Tag Archives: direct-acting antivirals

An “Ally” For Hepatitis C Genotype 3

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A new study (Hepatology 2015; 61: 1127-35) shows that an all-oral 12 week treatment of daclatasvir (DCV) with sofosbuvir (SOF) is effective in the difficult-to-treat Hepatitis C virus (HCV) genotype 3 patients. In this study, the “Ally-3” phase III study, 101 treatment-naïve and 51 treatment experienced patients were treated with a daily regimen of DCV 60 mg and SOF 400 mg.

Key findings:

  • SVR12 was 90% in treatment-naïve, and 86% among in treatment experienced.
  • Among patients without cirrhosis, the SVR12 was 96%, compared with 63% of those with cirrhosis (based on FibroTest scores)

Related blog posts:

Bottomline: This new regimen is a promising addition to the new crop of HCV drugs which will be affordable when?

A second study (Hepatology 2015; 61: 1174-82) examined the minimum target pricing for direct-acting antivirals (DAA) for HCV.  Using data on manufacturing costs, derived in large part from experience with HIV antivirals, the authors calculate that a minimum cost for a 12-week course of combination DAA could be US $171-360 per person without genotyping and the drug costs alone from US $122-192 per person.  Of course, these costs are completely theoretical and complete fantasy, at least until 2027 when some of the patents expire.

Related post: HCV Treatments: “Sticker Shock” or “Low Value …

Briefly noted: Hepatology 2015; 61: 1261-68.  N=986 Koreans with HBsAg carrier status and 40 years of age or older.  FIB-4 is highly predictive of hepatocellular carcinoma (HCC) risk in those with chronic hepatitis B. FIB-4 was defined based on age x AST , PLTS, and ALT.  Since a high FIB-4 reflects liver fibrosis, it is not unexpected that high levels were associated with HCC. A FIB-4 >/= 2.4 showed an adjusted Hazard Ratio of 21.34.

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.

Related blog posts:

 

Understanding IL28B

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Interleukin-28B (IL28B) has been a phenomenal discovery in the field of hepatitis C (HCV); yet, with the emergence of direct-acting antiviral (DAA) agents, its importance has been overshadowed.  While the long-term significance of IL28B is unclear, for now, it has significant clinical utility.  Three reviews/commentaries help elucidate its role:

▪                Hepatology 2012; 56: 361-66. IL 28B Genetics and Biology

▪                Hepatology 2012; 56: 367-372 Clinical Utility of IL28B

▪                Hepatology 2012; 56:  373-380 Relevance of IL28B in age of DAAs

Key points from these references:

African-Americans are less likely to respond to treatment with pegylated interferon (PEGIFN) (and ribavirin [RBV]) in large part due to a low frequency of favorable alleles (C/C genotype) to IL28B.

Predictors of response to treatment with PEGIFN/RBV:

▪                CC IL28B genotype: OR 5.9 (compared to non-CC genotype)

▪                HCV RNA level ≤600,000 IU/mL: OR 3.1 (compared to >600,000 IU/mL)

▪                Degree of fibrosis, metavir F0-2: OR 2.7 (compared with F3-F4)

▪                Rapid virological response: OR 9.1 (compared with non-RVR non CC genotype)

Overall CC genotype is associated with double the sustained virological response (SVR).

Vitamin D also plays an important role in innate immunity and deficiency is associated with lower SVR.

Algorithm for use of IL28B (applicable to patients ≥18 years):

▪                Consider obtaining IL28B in all genotype 1 patients:  

▪                If CC genotype and does not have risk factors for poor response (including cirrhosis, high viral load), then likely to treat with PEGIFN/RBV and monitor for RVR.  In patients without RVR, addition of DAA would be reasonable.

▪                If risk factors for poor response or if non-CC genotype (C/T or T/T), then consider use of DAA at onset of therapy

DAAs are expensive.  Boceprevir (BOC) costs $26,000 for 24 weeks & $48,000 for 44 weeks.  Telaprevir (TVR) costs $49,000 for 12 weeks.  These costs are in addition to costs for PEGIFN/RBV which is approximately $30,000.  The cost of testing IL28B status is approximately $300.

In patients with CC IL28B genotype, the main advantage of DAAs may be to shorten treatment course by increasing the likelihood of RVR; though with TVR, the SVR was improved even among CC genotype patients in the “ADVANCE” trial (90% compared with 64%).  In non-CC IL28B genotype, TVR or BOC is associated with > 2-fold increase in SVR.  The specific response rates for both TVR and BOC are available in these references.

Related blog entries

Pediatric HCV Guidelines

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Curing Hepatitis C without interferon

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In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble