Challenges of antiviral therapy
In recent years, encouraging advances have been made in the treatment of hepatitis C virus (HCV) infection, including more cost-effective treatment, confirmation of the importance of ribavirin (RBV) antiviral therapy, identification of differences in virologic response to treatment across HCV genotypes and ethnic groups, and the introduction of individualized treatment regimens tailored to the patient’s virologic response. “The importance of individualized treatment regimens based on the virological response of patients has been confirmed.
However, there are still great challenges in the antiviral treatment of HCV infection, such as the treatment of refractory patients (genotype 1, combined with cirrhosis, metabolic syndrome, obesity, etc.), and there are also many questions that deserve further exploration, such as what is the mechanism of action of RBV, why some patients are prone to relapse, and why some slow-respondingpatients can be treated with high-dose RBV. Some slow-respondingpatients receive high-dose RBV therapy and obtain a sustained virological response (SVR), while others do not have any virological response to RBV therapy.
In response to these questions, Prof. Jensen proposed a “roadmap for future treatment research”: (1) individualize treatment regimens according to the virological response of patients; (2) combine protease inhibitors and polymerase inhibitors in treatment; (3) further (3) further evaluation of the role of bioartificial livers; and (4) gradual removal of interferon (IFN) and RBV from treatment.
Research related to antiviral treatment regimens
Professor Jensen presented the current research on antiviral therapy for HCV infection.
Many studies have shown that for patients with HCV genotype 1 infection, a 24-week regimen is sufficient if a rapid virological response (RVR) is achieved during 24 weeks of RBV therapy. However, the optimal duration of treatment for patients with HCV genotype 2 or 3 infection is uncertain, and studies have shown an increased risk of relapse if the RBV course is shorter than 24 weeks.
Unlike most researchers who have focused on shortening the course of RBV, one investigator applied high-dose RBV in a study to improve outcomes. In that study, an RBV dose of 2540 μg/d, equivalent to three times the normal dose, resulted in an SVR of 90% and avoided many adverse effects.
There are also studies for the combination of pegylated interferon (PEG-IFN) and RBV. The duration of the combination is still to be further determined, and it has been demonstrated that 12 weeks of treatment is not sufficient to maintain the desired RVR.
It has been demonstrated that 72 weeks of high-dose PEG-IFN/RBV treatment enhances virologic response in slow-responding patients. However, it remains a challenge to define slow-responding patients and when to switch to long-term therapy.
New drug development
Professor Jensen also talked about the development of antiviral drugs.
The results of preliminary clinical trials have shown that protease inhibitors (boceprevir and telaprevir) with PEG-IFN/RBV can significantly improve SVR rates and also significantly shorten the course of therapy, which gives hope to patients with refractory hepatitis C. The development of specific targeted anti-HCV therapeutics is flourishing, and new drugs are emerging, which has become an important direction for anti-HCV drug research.
With the continued development of new drugs with low resistance rates, high efficacy and few side effects, and the advancement of individualized treatment regimens, it is believed that a new breakthrough in the treatment of CHC patients will occur in the near future.
New results in the treatment of hepatitis C
Long-term, effective antiviral therapy can reverse liver fibrosis
In the United States, 775 patients with HCV were followed for 5 years and their liver biopsies were scored using the Knodell (inflammation) and Ishak (fibrosis) scoring systems. The results showed that IFNTx treatment delayed the progression of liver tissue fibrosis compared with no IFNTx (IFN or PEG-IFN alone, combined with or without RBV) treatment. Among HCV patients who acquired SVR, liver tissue fibrosis could be reversed in most patients after continuing treatment for 5 years.
Effect of antiviral therapy on liver histology in patients who have not acquired SVR
The current view is that if HCV patients do not obtain SVR after treatment with IFN (alone or in combination with RBV) they are considered to be ineffective in treatment. However, in this DDW meeting, a study by American scholars on the histological response to antiviral therapy in patients with hepatitis C showed that liver biopsy results suggest disease improvement even if SVR is not obtained, as long as the patient responds to the drug.
The study included 1586 patients with HCV, and after a mean of 45 weeks of PEG-IFN or PEG-IFN/RBV treatment, liver biopsy scores showed that the duration of HCVDNA below detectable levels was positively correlated with improved liver necroinflammation (NIF) and fibrosis, and negatively correlated with NIF and fibrosis progression. Patients who received SVR had the most significant improvement in liver histology. Significant improvements in liver histology were also observed in HCV relapsers compared to treatment non-responders.
Reduced Hb concentrations and SVR
It was previously thought that PEG-IFN/RBV treatment of chronic HCV infection could cause 30% of patients to discontinue the drug due to the development of anemia, which is commonly corrected clinically with erythropoietin (EPO), but the relationship between anemia and SVR is not clear. A 48-week study of 3070 patients with HCV genotype 1 was conducted in the United States, in which subjects received PEG-IFN/RBV antiviral therapy and underwent regular testing of hemoglobin (Hb).
The results showed that HCV genotype 1 patients receiving antiviral therapy had the greatest probability of SVR when Hb concentrations were reduced to the lowest point. the efficacy of EPO varied with the timing of administration, with EPO therapy contributing to SVR in patients who developed anemia early in antiviral therapy (≤8 weeks), while EPO therapy did not contribute to SVR in patients who developed anemia after 8 weeks. The main role of EPO is to prevent discontinuation of antiviral therapy in patients who become anemic early in the course of treatment.
Anti-HCV treatment regimen
The recommended duration of treatment with PEG-IFN/RBV for HCV genotype 2 and 3 infected patients is 24 weeks. A meta-analysis by scholars at the University of Missouri on the duration of anti-HCV treatment with PEG-IFNα-2a/2b in combination with RBV showed that among patients with RVR after treatment, those with a shorter duration (≤16 weeks) had no significant improvement in end-of-treatment response (ETR) compared to those with a standard duration (24 weeks) (OR=1.04, P=0.80), but a significantly lower SVR rate (OR=1.65, P=0.65). (OR=1.65, P=0.02) and an increased recurrence rate (OR=2.81, P5.0logIU/ml) combined with IR (insulin resistance index HOMA-IR ≥2) in 14 HCV-infected patients who underwent an exercise diet intervention for more than 3 months.
Virological response to PEG-IFNα-2b/RBV treatment was evaluated in 11 patients who received the exercise diet intervention and showed significant reductions in body mass index (BMI), waist-to-hip circumference ratio, platelet count, gamma glutamyl transpeptidase, total cholesterol, low-density lipoprotein cholesterol, volatile fatty acids and saturated fatty acids levels after (177±93) days of exercise diet intervention. HOMA-IR and systemic insulin sensitivity index were significantly improved.
All three HCV genotype 2 infected patients achieved RVR, and of the eight HCV genotype 1 patients, one achieved RVR and the remaining seven achieved early virologic response (EVR).
This study suggests that dietary and exercise interventions improve IR in CHC patients with comorbid IR, and that improving IR with lifestyle interventions prior to antiviral therapy enhances virologic response to PEG-IFN/RBV in patients.
Impact of depression on antiviral efficacy
Patients with CHC often experience depressive symptoms during treatment, which not only affects the efficacy of antiviral therapy, but also leads to discontinuation of the drug in some patients. This issue has been studied in the United States.
The researchers divided 129 first-time patients into two groups: group A (n=57) was assessed for depressive symptoms using a depression scale regularly during treatment; group B (n=72) had patients report depressive symptoms themselves. Antidepressant medication was initiated when depressive symptoms were identified.
The results showed that there was no statistically significant difference between the two groups in terms of SVR acquisition rate after antiviral therapy and medication adherence; however, the application of antidepressants early in the course of antiviral therapy (within the first 12 months) significantly improved patients’ treatment adherence.
Treatment of pediatric patients with chronic hepatitis C
Previous studies have shown that treatment of adult CHC patients with PEG-IFN instead of regular IFN can both enhance the efficacy and improve the quality of patient survival.
In this session, scholars from the University of Copernicus, Poland, reported the results of a study of PEG-IFNα-2a/RBV in the treatment of pediatric CHC patients.
The study was conducted in 26 CHC patients aged 12 to 18 years old, in which group A (n=17) received PEG-IFNα-2a/RBV for 48 weeks and group B (n=9) received regular IFN for 2 to 8 months before changing to PEG-IFNα-2a/RBV to continue treatment until 48 weeks.
This study confirmed that PEG-IFNα-2a combined with RBV is a safe and effective treatment for CHC in children, and the shorter the duration of HCV infection, the better the efficacy.
That said, further studies are needed to evaluate the efficacy of replacing regular IFN with PEG-IFNα-2a/RBV therapy in the treatment of pediatric CHC patients.