While the emergence of multiple highly-active agents for Hepatitis C has been a terrific advance, there are a small subset of patients who have not responded to them in almost all clinical trials. A recent study (M Bourliere et al. NEJM 2017; 376: 2134-46) has identified a highly-effective combination regimen for this population: sofosbuvir/velpatasvir/voxilaprevir x 12 weeks
The authors conducted two phase 3 trials in patients who had not responded to a direct-acting antiviral (DAA) regimen previously. POLARIS-1 and POLARIS-4. 46% of patients had compensated cirrhosis Key findings:
- POLARIS-1: 96% of combination group had a sustained virologic response (SVR) compared with 0% of patients receiving placebo
- POLARIS-4: the triple combination had a SVR of 98%, whereas 90% had SVR with dual therapy (sofosbuvir-velpatasvir)
- Among patients receiving active treatment, less than 1% discontinue treatment due to advers events.
My take: This triple therapy is highly effective in patients who were previously-treated with DAA for HCV.
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JB Schwimmer et al. Gastroenterol 2016; 151: 1141-54. Using a double-masked trial with 169 children with NAFLD, the use of cysteamine bitartrate for 1 year did not reduce histologic activity scores, but did reduce liver aminotransferase levels.
NA Terrault et al. Gastroenterol 2016; 151: 1131-40. The authors collected data from 2099 participants in the HCV-TARGET study who mainly received ledpasvir-sofosbuvir (311 received therapy in combination with ribavirin). The study included 25% blacks, 66% with genotype 1A, 41% with cirrhosis, 50% with prior treatment, and 30% who were receiving proton pump therapy. Key finding: SVR12 rates varied from 95% to 97% based on duration of therapy. Factors that predicted SVR12 included higher albumin (>3.5 g/dL), lower total bilirubin (<1.2), absence of cirrhosis, absence of proton pump inhibitor therapy.
KR Olson et al. NEJM 2017; 376: 268-78. This case report of an 18 yo woman with acute liver failure provides a helpful review. For Wilson’s disease, the article reviews rapid diagnostic criteria: “a screen that shows a ratio of alkaline phosphatase (IU per liter) to total bilirubin (mg per deciliter) of lower than 4.0 and then subsequently shows a ratio of aspartate aminotransferase (IU per liter) to alanine aminotransferase (IU per liter) of higher than 2.2 has been described as 100% sensitive and specific for the diagnosis of Wilson’s disease.” Making this diagnosis quickly is crucial and allows these patients to be UNOS status 1A, “the only cause of acute liver faliure that allows a patient with preexisting liver disease to be listed as status 1A”
Among children older than 10 years of age, Wilson’s disease accounted for 90% of metabolic disease.
While access to HCV treatment remains the biggest obstacle, recent studies show that the rates of HCV eradication, even in the toughest cases, now approaches 100%.
- E Lawitz et al. Gastroenterol 2016; 151: 893-901.
- EJ Gane et al. Gastroenterol 2016; 151: 902-9.
- Editorial: M Buti pgs 795-8.
Most prior studies examined the use of two direct-acting antivirals (DAAs) with or without ribavirin. These DAAs targeted nonstructural (NS) proteins necessary for HCV replication: NS3 protease, NS5B polymerase, and NS5A protein.
These two new studies examined whether treatment with a DAA targeting all 3 NS proteins would be effective and possibly allow shorter treatments. It is noted that currently only treatment-naive genotype 1 (w/o cirrhosis) patients have a regimen that is recommended for only 8 weeks; these patients also should have HCV-RNA<6,000,000 IU/mL.
Lawitz et al studied the combination of sofosbuvir-velpatasvir and GS-9857 (voxilaprevir) for 6-8 weeks (one treatment group received ribavirin); n=197. Among treatment-naive patients w/o cirrhosis, SVR12 was 100% after 8 weeks of treatment and 94% of treatment-naive patients with cirrhosis. Among treatment-experienced patients treated for 12 weeks, 100% of all patients (w and w/o cirrhosis) achieved SVR12.
Gane et al studied the effectiveness of the combination of sofosbuvir-velpatasvir and GS-9857 in HCV genotypes 2, 3, 4, and 6 (as well as 1 with 1b); n=128. After 8 weeks of treatment, SVR12s were achieved in 93% of treatment-naive patients with cirrhosis. After 12 weeks, treatment-experienced patients with and without cirrhosis had SVR12s of 97% and 100% respectively.
My take: This combination of therapies should allow shorter treatment regimens in treatment-naive patients and effective rescue therapy for previous DAA failures. Now that we can cure almost everyone with HCV, how do make therapies affordable and accessible?
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The large randomized pediatric entecavir study for Hepatitis B virus (HBV) is now in print: MM Jonas et al. Hepatology 2016; 63: 377-87. Full link to this study on previous blog: Pediatric Entecavir Data This study has led to FDA approval for use of entecavir in children as young as 2 years. One interesting aspect of the study was the 2.6% drug resistance rate in the second year of the study. This further validates current recommendations to treat children with “immune active” phases (e.g. abnormal transaminases and abnormal histology).
H Roberts et al. Hepatology 2016; 63: 388-97. This study provides prevalence data for chronic HBV, 1988-2012. During 2011-12, there were approximately 850,000 Americans with chronic HBV infections. Migration of persons from HBV endemic countries has “largely contributed to prevalence rates remaining constant since 1999.”
JM Wilder et al. Hepatology 2016; 63: 437-44. This study showed that ledipasvir/sofosbuvir was similarly effective in black and non-black patients, with SVR12 rates of 95% and 97% respectively. This is important because older interferon-based treatments were much less effective in black patients.
TB Dick et al. Hepatology 2016; 63: 634-43. This review provides in-depth guidance regarding drug-drug interactions relevant to the new direct-acting antiviral agents used to treat Hepatitis C viral infection.
NY City Data for HIV, HBV, HCV
The AASLD-IDSA Recommendations for Hepatitis C Virus have been published (Hepatology 2015; 62: 932-954). The entire report is accessible from hcvguidelines.org and from the link: HCV Guidance 2015. While having a hard copy is easy to work with, the HCVguidelines website is likely to remain more up-to-date.
A few recommendations to highlight:
- #6. “Antiviral treatment is recommended for all patients with chronic HCV infection, except those with limited life expectancy due to nonhepatic causes (I-A)
- #7. “If resources limit the ability to treat all infected patients immediately as recommended, then it is most appropriate to treat those at greatest risk of disease complications” (see Tables 3 and 4)
- #8. “Use of noninvasive testing or liver biopsy is recommended in order to assess the degree of hepatic fibrosis and, hence, the urgency of immediate treatment. (I-A)”
Other Hepatology studies of interest, briefly noted:
Hepatology 2015; 62: 684-93. Nucleos(t)ide analog “treatment does not increase the risk of renal and bone events in general. Nucleotide analogs may increase the risk of hip fractures, but the overall event rate is low.” This study examined 46,454 untreated chronic hepatitis B patients in comparison to 7,046 treated patients.
Hepatology 2015; 62: 715-25. This study looked at the safety of simeprevir and sofosbuvir in hepatitis C-infected patients. “Adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment.”
Hepatology 2015; 62: 773-83. This study found that “NAFLD is independently associated with subclinical myocardial remodeling and dysfunction.”
Bruce Munro, Atlanta Botanical Gardens
A recent commentary (J Chhatwal et al. Clin Gastroenterol 2015; 13: 1711-13) makes the point that HCV treatment is looking a lot better lately with regard to cost.
- “Sofosbuvir-based treatment in 2015, on average, costs 54% of the wholesale acquisition cost”
- When considering the recent discounts, “the cost of treatment decreased to $56,000…and the cost per SVR decreased to $58,000.” The cost of an SVR with the first generation protease inhibitors, boceprevir and teleprevir, has been estimated to have been $213,000.
- “The discounted cost of treating 1 person with HIV in the United States is $315,000 in 2014 US dollars.” Thus, curing HCV which is more deadly, at 18% of the cost, looks more favorable.
- More discounts and more competition are expected.
Bottomline: Based on these cost considerations, the authors state that HCV treatment should be used broadly and not solely in those with advanced fibrosis.
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S Naggie et al. NEJM 2015; 373; 705-13. Among patients coinfected with HIV-1 and HCV (genotypes 1 and 4), 12 weeks of ledpasvir and sofosbuvir resulted in a 96% sustained HCV virological response.
DL Wyles et al. NEJM 2015; 373; 714-25. Among patients coinfected with HIV-1 and HCV (genotype 1), 12 weeks of daclatasvir plus sofosbuvir resulted in a 97% sustained HCV virological response.
HA Innes et al. Hepatology 2015; 62: 355-64. Review of a Scottish HCV clinical database showed that a sustained viral response was associated with a reduced liver mortality (adjusted Hazard Ratio 0.24), a reduced non liver mortality (aHR 0.24) and reduced behavioral events (eg. violence-related injury aHR 0.51). The latter improvement suggests that HCV eradication leads to healthier lives.
Also, seeing as today is ICD-10 Rollout: ICD-10: Source for humor? | gutsandgrowth
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