Hepatitis C Relapse After Treatment –Spontaneously Cleared in Some

H Kuriry et al. Clin Gastroenterol Hepatol 2021; 19: 2398-2406. Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection

This retrospective case-control study identified 93 patients out of 1032 with chronic HCV infection who had a relapse of detectable infection following treatment. Key findings:

  • 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy
  • The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse. Low level RNA was identified in only 1 persistent relapser
  • There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses
  • The authors note that one limitation of the study was a false positive PCR assay –though this does not negate their message that retesting is important before retreatment
  • The relatively high relapse rate (9%) in this cohort is likely related to the use of first-generation DAA therapy
  • The timing of retesting in the 12 with spontaneous clearance was variable. 7 who had repeat testing at 3 months were all negative.

My take: In those with a low level virological relapse after DAA therapy for HCV, it is a good idea to repeat testing before consideration of further treatment.

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Huntingdon Lake, Sandy Springs (from Suzan)

Improvement in Hepatitis C Mortality Rates from 2005 to 2017

EW Hall et al. Hepatology 2021; 582-590. Open Access. County-Level Variation in Hepatitis C Virus Mortality and Trends in the United States, 2005-2017

The authors used county-level HCV death rates and assessed trends in HCV mortality from 2005 to 2013 and from 2013 to 2017; the study is derived from mortality data from the National Vital Statistics System.

Key Findings:

  • Nationally, the age-adjusted HCV death rate peaked in 2013 at 5.20 HCV deaths per 100,000 persons and decreasing to 4.34 per 100,000 persons in 2017
  • There was heterogeneity in HCV mortality with the highest rates being concentrated in the West, Southwest, Appalachia, and northern Florida. 80% of counties had improvement in HCV mortality

My take: This study showed widespread improvement trends in HCV death rates from 2013 to 2017 and provides benchmarks for further progress. However, other studies have shown increasing rates of HCV tied to opioid crisis which could impact long-term outcomes as well.

Related blog posts:

Treating Pediatric Hepatitis C Infections is Cost-Effective. Plus COVID-19 mRNA Vaccine Study

E Greenaway et al. J Pediatr 2020; DOI:https://doi.org/10.1016/j.jpeds.2020.08.088. Free full text: Treatment of Chronic Hepatitis C in Young Children Reduces Adverse Outcomes and Is Cost-Effective Compared with Deferring Treatment to Adulthood

Methods: A state-transition model of chronic HCV was developed to conduct a cost-effectiveness analysis comparing treatment at age 6 years vs delaying treatment until age 18 years

Key findings:

  • After 20 years, treating 10 000 children early would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths
  • The incremental cost-effectiveness ratio of early treatment compared to delayed treatment was approximately $12 690/quality-adjusted life-years gained and considered cost-effective

My take (=conclusion from authors): Delaying treatment until age 18 years results in an increased lifetime risk of late-stage liver complications. Early treatment in children is cost effective. Our work supports clinical and health policies that broaden HCV treatment access to young children.

Related blog posts:

FP Polack et al. NEJM Full text link: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Published data on the Pfizer/BioNTech vaccine

Emerging Targets for Hepatitis C -Part 2

The best review on new therapies for HCV that I’ve read in quite a long time:

Hepatology 2013; 58: 428-38

First the abbreviations:

  • ASV -Asunaprevir
  • BOC -boceprevir
  • DAA -direct-acting antiviral
  • DCV -daclatasvir
  • DNV -danoprevir
  • NI -nucleos(t)ide inhibitor
  • NNI -nonnucleos(t)ide inhibitor
  • SIL -silibinin
  • SOF -sofosbuvir
  • TVR -telaprevir

More terminology:

  • First-generation NS3/4A protease inhibitors (TVR, BOC) are “defined as agents that display potent activity on HCV-1 but oppose a low barrier to selection of resistant viral variants and are not effective on all viral genotypes.”
  • Second generation NS3/4A protease inhibitors are “defined as agents that pose a high barrier to the development of viral resistance, retain activity against the viral variants that are resistant to first-generation compounds, and are active across all HCV genotypes.”
  • First-wave therapies are covalent linear inhibitors and second-wave therapies are either non covalent linear or macrocyclic inhibitors.

What are the weapons?

Some second-wave, first generation NS3/4A PIs: faldaprevir, asunaprevir, sovaprevir, simeprevir, danoprevir, and vaniprevir.  These agents have similar clinical efficacy as BOC and TVR but are easier to administer, usually once-a-day.  Some of these agents have better activity  against several genotypes.

MK-5172, 2nd-generation NS3/4A PI,  has pan-genotype activity & maintains antiviral activity against most mutations that confer resistance to 1st-generation PIs.

DCV, a NS5A inhibitor, has potent HCV activity but a low barrier for viral resistance; thus, it is likely to be used in combination with other agents.  Multiple NS5A inhibitors are in development.

SOF, a NS5B polymerase inhibitor, is being studied in interferon-free combinations.  Viral resistance has been rare in clinical studies with this agent.  Multiple other agents in this class are in study.

NS5B polymerase inhibitor NNIs bind to less conserved sites on HCV; thus, initial results have not been as promising.  Several NNIs, including setrobuvir and lomibuvir (& others), are being tested in combination in all-oral, interferon-free regimens.

SIL, a NS4B binding inhibitor, is an intravenous agent that has shown some efficacy in liver transplant patients.  Other oral agents, like clemizole, are being investigated.

How these agents may be useful:

  1. “The first step forward in anti-HCV therapy will be the introduction of a second-wave PI to used in combination with PEG-IFN/RBV.” Simeprevir, faldaprevir, and ritonavir-boosted danoprevir (DNV) will be easier to administer than TVR or BOC as they can be given once-daily.  In addition, these drugs are more active against genotypes 2, 4, 5, and 6.  In fact, ritonavir-boosted DNV in combination with PEG-IFN/RBV had 100% SVR efficacy for patients with HCV-4 in one trial.
  2. Next, will be NS5A and NS5B inhibitors to be used in combination with previous agents.  These agents will compete with second-wave PIs but “whether they will provide a true innovation in terms of viral cure rates, safety profile, or patient tolerability is still to be demonstrated.”  These agents work better with other DAAs.
  3. Finally, all-oral combinations will enter the market.  “The first all-oral anti-HCV regimen will be likely available in 2014 for HCV-2 and HCV-3 patients.”  SOF with RBV has had good success rates in previous studies.

Potential Problems:

  • Many of these investigational agents have been studied in easy-to-cure populations.
  • Lack of data in advanced fibrosis/cirrhosis.
  • Safety questions in post-transplant populations.
  • Affordability.  “It is possible that these innovative regimens will be confined to groups of patients in whom TVR/BOC or PEG-IFN/RBV are either ineffective or unsafe.”  Some patients may receive ‘maginally less effective and less tolerable drugs for cost-containing issues.’
  • Drug resistance.  This is likely to become a clinical problem with all oral IFN-free regimens. with TVR/BOC, resistance has limited significance due to HCV quasispecies reverting back to wild-type virus after stopping TVR or BOC.  It is unclear if this will be the case with other DAAs.



Emerging Targets for Hepatitis C -Part 1

The latest advances in hepatitis C are related in several recent publications:

  1. Hepatology 2013; 57: 2143-54.
  2. Hepatology 2013; 57: 2155-63.
  3. Clin Gastroenterol Hepatol 2013; 11: 612-619.

The first two studies provide specific information about the effectiveness of Faldaprevir combined with peginterferon alfa-2a/ribavirin (PEG/RBV) in treatment-naive patients and patients with prior nonresponse respectively.  The third reference provides the big picture regarding all of the emerging treatments.

In the first study, the “SILEN-C1” phase 2 trial, 429 patients without cirrhosis were randomized to several treatment arms.  423 of the 429 patients were genotype 1.  This large study involved 89 centers in 15 countries.  All of the treatment groups received PEG/RBV along with either placebo, faldaprevir 120 mg with lead-in (LI), faldaprevir 240 mg LI and faldaprevir 240 mg without LI.   Faldaprevir is a NS3/4A protease inhibitor which can be administered orally once a day.  Results: SVR achieved in 56% (placebo), 72% (faldaprevir 120mg LI), 72% (faldaprevir 240 mg LI), and 84% (faldaprevir 240 mg without LI).  Discontinuation rates were 1%, 4%, 11%, and 5% for the aforementioned treatment groups.

In the second study, the “SILEN-C2” trial, 290 non cirrhotic genotype 1 patients with either no response or partial response to previous treatment underwent a 48 week treatment trial with a similar design as the SILEN-C1. Results: SVR rates among partial responders were 32% (faldaprevir 240 mg LI), 50% (faldaprevir 240 mg without LI), and 42%(faldaprevir 240 mg BID/LI).  Among null responders, SVR rates were 21% (faldaprevir 240 mg LI), 35% (faldaprevir 240 mg without LI), and 29% (faldaprevir 240 mg BID/LI).  Adverse reactions were higher in those on higher doses and included anemia, rash, indirect hyperbilirubinemia, and nausea. Discontinuation rates were 6%, 4%, and 23% for the aforementioned treatment groups.

The third study provides a landscape of current treatment and emerging treatments.  Given the improvement in SVR among genotype 1 patients, the use of either telaprevir or boceprevir in combination with PEG/RBV is the “new standard of care” among adult patients with HCV.  Studies supporting telaprevir include the ADVANCE study, the REALIZE trial, and the OPTIMIZE study.  For boceprevir, its effectiveness was demonstrated with SPRINT-2, and RESPOND-2.

Both boceprevir and telaprevir, are NS3/4A serine protease inhibitors and are considered direct acting antivirals (DAAs). On the horizon:

  • Simeprevir -NS3/4A protease inhibitor.  Studies: PILLAR, ASPIRE.  SVR: 75-86% in treatment-naive patients. Once daily, no rash or increased anemia.  Hyperbilirubinemia can occur.
  • Faldaprevir -see above studies.
  • Danoprevir -NS3/4A protease inhibitor. Study: DAUPHINE. For genotypes 1 and 4. 100% SVR in genotype 4.  Rates of withdrawal with danoprevir were similar to placebo.
  • Daclatasvir -NS5A replication inhibitor. Study: COMMAND-1. For genotypes 1 and 4.
  • Sofosbuvir -NS5B polymerase inhibitor. Studies: PROTON, ATOMIC. For genotypes 1, 4, and 6.
  • Multiple DAAs in combination. Studies: MATTERHORN, INFORM-SVR, AVIATOR, ELECTRON, SOUND-2

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Hepatitis C Virus Sexual Transmission and Monogamy

Numerous sources state that there is a low risk of transmitting Hepatitis C virus (HCV) among monogamous heterosexual couples.  More information on this subject has been published (Hepatology 2013; 57: 881-89).

In this study, 500 couples were studied; all were long-term heterosexual partners and all were HIV-negative.  The index partner was anti-HCV positive with a median age of 49 years and had a median of 15 years with their partner.  Condom use was infrequent among the study participants.

Key finding: HCV prevalence among partners was 4% (n=20) and ~2% (n=9) had concordant genotype/serotype.  The maximum prevalence of HCV transmission among these sexual partners was 1.2%.  Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission was reported as 0.07% per year or approximately one per 190,000 sexual contacts.

Some of the interesting aspects of the study included details of sexual activity and discussion of factors that may increase HCV transmission.  With regard to sexual activity, 30.4% of the couples reported prior anal intercourse and more than 90% reported oral sex (by both partners); however, both of these activities were reported as infrequent: typically 0 per month for anal intercourse and 3 contacts per month for oral sex.  With regard to HCV transmission, the authors did not identify any risk factors in the current study but did note that this may be influenced by viral titer, integrity of mucosal surfaces, and the presence of other infections.

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More options for Hepatitis C

As noted in numerous blog entries (see below), there has been increasing availability of new and more effective treatments for Hepatitis C virus (HCV).  Two more drugs have promising results:

  • NEJM 2013; 368: 34-44
  • NEJM 2013; 368; 45-53

The first study provides encouragement with regard to sofosbuvir (previously known as GS-7977) which is a direct-acting nucleotide polymerase inhibitor targeting the NS5B polymerase.

In this open-label study, there were eight groups of patients.  Of 40 previously untreated patients (genotype 2 or 3), all patients received sofosbuvir (400 mg daily) for 12 weeks.  All 10 who received the study drug with ribavirin (& without interferon) and all 30 who received the study drug with ribavirin and peginterferon had a sustained virologic response (SVR) at 24 weeks.  Among patients with sofosbuvir monotherapy, 6 of 10 had a SVR.  Among HCV genotype 1 patients, 21 of 25 (84%) previously untreated patients had a SVR. The most common adverse effects were headache, fatigue, insomnia, rash and anemia.

The second study also was a phase 2a, open-label study for HCV genotype 1 non-cirrhotic patients using ABT-333 and ribavirin.  ABT-333 is a nonnucleoside NS5B polymerase inhibitor.  Results: 17 of 19 (89%) patients in group 1 (Rx with ABT-333, ribavrin, ABT-450, and ritonavir), 11 of 14 (79%) patients in group 2 (Rx with same drugs at lower doses of latter two drugs) had extended rapid virologic response.  SVR was achieved in 95% and 93% respectively.  Groups 1 and 2 were previously untreated.  Group 3 were patients who had either a null or partial response to previous treatment achieved a 47% SVR.  The most common adverse effects were abnormalities in liver function tests, headache, fatigue, insomnia, pruritus, nausea and rash.


These preliminary results suggest that Sofosbuvir is effective in all genotypes and may allow a short duration all-oral regimen.  ABT-333 similarly is effective in an all oral regimen in genotype 1 patients.

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Learning a new language for HCV

There is bad news for those of us finally comfortable with the terms and abbreviations of the hepatitis C virus lexicon, like rapid virological response (RVR) and complete early virological response (cEVR).  A new consensus is emerging that more precise nomenclature is needed in this era of direct-acting antivirals (DAA) (Hepatology 2012; 56: 2398-2403).

The problem is that with the use of DAA, drugs that use a 4-week lead-in have their RVR checked at 8 weeks rather than 4 weeks.  Similar problems are present with the other terminology in current use.

RVR should be reported as W4U-tnd.  W4 indicates week 4, U indicates viremia unquantifiable, tnd indicates whether target HCV RNA was not detected (td indicates detected). If there is a lead-in, then LI-w/d-W8U-tnd.

Other terms:

  • vRVR or very rapid virological response is now W2U-tnd
  • eRVR or extended RVR refers to undetectable HCV RNA at week 4 and 12 and is now W4-12U-tnd
  • cEVR refers to undetectable HCV RNA at 12 weeks is now W12U-tnd
  • pEVR or partial EVR indicates at least 2 log10 decrease in HCV RNA after 12 weeks of treatment.  New lingo: W12[-2]
  • SVR or sustained virological response is now SVR12-tnd (if 12 weeks after Rx) and SVR24-tnd (if undetectable HCV RNA 24 weeks after Rx)
  • LLOQ indicates the  lower limit of quantitation.  A value <LLOQ is not necessarily “undetectable.”

You may need the hepatology ‘rosetta’ stone session before your next meeting with your liver expert.

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Vaniprevir for HCV

Vaniprevir (MK-7009) is a hepatitis C virus (HCV) NS 3/4A protease inhibitor.  A phase II study has shown that vaniprevir can be an effective agent in combination with pegylated interferon alpha-2a (PEG-IFN) and ribavirin (RBV) (Hepatology 2012; 56: 884-93).

This double-blind, placebo-controlled study examined 94 patients with treatment-naive genotype 1 HCV.  In combination with PEG-IFN/RBV, patients received either placebo, vaniprevir 300 mg BID, 600 mg BID, 600 mg QD or 800 mg QD for 28 days & then open-label PEG-IFN/RBV for 44 weeks.  There were 18-20 patients in each group.

With all of these vaniprevir doses, there was a rapid two-phase decline in viral load; the HCV RNA level was approximately 3log10 IU/mL lower in vaniprevir-treated patients than placebo.  Rapid viral response occurred in 68.8-83.3% of vaniprevir-treated patients compared to 5.6% of control patients.  Sustained virologic response was higher but did not reach statistical significance.

Resistance to vaneprevir with variants at R155 and D168 was detected in a small number of patients.  The authors note that treatment outcomes were not related to interleukin-28B genotype.

The potential advantage of vaneprevir over currently available triple therapy agents (eg. telaprevir and boceprevir) would be easier administration, QD or BID, and possibly more favorable side effect profile.

Take home message: more treatment options, including vaneprevir, for HCV are on the horizon.

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Missing “C”

Ascertainment rates for pediatric hepatitis C virus (HCV) are as bad as in adults with HCV (J Pediatr 2012; 161: 915-21).

As noted in previous blog entries, it has been recommended by the CDC that adults born between 1945-65 undergo a one time screening for HCV due to the high frequency of undetected cases along with improvements in therapy.  The same rationale may apply to children in the near future as some of these therapies are shown to be safe and effective in the pediatric population.

In the meanwhile, it is apparent that most pediatric HCV cases remain undetected.  In the aforementioned study, the investigators examined statewide data from Florida and data from health departments across the United States.  This was compared with data from NHANES III which reported HCV prevalence of 0.2% in children 6-12 years old and 0.4% of 13-18 year olds.  The absolute prevalence may be higher as NHANES did not capture some populations at high risk, like homeless or incarcerated youth.


  • From 2000-2009, only 2007 children were identified as HCV-antibody positive in Florida.  During this period, it is estimated that this represents about 12% of the expected number of cases (n=12155).
  • In Dade county which has 13 pediatric gastroenterologists, 100% responded to an online questionnaire.  They reported caring for 31 cases of HCV in 2009 and another 55 in the preceding 5 years.  This indicates that 1.6% of the expected number of HCV-antibody-positive children in this region received care in 2009 and 2.8% over previous 5 years.
  • Nationwide, only two states (VT, MA) identified more than 20% of expected cases.

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