Category Archives: Hepatology

Don’t Give Up Too Soon (with Hepatitis B treatment)

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A recent study shows that ongoing treatment with entecavir is usually effective in “primary nonresponders” (Hepatology 2014; 59: 1303-10).

This study retrospectively reviewed a study with 1254 treatment-naive patients who received entecavir (ETV) 0.5 mg/day for >6 months. Only 16 (1.28%) patients were considered “primary nonresponders.”  The latter was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD or <1 log drop after 3 months by EASL.

Key findings:

  • The probability of achieving a virologic response (HBV DNA <15 IU/mL) was 95.8% at 54 months among these “nonresponders”
  • Primary nonresponders did not have ETV resistance; however, 13 (1%) of the entire cohort developed ETV resistance.
  • In this treatment cohort, the 5-year cumulative risk of hepatocellular carcinoma (HCC) was 2.5%.  Previous studies have shown that HBV suppression lowers the risk of HCC.

Take-home message: 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

Keeping Track of HCV Trials -Three More

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Recently three more trials of all oral regimens for HCV have been published in the NEJM.  A useful summary of their effectiveness is available in the associated editorial.  Here’s the link and an excerpt:

http://nej.md/1hhae91 

Welcomed and exciting results from three large, controlled trials of different regimens of oral antiviral agents for chronic hepatitis C, genotype 1, have now been published in the Journal.1-3 The regimens all included the combination of ledipasvir and sofosbuvir, two new direct-acting antiviral agents with potent activity against hepatitis C virus (HCV). The two drugs were given as a single tablet once daily for 8, 12, or 24 weeks, with or without ribavirin. The results were consistent and striking: the various regimens yielded rates of sustained virologic response of 93% to 99%. The combination of ledipasvir and sofosbuvir alone (without ribavirin) for 12 weeks was associated with response rates of 94% in the ION-2 study and 99% in the ION-1 study.1,2 Extending therapy to 24 weeks increased the rate minimally (to 98% and 99%, respectively). In contrast, adding ribavirin provided no further benefit, regardless of duration. In previously untreated patients without cirrhosis, shortening the duration of therapy (without ribavirin) to 8 weeks did not lessen the rate of response (94%, vs. 95% with 12 weeks of therapy in the ION-1 study).3 Importantly, the single-tablet regimen was easy to administer and had few side effects; among the 539 patients who received ledipasvir and sofosbuvir alone for 12 weeks in these three trials, only 2 stopped therapy early because of adverse events.

The rates of response to ledipasvir and sofosbuvir were virtually the same in all subgroups of patients, regardless of patients’ age, sex, race, liver-enzyme levels, HCV genotype (1a vs. 1b), preexisting antiviral resistance variants, or host genetic factors. Even in the difficult-to-treat patients who had not had a sustained response to a previous course of the most effective interferon-based therapies,4 the response rate at post-treatment week 12 was 94%. In this group of patients, the presence of cirrhosis was associated with a slightly lower response rate (88%, vs. 95% without cirrhosis), but with the longer course of treatment (24 weeks), these differences disappeared (100% in both groups).2 Preliminary studies with interferon-free drug combinations in patients with other HCV genotypes (2 or 3) suggest that high rates of response can be expected with those HCV strains as well.5

The combined results of the three trials include 1952 patients, of whom 97% had a sustained virologic response. Among the 3% who did not have a response, almost half were lost to follow-up or withdrew consent… Relapses were more common with shorter courses of therapy: 5% of patients who received 8 weeks of treatment had a relapse, as did 2% of those who received 12 weeks and 0.2% of those who received 24 weeks of treatment…

Ledipasvir and sofosbuvir are not the only promising antiviral agents for hepatitis C on the near horizon. Several other all-oral antiviral regimens have performed similarly in phase 2 studies, with sustained response rates in the range of 90% or higher.6,7 Thus, there are likely to be several options for oral therapy of hepatitis C within the next year.

  1. The availability of effective, oral regimens of therapy for hepatitis C will lead to major changes in the management of this disease and probably affect both its morbidity and its mortality…The limitations and medical barriers to treatment, however, may now largely disappear. The ease of administration, short duration of treatment, and minimal side effects of all-oral regimens will probably mean that most persons will qualify for therapy. Collectively, these regimens promise to transform hepatitis C from a condition requiring complex, unsatisfactory therapies and specialist care to one that can be effectively treated and easily managed by a general physician with few contraindications and side effects.
  2. Unfortunately, not all barriers to treatment will be lifted. The major limitation remaining will be economic. The current cost of a 12-week regimen of sofosbuvir alone is $84,000, or $1,000 per tablet.11 The addition of ledipasvir will add to the costs, and these estimates do not include expenses for diagnostic assays, monitoring, and physician visits…

Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a safe and effective therapy for hepatitis C.

References:

  1. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1316366.
  2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1402454.
  3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. DOI: 10.1056/NEJMoa1402355.

Related tweets (with links to abstracts/full text) from NEJM twitter feed:

  • ION-1: Sofosbuvir and ledipasvir (12 or 24 wks) achieved high (98 or 99%) SVR rates in untreated pts w/ HCV.
  • ION-2: Sofosbuvir and ledipasvir (12 or 24 wks) achieved high SVR rates in pts w/ HCV who failed prior Tx. 
  • TURQUOISE II: SVR achieved at 12 wks in 92% of pts w/ HCV and cirrhosis, and in 96% at 24 wks.

It is Hard to Keep Track…

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of all the new Hepatitis C virus (HCV) studies that are being published.  A recent study shows that the combination of sofusbuvir with either ledipasvir or GS-9669 was effective for HCV genotype 1 infections (Gastroenterol 2014; 146: 736-43).

Two years ago publication of this study would have been met with incredible enthusiasm.  However, now this study, while important, is part of a big trend showing that oral HCV therapies are going to make the treatment of HCV easier, safer, and expensive.  Ledipasvir (LDV) is a NS5A inhibitor and  GS-9669 is a NS5B non-nucleoside inhibitor.

The particulars of this study:  113 patients were enrolled.  All patients received sofusbuvir (400 mg daily).  LDV was dosed at 90 mg daily and GS-9669 at 500 mg daily.  Three of the four treatment arms used ribavirin (RBV) with 1000 mg for those patients <75 kg and 1200 mg for those patients >75 kg.

Four arms:

  1. SOF/LDV/RBV 12 weeks–n=25 treatment-naive (TN)/n=9 null responders (NR)
  2. SOF/GS-9669/RBV 12 weeks –n=25 TN/10 NR
  3. SOF/LDV or SOF/LDV/RBV 12 weeks–n=19 NR with cirrhosis
  4. SOF/LDV/RBV for 6 weeks –n=25 TN (noncirrhotic)

Key Results:

  • Group 1 had SVR12 of 100%, group 2 had SVR 12 of 92%, and group 4 (6 week Rx) had SVR12 of 68%.
  • Among cirrhotic NR, SVR12 was achieved in 9 (100%) of those with triple therapy (SOF/LDV/RBV) and 7 (70%) of those with SOF/LDV dual therapy.

Take home message: Oral direct-acting agents in combination are effective in all groups of patients affected by HCV, included those with cirrhosis and prior null responders.

An editorial (Clin Gastroenterol Hepatol 2014; 12: 533-36) titled “The End of Hepatitis C” indicates that “interferon-free treatment is likely to become the new standard of care within the next 12-18 months.”  However, the potential price tag for treating 3.2 million infected individuals in the U.S. would be about $270 billion in drug costs alone.

A related NEJM article: (link) “Curing Chronic Hepatitis C –The Arc of a Medical Triumph.”  And another study, (link) Sapphire II, showed the effectiveness of other oral agents for HCV.  This study examined ombitasvir, ritonavir, and dasabuvir in 394 patients.

More HCV study results will be reviewed later this week on this blog.

Related blog posts:

 

Revising the Textbooks on Isoniazid Hepatotoxicity

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Previously, isoniazid (INH) hepatoxicity has generally been described as “idiosyncratic.”  New research shows that INH-induced hepatotoxicity is often associated with anti-INH and anti-cytochrome P450 antibodies (Hepatology 2014; 59: 1084-93, editorial 746-48).

Background: INH is a crucial treatment for tuberculosis.  About 10% of patients receiving monotherapy may develop mild elevations (<3-fold the upper limit of normal) of alanine aminotransferase.  However, 0.5-1% develop overt hepatitis and some develop acute liver failure (ALF).  Risk factors for ALF include female gender, age >35 years, cotreatment with other tuberculosis medications, INH dose >50 mg/kg, ethanol use, and slower metabolic pathways (slow acetylator N-acetyltransferase 2 or cytochrome (CYP) P450 2E1 genotype).

The authors utilized two patient groups: 19 from the ALF study group registry who had >50% likelihood of IHN toxicity and 20 control patients who were receiving INH prophylaxis.  In this control group, 15 had no liver injury and 5 had mild hepatitis. The authors utilized several immunoassays.

Key findings:

  • 15 of 19 cases of INH-associated ALF had detectable antibodies: 8 anti-INH and 11 had antiCYP2E1 Abs.
  • None of these antibodies were detected from INH-treated controls

Bottomline: from the authors of the study “Although the presence of these antibodies only in INH-induced liver failure suggests that INH-induced liver injury is immune mediated, there is no evidence that these Abs are actually responsible for the liver injury.”

In this same issue is a lengthy guideline on the “Evaluation for Liver Transplantation in Adults”: http://t.co/AnnJHHVNh0

Related blog post:

Liver toxicity -where to look online | gutsandgrowth

Curing Iron Overload with Liver Transplantation

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The role of hepcidin in iron metabolism has been described in detail.  Yet, a new study provides another line of evidence that the liver has a primary role in regulating iron absorption (Hepatology 2014; 59: 839-47, editorial 749-50).

Background: Hereditary hemochomatosis (HH) is mainly due to defects in the gene encoding the human hemochromatosis protein (HFE), particularly the C282Y mutation.  Initially, HH was thought to be related to the role of HFE in regulation iron absorption at the intestinal crypt.  However, the discovery of hepcidin, which is mainly secreted by the liver, was shown to regulate iron absorption through its interaction with ferroportin, the cellular iron exporter. With HH, inappropriately low hepcidin was associated with excessive iron absorption.

Despite this understanding, many questions remain, especially regarding the fact that some C282Y homozygotes have a normal serum ferritin and transferrin saturation.  In addition, whether liver transplantation prevents further iron overload in patients transplanted for HH is not entirely certain.

Methods: This study evaluated 18 liver transplant (LT) patients with HH and who were homozygous for C282Y mutations.  16 of these patients had HCC.  All patients underwent iron evaluations (iron, hepcidin, hepatic iron concentrations) prior to LT and most (n=11) had evaluations following LT with a median followup of 57 months.

Key findings:

  • After LT, no patients received iron depletion therapy (eg. phlebotomy).  9 of 11 had no iron overload based on bloodwork (normal transferrin saturation) and MRI without iron overload.
  • One patient with hereditary spherocytosis continued to have iron overload, and one patient with metabolic syndrome had mild iron overload.
  • Hepcidin was normal (11.12 nmol/L) in 10 patients at the end of followup and low in one patient with iron deficiency anemia; prior to LT, serum hepcidin levels were low in all patients (mean 0.54 nmol/L)

Bottomline: This study shows that LT corrects hepcidin dysregulation caused by the HFE mutation and that post-LT HH patients do not require phlebotomy.  Thus, HH is clearly a liver disease and not an intestinal disease.

Related blog post: Help with hepcidin | gutsandgrowth (with annotated references)

“More to It Than Meets the BMI”

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This blog post title is quoted from a clever editorial which reviews the use of BMI and the effect of obesity with outcomes after liver transplantation (Liver Transpl 2014; 20: 253-54, related article pages 281-90.)

Key points from editorial and study:

  • Study enrolled 202 consecutive adult (mean 51 years) patients (200-2010) as part of cohort study.  Data was obtained at time of transplantation and reviewed with retrospective analysis. NAFLD was transplant indication in 7%.
  • “Use of BMI as a marker of obesity is flawed.” Authors showed only 86% agreement between calculated BMI and percent body fat as measured with DXA.
  • Patients with high BMI due to greater lean muscle mass may have improved outcomes.  Sarcopenia (loss of muscle mass) likely has greater effect on outcomes.
  • The study shows that the combination of diabetes and obesity increases the risk of complications and prolongs hospital stays (5.81 days, P<0.01).
  • Metabolic risk factors had no effect on 30-day, 1-year, or 5-year patient survival.

Another article in same issue: Liver Transpl 2014; 20: 311-22. This study retrospectively examined 148 normal-weight, 148 overweight, and 74 obese patients who underwent living donor liver transplantation. Key finding: “there were no differences in graft survival [hazard ratio (HR) =0.955] or recipient survival [HR = 0.90]” between these groups.  Obese patients do require larger grafts which can delay identifying suitable donor.

Bottomline from editorial: “this study shows us that the combination of diabetes and obesity dramatically increases the risk of complications” but not survival.  “If there comes a day when the cost of a human life is less than the cost of a 6- to 7-day hospital stay, that is the day to reckon. None of us may survive.”

Related blog post:

Sarcopenia, fatigue, and nutrition in chronic liver … – gutsandgrowth

HCV Website -No “Cat on The Roof”

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A joke I heard a long time ago:

A guy asks his friend to check up on his cat while he is away on a trip.  He calls to see how kitty is doing.  His friend says, “Sorry but she died.”  In response, he tells his friend, “you should have broken me the news a lot more gently.  Maybe you could have said she was up on the roof and the next time I called it would have been easier to accept the news.”  A few years pass and he again asks his friend for a favor, this time to check up on his grandmother while he is away on a trip.  He calls to see how granny is doing.  His friend says, “Oh, she is up on the roof.”

The AASLD and “the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), announced the launch of a new website,HCVguidelines.org, that offers up-to-date recommendations for testing, managing, and treating hepatitis C virus (HCV) infection.”

The website clearly dismisses the previous established breakthrough treatments of telaprevir and boceprevir “because they are markedly inferior.”

For anyone who has been confused with the onslaught of new work on HCV, the website spells out in clear detail the best regimens for HCV treatment now that both sofusbuvir and simeprevir are available.

Bottomline: The website makes it clear that both telaprevir and boceprevir are up on the roof.

Related blog posts:

Population-Based Outcomes for Primary Sclerosing Cholangitis

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A study from the Netherlands examined the outcomes for Primary Sclerosing Cholangitis (PSC) (Hepatology 2013; 2045-55). Using four independent hospital databases with 44 hospitals, allowed the investigators to identify 590 PSC patients from a population of almost 8 million. Median followup was 92 months. Mean age at diagnosis was 38.9 years.  A second comparison cohort of 450 patients was identified from three Dutch transplantation centers outside the study area.  134 (30%) of this cohort were present in the population-based cohort.  An IBD comparison group of 722 cases was identified as well from a population of 271,000 patients.

Results:

  • Prevalence: 6 per 100,000.  This is significantly lower than previous estimates.  The authors emphasize the problem with previous epidemiology studies and the need for population-based studies with rigorous case-finding.
  • Survival, estimated at 21.3 years for the entire cohort following diagnosis, was better than previous studies and this may indicate less selection bias than tertiary referral center studies.  It could also reflect diagnosis of milder cases with newer imaging techniques.
  • 402 (68%) of PSC patients were diagnosed with inflammatory bowel disease.
  • 23 (4%) had autoimmune hepatitis overlap.
  • Colorectal cancer was 10-fold increased compared to ulcerative colitis controls and developed at a younger age (39 years compared with 59 years).
  • Cholangiocarcinoma (CCA) was nearly 400-fold increased risk.  The cumulative risk of CCA was estimated at 20% after 30 years following PSC diagnosis.
  • During followup, there were 97 deaths; 73 (75%) were PSC-related.

Related blog posts:

Liver fibrosis in determining treatment for Hepatitis B

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A recent editorial reviews current guidelines and makes the point that while patients with advanced fibrosis should receive antiviral treatment, treatment is also recommended for patients with high levels of HBV DNA and active liver disease (Clin Gastroenterol Hepatol 2013; 11: 1500-02).  The related study (Clin Gastroenterol Hepatol 2013; 11: 1493-99) indicated that guidelines do not predict accurately which patients have ≥F2 fibrosis.  The editorial argues that the study’s conclusions are “misguided” because ALT and HBV DNA are not used solely for identifying patients with fibrosis.

Key points:

  • 18-47% of HBV-related HCC occurs in the absence of cirrhosis.
  • Guidelines “agree that treatment should be initiated in non-cirrhotic patients with serum HBV DNA >20,000 IU/mL and alanine aminotransferase (ALT) levels higher than 2 times upper limit of normal (ULN) or histologic evidence of moderate-to-severe inflammation or fibrosis.”
  • For HBeAg-negative patients, AASLD guidelines suggest a lower threshold for HBV DNA (>2000 IU/mL) along with ALT >2 times ULN or ALT 1-2 times ULN with concerning liver biopsy (particularly in age >40 years).
  • “Since treatment does not eradicate the virus…and in many instances [is] lifelong treatment, we agree with Sanai et al that criteria for initiating hepatitis B treatment in guidelines must be carefully weight to avoid unnecessary treatment.”

Related blog posts:

It is a Question of Fairness

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One of my professors in medical school frequently described ethical issues in terms of some things being unfair and some things being unfortunate.  A report in this month’s Liver Transplantation (2013: 19: 1330-42; editorial 1287-88) indicates that sometimes an individual does not receive a liver transplant due to an unfair allocation policy.  One potential problem with the current UNOS distribution is the use of exception points.  Because the Model for End-Stage Liver Disease (MELD) score does not work well for all patients, there are both recognized exceptional diagnoses (REDs) (eg. hepatocellular carcinoma) and non-REDs (eg. cholangitis).  The purpose of these exception points is to account for some conditions that may increase the risk of dying on the transplant list in which the MELD score is not an adequate predictor.

In this study of adult liver transplant candidates between 2002-2011, the authors examined non-REDs; among a cohort of 58,641, 7.4% applied for a non-RED.  The number of non-REDs increased over the course of the study.  In addition, approval rates which were <50% in 2002 increased to nearly 75% in 2010. Candidates with approved exceptions were more likely to undergo transplantation (68.3% vs. 53.4%, P <0.001).

There was significant variability among transplant centers with regard to requesting exception points. Centers with higher median MELD score at transplantation were more likely to have candidates with non-RED applications. The net result was that women, African-Americans, Hispanics, and patients with Medicaid insurance were statistically less likely to have an exception application.

In pediatrics, non-RED applications are more common. Thus, the problem of equitable distribution could be even greater among pediatric patients.

Bottomline: While physicians have a duty to their patients, it is vital to make sure that every effort is made to allocate organs in a fair manner.  Since the use of non-RED applications is inconsistent, it suggests that some transplant centers are utilizing this tool inappropriately (?too often, ?too few).  This report indicates that more work is needed to have a fair transplant allocation system.

Related blog posts: