Category Archives: Hepatology

HCV Guidelines Updated

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For those trying to stay up-to-date, a headline from The Onion: “Nation’s Third-Graders Now Eating At A Ninth-Grade Level”   .

And, from American Association for the Study of Liver Diseases (AASLD):

AASLD and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), released the latest section of www.hcvguidelines.org.

The new section, “When and in Whom to Initiate HCV Therapy,” offers clinicians information on:

  • How to prioritize patients who will derive the most benefit, or will have the greatest impact on limiting further HCV transmission.
  • When to treat patients with complications such as advanced fibrosis, compensated cirrhosis, liver transplant, or severe extra-hepatic complications.
  • Additional conditions that warrant prioritization of treatment.

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A New Villain for Hepatitis C

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A recent article (Hepatology 2014; 59: 2403-12) notes a changing perception for Hepatitis C (HCV) genotype 3.  Previously, HCV genotype 3 was considered easy-to-treat with pegylated interferon and ribavirin.  Along with genotype 2, treatment for genotype 3 was given for half the duration as treatment for genotype 1; in addition, the response was much better than genotype 1 (~70-80% compared with ~50%).

With new treatments, the situation has changed.  In the U.S., genotype 1 accounts for about 70% of all infections and worldwide about 60% of all HCV infections.  In contrast, genotype 3 accounts for 10-15% of the world HCV reservoir.

Specific problems (alluded to by the authors) with genotype 3:

  • Increased steatosis
  • Increased liver fibrosis progression
  • Increased risk of hepatocellular carcinoma (HCC)
  • Increased risk of end-stage liver disease
  • Reduced sustained virological response (SVR) after direct-acting antiviral therapies

While the newest therapies have dramatically increased SVR rates for genotype 1 and improved treatment for genotype 2, this is not the case with genotype 3 thus far.  Instead of being a good genotype, genotype 3 is now a villain.

Another article provides additional data on HCV genotype 3 (Hepatology 2014; 60: 98-105).  In this study of U.S. Veterans with HCV (n=110,484), there were 8,337 with genotype 3.  In this group, despite being younger, they had a higher risk of cirrhosis (HR 1.40) and hepatocellular carcinoma (HCC) (HR 1.66) in comparison to HCV genotype 1.

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Probiotics for Hepatic Encephalopathy

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A recent open-label, randomized prospective study (Clin Gastroenterol Hepatol 2014; 12: 1003-08) indicates that probiotics (VSL#3) can be effective as primary prophylaxis of hepatic encephalopathy (HE) in at risk patients with cirrhosis.

While cirrhosis-related HE is an uncommon problem in pediatric gastroenterology/hepatology, there are few effective therapeutic options.  This study randomly assigned the 160 patients to groups given probiotics three times daily or to controls (no test article).  These patients were studied extensively including psychometric analysis, glucose hydrogen breath tests, critical flicker fusion, and lactulose hydrogen breath tests to assess orocecal transit time.

Key result: Three months of probiotics reduced HE scores.  Seven probiotic subjects developed overt HE which was significantly lower than the 14 patients in the control group (P<.05).

Bottomline: Probiotics may reduce the development of overt HE in patients with cirrhosis.

Does Chemotherapy Cause Hepatitis C Viral Relapse?

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A recent study (Clin Gastroenterol Hepatol 2014; 12: 1051-54) examined whether a sustained virological response (SVR) to hepatitis C (HCV)can be undermined by chemotherapy.

In this study with 30 patients who had an SVR before cancer diagnosis, chemotherapy, started at a median of 72 months after SVR, did not induce a viral relapse in any patient.

 

The Future is Now (for Hepatitis C)

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Three more impressive hepatitis C (HCV) studies have been published (in print):

  1. NEJM 2014; 370: 1973-82
  2. NEJM 2014; 370: 1983-92
  3. NEJM 2014; 370: 1993-2001

In the commentary on these three studies (pages 2043-47), the authors note that only a year ago, they had “speculated that highly effective interferon-free regimens would be available and should revolutionize the treatment of HCV infection…Now, we would have to say that the future is here.”

In the first study, “TURQUOISE-II,” 380 patients with Child-Pugh class A cirrhosis received either 12 weeks or 24 weeks of ritonavir (ABT-450/r), ombitasvir (ABT-267), dasabuvir (ABT-333) and ribavirin.  In the 12 week group, the sustained virologic response (SVR) was 91.8% whereas the 24 week group had an SVR of 95.9%.

In the second study, “PEARL-III and PEARL-IV,” 419 patients with genotype Ib and 305 patients with genotype 1a received 12 weeks of ritonavir, ombitasvir, dasavuvir, and ribavirin (or placebo) for 12 weeks.  For genotype 1b, SVR were 99.5% with ribavirin and 99% without ribavirin.  For genotype 1a, SVR were 97% and 90.2% respectively.

In the third study, “VALENCE,” among 419 patients with genotype 2 or 3 (21% with cirrhosis, and 58% previous interferon-based treatment), patients were treated with sofusbuvir-ribavirin or placebo for 12 weeks; the genotype 3 patients treatment was extended to 24 weeks (unblinded) after data emerged indicating a need for longer treatment course.  For the genotype 2 patients, SVR was met in 93%.  For genotype 3 patients, 85% who received a 24 week course had an SVR.

Key Points (from editorial):

  • In the first two studies, SVR was approximately 96% in untreated and treated patients without cirrhosis.
  • Patients with cirrhosis had a response rate of approximately 90%.
  • Ethnicity, IL28B, and baseline HCV RNA were not important factors in predicting response.
  • “In the era of potent DAA (direct-acting antivirals), …response-guided therapy is no longer necessary” because by week 4 of treatment, 99% of patients had non-quantifiable HCV RNA.
  • Drug resistance against these DAAs is common in preclinical studies; therefore, combination regimens are important.  “In the case of sofosbuvir and ledipasvir, a two-drug combination is sufficient…Sofosbuvir seems to have a high genetic barrier to resistance.”
  • “Perhaps the more important achievement of these interferon-free regimens is the lower rate and severity of side effects.”

Related (recent) blog posts:

Treating HCV Helps Diabetics

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There is more data confirming that HCV treatment helps diabetic patients (Hepatology 2014; 59: 1293-1302).

Using a large National Health Insurance Research Database with more than 2.2 million Taiwanese residents diagnosed with diabetes, the authors were able to identiy 1411 HCV-treated patients, 1411 untreated patients, and 5644 uninfected/untreated controls.

Key results:

The risk of end-stage renal disease (ESRD), ischemic stroke and acute coronary syndrome (ACS) were all lower in the HCV-treated patients compared to untreated patients and compared to uninfected/untreated controls:

  • 84% reduction in the risk of ESRD
  • 47% reduction in the risk of ischemic stroke
  • 36% reduction in the risk of ACS

Why does HCV treatment reduce these diabetic complications? While the mechanisms have not been fully elucidated, it is “most likely mediated via viral clearance” which subsequently improves insulin resistance.

While this study has several limitations inherent to a study using a database, the design took efforts to minimize bias and confounding.

HCV Treatments: “Sticker Shock” or “Low Value”

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Two more commentaries/articles on hepatitis C virus treatments help with the perspective of cost.

In the first (Hepatology 2014; 59: 1246-49), the authors note that costs with HCV treatment have escalated along with improvements in SVR rates.  And, though the new 12-week therapy costs will exceed $84,000, they point out that current total cost of “therapy to achieve SVR…including management of complications, the price of treatment actually increases to $172,889 to $188,859 per SVR.”  They also note that HIV therapy averages $2000-$5000 a month and due to lifelong need, this exceeds more than one-half million dollars in treatment cost.  In addition, they note that gents like interferon have side effects that can be life-threatening. “Still, it remains unanswered if the new [HCV] agents are worth their price.”

In the second from GI Hep News, Panel calls new hepatitis C drug ‘low value.’

Here is an excerpt:

A panel of California medical experts says two new, once-daily drugs for hepatitis C represent low-value treatment alternatives for the condition because of their high price tags.

The drugs, Gilead Sciences’ sofosbuvir (Sovaldi) and Johnson & Johnson’s simeprevir (Olysio), cost more than $1,000 per pill, pushing the price for the recommended 12-week course of treatment of sofosbuvir to close to $90,000 and treatment with simeprevir to around $66,000, according to the California Technology Assessment Forum (CTAF), an independent group originally convened by the insurance industry to evaluate costs and benefits of treatments….

Replacing current care with sofosbuvir-based regimens would increase drug expenditures by $18-$29 billion per year in California alone, the report estimated. Gilead Sciences has maintained that the drug’s up-front costs are justified given that it could decrease the number of patients who ultimately suffer liver failure and need transplants. However, CTAF said it would take 20 years for payers to recoup two-thirds of the drug’s cost.

Take-home message: The newest and best HCV treatments are costly.  These drugs may really boost medical tourism where these drugs will be sold a lot more cheaply.

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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.

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