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  ID Week
Oct 8-12 2014
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HCV at ID Week 2014
  October 8-12, Philadelphia, PA
David H Shepp, MD
Associate Professor of Medicine
Hofstra-North Shore LIJ School of Medicine
NS5a Inhibitors. No area of medical therapeutics is changing more rapidly than treatment of HCV. Interferon-based therapy has been the standard of care for many years, first alone, then in combination with ribavirin, and for the past several years in combination with both ribavirin and a single directly acting antiviral (DDA). In the past year, interferon-free options became possible for some patients by combining the nucleotide polymerase inhibitor sofosbuvir with either ribavirin or the second generation protease inhibitor simeprevir, although access to treatment has been restricted due to the extraordinarily high cost of these new agents. The next phase of HCV treatment begins now with the introduction of agents in the very potent NS5a inhibitor class into clinical practice. Studies using NS5a inhibitor-containing regimens were presented during ID Week.
Patients with HCV-related cirrhosis and those who previously failed interferon-based therapy are at higher risk to fail retreatment with interferon, ribavirin plus a directly acting antiviral (DAA). A pooled analysis of 3 previously published studies demonstrated that the two-drug combination of sofosbuvir, a nucleotide polymerase inhibitor and ledipasvir, an NS5a inhibitor is similarly active in both of these hard to treat patient groups [1]. The combined analysis of the ION-1, 2 and 3 studies [2,3,4] included 1952 genotype (GT) 1-infected participants; 224 (16%) had compensated cirrhosis (Child-Pugh class A) and 231 had failed interferon-based therapy. Treatment was given for 8, 12 or 24 weeks with and without ribavirin, although the 8 week study arm did not enroll cirrhotics. Sustained virologic response at 12 weeks (SVR12) was achieved in 92-99% in all subgroups except those who were both treatment-experienced and cirrhotic, who did best with 24 weeks of treatment. The comparison of 8 and 12 weeks of therapy showed similar SVR12 rates (94 and 96%). More treatment failures due to viral relapse were seen with the shorter duration (5% vs 1%) and relapse was more common with high baseline HCV RNA levels. Among those with baseline RNA ≥6 million relapses rate was 10% and 1% with 8 and 12 weeks of treatment, respectively. When <6 million, the relapse rate was 2% with either duration. Addition of ribavirin did not improve responses in any subset.
Shortly before the presentation, the FDA approved the fixed dose combination of these two drugs (Harvoni, Gilead Sciences) to treat HCV GT 1 infection. Ledipasivir thus becomes the first drug in the NS5a inhibitor class to be approved. The combination provides a one tablet once daily interferon and ribavirin free regimen that can cure HCV GT1 infection in as little as 8 weeks for either treatment naive or experienced patients without cirrhosis and HCV RNA <6 million, and 12 weeks for those with cirrhosis or an HCV RNA ≥6 million. Twenty-four weeks of treatment appears to provides optimal treatment for those who are both treatment-experience and cirrhotic.
A pooled analysis of two previously published [5,6] phase 3 studies of an investigational, interferon-free, multi-drug, NS5a inhibitor-containing regimen was undertaken to identify correlates of treatment failure [7]. Non-cirrhotic, GT1 patients who were either treatment-naive or interferon/ribavirin experienced received ombitasvir, an NS5a inhibitor, ABT-450, an HCV protease inhibitor boosted with ritonavir, dasabuvir, a non-nucleoside polymerase inhibitor ("3D" regimen) & ribavirin for 12 weeks. SVR12 was achieved in 96% of 770 patients. The only factor associated with a small but statistically significant difference in SVR12 rate was BMI ≥30 (92% vs. 97% for BMI <30). Prior treatment experience, age, gender, IL28B genotype, baseline HCV RNA, fibrosis stage and GT 1 subtype had no significant effect on response. The lack of statistical correlates of treatment failure is not surprising given the very small number of treatment failures with this regimen.The analysis did not include patients with cirrhosis and in fact, the study population was heavily skewed toward patients with little fibrosis (73% F0-1). Other studies have shown that the efficacy of 3D & ribavirin improves slightly from 89 to 94% in patients with compensated cirrhosis and GT 1a when treatment is extended to 24 weeks [8] and that the addition of ribavirin to 3D is not necessary for treatment naive, non-cirrhotic GT 1b patients [9]. Symptomatic adverse events such as headache nausea, pruritis, fatigue, insomnia, weakness and diarrhea all were reported somewhat more often in those on 3D & ribavirin compared to a group taking placebos for 12 weeks before receiving active treatment. Importantly, ALT and AST elevations were less common in those on active drug, while 2.5% on the active regimen had grade 3/4 bilirubin elevation due to inhibition of the bilirubin transporter OATP1B1 by ABT-450. FDA approval of this novel multi-drug regimen is anticipated in the near future.
Another NS5a inhibitor likely to receive FDA approval in the near future is daclatasvir. Daclatasvir has clinically important activity against all HCV genotypes. Posters describing use of daclatasvir with interferon and ribavirin for treatment of GT1b [10] and 4 [11], and in combination with the HCV protease inhibitors asunaprevir for GT 1b [12] were presented. This latter interferon-free strategy targeted to GT 1b will not be developed further, and going forward, use of daclatasvir with interferon will bemuch less desirable than use of interferon free regimens. Ongoing phase 3 studies of daclatasvir with other DAAs should demonstrate preferred ways to use of this very promising agent. Importantly, a pharmacokinetic study showed no interaction of daclatasvir with methadone or buprenorphine [13].
Understanding Viral Relapse. Interferon-free regimens that combine high potency and a high genetic barrier to resistance are capable of rapidly suppressing HCV replication to undetectable levels in essentially all adherent patients, and will result in SVR rates in the range of 90% or more. Treatment failures are uncommon but result from viral relapse after completion of the prescribed duration of therapy. The factors that lead to relapse are not yet well defined. To understand the mechanisms underlying cure and relapse and potentially develop potential markers of relapse that would allow additional treatment targeted to those at greatest risk, investigators at the NIH assessed levels of interferon pathway gene expression in liver biopsies [14] in patients with HCV GT1 infection who were treated with sofosbuvir & ribavirin for 24 weeks in a previously published trial [15]. Sofosbuvir & ribavirin is currently considered an alternate regimen for patients with GT1 who cannot tolerate interferon, and does not result in optimal SVR rates. Paired biopsies were available in 25 study participants. All had undetectable HCV RNA at end of treatment; 18 had SVR and 7 relapsed. Intrahepatic levels of numerous interferon-stimulated genes were elevated before treatment and declined by end-of-treatment. Expression of genes for type II and III interferons also declined but in some patients, genes of interferon alpha 2 (a type I interferon) were induced. Those with SVR had significantly higher levels than those who relapsed. This finding suggests induction of interferon alpha may play a critical role in preventing HCV relapse and failure of this component of host innate immunity may identify patients at risk for relapse who may benefit from additional interventions or longer duration of therapy. Additional studies to confirm these findings and identify clinically accessible markers of interferon alpha induction are needed.
Staging. In a symposium on HCV, David Thomas from Johns Hopkins reviewed the current status of techniques to assess stage of liver fibrosis in HCV and thereasons why staging will continue to be important in an era where treatment for HCV will be safe and curative in most individuals [16]. In the era of interferon-based treatment, reasons to stage liver disease were 2-fold; to avoid treatment with a low efficacy, poorly tolerated regimen in those with early disease and to appropriately manage patients with cirrhosis, for example to detect and treat varices and screen for hepatocellular carcinoma (HCC). The reasons to screen now are the same, but with a different emphasis. Since new treatments are safe and highly effective, avoiding treatment is no longer an issue. Instead, because of extreme cost, many prescription drug insurances are limiting access to new medications to those with evidence to advanced fibrosis, so staging now may be needed in order to implement treatment. After achieving a cure, fibrosis is reduced and risk for HCC declines but is not eliminated, so patients with cirrhosis will continue to need monitoring for HCC after treatment. How and which patients to monitor after cure remains to be defined. Dr Thomas reviewed methods for staging. Liver biopsy has been the "gold standard" for assessing fibrosis stage and diagnosing cirrhosis, although ample evidence now shows it suffers from sampling error and non-reproducible results. Biopsy also has a low but finite complication rate, may involve pain and is "scary' for patients. Non-invasive tests to assess fibrosis now appear to offer similar diagnostic accuracy for assessing fibrosis and predicting risk for clinical complications, and are preferred to biopsy for routine assessment. The APRI and FIB-4 indices are calculated from routinely available blood tests and have similar accuracy to the more expensive propriety "FibroSure" test. Fibroscan, an ultrasound technique that quantifies liver stiffness is also very useful but can be hard to interpret in certain patients and is not yet widely available. All of these non-invasive tests give reliable results at the extremes where they accurately make or exclude the diagnosis of cirrhosis. Intermediate values may be harder to interpret. One approach is to start with the simple cheap blood test indices, adding fibroscan when results give an intermediate value. Liver biopsy may still be considered when results of non-invasive tests conflict or when there is clinical suspicion of another coexisting liver disease. An important unanswered question in HCV management is whether all patients with pre-treatment cirrhosis will continue to warrant HCC surveillance after cure. Cases of HCC have continued to occur after cure but at substantially lower rates. Monitoring fibrosis stage after cure may identify patients at low risk of complications of cirrhosis, but studies with large numbers of patients and long-term follow-up will be needed to determine if surveillance can be discontinued in patients no longer meeting criteria for cirrhosis after successful HCV treatment.
Treatment as Prevention. Until now, major obstacles to treating large numbers of HCV-infected individuals have included the low efficacy and tolerability of interferon-based regimens and the need for an invasive procedure (liver biopsy) to stage liver disease. With the current availability of interferon-free regimens for some types of HCV infection, the recent FDA approval of the a simple, highly effective interferon-free regimen for GT1 infection, the approval of several more regimens anticipated soon, and the shift to non-invasive staging of liver disease, these obstacles are falling. These developments make a dialogue about a "treatment-as-prevention" strategy for HCV possible, although daunting obstacles to implementation still exist. Shruti Mehta, also from Johns Hopkins, gave a very thought provoking talk exploring the possibility of HCV eradication [17]. She reviewed statistical modeling studies which demonstrate that in theory, a high rate of diagnosis, linkage to care and successful treatment, would eradicate the US HCV epidemic within a matter of several years. However, many obstacle stand between theory and practice. Only about 50% of HCV cases in the US are currently diagnosed and more than 80% of new transmissions occur in people who inject drugs (PWID), a community of individuals poorly linked to the health care system. Obstacles to improving diagnosis rates in PWID include asymptomatic infection, low awareness of HCV risk, low awareness of the health consequences of HCV, low implementation of testing recommendations by health care providers and an inadequate testing infrastructure. Obstacles to linkage to care include active substance use, lack of insurance and other completing health priorities (eg, treatment of substance abuse and its other medical consequences). Obstacles to successful treatment include an inadequate health care infrastructure to deliver comprehensive care, including education and prevention services, to a high-need population, non-adherence to treatment, reinfection, and the extraordinarily high cost of new HCV medications, which has resulted restricted access. Current treatment guidelines call for prioritizing treatment of patients with advanced liver fibrosis, which is clearly important. However, Dr Mehta presented data showing that this strategy will do almost nothing to prevent new infections. Studies of the ALIVE cohort, a group of PWID in Baltimore show the frequency of drug injection and needle sharing correlates inversely with age. As a result transmission of HCV occurs predominantly in young PWID who share drugs in networks of other PWID of similar age. Older active and former PWID are more likely to be linked to health care and have advanced liver disease, but since they contribute little to transmission, treating them will not impact the HCV epidemic. Additionally, many prescription drug payers are now requiring proof of abstinence from drug use as a condition of access to HCV treatment, a requirement that would eliminate from treatment those who may still be at risk to transmit.
In the final section of the talk, Dr Mehta shared an outreach strategy that has been successful in diagnosing and linking to care many young drug users in a community in India. This strategy identifies key individuals in the drug use network, providing them with "coupons" to distribute to other individuals in the network. Those who return may redeem the coupons after participation in testing and prevention education, and are then given more coupons to distribute within the network. If treatment was added to the services offered to infected individuals identified by this technique, the risk of reinfection for those who continue to use drugs could be greatly decreased by reducing the HCV reservoir within the drug use network.
This presentation brings into focus the short-sightedness of the policies of both the pharmaceutical and health insurance industries which have led to the current situation where access to new HCV treatments is severely restricted. Continuation of these policies means these powerful, safe and effective tools cannot be used to impact HCV transmission.The restrictions do not arise from concerns about the safety or efficacy of these new regimens. Instead they are purely a response to their unprecedented cost. There is an urgent need for manufacturers and health insurance providers to work together to significantly reduce the cost of medication while allowing the number of HCV-infected individual treated to increase dramatically. This would permit the developers of these innovative new treatments to protect deserved profits without losing the opportunity for a major public health benefit from expanded indication to treat HCV.
1. Sulkowski M, et al. abstract 1223.
2. Afdhal N, et al. N Engl J Med, 2014; 370:1889.
3. Afdhal N, et al. N Engl J Med, 2014;370:1483.
4. Krowdley KV, et al. N Engl J Med, 2014;370:1879.
5. Zeuzem S, et al. N Engl J Med, 2014;370:1604.
6. Feld J et al. N Engl J Med, 2014:370;1594.
7. Feld JJ, et al. abstract 1222
8. Poordad F, et al N Engl J Med, 2014370:1973.
9. Ferenci P, et al. N Engl J Med, 2014;370:1983.
10. Brunetto M, et al. abstract 820.
11. Hezode C, et al. abstract 819.
12. Jensen DM et al. 821.
13. Garimella T, et al. 1166.
14. Meissner E, et al. abstract LB-4.
15. Osinusi A, et al. JAMA, 2013;310:804
16. Thomas D. abstract 63.
17. Mehta S. abstract 65.