Category Archives: Hepatology

Why Some Genetic Mutations May Be Helpful: HFE

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When one looks at diseases, it is important to consider that the mutations that cause the disease may confer other selective advantages.

A classic example has been sickle-cell disease.  The heterozygous state is usually asymptomatic and makes an individual less prone to malaria.  “In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and will tend to be selected out of the affected population via natural selection.” —Sickle–cell disease – Wikipedia, the free encyclopedia

Another common disorder is hemochromatosis.  A recent letter in the New England Journal of Medicine (NEJM 2013; 369: 785-6) explains why having the HFE gene could be advantageous.  According to the authors the genetic mutation arose in Celtic populations who were notably taller than other populations.  As such, the authors hypothesized that the patients with HFE hemochromatosis would have better growth by having an abundant supply of iron during periods of rapid development.

They assessed a cohort of 176 Swiss patients with HFE hemochromatosis.  93% were homozygous for the C282Y mutation, 7% had a compound H63D-C282Y mutation.  All of the patients had verified iron overload determined as a ferritin > 300 mcg/L or a transferrin saturation >45%.

Compared with an age-matched, sex-matched Swiss reference population, men with hemochromatosis (n=120) were 4.3 cm taller on average. In women (n=56), the difference was 3.3 cm.  To avoid bias due to population origin, the cohort was also compared with data from Ireland where the data remained validated.

Take-home message: Extra iron in the first two decades of life promote better growth (and probably other advantages).  However, iron overload later in life can lead to cirrhosis, diabetes, heart disease, and reproductive problems.

Related blog post:

AASLD Hemochromatosis Guidelines:

Looking at the Tenofovir Data Another Way

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In last Friday’s post, this blog reviewed 5-year data on tenofovir usage which showed that tenofovir could reverse fibrosis/cirrhosis.  Another study using the same cohort examined the efficacy of tenofovir in patients with high viral load (HVL) at baseline (Hepatology 2013; 58: 505-13).

From an initial total of 641 patients enrolled in GS-US-174-0102 (n=375) and GS-US-174-0103 (n=266), the authors identified 129 (20%) with HVL.  HVL was defined as having ≥9 log10 copies/mL.  After an initial 48 weeks of randomization between tenofovir (HVL n=82) or adefovir (HVL n=47), patients received an additional 192 weeks of therapy with tenofovir in an open label extension.

Results:

  • By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL
  • High HVL patients took longer to achieve undetectable HBV DNA, but by week 96 the results were similar in both groups
  • Patients who received tenofovir during the initial 48 weeks achieved undetectable HBV DNA quicker than those who had received adefovir initially
  • There were similar rates of histologic regression in both HVL and non-HVL patients

This study evaluated only patients in the ‘immune clearance’ phase of HBV and therefore cannot be extrapolated to those in the immune tolerant phase.

Changing the Outcome for Hepatitis B

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Much of hepatology relies on surrogate markers to convey whether treatments are effective.  For hepatitis B virus (HBV), some of these markers include serology (eg. development of HBV e antibody), improvements in biochemistry (eg. transaminases) as well as histology.  Of these, improved histology is likely to have the most bearing on clinical outcomes like progression to end-stage liver disease and hepatocellular carcinoma.  A previous study of lamivudine has indicated that regression of fibrosis can reduce the rate of hepatocellular carcinoma (NEJM 2004; 351: 1521-31).

As such, the results of long-term use of agents like tenofovir have been awaited.  Since tenofovir along with entecavir are considered 1st line agents, their use has become commonplace for the treatment of HBV.  Now 5-year data are available in a large cohort (Lancet 2013; 381: 468-75).

The data from this study was derived from an open-label cohort that followed 48-week double-blind comparison trials. 489 patients completed 240 weeks of treatment.  348 patients had biopsy results available at baseline and at week 240.

Key findings:

  • 304 (87%) of those with biopsies at study completion had histologic improvement.
  • 176 (51%) had regression of fibrosis
  • 71 of 96 (74%) who had cirrhosis at baseline no longer had cirrhosis (≥1 unit decrease in Ishak fibrosis score)
  • 3 of 252 without cirrhosis at baseline progressed to cirrhosis at week 240
  • No evidence of resistance to tenofovir was evident.  Nearly all patients on tenofovir had undetectable HBV DNA
  • Adverse safery events were rare

As with all studies looking at liver histology, there were limiting factors including potential sampling errors and variable interpretation.  The authors sought to minimize this by using an independent pathologist.   Another strength of the study was the broad range of patients to make these findings broadly applicable.

Take-home message: Tenofovir treatment for 5 years is safe and effective.  Long-term suppression of HBV can lead to regression of fibrosis and reversal of cirrhosis.

Related blog posts:

Big Interferon-free Hepatitis C Study

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Every week there is more information on clinical trials for hepatitis C; I am waiting for this to translate into improvements for the pediatric population.

This week’s biggest publication: NEJM 2013; 369: 630-9.  This was a phase 2b randomized open-label trial of faldaprevir (a NS3/4A protease inhibitor) in combination with deleobuvir (a non nucleoside NS5B polymerase inhibitor).  In total, 5 different regimens were examined, most in combination with ribavirin.  The authors recruited 362 HCV genotype 1 patients who were randomized into these treatment groups & he sustained virologic response 12 weeks after completion of therapy

  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 16 weeks (TID16W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 28 weeks (TID28W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 40 weeks (TID40W) –>52%
  • Faldaprevir 120 daily, deleobuvir 600 two times a day, and ribavirin for 28 weeks (BID28W) –>69%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, without ribavirin for 28 weeks  (TID28W-NR) –>39%

Rates of SVR were higher among genotype 1b, 56-85%, compared with 1a, 38-43% (when excluding non-ribavirin group).  Genotype 1a patients with IL28B CC had similar response (58-84%) to genotype 1b patients.  Genotype 1a patients were much more likely to relapse if not treated for at least 28 weeks.

Adverse effects were common and reported in 94% of participants; 9% had severe adverse reactions.  Gastrointestinal and dermatologic advents events were the most frequent.  Also, faldaprevir resulted in jaundice (unconjugated hyperbilirubinemia) in many patients (16-28% of patients who took ribavirin in their regimens).

This large study showed that when these oral antiviral are used in combination with ribavirin that results are similar to current standard of care treatments for adult patients.  For telaprevir or boceprevir, along with pegylated interferon and ribavirin, phase 3 trials showed SVRs between 68-75%.

Related blog posts:

Data on Chelators for Wilson Disease

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A recent retrospective analysis on 405 patients with Wilson disease analyzed the efficacy and safety of oral chelators for Wilson disease (Clin Gastroenterol Hepatol 2013; 11: 1028-35).

The authors noted that there were frequent changes in medication; in total, 471 monotherapies were analyzed: 326 patients with D-penicillamine (DPA) and 141 with trientine.  Trientine was a first line treatment in only 38 patients.  About 50% of patients presented with hepatic symptoms, about 20% neurologic symptoms, about 15% with combined hepatic/neurologic symptoms and the remainder, ~10%, were asymptomatic.

  • 9 of 326 with DPA and 3 of 141 with trientine underwent liver transplantation.
  • Adverse effects were more common with DPA, including arthralgias (8.9%), proteinuria (6.1%), ANA antibodies (6.7%), gastric complaints (2.5%) and polyneuropathy (1.8%).  28.8% of DPA stopped therapy due to adverse effects.
  • Adverse effects with trientine resulted in stopping treatment in 7.1% and included arthralgias in 2.8%, and gastric complaints in 1.4%.
  • Hepatic improvements were observed in >90%

The authors summarize their findings:

“Both DPA and trientine were equally and highly effective in controlling liver disease…In light of recent reports of hepatic deterioration under zinc therapy, the current data emphasize the role of these chelating agents in the treatment of symptomatic hepatic patients.”

Related blog post:

Finding the Right Specialist | gutsandgrowth This post has link to AASLD guidelines for Wilson disease.

Emerging Targets for Hepatitis C -Part 2

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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

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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

Related blog posts:

Tattoos: a marker for Hepatitis C

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A recent study has found that tattooing was independently associated with hepatitis C virus (HCV) infection, even in those without traditional risk factors (Hepatology 2013; 57: 2117-23).

The authors of this large, multicenter, case-control study analyzed demographics and risk factors for HCV among 3,871 patients including 1,930 who had chronic HCV infection.  As in previous studies, a history of injection drug use (IDU) and blood transfusion prior to 1992 were associated with an increased risk of HCV.

After excluding patients with these risk factors, there were 465 patients with HCV and 1,421 controls.  Among these individuals, after controlling for age, sex and ethnicity, HCV-positive patients had an OR of 5.17 of having had one or more tattoos compared to the control patients.

Previous studies have not been definitive about whether tattoos represent a specific risk factor or an epiphenomenon.  That is, tattoos are known to be more common among individuals with IDU.  And, this study does not really settle the question either.  “Underrepresentation due to self-reporting of intravenous drug use is a concern that could confound our result.”  In addition, the authors note that commercial parlors have not been implicated in HCV transmission.

Bottomline: Individuals with tattoos are more likely to have HCV.  For individuals who insist on tattoos, avoid nonprofessional settings to limit the risk of HCV acquisition.

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