Treatment of hepatitis C virus infection with direct-acting antiviral agent-based regimens in Iranian patients with hereditary bleeding disorders

The current bicentric, retrospective study was performed on patients selected from two centers of Middle-East Liver Diseases (MELD) center (Tehran, Iran) and Iranian Comprehensive Hemophilia Care Center (ICHCC) (Tehran, Iran). Patients with HBD aged above 18 years who had HCV infection for at least six months and a positive result for HCV RNA by RT-PCR undergoing CHC therapy with SOF-based IFN-free regimens from 2015 to 2019 in the two above-mentioned centers were enrolled in this study. Besides, patients co-infected with HIV, the ones with cirrhosis, and patients with a history of IFN-based therapy were also included. Patients who had previously responded to treatments such as IFN or other available options and were not treated with DAA-based regimens were excluded. Two researchers extracted the required information by evaluating patients' electronic records at MELD Center and paper-based records at ICHCC.

In Iran, SOF/DCV, SOF/LDV, and SOF/VEL were available as generic forms, and patients undergo a 12- or 24-week therapy with or without RBV, based on HCV genotype, previous treatment experience, and having cirrhosis according to national and international guidelines [10, 13‐15]. From 2015 to 2019, the standard of care for the management of CHC had updated regularly but the common treatment discipline in these years was that patients with cirrhosis, previous treatment experience, or HCV genotype-3 need a more intensified treatment. Moreover, case-by-case clinical decisions outside the therapeutic guidelines were made by the treating physician to provide the patients desirable benefits [10‐13]. HCV DAA-based regimens can be used alongside anti-HIV regimens with consideration of drug–drug interactions. In this regard, DCV dose adjustment is needed considering the anti-HIV regimen [16]. Sofosbuvir interaction with anti-epileptic drugs (such as phenytoin, phenobarbital, and carbamazepine) and amiodarone was considered before starting treatment with DAA. In cases with drug–drug interactions, we consulted with their specialists to switch their treatments to remove the proposed drug–drug interaction.

Complete blood cell count, liver enzymes, and HCV RNA using RT-PCR were performed before starting treatment, four weeks after initiation of treatment, and 12 weeks after the completion of treatment. Liver stiffness measurement (LSM) was also performed to detect cirrhosis before starting treatment. However, in cases where clinical (e.g., esophageal varices) or paraclinical (e.g., ultrasound findings) pieces of evidence were strongly in favor of cirrhosis, the LSM was ignored.

A patient with no history of treatment for CHC was called treatment-naïve. If IFN or peg-IFN is used in the previous treatment, the treatment history is considered as IFN-based treatment history, and if the previous treatment was IFN-free, using a combination of DAAs, it was considered as DAA-based treatment history. Patients who discontinued treatment, who did not refer during treatment, or did not test for HCV RNA, 12 weeks after the completion of treatment were called treatment discontinuation, lost to follow-up on treatment, and lost to follow-up for SVR evaluation, respectively. Moreover, conditions with undetectable results for HCV RNA four weeks after initiation of treatment and 12 weeks after the completion of treatment were called rapid virologic response (RVR) and SVR, respectively. Cases that do not reach SVR were considered a virologic treatment failure.

Our primary endpoint in the present study was to evaluate the SVR rate in patients with HBD and CHC treated with SOF-based IFN-free regimens.

All data were transferred into SPSS version 23.0 (IBM Corp.). Data obtained from quantitative variables with normal distribution were expressed as mean ± standard deviation (SD) and those from variables that deviated from normal distribution as median and interquartile range. The Kolmogorov–Smirnov test was used to determine the normal distribution of variables. Qualitative variables were also expressed as absolute value and percentage. HCV RNA level was also expressed in logarithmic form.

A total of 147 patients with HBD and CHC started treatment with DAA-based regimens. The mean (± SD) age of 147 patients was 41.1 (± 11.6) years, and 94.6% were male. Six (4.1%) patients were co-infected with HIV, and 37 (25.2%) had cirrhosis (five with decompensated cirrhosis). HCV genotypes-1 and -3 with 98 (68.1%) and 30 (20.8%) patients had the highest frequency, respectively. Of these 147 patients, 113 had hemophilia A (HA), 19 had hemophilia B (HB), eight had von Willebrand disease (VWD), one had Glanzmann disorder, and six had other disorders. The median values of hemoglobin (Hb), AST, and ALT before the treatment were 15.7 g/dL, 38 IU/L, and 42 IU/L, respectively. The mean HCV RNA level at baseline was 6.0 log₁₀ IU/mL (Table 1). The anti-HIV regimens in the 6 patients with HIV-HCV co-infection were zidovudine + lamivudine + efavirenz (two patients), tenofovir + lamivudine + efavirenz (two patients), lopinavir/ritonavir + efavirenz (one patient), and lopinavir/ritonavir + lamivudine + tenofovir (one patient). Five patients with HIV-HCV co-infection were treated with SOF/LDV ± RBV that did not need a dose adjustment. However, one patient with HIV-HCV co-infection was subjected to DCV dose adjustment from standard 60 mg dose to 90 mg dose. The baseline characteristics except for the type of HBD (P < 0.05) were not different between patients who were evaluated for SVR and patients with treatment discontinuation or loss to follow-up (Table 1).

Treatment with DAA-based regimens was started for 147 patients with HBD and CHC. One patient discontinued the treatment arbitrarily after one month, with no side effects. Moreover, 9 patients did not refer during the treatment course, and it was not clear whether they completed the treatment or not. Five patients completed the treatment course but did not refer 12 weeks after treatment completion to determine SVR. The remaining 132 patients completed the treatment and were available for the evaluation of SVR (Fig. 1). Of the 147 patients who received DAA-based treatment, SOF/LDV + RBV was the most common regimen administered to 53 (36.1%) patients. SOF/LDV and SOF/DCV ± RBV regimens were other common regimens in this study. The regimens, treatment courses (12 or 24 weeks), and RVR and SVR rates are shown in Table 2. Regardless of HCV genotype, therapeutic regimen, HIV co-infection, liver disease status, and HCV RNA level at baseline, the HCV RNA was undetectable in all the 132 patients, 12 weeks after treatment completion (SVR rate: 100%, 95% CI 97.2–100%). Of these 132 patients, HCV RNA was evaluated on blood samples of 100 patients four weeks after the treatment initiation, of which only six were detectable, who finally achieved SVR. The characteristics of these six patients that didn’t achieve RVR are shown in Table 3. Of the 15 patients whose SVR status was unknown due to the reasons stated, HCV RNA detection was performed on the blood samples of nine of them, four weeks after the treatment initiation, which all were undetectable. Therefore, the overall RVR rate was 94.5% (95 CI 88.4–98.0%) in the present study (Table 2).

Among 132 patients with follow-up, none expired during treatment or 12 weeks after treatment termination, and no significant side-effect causing treatment discontinuation was observed. In three patients that treatment was commenced with RBV, due to gastrointestinal bleeding, RBV was removed from the treatment course. Despite the removal of RBV from treatment, all of these three patients achieved RVR and SVR. Week-4 Hb reduction was more prominent in patients treated with RBV (38.1% with > 2 g/dL Hb decline) than those who did not receive RBV (3.2% with > 2 g/dL Hb decline).