“C-it” and Find Out: 2023 Updates to the Hepatitis C Guidelines

By: 

• Myrdjine R. Cadet, Pharm D Candidate
  Barry and Judy Silverman College of Pharmacy, Nova Southeastern University

• Ludchana Cherenfant, Pharm D Candidate
  Barry and Judy Silverman College of Pharmacy, Nova Southeastern University

• Elizabeth Sherman, PharmD, AAHIVP
  Barry and Judy Silverman College of Pharmacy, Nova Southeastern University
  South Florida, Southeast AIDS Education and Training Center

Introduction

In May 2023, the Infectious Disease Society of America (IDSA) and the American Association for the Study of Liver Disease (AASLD) published updates to the hepatitis C virus (HCV) guidelines. Updated areas include an ongoing emphasis on universal HCV screening; new recommendations to address management of incomplete treatment adherence; the simplified treatment with minimal monitoring approach and expanded eligibility for this approach;  management and treatment recommendations for solid organ transplant recipients; expanded treatment and retreatment recommendations for children and adolescents; and screening, management, and treatment recommendations for unique and key populations. The updated HCV guidelines were published in Clinical Infectious Diseases and can be found at this link: Hepatitis C Guidance 2023 Update. This SE AETC newsletter article is focused on three specific updates: the management of incomplete DAA (direct-acting antiviral) adherence, simplified HCV treatment for treatment-naïve adults with HCV-HIV coinfection, and the management of HCV after solid organ transplantation. Providers are encouraged to access the full guideline to explore updates to other key areas.

Management of Incomplete DAA Adherence

Direct-acting antivirals (DAAs) have made a significant impact on the treatment of HCV infection, but some patients may not totally adhere to treatment plans. The number of people who do not adhere to DAAs is unknown, but studies suggest the rate is somewhere between 11-40% (Serper et al, 2019). Most people who miss DAA doses go back to their routine quickly. One study demonstrated 61% of nonadherent episodes lasted only 1 to 2 days (Cunningham et al., 2018) which did not greatly affect sustained virologic response (SVR). Despite the non-adherence, SVR12 was 94% among both DAA adherent (≥ 90% of doses) and nonadherent (<90% of doses) patients. Though, longer periods of non-adherence have the potential to affect SVR. For this reason, the HCV guideline includes a new algorithm for the management of incomplete adherence that deals with the real-world scenarios providers usually face. Figure 1 reviews the recommended HCV treatment regimen and duration with interruption, including whether to continue with the original number of doses or to extend therapy. The recommendations in this figure apply to treatment-naïve patients without cirrhosis or with compensated cirrhosis receiving glecaprevir/pibrentasvir or sofosbuvir/velpatasvir. For retreatment recommendations, providers should refer to the 2023 guidelines document.

Figure 1: Recommended management of incomplete adherence to DAA treatment.
Adapted from Bhattacharya et al., 2023.

Simplified HCV Treatment for Treatment-naïve Adults with HCV-HIV Coinfection

People with HIV are now included in the guidance’s simplified HCV treatment algorithm. The simplified HCV treatment algorithm for treatment-naïve adults without cirrhosis or with compensated cirrhosis include: 8 weeks of glecaprevir 300mg/pibrentasvir 120mg taken with food or 12 weeks of sofosbuvir 400mg/velpatasvir 100mg. These two pan-genotypic therapies both help simplify treatment by removing the need for HCV genotype testing (Dieterich, 2019). The updated simplified treatment algorithm includes minimal pre-treatment and on-treatment clinical interventions and expanded eligibility, including persons with HIV.

The minimal on-treatment monitoring approach, studied in the MINMON trial, included 400 HCV treatment-naïve participants over the age of 18 from 38 sites across Brazil, South Africa, Thailand, Uganda and the United States (Solomon et al., 2022). At entry, 42% were living with HIV. Participants who were pregnant or became pregnant, breastfeeding and/or had chronic hepatitis B virus (hep B surface antigen positive) were excluded from the trial. However, participants with resolved HBV infection (hep B core positive, with or without hep B surface antibodies) were deemed eligible. All participants received a 12-week course of once daily sofosbuvir 400mg/velpatasvir 100mg. (Bhattacharya et al., 2023a). Results demonstrated the minimal monitoring approach as being safe and effective as 95% of participants achieved SVR. SVR rates were comparable in those with HIV coinfection (96.5% of participants coinfected with HIV achieved SVR).

Minimal monitoring includes four components (1) no pretreatment genotyping, (2) no scheduled on-treatment visits or laboratory monitoring, (3) patients dispensed the full treatment course at treatment initiation, and (4) patients are contacted remotely to assess DAA adherence at 4 weeks and for post-treatment assessment of cure (SVR). This new approach may remove cost barriers and improve treatment access by reducing costly diagnostics. Although the MINMON and SIMPLIFY trials identify that minimal monitoring does not compromise safety or efficacy, optimal adherence at week 4 remains a high predictor of treatment success (Cunningham et al., 2018).

Management of HCV After Solid Organ Transplantation

The updated HCV guidelines include management and treatment recommendations in the transplantation setting, including specific clinical scenarios such as treatment of recurrent HCV infection post liver and kidney transplant, timing and treatment of HCV-viremic liver grafts in nonviremic recipients, and timing and treatment of HC-viremic non-liver grafts in nonviremic recipients.

Treatment of Recurrent HCV infection Post Liver and Kidney Transplant

Clinical trial data provide strong evidence supporting the safety of DAA treatment in patients who have undergone solid organ transplants (Reau et al., 2018a). Table 1 provides recommendations for HCV treatment post-transplantation.

The open-label MAGELLIAN-2 trial evaluated the safety and efficacy of a 12-week course of once-daily glecaprevir 300mg/pibrentasvir 120mg for 100 patients with chronic HCV infection who had just undergone liver or kidney transplant: 80 participants had undergone liver transplant and 20 participants had undergone kidney transplant. Inclusion criteria consisted of a positive anti-HCV antibody test and a plasma HCV RNA of 1,000 IU/mL or greater, evidence of chronic HCV infection, HCV treatment naïve or experienced (prior treatment with IFN, pegylated IFN with or without RBV, or sofosbuvir plus RBV with or without pegylated IFN that completed >/=2 months ago), received a deceased or living donor liver or kidney transplant >/= 3 months before screening, and maintained on a stable immunosuppression regimen such as tacrolimus, sirolimus, everolimus, mycophenolic acid, azathioprine. The trial excluded those with cirrhosis (confirmed by liver biopsy within 6 months before screening), evidence of hepatitis B virus or HIV, those whose immunosuppressive regimen included cyclosporine doses >100 mg/day or prednisone doses >10mg/day as well as treatment experienced persons with genotype 3 infection (Reau et al., 2018a). Overall, SVR12 was 98%.

Another study demonstrated the safety and effectiveness of using sofosbuvir/velpatasvir to treat HCV in persons who had undergone liver or kidney transplantation in Asia. No treatment-related serious adverse events were reported and an overall SVR12 was achieved in 98% of participants (Wei et al., 2019). Participants who achieved SVR with treatment post-transplant had lower rates of liver fibrosis progression and lower mortality rates compared to those who failed therapy.

Timing and treatment of HCV-Viremic Liver Grafts in Nonviremic Recipients

Initiating HCV treatment early in patients receiving HCV-viremic liver grafts is proven safe and effective. One study demonstrated that recipients of grafts from HCV-viremic donors became viremic by day 3 post transplantation (Cunningham et al., 2018). The Guidance Panel suggests initiating therapy within at least 2 weeks after transplantation, but preferably within 1 week, when the patient is clinically safe will avoid many HCV-related complications (Cunningham et al., 2018). Table 2 reviews these treatment recommendations.

Timing and treatment of HCV-Viremic Non-Liver Grafts in Nonviremic Recipients

HCV treatment should be initiated as soon as possible in HCV-seronegative patients who undergo transplant with a non-liver graft from an HCV-viremic donor. The MYTHIC trial demonstrated the safety and efficacy of initiating HCV treatment as early as possible to nonviremic recipients of HCV-viremic non-liver grafts. This trial used once daily glecaprevir 300mg/pibrentasvir 120 mg for 8 weeks as the treatment approach. All 30 participants achieved SVR12 and no significant HCV-related adverse effects were reported (Cunningham et al., 2018). Based on this trial, the initiation of treatment (recommended for HCV-negative recipients of a non-liver solid organ graft from HCV-viremic donor) is used as prophylactic (immediately prior to transplantation or day 0 post transplantation) or preventive (day 0 to day 7 post transplantation as soon as the patient is clinically stable) (Cunningham et al., 2018). Table 3 reviews the recommended treatment approach in this patient population.

Drug-to-drug Interactions Between DAAs and Transplant Medications

Important drug-drug interactions unique to the posttransplant setting should be addressed prior to the start of any DAA therapy. In general, DAA regimens that contain protease inhibitors have the potential to increase drug levels of cyclosporine and tacrolimus and inhibit sirolimus and everolimus. Table 4 provides an overview of drug interactions between immunosuppressive agents and DAA agents for HCV.

Conclusion

With the availability of new evidence-based trails, IDSA and AASLD provided signficant updates to the previous HCV guidelines. Clinicians should be aware of meaningful updates to various sections including management of incomplete treatment adherence, the simplified HCV treatment algorithm, and treatment recommendations in the transplantation setting. All treatment services are key prevention strategies to manage and eliminate heptatis C virus.