treatment course for HIV-infected patients.
Contemporary HCV treatment trials with directly acting antiviral (DAA) agents have shown that HIV infection status no longer independently impacts treatment outcomes 11,12 . Therefore, shorter HCV treatment regimens are likely to be as effective in HIVinfected individuals as their non-infected counterparts. Our study describes treatment outcomes of a short (8 week) course of SOF/ LDV in HIV/HCV co-infected patients.

Methods
We performed a retrospective review of all HIV and HCV co-infected patients, for whom an 8-week SOF/LDV treatment course was initiated from November 1, 2014 until April 30, 2016. The treatment decision for short course therapy was made by individual clinic providers at two clinics based at Yale Health system in New Haven, CT, USA: Nathan Smith Clinic and the Haelen Center.
Eligibility criteria for the study included all adult (age >18 years) patients with confirmed HIV infection who had HCV genotype 1 infection. Only individuals for whom treatment with an 8-week course of SOF/LDV was intended, were included in the analysis.
Electronic medical records of eligible patients were reviewed. Data collected included demographics, HIV clinical data (CD4 count, HIV VL, antiretroviral treatment (ART)), and laboratory data, including complete blood counts, electrolytes, and liver function tests and biopsy results. Plasma HCV viral loads and genotypes were determined at our lab using COBAS Ampliprep/ COBAS Taqman HCV Test, v2.0 (Roche Diagnostics, Indianapolis, IN, USA). Assessment of liver fibrosis stage at time of treatment initiation was determined by one or more of the following: liver biopsy and non-invasive liver fibrosis scores, such as AST to platelet ratio index (APRI) 13 and fibrosis-4 (FIB-4) score 14 . Patient-reported adverse events and reasons for noncompletion or discontinuation of treatment were based on documentation in electronic medical records. Data were recorded and analyzed using descriptive statistics in Microsoft Excel, v2013. Overall SVR 12 rate was defined as the proportion of individuals for whom an 8-week treatment course was initiated that had undetectable HCV viral loads 12 weeks after completion of therapy.
Study approval was obtained from the Yale University Human Investigations Committee (number 1506016104).
Eighteen patients (95%) completed 8 weeks of therapy. One patient was non-adherent due to active substance abuse and only completed the first 4 weeks of treatment. Adverse events while on treatment were reported by 6 patients as follows: diarrhea (n=1), abdominal pain (n=1), nausea (n=1), poor appetite (n=1), diffuse joint pains (n=1), and pruritus without rash (n=1). One patient who experienced fatigue due to influenza temporarily discontinued treatment for 7 days, but resumed treatment afterwards. There were no cases of renal insufficiency, including patients who were on HIV protease inhibitors and tenofovir/ FTC. Overall, SOF/LDV was well tolerated with no treatment discontinuations due to adverse effects.
All eligible patients had at least one HCV VL assay performed either at week 4 or week 8 of treatment and at 12 weeks following completion of therapy. At week 4 of treatment, 11 of 12 patients for whom there was available data, had undetectable HCV VLs; one patient had viremia that was less than the lower limit of detection of the assay (< 15 IU/ ml). At week 8 of treatment, 11 of 12 patients, who had available HCV VLs, had undetectable HCV VLs. The patient who had detectable HCV VL at week 8 had completed only 4 weeks of therapy and was subsequently non-adherent due to active substance use. In total 18 of the 19 patients achieved SVR 12. Therefore, overall SVR 12 rate was 95% ( Table 2). The two patients who had cirrhosis also achieved SVR 12. There is interest in shorter HCV treatment durations for a number of reasons: the prohibitive cost of newer DAAs 18 , and issues of adherence and potential development of resistance or toxicity.
Kowdley et al. showed in a post hoc analysis that an 8-week treatment regimen of SOF/LDV resulted in a high SVR 12 rate among non-cirrhotic HCV infected individuals with genotype 1 infection that was non-inferior to an 8-week regimen with ribavirin or a 12-week regimen without ribavirin 10 . Lower relapse rates were observed among patients receiving 8 weeks of SOF/LDV who had baseline HCV RNA levels <6 million IU/ml (2%; 2 of 123). However, this study did not include HIV-infected individuals.
In a subsequent real-world multi-national retrospective study of 634 patients, an 8-week course of SOF/LDV resulted in an overall SVR 12 of 98.1% in non-cirrhotic treatment-naïve individuals regardless of HCV VLs. This study included 16 HIVinfected individuals, and for those with VL >6 million IU/ml, 100% achieved SVR 12 9 . Unlike the previous study, this study found that pre-treatment HCV VL >6 million IU/ml in a subset of patients with HIV infection did not affect treatment outcomes, including relapse rates.
Our study, showing an SVR 12 of 95%, is similar to the rates observed in a German cohort of 28 HIV-HCV co-infected patients, who showed a 96% response rate to 8 week therapy using SOF/LDV (GECCO-01 study) 8 . All patients in the trial were on antiretroviral therapy with a median CD4 count of 604 cells/mm 3 . However, the cohort consisted of predominantly Caucasian and male patients (89%). Our patient demographic was different with more women (26% versus 11%), and comprised a majority of African-American patients (63%).
It is important to highlight that not all DAA-based 8 week treatment courses for HIV-infected patients have yielded satisfactory results. The phase 3 ALLY-2 study, explored 8-week and 12-week SOF/daclatasvir treatment courses in HIV-infected individuals with HCV genotypes 1-4 19 . For treatment-naïve patients with HCV genotype 1, SVR 12 was 96% in the 12-week arm and 76% in the 8-week arm. However, it was observed that patients with HCV VL <2 million IU/ml performed better than those with viral loads >2 million IU/ml (SVR 12 of 100% versus 62%) supporting excellent efficacy with lower viral loads 19 .
Our 95% SVR 12 rate in individuals placed on short course treatment may be attributable to certain factors: excellent adherence (supported by well controlled HIV infection) and selection of individuals with low HCV viral loads, factors that are associated with higher likelihood of cure 17,20 . It is remarkable that 26% of subjects were women and almost two-thirds were African-American; two groups that are often under-represented in HCV treatment studies, and this thereby increases the generalizability of the study results. The two individuals with cirrhosis also achieved excellent treatment results. In spite of the small number of patients in our study, the concordance of our findings with the European cohort in the GECCO-01 trial, as well as the multi-center study reported by Kowdley et al, lends support to its validity.
A limitation of our study is that it was retrospective, therefore data captured was dependent on the quality of documentation by patient providers. Our patient demographic may not be representative of patients in settings different from ours. There may be a treatment selection bias, whereby patients who were more likely to adhere to therapy and had characteristics favorable to achieving an optimal response were initiated on therapy by their clinic providers. Due to the low number of patients with cirrhosis in our cohort, it is not advisable to extend the conclusions to this subgroup.
In summary, our study provides support for the use of an 8-week course of SOF/LDV as an effective treatment option for HIV and genotype 1 HCV co-infected individuals with HCV viral loads <6 million IU/ml.

Ethical statement
This medical review was approved by Yale University Human Investigations Committee (number 1506016104); individual patient consent was not required in this retrospective chart review.
Author contributions OO and MM conceived of the project; OO, RH and MM collected study data; OO, RH, MV, MSV and MM participated in data analysis, drafting and revision of the manuscript.

Grant information
The author(s) declared that no grants were involved in supporting this work. General: This is a small retrospective study that adds to the evidence that those with HCV (genotype 1)-HIV co-infection and low viral load can be treated successfully with 8 weeks of Sofosbuvir/Ledipasvir. Adherence matters as the one treatment failure did not complete treatment. The data from this cohort (two patients not described) are not strong enough to recommend this strategy for those with established cirrhosis. On-treatment monitoring of HCV PCR adds little to treatment.

Open Peer Review
Specific comments: 1. The introduction is a bit dated. We should no longer need to justify treatment of those with HIV co-infection as a priority population. The simple fact of HCV infection means that these individuals should be offered treatment.
2. Introduction points out that HIV infection status no longer independently impacts treatment outcomes. The introduction should ALSO point out that those with HCV without HIV, NO cirrhosis and low viral load can be successfully treated with 8 weeks of SOF/LDV. The introduction should ALSO point out that those with HCV without HIV, NO cirrhosis and low viral load can be successfully treated with 8 weeks of SOF/LDV. 3. Two patients were thought to be cirrhotic but clinically compensated -how compensated? They should be described further and they should be pointed out in Table 3 -what were platelet counts, INR, albumin,  Bilirubin. 4. The discussion is repetitive -should not repeat what was said in introduction 5. Study presents data of on-treatment HCV PCR monitoring. Do the authors think that this is required?

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Partly

Are the conclusions drawn adequately supported by the results? Yes
No competing interests were disclosed.

Competing Interests:
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
Author Response 14 Sep 2018 , Yale University, USA

Merceditas Villanueva
General: This is a small retrospective study that adds to the evidence that those with HCV (genotype 1)-HIV co-infection and low viral load can be treated successfully with 8 weeks of Sofosbuvir/Ledipasvir. Adherence matters as the one treatment failure did not complete treatment. The data from this cohort (two patients not described) are not strong enough to recommend this strategy for those with established cirrhosis. On-treatment monitoring of HCV PCR adds little to treatment.

Response-Thanks for the comment.
Regarding the concern about recommending short course treatment for cirrhotics, we acknowledge in the limitations section that… "Due to the low number of patients with cirrhosis in our cohort, it is not advisable to extend the conclusions to this subgroup." Also, we agree that on-treatment monitoring of HCV viral loads adds little to treatment especially as there are no "stoppage" rules based on pre-set viral load decay parameters monitored over time.
there are no "stoppage" rules based on pre-set viral load decay parameters monitored over time. We captured HCV viral load assessments as checked by clinic providers which was based on the clinic HCV treatment protocol at the time the study was conducted.
Specific comments: 1. The introduction is a bit dated. We should no longer need to justify treatment of those with HIV co-infection as a priority population. The simple fact of HCV infection means that these individuals should be offered treatment.
Response-we agree that there is no longer a need to justify treatment of HIV infected patients with HCV as they experience similar treatment outcomes. We have eliminated the sentence "owing to this the treatment of HCV infection is prioritized for persons infected with HIV" from the revised manuscript 2. Introduction points out that HIV infection status no longer independently impacts treatment outcomes. The introduction should ALSO point out that those with HCV without HIV, NO cirrhosis and low viral load can be successfully treated with 8 weeks of SOF/LDV. 3. Two patients were thought to be cirrhotic but clinically compensated -how compensated? They should be described further and they should be pointed out in Table 3  Ogbuago and coworkers provide a small study on 19 HIV-HCV coinfected individuals that were treated with an 8-weeks course of sofosbuvir and ledipasvir. Overall, the SVR rate is 95% with only one individual not responding who was in-adherent. The study, although small, adds knowledge to the existing literature.
Minor comments: The authors should point out more clearly that they are dealing with a difficult-to-treat population here: A high percentage of AAs, high levels of IDU, and high BMI. This values the results even more.
In the Introduction the authors should point out that DAAs have changed treatment paradigms in HCV, but that 12 weeks treatment duration still proved to be the threshold hard to beat. It only worked so far with this regimen presented here. It will however change with new compounds.
In the discussion, the description of the ION-3 trial is slightly inaccurate: The non-inferiority of the 8-weeks regimen was an endpoint of the study. The 6 mil viral load threshold was a post-hoc-analysis.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes

Are the conclusions drawn adequately supported by the results? Yes
No competing interests were disclosed.

Competing Interests:
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. In response to Dr Ingiliz's comments: It is correct that our cohort consisting of predominantly AAs, current or ex-IDUs, with high median BMI, and who are HIV co-infected are traditionally hard to treat populations so that it does make the treatment results all the more remarkable and in spite of the small sample size. This is now reflected in the discussion as follows: "The high SVR12 rate in our study is even more remarkable given that all patients were HIV infected and a significant proportion were African-American, had a high BMI and were active or current IDUs, all of which are characteristics of traditionally hard to treat populations. " We have modified the sentence in the Introduction referencing 8-week and 12-week treatment regimens to suggest as accurately pointed out that for currently approved DAA regimens, 12-week treatment duration remains the standard for most patients, while 8 week regimens may be used for "selected cases". This is now reflected in the introduction as follows: "While 12-week DAA-based treatment regimens remain the standard treatment course for most HCV infected patients, emerging data suggests that 8-week rather than 12-week regimens may be effective for treatment among selected patients " The paragraph has been rephrased to accurately reflect the primary results of the open label randomized ION-3 study as well as post hoc analysis as follows: "Kowdley in a phase 3 open label randomized trial, showed that an 8-week treatment et al, regimen of SOF/LDV resulted in a high SVR 12 rate among non-cirrhotic HCV infected individuals with genotype 1 infection that was non-inferior to an 8-week regimen with ribavirin or a 12-week regimen without ribavirin . In a post hoc analysis, lower relapse rates were observed among patients receiving 8 weeks of SOF/LDV who had baseline HCV RNA levels <6 million IU/ml (2%; 2 of 123)." None Competing Interests: