June 15, 2014

A Home Run for Hepatitis C Treatment

Medscape Gastroenterology

Digestive Disease Week (DDW) 2014

William F. Balistreri, MD

June 05, 2014

HCV Antivirals: You Can't Tell the Players Without a Program

The rosters change almost daily, and new leaders emerge as the statistics accumulate rapidly. No, I am not referring to Major League Baseball; I am talking about antiviral agents used to treat hepatitis C virus (HCV) infection.

The past year has already seen the approval of new direct-acting agents and a change in recommendations.[1] And now, data from recent clinical trials have generated further excitement and promise -- that in the year of the 25th anniversary of its discovery, HCV can be cured.

At Digestive Disease Week (DDW) 2014, investigators updated attendees on the pace of progress in the discovery and validation of novel antivirals. The bottom line is that clinicians will soon have the option of using all-oral, interferon-free regimens that are highly effective against all HCV genotypes in all patients -- with "special population" designations no longer needed. There are clearly logistical details that will prove to be unique to each treatment regimen, and perhaps genotype-specific; however, these will be resolved with broader experience.

A Future Without Hepatitis C

But first, let's look at the not-so-distant past. An analysis presented at DDW indicates that overall treatment rates for patients with chronic HCV have been "dismally poor" and that treatment completion of both dual- and triple-therapy regimens -- pegylated interferon (pegIFN) and ribavirin (RBV) with or without a protease inhibitor, telaprevir or boceprevir -- is suboptimal in the real-world clinical setting.[2]

This comes at a high cost. Hasan and colleagues[3] reported that the cost of curing HCV genotype 1 with the triple-drug regimen was $125,000-$154,000. This estimate includes the associated costs of utilization of provider services, prescriptions, over-the-counter drug use, laboratory tests, and hospitalizations. These data indicate the need for simpler, safer, less expensive, and more effective options.

In the past month, a series of articles was published in the New England Journal of Medicine describing several new and different regimens. These strategies, based on an improved understanding of the HCV life cycle, have consistently produced rates of sustained viral response (SVR) of more than 90% after brief (8-24 weeks) periods of administration.

Accompanying editorials attest to the impact of these advances in treatment efficacy and safety, while highlighting the challenges presented by these "breakthrough medications." Chung and Baumert[4] state that "it may now be possible to imagine the global eradication of HCV infection"; however, they cite the need for early diagnosis and cost reduction, especially in low-income countries.

Jayasekera and colleagues[5] and Hoofnagle and colleagues[6] project that the use of these new agents will reduce the intensity of follow-up monitoring; the rate of hospitalizations for adverse effects; dependence on specialist care; and resource demands associated with disease progression, including those for liver transplantation and management of end-stage liver disease and liver cancer. However, with drug costs that may exceed $90,000 per course, it remains to be seen how these remarkable advances will extend to the estimated 150 million people with HCV infection living outside the targeted high-income markets for these agents.

Barriers to Care

Access to these medications is limited by case recognition. Recent recommendations for birth-cohort screening for HCV infection among US adults are predicated upon the belief that only a fraction of Americans with the infection has been diagnosed.

On the basis of data generated from a community-wide HCV screening project and a registry of known HCV patients, Kim and colleagues[7] calculated the proportion of more than 21,000 community residents with undiagnosed HCV infection. The overall prevalence was 2.2%; the age- and sex-specific HCV prevalence was highest (3.3%) in men aged 35-39 years and 45-49 years and lowest (1.0%) in women aged 30-34 years. Most had not been diagnosed.

These data support community-wide programs to institute birth-cohort-based screening as well as appropriate risk-based screening in individuals outside the birth cohort.

Antiviral Agents Soon to be Available

Although the results of multiple recent clinical trials have been reported, we will be unable to discuss all of the agents, studies, combinations, and screening and administration issues. I will therefore highlight a few strategies that have emerged.

Sofosbuvir-Based Regimens

Sofosbuvir (SOF) is a HCV NS5B nucleotide polymerase inhibitor. Several studies have demonstrated high SVR rates in patients with genotypes 1-6 infection treated with SOF combined with RBV with or without pegIFN for 12 or 24 weeks. High efficacy rates were demonstrated across many patient subtypes, including those considered difficult to treat (eg, HIV/HCV coinfection, treatment-experienced patients, and those with cirrhosis).

Many presentations at DDW 2014 described the efficacy and safety of SOF -- often used in combination with ledipasvir (LDV) -- without pegIFN. Subtle differences in response rates and ideal duration of therapy according to genotype were also reported, and these will ultimately be codified in guidelines.

Jacobson and colleagues[8] reported that the fixed-dose (single tablet) combination of SOF 400 mg/LDV 90 mg administered once daily for 12 weeks was highly effective and well tolerated in treatment-naive patients infected with HCV genotype 1, including those with cirrhosis. The addition of RBV did not enhance the SVR rate.

Kowdley and colleagues[9] reported that 8-week treatment with the fixed-dose combination regimen of SOF/LDV, with or without RBV, produced SVRs similar to those achieved with a 12-week regimen in noncirrhotic, previously untreated patients infected with HCV genotype 1.

Phase 3 studies[10] of SOF-based regimens have demonstrated high efficacy of this combination across genotypes, even in patients with multiple traditional negative predictors of diminished efficacy. SVR rates were somewhat lower in patients who had negative predictors; therefore, strategies focusing on addressing these hardest-to-cure populations may be required.

Patients who are considered more difficult to treat owing to advanced liver disease, genotype 3 infection, or previous treatment failure were studied by Gane and colleagues.[11] They reported that regimens involving SOF/LDV with or without RBV were efficacious in patients with more advanced liver disease and in those with previous treatment failure. In patients infected with the difficult-to-treat HCV genotype 3, the addition of RBV to SOF/LDV enhanced the SVR rate. The regimen was generally safe and well tolerated, with no additional safety issues in patients with decompensated liver disease.

Kwo and colleagues[12] reported that the SOF/LDV fixed-dose combination tablet can effectively be used to treat a population of treatment-experienced patients with HCV genotype 1 infection. The addition of RBV to the treatment, or extending the treatment from 12 weeks to 24 weeks, did not significantly increase the final SVR12 rates. Adverse events and laboratory abnormalities were more common in recipients of SOF/LDV with RBV and consistent with the safety profile of RBV.

Two additional studies documented successful retreatment.[13,14] In particular, the study reported by Nyberg and colleagues[14] included patients infected with HCV genotype 2 and genotype 3 in whom treatment had previously failed. Overall SVR rates were 100% for genotype 2-infected patients and 96% for genotype 3-infected patients after retreatment with SOF regimens for a longer duration.

Safety profile. In all of these clinical trials of SOF-containing regimens, adverse events and laboratory abnormalities were more common with pegIFN- or RBV-containing regimens, and SOF did not contribute to the frequency or severity of these expected events. Gordon and colleagues[15] also observed low rates of treatment discontinuation and no duration-related side effects.

Sofosbuvir was approved by the US Food and Drug Administration (FDA) in December 2013 for clinical use in the United States. Ledipasvir is not FDA-approved. On the basis of projections from Markov modeling and compared with current treatment regimens, sofosbuvir-based regimens should yield good future health outcomes and less liver disease complications and deaths across all genotypes, levels of treatment experience, severity stage, and coinfection status.[16]

ABT-Based Regimen

AbbVie's (North Chicago, Illinois) investigational HCV regimen consists of the following fixed-dose combination:

  • ABT-450 (an HCV NS3/4A protease inhibitor), 150 mg dosed with ritonavir 100 mg daily (ABT-450/r);

  • ABT-267 (a nonnucleoside NS5A inhibitor), 25 mg daily (ombitasvir); and

  • ABT-333 (a NS5B RNA polymerase inhibitor), 250 mg twice daily (dasabuvir).

This 3-drug (3D) regimen is administered with or without weight-based RBV. The multitargeted antiviral combination with 3 different mechanisms of action interrupts the HCV replication process, with the goal of optimizing SVR rates across different patient populations.

At DDW 2014, several investigators presented the results of clinical trials of this regimen. Kowdley and colleagues[17] conducted a double-blind, placebo-controlled study in noncirrhotic, treatment-naive patients with chronic HCV genotype 1 infection. Patients were randomly assigned to receive the coformulated 3D regimen or matching placebo for 12 weeks.

The intention-to-treat SVR12 rate for active drug recipients was 96%; on-treatment failure and post-treatment relapse occurred in 0.2% and 1.5% of patients, respectively. The most common treatment-emergent adverse events were fatigue and headache (approximately 30% each); discontinuation as a result of these events occurred in 0.6% of patients in each arm.

The interferon-free, 12-week 3D regimen was also effective in noncirrhotic, treatment-experienced, genotype 1-infected patients, a group typically associated with the lowest response rates.[18] The 3D plus RBV regimen led to an SVR12 of 96%.

Andreone and colleagues[19] also reported that a 12-week regimen of ABT 450/r/ABT-267 and ABT-333 with or without RBV achieved high rates of SVR12 (97% with 3D plus RBV, and 100% with 3D alone) in treatment-experienced patients. The regimen was generally well tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events.

In a phase 3 study of an all-oral, interferon-free regimen exclusively in HCV genotype 1-infected patients with compensated cirrhosis, treatment with 3D and RBV resulted in high rates (92%-96%) of SVR12 in both the 12- and 24-week treatment arms.[20]

This highly effective, well-tolerated, 3D HCV regimen is under FDA review.

Other Regimens

Another all-oral, ribavirin-free, interferon-free combination of 3 direct-acting agents -- daclatasvir (an NS5A inhibitor), asunaprevir (an NS3 inhibitor), and BMS-791325 (a nonnucleoside NS5B inhibitor) -- was shown to induce SVR12 in 92% of treatment-naive patients with chronic HCV genotype 1 infection.

Hassanein and colleagues[21] report that 12 weeks of the all-oral treatment combination achieved SVR12 in all noncirrhotic patients with genotype 4 infection, with no virologic failures. These results extend the potent antiviral activity of this regimen to patients with HCV genotype 4 infection, while maintaining the positive tolerability and safety profile documented previously in patients infected with genotype 1. The investigators state that the rapid attainment of SVR suggests that perhaps an even shorter duration of therapy or elimination of 1 of the agents in the combination may be as efficacious.

This regimen is not FDA approved.

Enhancing the Outcome

It was reported that statin use is associated with SVR in patients with HCV treated with pegIFN and RBV, independent of host metabolic factors.

Sanchez and colleagues[22] used the Veterans' Affairs Clinical Case Registry to conduct a retrospective cohort study of veterans infected with HCV genotypes 1, 2, and 3 who received treatment between 2002 and 2008. They found that continuous statin use was associated with increased SVR that persisted after adjustment for age, race, sex, body mass index, genotype, diabetes, hypertension, fibrosis, and high-density lipoprotein and low-density lipoprotein cholesterol levels. Although the mechanism responsible for this observation was not defined, it is known that statins have antiproliferative, antiangiogenic, and anti-inflammatory effects on hepatic cells.

Further studies are warranted to explore whether statin use will significantly reduce progression of liver fibrosis in patients with advanced chronic HCV infection treated with the new antiviral regimens.

A Final Note

Coffee drinking has been associated with a reduced risk for progression to cirrhosis and hepatocellular carcinoma. The mechanism is unclear, but caffeine has been proposed to have antifibrotic and antineoplastic effects.

Among HCV-infected veterans, overall coffee intake (but not decaffeinated coffee intake) was inversely associated with advanced fibrosis.[23] Coffee intake was higher in those with mild fibrosis compared with advanced fibrosis, although none of the comparisons were significant because of the sample sizes. In multivariate analysis adjusting for age, diabetes, alcohol use, obesity, and soda consumption, the inverse association between the number of daily cups of coffee and advanced fibrosis persisted.

So, have a cup of coffee -- it will help us to stay alert as we wade though the continually emerging and voluminous, yet exciting, data on the cure of HCV infection. We eagerly await the next inning.

References

1. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ Accessed May 25, 2014.

2. Vutien P, Kim Y, Brooks L, Livornese R, Nguyen MH. Low treatment rates and suboptimal treatment completion rates to hepatitis C virus (HCV) therapy: a real-world analysis of a large US cohort. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 648.

3. Hasan SS, Sears DM, Lorden AL. A real world analysis of the cost of current HCV treatment. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 377

4. Chung RT, Baumert TF. Curing chronic hepatitis C -- the arc of a medical triumph. N Engl J Med. 2014;370:1576-1578.

5. Jayasekera CR, Barry M, Roberts LR, Nguyen MH. Treating hepatitis C in lower-income countries. N Engl J Med. 2014;370:1869-1871.

6. Hoofnagle JH, Sherker AH. Therapy for hepatitis C -- the costs of success. N Engl J Med. 2014;370:1552-1553.

7. Kim WR, Wi CI, Larson JJ, Yawn BP, Yao JD, Therneau TM. The tip of an iceberg -- who is known to have hepatitis C? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1028.

8. Jacobson IM, Marcellin P, Mangia A, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-naive genotype 1 HCV-infected patients: the phase 3 ION-1 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2038.

9. Kowdley KV, Gordon SC, Reddy KR, et al. Sofosbuvir/ledipasvir with and without ribavirin for 8 weeks compared to sofosbuvir/ledipasvir for 12 weeks in treatment-naive non-cirrhotic genotype 1 HCV-infected patients: the phase 3 ION-3 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 764.

10. Jacobson IM, Christensen C, Conway B, et al. Sofosbuvir-based regimens are associated with high SVR rates across genotypes among patients with multiple negative predictive factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 647.

11. Gane E, Hyland RH, Pang P, Symonds WT, McHutchison JG, Stedman CA. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in HCV infected populations including decompensated patients and patients with prior sofosbuvir treatment experience. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 238.

12. Kwo PY, Reddy KR, Pockros PJ, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-experienced genotype 1 HCV-infected patients: the phase 3 ION-2 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 236.

13. Jacobson IM, Sulkowski M, Hassanein T, et al. Successful retreatment of HCV genotype-1 infected patients who failed prior therapy with peginterferon + ribavirin plus 1 or 2 other direct-acting antiviral agents with sofosbuvir. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 237.

14. Nyberg LM, Lalezari J, Ni L, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 239.

15. Gordon SC, Towner W, Aggarval A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 650.

16. Saab S, Gordon SC, Park H, Ahmed A, Younossi ZM. A decision analytic Markov model to evaluate the health outcomes of sofosbuvir for previously untreated patients and those without treatment options with chronic hepatitis C virus. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 474.

17. Kowdley KV, Feld JJ, Coakley E, et al. SAPPHIRE I: phase 3 placebo-controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 631 treatment-naive adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 475.

18. acobson IM, Zeuzem S, Baykal T, et al. SAPPHIRE II: phase 3 placebo- controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 394 treatment-experienced adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 235.

19. Andreone P, Colombo M, Enejosa JV, et al. PEARL II: randomized phase 3 trial of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333 with or without ribavirin in hepatitis C virus genotype 1b-infected, treatment-experienced patients. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 929e.

20. Kowdley K, Poordad F, Trinh R, et al. TURQUOISE-II: SVR12 rates of 92%-96% in 380 hepatitis C virus genotype 1-infected adults with compensated cirrhosis treated with ABT-450/r/ABT-267 and ABT-333 plus ribavirin (3D+RBV). Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2039.

21. Hassanein T, Everson GT, Sims K, et al. All-oral therapy with daclatasvir in combination with asunaprevir and Bms-791325 for treatment-naive patients with chronic HCV genotype 4 infection. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 763.

22. Sanchez MJ, Augustin S, Balakrishnan M, Lo Re V, Tate JP, Garcia-Tsao G. Statin use is associated with sustained virological response in patients with hepatitis C treated with pegylated interferon and ribavirin, independent of host metabolic factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1050.

23. El-Serag H, Kuzniarek J, Ransey DJ, Tabasi ST, White DL, Kanwal F. Beverage intake and the risk of advanced fibrosis in HCV: coffee, tea, or soda? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 775.

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