Tag Archives: telaprevir

Telaprevir-Based HCV Therapy is Expensive Too

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With the arrival of newer expensive hepatitis C virus (HCV) therapies, there has been an effort to prove that the costs are within reason.  One study (Hepatology 2014; 60: 1187-95) looking at this issue examines the cost of a sustained virological response (SVR) with the previous best therapy: Telaprevir-Based Triple Therapy.

Design: Records from 147 patients who received telaprevir-based triple therapy in 2011 were reviewed.

According to the authors (supported by Gilead Sciences), median cost of care was $83,721 per patient and the median cost per SVR was $189,338.  The costs of two of the drugs, telaprevir and pegylated interferon, accounted for 85% of the total costs.  Other costs included adverse management (8%), ribavirin (4%), professional fees (2%), and laboratory fees (1%).

The main reason besides pharmaceutical prices for the high costs were the SVR rate of 44%.

Bottomline: If a patient requires HCV therapy, the newer, more effective, expensive agents are likely to compare favorably with the less new, less effective, expensive medications.

Related blog posts:

Also noted: Hepatology 2014; 60: 1211-21.  “WELCOME” Study tested whether 15-18 months of docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) decreased liver fat and histology in nonalcoholic fatty liver disease (NAFLD). n=101, with 51 in treatment group. Findings the DHA+EPA had a “trend toward improvement in liver fat” percentage but no improvement in fibrosis.

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.

 

 

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

The cost of progress in treating Hepatitis C

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Background information on Hepatitis C (HCV):

  • —170 million people worldwide infected with HCV, 2.7 milllion people in U.S. infected
  • —27% of worldwide cases of cirrhosis are due to HCV
  • —25% of cases of hepatocellular carcinoma are due to HCV
  • —Established treatment with pegylated interferon (PEG IFN) and ribavirin have ~40% response rates in genotype 1 (74% of HCV in U.S.) and relapses are not uncommon among responders

New treatments for Hepatitis C (in combination with previous treatments):

  • —Two new drugs: Boceprevir (BOC) & Telaprevir (TVR)
  • —Overall sustained viral response (SVR) with BOC combination 63-66% vs 73-79% with TVR combination treatment
  • —Both trials demonstrate marked improvement over previous
  • Mechanism of action: —Protease inhibitor binding to NS3 HCV target
  • —BOC: Wholesale cost $1100/week (20-44 weeks)
  • —TVR: 12weeks cost: $49,000
Previous treatments for hepatitis C typically cost about $5000 per month (http://www.familydrugguide.com/family/ub/view/Consumer_Reports_Health/526033/4/hepatitis_c_drugs).  The addition of these newer drugs could add another $50,000 to the cost of treatment.  In some cases which respond well to the newer treatments, shorter treatment periods will lower the increase in cost.  Although these drugs are expensive, they may be lifesaving and may obviate the need for liver transplantation.  Due to the potential complications of HCV, more medications are in the pipeline.  They may be easier to take but are likely to be expensive as well.  The safety & effectiveness of these medications have not been demonstrated in published pediatric studies.
Article References:
  • Hepatology 2011; 54: 1433.  Updated AASLD HCV treatment guidelines
  • NEJM 2011; 364: 1195-206, Editorial pg. 1272. Addition of boceprevir, in 1097 previously untreated pts increased SVR. In whites, 40%–>67% & in blacks from 23% –>42%. Medication given after lead-in of 4 weeks. More frequent anemia in boceprevir-treated patients (SPRINT-2 study).Boceprevir dosing: 800mg (4 capsules) TID with food. (trying to space out doses evenly).
  • NEJM 2011; 365: 1014. n=540. Telaprevir study: extended SVR 72%. In pts with rapid viral response (RVR) at 4 & 12 weeks (no detectable HCV), Telaprevir12weeksPegRbv24 was as effective as Telprevir12weeksPegRbv48. Dosing for study: Teleprevir 750mg TID, PEGalfa-2a 180mcg/wk, RBV1-1.2gm per day.  Rash in 37% (severe in 5%), anemia in 39% (severe in 6%).
  • NEJM 2011; 364: 2405, 2417, 2429 (review). Telaprevir addition:  up to 75% response in HCV genotype 1 pts. n=1095 in 1st study, n=833 in 2nd study (re-treatment study)
  • Gastroenterology 2011; 140: 746. Summary of results of boceprevir (used with IFN -alfa 2b 1.5/kg) & telaprevir (used with IFN -alfa 2a 180mcg). “Similar effectiveness” thus far. Telaprevir used for 12 weeks without lead-in period.  TVR: most frequent problem -rash & then anemia.  In practice, dosing in adults: Telaprevir will be used at 750mg TID in combination with IFN-2a 180mcg & RBV 1-1.2g/d. & used for 1st 12 weeks of Rx. This will allow ~50% of patients to have shorter Rx duration:  if HCV RNA RVR –>24week total vs 48week total in those w/o RVR.  Both drugs best for genotype 1.