PDG13 CURRENT PRESCRIPTION PROFILE OF RIBAVIRIN FOR HEPATITIS C IN BRAZIL AND THE BUDGET IMPACT ANALYSIS ON UPDATED RECOMMENDATIONS FOR ITS USE BETWEEN 2020 AND 2024 IN THE BRAZILIAN PUBLIC HEALTH SYSTEM
Karen Cristine ToniniB. Pinheiro dos SantosTiago Dahrug BarrosMarcello ToniniGláucio MosimannMessias LemosJosé Nilton Neris GomesSimone Monzani VivaldiniNathália Dalla Vecchia FernandesElton Carlos de AlmeidaGérson Fernando Mendes Pereira
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Hepatitis C
Ribavirin, once a staple of hepatitis C treatment, has significant drawbacks, including treatment-limiting side effects, the requirement for intensive laboratory monitoring, the need for frequent dose adjustments, and teratogenicity. These factors make it difficult to escalate ribavirin-based HCV treatment to most infected patients globally. Most studies have shown comparable response rates between ribavirin-inclusive and ribavirin-sparing regimens in uncomplicated patient populations. However, ribavirin is still used in the management of patients who have failed previous therapy as well as those with decompensated liver disease. In this review, we explore the evidence supporting the use of ribavirin in the current climate of hepatitis C treatment with oral combination direct-acting antiviral agents.
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Since hepatitis C virus (HCV) was first identified in 1989, the impact of HCV infection on the HIV-infected population has been steadily increasing. It is now known that HCV affects the course and treatment of HIV disease in coinfected individuals (those infected with both HCV and HIV). Although there are significant data regarding the treatment of HCV in non-coinfected individuals, there are numerous questions that still remain regarding how to monitor and treat HCV infection in the coinfected population. This article reviews the available data regarding treatment of HCV in the coinfected population as well as how these individuals should be monitored, before and during HCV therapy, as well as how to address the numerous side effects associated with HCV treatment. To meet the demands of the coinfected population, HIV nurses must be willing to expand their knowledge to support, educate, assess, and advocate for coinfected individuals.
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Hepatitis C
Viral Hepatitis
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Combination therapy
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Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production.
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Background/Aims Ribavirin significantly enhances the antiviral response of interferon-α (IFN-α) against Hepatitis C virus (HCV), but the underlying mechanisms remain poorly understood. Recently, p53 has been identified as an important factor involving the suppression of HCV replication in hepatocytes. We, therefore, decided to investigate whether and how ribavirin inhibits the replication of HCV by promoting the activity of p53. Methods HepG2 and HCV replicons (JFH1/HepG2) were utilized to study the relationship between ribavirin and p53. The effect of ribavirin on cell cycles was analyzed by flow cytometry. The activation of p53 and the signaling pathways were determined using immunoblotting. By knocking down ERK1/ERK2 and p53 utilizing RNA interference strategy, we further assessed the role of ERK1/2 and p53 in the suppression of HCV replication by ribavirin in a HCV replicon system. Results Using HepG2 and HCV replicons, we demonstrated that ribavirin caused the cell cycle arrest at G1 phase and stabilized and activated p53, which was associated with the antiviral activity of ribavirin. Compared to either ribavirin or IFN-α alone, ribavirin plus IFN-α resulted in greater p53 activation and HCV suppression. We further identified ERK1/2 that linked ribavirin signals to p53 activation. More importantly, knockdown of ERK1/2 and p53 partially mitigated the inhibitory effects of ribavirin on the HCV replication, indicating that ERK1/2-p53 pathway was involved in the anti-HCV effects of ribavirin. Conclusion Ribavirin stimulates ERK1/2 and subsequently promotes p53 activity which at least partly contributes to the enhanced antiviral response of IFN-α plus ribavirin against HCV.
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The treatment of chronic hepatitis C (CHC) infections took a great step forward in 2011 when the first direct-acting antivirals (DAAs) were approved for therapy by the US Food and Drug Administration for patients infected with genotype 1 CHC. This milestone increased sustained virological response (SVR) rates overall and particularly for interleukin-28 (IL-28) C/T patients, patients with genotype 1b infections, and previous relapsers. The phase 3 trials leading up to the approval of boceprevir and telaprevir showed significant increases in SVR rates in comparison with those achieved with pegylated interferon (PEG-IFN)/ribavirin dual therapy (67%-68% versus 40%1 and 69%-75% versus 44%,2 respectively). Undoubtedly, the addition of these protease inhibitors has improved our ability to cure genotype 1 CHC infections; however, the addition of these agents to the treatment regimen has come at a substantial cost: the health care monitoring that is required and adverse events resulting in significant morbidity and even mortality among patients with cirrhosis.3 In addition to potentiating the anemia seen with PEG-IFN and ribavirin, boceprevir and telaprevir have their own unique side effects. There are also numerous drug-drug interactions that must be addressed with these new agents because of their cytochrome P450 system metabolism. Furthermore, these agents are not approved for non–genotype 1 CHC infections. Mericitabine (R7128) is a selective nucleoside analogue inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B RNA–dependent RNA polymerase. A nucleoside analogue inhibitor has several advantages, including low rates of resistance and broad genotypic coverage.4 Initial studies showed no evidence of resistance in patients treated for 14 days with mericitabine monotherapy,5 and follow-up studies demonstrated antiviral activity across all HCV genotypes.6 This issue of Hepatology presents two large, multicenter, phase 2b clinical trials investigating the efficacy of mericitabine plus PEG-IFNα2a and ribavirin versus PEG-IFNα2a and ribavirin alone. Wedemeyer et al.7 in the PROPEL trial used 4 experimental arms with 500 or 1000 mg of mericitabine twice daily for 8 or 12 weeks and a fifth control arm with PEG-IFN and ribavirin alone in a treatment-naive genotype 1 or 4 CHC population. A response-guided therapy approach was used in all treatment arms; patients for whom HCV RNA was undetectable in serum (virus negativity) at weeks 4 to 22 [extended rapid virological response (eRVR)] discontinued therapy at week 24, whereas all other patients continued PEG-IFN and ribavirin for a total treatment duration of 48 weeks. Patients who received mericitabine showed a high rate of early responses to therapy, with 80% in treatment arms A to D achieving virus undetectability at week 12; however, the SVR rates were not statistically different across the various mericitabine-treated groups or in comparison with PEG-IFN and ribavirin. Although these results did not demonstrate appreciably superior responses in comparison with the standard of care, it is notable that mericitabine demonstrated a high barrier to resistance, and the drug was well tolerated without additional side effects beyond those expected with PEG-IFN and ribavirin alone. Pockros et al.8 subsequently carried out a second study to investigate treatment regimens with a longer course of mericitabine combined with PEG-IFN and ribavirin. This similarly large, multicenter, double-blind, parallel-group study in treatment-naive genotype 1 and 4 patients randomly assigned patients to receive either 24 weeks of mericitabine (1000 mg twice daily) or a placebo in addition to PEG-IFN and ribavirin. Mericitabine-treated patients who achieved an eRVR discontinued all treatment at week 24; all others completed 48 weeks of treatment with PEG-IFN and ribavirin. The SVR rate was higher for the mericitabine-treated patients (56.8%) versus the patients receiving PEG-IFN and ribavirin alone (36.5%). Fewer patients in the placebo group achieved eRVR; however, the overall relapse rates were comparable (27.7% and 32% for the mericitabine and placebo groups, respectively). The safety profile of mericitabine was acceptable, with no differences in side effects in comparison with the placebo; a resistance analysis of the 31 patients who met the criteria for resistance monitoring demonstrated no evidence of genotypic or phenotypic resistance to mericitabine. The high dropout rate in this study was notable: 59 patients (35.5%) were prematurely withdrawn, with the majority of the withdrawals (67.8%) due to nonsafety reasons, and it should be noted that fewer patients in the mericitabine group discontinued treatment for safety reasons (6 versus 13). Recent viral pharmacokinetic studies with mericitabine may help to explain the relatively modest increases in SVR rates observed in the JUMP-C and PROPEL trials. Guedj et al.9 analyzed the rates of viral decline in 32 treatment-experienced genotype 1 patients given mericitabine (750 or 1500 mg once or twice daily for 14 days) and found that 12 of the 32 patients exhibited a monophasic viral decline slower than that seen with PEG-IFN or other DAAs with their typical biphasic pattern. Twice daily treated patients showed antiviral effectiveness of 0.98 (750 mg twice daily) and 0.997 (1500 mg twice daily), whereas the once daily groups showed effectiveness of 0.80 and 0.90, respectively. Discontinuation of the drug led to a rapid rebound of the viral load to pretreatment levels. In all, the slower rates of viral decline and the rapid rebound after drug discontinuation suggest that although there is less resistance with mericitabine in comparison with the currently approved protease inhibitors, this agent is less potent than other DAAs and is likely to not be useful as a backbone therapy with PEG-IFN and ribavirin as seen in the PROPEL trial, particularly when it is used with response-guided therapeutic regimens. Furthermore, this low potency would explain the similar relapse rates seen in the mericitabine groups from both trials in comparison with their respective placebo arms (27.7% versus 32.0% in the JUMP-C trial and 29.3% versus 31.1% in the PROPEL trial). The holy grail of CHC treatment is an all-oral, interferon-free regimen, and certain characteristics of mericitabine suggest that it may be more effective in conjunction with other DAAs rather than as part of a traditional PEG-IFN–based regimen. The resistance profile of mericitabine is notable only for the S282T serine-to-threonine substitution, which leads to a 15% reduction in replication capacity in comparison with the wild type.10 A pooled analysis of more than 600 patients who were given mericitabine in phase 1/2 trials demonstrated no evidence of genotypic resistance when it was administered as monotherapy, in combination with PEG-IFN and ribavirin, or in conjunction with other DAAs. The INFORM-1 study investigated mericitabine in combination with the nonstructural protein 3/4 protease inhibitor danoprevir and showed a steady, rapid decline in HCV RNA through 13 days of treatment in 72 of 73 patients without evidence of viral breakthrough due to resistance.11, 12 An in-depth analysis of the HCV quasispecies from the 14 patients who still had detectable HCV RNA at the end of 13 days showed no evidence of the known mericitabine resistance mutation S282T and, more importantly, no enrichment of the preexisting protease inhibitor resistance variants that were present at the baseline.13 Therefore, mericitabine may prevent the selection of danoprevir-resistant mutants, and phase 2 and 3 trials combining these agents in an interferon-free regimen are needed. Interestingly, an IL-28 polymorphism may also be important outside PEG-IFN regimens: IL-28 CC patients had a greater mean reduction in HCV RNA than non-CC patients (5.01 log versus 4.59 log) in the INFORM-1 study.14 This was also seen in the JUMP-C trial, in which mericitabine-treated patients with the IL-28B CC genotype were found to have a 100% end-of-treatment response rate, but this was tempered by a relapse rate of more than 20%. The authors attributed the high relapse rate to the response-guided therapy (i.e., 24 weeks) that these patients received. However, further study is required to better understand which genotypic and phenotypic variants predict a response and a risk for relapse. In summary, JUMP-C and PROPEL were not the great leaps forward that their monikers would have predicted them to be, but instead they may represent smaller steps toward the goal of an all-inclusive, effective treatment for CHC. Interferon-free trials with mericitabine in conjunction with other DAAs are ongoing and offer hope for those in need of treatment. Dawn M. Torres, M.D.1 Stephen A. Harrison, M.D.2 1Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD 2Division of Gastroenterology and Hepatology, Department of MedicineSan Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX
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Because most patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are injection drug users (IDUs) who might have been exposed to multiple HCV genotypes while sharing needles, coinfection with distinct HCV genotypes could be frequent in them. Blood samples from 203 coinfected IDUs who did not respond to at least 24 weeks of interferon (IFN)-based therapies were analyzed. At baseline, 131 patients had HCV genotype 1, 4 had HCV genotype 2, 52 had HCV genotype 3, and 16 had HCV genotype 4. Changes in HCV genotype were not found in any patient when samples obtained before and after HCV therapy were compared. HCV therapy did not appear to select for IFN-resistant HCV genotypes that might have been present at baseline. Coinfection with distinct HCV genotypes is unlikely in former IDUs coinfected with HIV and does not explain the lower efficacy of HCV therapy in this population.
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Hepatitis C is a worldwide problem that frequently results in end-stage liver disease and its complications. Treatment for hepatitis C virus (HCV) has been rather ineffective but several recent studies have clarified the role of interferon and ribavirin therapy. In line with therapeutic progress in HIV infection, hepatitis C is now entering the era of multidrug antiviral therapy. Ribavirin is an orally active synthetic guanosine analogue with theoretical antiviral and immunomodulatory actions. In this review we have evaluated the role of interferon and ribavirin in treatment-naive patients, relapsers and non-responders. In naive patients the combination results in improved end-of-treatment and sustained response rates, with an overall 41% sustained virological response rate in patients treated for 48 weeks. Therapeutic benefit also extends to the traditionally difficult to treat patients (genotype 1, high vital load and advanced fibrosis). The addition of ribavirin to interferon has also resulted in an increased toxicity profile, which has made therapy more difficult for both the patient and managing physician. However, the significant improvement in response rates for all patients makes combination therapy the most appropriate choice as the first-line therapy for suitable patients with chronic viral hepatitis C. Appropriate management with interferon and ribavirin includes assessing the patient's HCV genotype to determine the optimal duration of therapy, assessing therapeutic efficacy by measuring HCV-RNA at 24 weeks and monitoring for the additional ribavirin side-effects.
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The majority of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection occurs among persons who inject drugs. Rapid improvements in responses to HCV therapy have been observed, but liver-related morbidity rates remain high, given notoriously low uptake of HCV treatment. Advances in HCV therapy will have a limited impact on the burden of HCV-related disease at the population-level unless barriers to HCV education, screening, evaluation, and treatment are addressed and treatment uptake increases. This review will outline barriers to HCV care in HCV/HIV coinfection, with a particular emphasis on persons who inject drugs, proposing strategies to enhance HCV treatment uptake and outcomes.
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Liver disease
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