Chronic hepatitis C virus (HCV) infection affects approximately 58 million people worldwide with approximately 1.5 million new infections each year. With the development of highly effective direct oral antivirals (VDAs) for the treatment of chronic viral C infection1-2the World Health Organization (WHO) decided in 2016 on a plan to eliminate viral hepatitis, including HCV, for 20303.
If the treatment of chronic infection is well established1-2therapeutic options for acute hepatitis are limited in terms of financial support worldwide. Since 06/11/2025, only the glecaprevir 300 mg/pibrentasvir 120 mg (G/P) combination for 8 weeks has been approved by the Food and Drug Administration (FDA). It is crucial that new combinations are validated and extended to all countries if we want to achieve the WHO elimination targets.
Only 20% to 40% of patients with acute viral C infection experience spontaneous immune-mediated recovery within 6 months following infection (11.2% in case of infection HIV Human immunodeficiency virus. In English: HIV (Human Immunodeficiency Virus). Isolated in 1983 at the Pasteur Institute in Paris; recent discovery (2008) rewarded by the Nobel Prize in Medicine awarded to Luc Montagnier and Françoise Barré-Sinoussi. associated4). The 60% to 80% who do not heal spontaneously develop a chronic viral C infection, with its hepatic but also extra-hepatic risks linked to cryoglobulinemic vasculitis or chronic inflammation.1-2.In the absence of approved treatment for acute hepatitis, the risk is, on the one hand, a delay in treatment at the stage of chronic infection for the patient and, on the other hand, a risk of dissemination of the viral infection in communities.
Increasing rates of acute C virus infection have been reported in populations with “high-risk” behaviors, such as people who inject drugs (IDU), people in deprivation of liberty, psychiatric patients, “homeless” people, and men who have sex with men (MSM) with or without HIV infection.5-6.Despite the availability of AVDs, which are highly effective and well tolerated for chronic infections, barriers exist in the cascade of care for these exposed populations.7 with the fear of a lack of adherence to treatments and follow-up. Indeed, the waiting time for confirmation of acute hepatitis (3 to 6 months) leads to a high rate of patients lost to follow-up.7.Accelerating the cascade of care in these populations is, however, a key element of the link to care and comprehensive treatment, especially since these patients are at risk of transmission/dissemination and a single early intervention reduces the risk of infection or reinfection.8participant in the WHO elimination project. Phylogenetic analysis and modeling investigated the risk of HCV transmission among MSM: epidemic doubling time is 0.44 years, with a significant rate of transmission occurring during acute infection9. Finally, early treatment in the acute stage is cost-effective due to reduced transmission costs and reduced infection rates.10.
Available therapies approved for the treatment of chronic infection have been evaluated in patients with acute or recently acquired infection. An open-label randomized phase IV trial with sofosbuvir/velpatasvir (SOF/VEL)(REACT) 6 or 12 weeks was carried out in 188 patients, 69% of whom were HIV-infected. The sustained virological response at 12 weeks post-treatment (PVR12) was, by intention to treat, 81.7% in the short arm and 90.5% in the long arm and 89.4% and 97.7% excluding non-virological causes of failure (death, re-infection, loss to follow-up): the treatment is certainly effective but it is therefore recommended not to reduce the treatment durations too much.11. Thus, HepNet, a one-arm phase II trial, showed the effectiveness of 8 weeks of SOF/VEL (100%) in the 20 compliant patients included.12.
A 6-week, open-label, one-arm trial of G/P in 30 patients (23 HIV-infected, 47% IVDU) showed PVR12 of 90% intention-to-treat and 97% per protocol13.Finally, many oral treatments without Interferon in patients coinfected with HIV for durations similar to the treatment of chronic hepatitis have reported PVR12 rates of 100% but the number of patients treated was often limited14justifying broader data to obtain the extension of marketing authorization (AMM) for these treatments from chronic infection to acute infection and therefore, a generalization of prescription.
New studies to collect more data
This is why retrospective studies and a prospective study were carried out to evaluate the effectiveness and safety of 8 weeks of G/P in adults and adolescents (over 12 years) with confirmed acute C viral infection, defined by one of the following combinations of criteria:
- HCV serology, negative HCV RNA and/or antigen, followed by positive HCV RNA or antigen, all over a period of 9 months;
- Negative HCV serology, HCV RNA and/or antigen, followed by positive HCV RNA or antigen, all within 11 months prior to screening AND HCV infection risk behavior within 6 months preceding the appearance of positive HCV RNA or antigen;
- Clinical signs and symptoms compatible with acute hepatitis (ALT > 5 ULN and/or jaundice) in the absence of a history of chronic liver disease or another cause of acute hepatitis, and positive HCV RNA or antigen, all in the 9 months preceding screening AND behavior at risk of HCV infection in the 6 months preceding the appearance of HCV RNA or antigen;
- Negative serology and positive HCV RNA or antigen over a period of 5 months before screening and initiation of G/P over a period of 6 months.
The analyzes were carried out for the entire population (FAS for full analysis set) and for the population excluding non-virological failures (modified FAS or mFAS). The mFAS endpoint was PVR12 with a superiority of 92.6%, the threshold determined in G/P registration studies for chronic infection15.
Two hundred and two adults were included in the FAS: 67.3% received a first delivery and 32.7% a second delivery; 189 patients (93.6%) underwent complete treatment with G/P and 13 patients (6.4%) stopped prematurely: 6 (3%) non-compliant, 2 (1%) lost to follow-up and 5 (2.5%) for other reasons. In FAS, 51 patients had non-virological failure: 39 (19.3%) for missing RVP12 data, 6 (3.0%) stopped G/P prematurely and 6 (3.0%) had re-infection. The mFAS analysis included 151 patients and 150/151 (99.3%; 95% CI: 96.3–99.9) had PVR12, which was above the threshold for effectiveness in chronic infection. In FAS analysis, the RVP12 was 74.3% and the virological failure rate was 0%. The relapse and re-infection rate after the final FAS follow-up visit was 0.5% and 3%, respectively. Intra-therapeutic elevations of alanine aminotransferase greater than 3 times the upper limit of normal with total bilirubin greater than 2 times the upper limit of normal have not been observed. All 53 patients with a baseline alanine aminotransferase AST Grade ≥ 2 improved to Grade 0/1 values on treatment. No hepatic decompensation events were observed and two patients experienced serious side effects attributed to G/P.
A prospective phase III study was carried out with the same inclusion and judgment criteria with 8 weeks of G/P and presented to the AASLD in November 2024 and to the AFEF in October 2025 (Llibre JM, Patrick M, Lank M, MillerMG, FredrickLM, WelhavenA, Semizarov D et al. AASLD 2024 and AFEF2025). 286 patients were included (including 234 naïve to C viral infection), 49.7% infected with HIV, 14.3% with IVDU, 60.1% at sexual risk including 66.4% MSM Man having sex with other men. The PVR12 rate was 100% in mFAS with 0.7% re-infection, 1.7% premature termination and 1.4% missing data.
In summary, the G/P combination for 8 weeks, like other AVDs at the doses and durations usually recommended for chronic infection, is effective and well tolerated in patients with acute hepatitis C.
All of these studies show the effectiveness of antiviral treatment and its excellent tolerance since treatment interruptions linked to AVD and serious side effects are marginal. They included a significant number of patients, including people at high risk of exposure to HIV, IDUs, MSM, in whom the relevance of treatment in the acute stage had historically raised questions, due to the chances of spontaneous recovery and the risks of non-compliance. observance Therapeutic compliance corresponds to strict compliance with the prescriptions and recommendations formulated by the prescribing doctor throughout a treatment, essential in the case of anti-hiv treatment. (We also speak of adhesion or adhesion.) treatment and follow-up. And this, although these patients represent the majority of people with acute hepatitis C8,17.These ulterior motives are not totally unjustified when we compare the intention-to-treat results and the per-protocol results: approximately 75 vs. 100% RVP12.
The benefits of treating acute hepatitis C
The immediate initiation of AVD allows a rapid decrease in the charge virale The plasma viral load is the number of viral particles contained in a blood sample or other container (saliva, CSF, semen, etc.). For HIV, viral load is used as a marker to monitor the progression of the disease and measure the effectiveness of treatments. The level of viral load, but even more so the CD4 count, contributes to the decision to treat with antiretrovirals. which limits the risks of transmission in populations at risk8,16.An authorization for AVD treatment of acute hepatitis C will limit the need for the theoretical period to confirm a chronic infection (More than 6 months of detectable viremia) authorizing the treatment and its reimbursement, will simplify the medical decision particularly for populations with “high-risk” behaviors, will reduce the risk of loss to follow-up and will reduce the risk of transmission in the community. If the benefit of treating acute C viral infection is firstly individual, by avoiding progression towards chronicity and its hepatic and extra-hepatic risks, it is also collective thanks to the reduction in the risk of transmission in communities.8,16.This benefit has been clearly shown in several studies, including a Dutch study where in patients infected with HIV, the risk of acute hepatitis C decreased by 50% in the 18 months following systematic antiviral treatment of acute hepatitis C while other sexually transmitted infections increased.8.
All of these results explain the extension AMM Marketing Authorization. Administrative procedure which authorizes a pharmaceutical laboratory to market a molecule. from the FDA of G/P from chronic infection to acute infection on June 11, 2025. We are awaiting this extension to the European Medicines Agency (EMA) to all AVDs for the treatment of acute hepatitis C even if it is true that in France we have few limits to using AVDs off-label, especially since the recommendations of the High Authority of Health call for treating acute hepatitis at the time of diagnosis2.
References
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