Telaprevir for Hepatitis C Retreatment: An Open Door on a Long and Winding Road

Article in Press

Telaprevir for Hepatitis C Retreatment: An Open Door on a Long and Winding Road

Gastroenterology
published online 23 August 2010.

Uncorrected Proof

Alessio Aghemo, MD

, Massimo Colombo, MD

"It is therefore clear that careful patient selection for DAAs-based therapies is mandatory.....

Clinicians and pharmaceutical companies are working hard to develop alternative and effective strategies for the retreatment of HCV patients with a previous treatment failure.....

it is easy to understand why the final data of the studies investigating the safety and efficacy of DAA agents in combination with PegIFN and Rbv were eagerly awaited by the hepatology community......

Final results from the Protease inhibition for Viral Evaluation study (PROVE3) show that the addition of telaprevir to combination therapy with PegIFN and Rbv determines significantly more SVRs than the current SOC, which, once again, achieved only modest rates of persistent viral eradication (14%) [retreatment of patients with prior experience & not achieving a cure]

......the addition of Rbv to PegIFN therapy is able to significantly increase the end of treatment response rates while concurrently reducing the posttreatment relapse rates....r

elapse rates were more than double in the absence of Rbv......

in the light of the higher SVR rates that can be achieved by the telaprevir-based regimens, it is easy to get carried away by such a scientific breakthrough and literally close an eye on the profound and worrisome clinical implications that the study by McHutchison et al carries. Undoubtedly, the management and treatment of patients with chronic HCV will become extremely more complicated, requiring increased scientific and clinical expertise to comply with the new challenges that this first generation of DAA agents will provide us with. Although the development of viral resistance to telaprevir was seen in only 12% of the patients receiving the triple therapy regimen, it is important to understand that these mutant viral strains will likely preclude other class-specific DAA agents based therapies to our patients (Gastroenterology 2007;132:1979–1998). Not only cross-resistance between telaprevir and boceprevir has already been demonstrated (Hepatology 2009;50:1709–1718), but it is highly likely that the antiviral activity of other NS3 protease inhibitors that are currently being developed will be negatively influenced by the presence of circulating HCV mutants as well ......

Even more worrisome is the theoretical preclusion of DAA agents cocktails that might permit maintained HCV replication suppression, such as a preemptive therapy to avoid the often dramatic course of HCV recurrence in liver transplanted patients (Clin Liver Dis 2003;7:585–602). Although this might seem unrealistic, a proof-of-concept study investigating the antiviral effect of a combination of a NS3 protease inhibitor and a polymerase inhibitor has shown no viral breakthrough during 14 days of therapy and HCV RNA undetectability in 63% of the treated patients (J Hepatol 2009;50[Suppl 380]:A1046). Even if these data are preliminary, they need to be kept well in mind when a patient is considered for a treatment with DAAs, and a risk/benefit evaluation is conducted at the individual level.....

The high rates of treatment discontinuation owing to adverse events reported in the telaprevir arms will provide us quite a challenge in the near future, especially considering that a Phase II study conducted on previous treatment failures by definition enrolls extremely motivated and well-prepared patients, which might not reflect well the everyday clinical practice. It seems highly likely that a dermatologist will become a constant presence in our clinics, as the skin side effects of telaprevir will affect roughly 50% of our patients, with ≥5% developing potentially severe rashes.....

On top of this, the every-8-hour administration of telaprevir will not only add more practical problems, because patients will be taking a total of 11 or 12 capsules (Rbv and telaprevir) in 4 different moments of their day, but it might also increase the risk of viral resistance as a consequence of relatively high chance of incorrect assumption of the 2 drugs....

.......Although the next years will be an exciting period to be involved in research and treatment of chronic hepatitis, still our optimism should be cautioned by the possibly serious problems this first generation of DAAs might bring...... It is our view that only through a dedicated continuing medical education program promoted by local and international scientific societies, and clustering of small hepatology centers around large-volume centers, with a dedicated laboratory facility and a multidisciplinary team of physicians, will this be achieved."


McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303.


Hepatitis C virus (HCV)-infected patients have greatly benefited from the recent drug developments starting from the introduction of the guanosine analog ribavirin (Rbv) in the late 1990s (Lancet 1998;352:1426–1432; N Engl J Med 1998;339:1485–1492) to finish with the development of pegylated interferon (PegIFN) at the beginning of the century (Lancet 2001;358:958–965; N Engl J Med 2002;347:975–982). Indeed, the therapeutic combination of the 2 drugs has elevated the achievable sustained virologic response (SVR) rates to nearly 50% in HCV-1 and -4 patients and 80% in HCV-2 and -3 patients (Gastroenterology 2010;138:108–115). However, even in the most favorable setting, roughly 50% of HCV-1 and -4 treated patients ultimately will not achieve a SVR, effectively being classified as treatment failures (Hepatology 2009;49:1335–1374). It is intuitive that these figures coupled with the decrease in newly acquired cases of HCV infection (J Hepatol 2008;49:625–633), will progressively shift the balance from the development of effective treatment options in naïve patients to the always growing treatment-experienced patient population. Unfortunately, current treatment options in the latter group of IFN-refractory patients are rather limited, because retreatment with PegIFN and Rbv leads to disappointing SVR rates, especially in those who failed to reach HCV RNA undetectability during the previous PegIFN plus Rbv course (Ann Intern Med 2009;150:528–540; Gastroenterology 2009;136:1618–1628), currently cautioning against the broad retreatment of these patients with PegIFN and Rbv (Hepatology 2009;49:1335–1374). In light of these findings, there is a strong need for the development of effective regimens to retreat patients with chronic infection who did not have an SVR to the previous therapy. The important technical advances in cell culture systems and replication assays introduced in the last decade (J Hepatol 2009;51:939–948; Hepatology 2006;43[Suppl 1]:S207–220), have dramatically changed the landscape of HCV infection finally providing researchers and pharmaceutical companies with the tools to develop and study directly acting antiviral (DAA) drugs for the treatment of chronic hepatitis C. Although many DAA agents remain in the early phases of development (Gastroenterology 2010;138:447–462), the orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV protease telaprevir, has finished Phase II evaluation (N Engl J Med 2009;360:1827–1838; N Engl J Med 2009;360:1839–1850) and is currently in the late stages of the Phase III registration trials that should lead to its broad commercialization in 2011. In the April 8, 2010, issue of the New England Journal of Medicine, McHutchison et al report on the final results of the Phase II, randomized, partially placebo-controlled, partially double-blind PROVE3 study, which was designed to assess the safety and efficacy of telaprevir in combination with PegIFN/Rbv in the re-treatment of HCV-1 patients with a previous treatment failure to PegIFN and Rbv therapy (New Engl J Med 2010;362:1292–303). In 53 international sites, 465 HCV-1 patients were randomly assigned to 4 different treatment groups to receive either telaprevir plus PegIFNalfa2a plus Rbv for 12 weeks followed by placebo plus PegIFNalfa2a plus Rbv for the next 12 weeks (T12PR24), telaprevir plus PegIFNalfa2a plus Rbv for 24 weeks followed by PegIFNalfa2a plus Rbv for the next 24 weeks (T24PR48), telaprevir plus PegIFNalfa2a for 24 weeks (T24P24), or placebo plus PegIFNalfa2a plus Rbv for 24 weeks followed by PegIFNalfa2a plus Rbv for the next 24 weeks as a control group (PR48). Telaprevir was given during the treatment period in a single initial dose of 1125 mg, followed by a dose of 750 mg every 8 hours thereafter; PegIFNalfa2a and Rbv were given at standard dose for HCV-1 patients. Randomization was stratified to balance race (black versus non-black) and previous virologic response (achievement or nonachievement of undetectable HCV RNA). The study was designed to have a 90% statistical power to detect a 25% difference in SVR rates, the primary end point of the study, between the telaprevir groups and the control group. The vast majority of the 465 enrolled patients were white (89%), 58% had HCV genotype 1a, and 16%, cirrhosis. Fifty-seven percent of the patients had a nonresponse to the previous treatment PegIFN plus Rbv treatment course, defined as the lack of HCV RNA undetectability; 36% were classified as relapsers, because HCV RNA was undetectable for ≥42 weeks of the previous treatment course with subsequent HCV RNA detectability during follow-up; and 7% had a breakthrough, that is undetectable HCV RNA during treatment but detectable at the end of the treatment period. In this particularly hard-to-cure treatment population, SVR rates were significantly higher in each of the 3 telaprevir groups than in the standard of care (SOC) control arm, being 51% for T12PR24, 53% for T24PR48, 24% for T24P24, and 14% in the SOC group. Not surprisingly, the SVR rates were higher in previous relapsers than in previous nonresponders, being 69% and 39% in the T12PR24 arm, 76% and 38% in the T24PR48 arm, 42% and 11% in the T24P24 arm, and 20% and 9% in the SOC arm, mimicking what already reported by retreatment studies with dual therapy (Gastroenterology 2009;136:1618–1628). Although the SVR rates did not differ significantly between the T12PR24 and the T24PR48 arms (51% vs 53%), the relapse rates were significantly lower in the latter group (4%) compared with the former (28%). This notwithstanding, viral breakthrough, the surrogate marker of the development of resistant variants, was observed in the same proportion (12%–13%) of the patients in the T12PR24 and T24PR48 arms, whereas it was much higher (32%) in the telaprevir arm without Rbv (T24P24). When looking only at the 2 telaprevir treatment regimens that received Rbv, breakthrough rates were significantly higher in previous nonresponders than in previous relapser patients both in the overall population (25% vs 2%) as in the single treatment arms (T12PR24: 20% vs 2% and T24PR48: 22% vs 2%). Logistic regression analysis identified assignment to the T12PR24 or T24PR48 group, baseline viral load <800,000 IU/mL and achievement of undetectable HCV RNA during the previous treatment course as independent predictors of an SVR.


Consistent with what has been reported in previous studies, rash, pruritus, and development of anemia were more commonly observed in the telaprevir regimens than the SOC group (N Engl J Med 2009;360:1827–1838; N Engl J Med 2009;360:1839–1850). The cumulative incidence of any rash-related event was 50% in the T12PR24 arm, 60% in the T24PR48 regimen, and 20% in the SOC arm. The severity of the rash was also greater in patients receiving telaprevir with a severe rash developing in 5% of patients in the T12PR24 group, 4% in the T24PR48 group, and 0% in the SOC group. These figures ultimately led to 5% of patients in the telaprevir groups discontinuing treatment for this side effect. Overall, discontinuation rates owing to side effects were more likely to occur in the telaprevir-based therapy (15%) than in the SOC arm (4%). Thus, the addition of telaprevir to the current SOC therapy as a retreatment strategy in HCV-infected patients who had not had a SVR to a previous therapy, significantly increased the likelihood of HCV eradication.


Comment.


Treatment with PegIFN combined with Rbv is the current SOC for patients chronically infected with HCV, with the currently attainable SVR rates, the surrogate definition of a cure of the disease, in the 40%–50% range in patients infected with the most common genotype 1 of HCV (N Engl J Med 2009;361:580–593). Although these figures represent a drastic improvement from the extremely low SVR rates that were obtained in these patients with IFN monotherapy in the 1990s (N Engl J Med 1986;315:1575–1578; Hepatology 1996;24:1366–1370), some important clinical and public health issues still remain unsolved in the treatment of chronic hepatitis C. Indeed, although local national health authorities are facing the difficult task of broadening the access to antiviral therapy that, even in rich world regions such as Europe and the United States, is estimated to reach only a minority of all prevalent HCV cases (1%–16%), mainly as a consequence of its elevated costs, poor tolerability profile, and lack of patient referral to a liver specialist (J Hepatol 2008;49:528–536; Hepatology 2009;50:1750–1755). Clinicians and pharmaceutical companies are working hard to develop alternative and effective strategies for the retreatment of HCV patients with a previous treatment failure. Because treatment options in these patients are rather limited, scientific efforts in this subset of patients have been geared toward exploring the efficacy of different treatment schedules (ie, extended treatment duration) or doses (induction dose of PegIFN); however, showing that the added benefits of these therapeutic strategies, especially in terms of cost effectiveness, can be considered at best marginal (Ann Intern Med 2009;150:528–540). To date, the most effective treatment regimen in this patient population is probably a 72-week combination of PegIFNalfa2a plus Rbv, which translates into SVR rates of only 16% in HCV-1–infected patients (Ann Intern Med 2009;150:528–540). A number that unfortunately shrinks to a mere 5% in patients with cirrhosis, that is more often found in previous treatment failures as it is considered to be one of the strongest negative moderators of treatment outcome (J Hepatol 2008;49:634–651; Antivir Ther 2009;14:577–584). In this context, it is easy to understand why the final data of the studies investigating the safety and efficacy of DAA agents in combination with PegIFN and Rbv were eagerly awaited by the hepatology community. Final results from the Protease inhibition for Viral Evaluation study (PROVE3) show that the addition of telaprevir to combination therapy with PegIFN and Rbv determines significantly more SVRs than the current SOC, which, once again, achieved only modest rates of persistent viral eradication (14%). The inclusion of an Rbv-free arm demonstrates once again that Rbv is indeed crucial to maximize the efficacy of antiviral treatment (N Engl J Med 2009;360:1839–1850). In fact, the addition of Rbv to PegIFN therapy is able to significantly increase the end of treatment response rates while concurrently reducing the posttreatment relapse rates (Gastroenterology 2006;131:1040–1048). Although the exact mechanisms behind this beneficial effect are still elusive (Nature 2005;436:967–972), recent data point to Rbv determining an improvement in the IFN signaling that amplifies the induction of interferon-stimulated genes that are responsible for the antiviral effect of the 2 drugs. This translates into a more rapid second-phase decrease of HCV RNA during treatment, reflecting clearance of the HCV infected hepatocytes, a mechanism that is crucial to prevent posttreatment relapse after drug withdrawal (Gastroenterology 2010, in press). This was the case also in the PROVE3 study, where, in the presence of similar end of treatment rates between the 3 telaprevir based regimens (T12PR24, 75%; T24PR48, 67%; T24P24, 54%), the relapse rates were more than double in the absence of Rbv when compared with the 2 groups receiving Rbv (53% vs 21%). Moreover, the addition of Rbv was also able to significantly reduce the rates of viral breakthrough during therapy, which most likely represents development of resistant viral strains. Indeed, this happened in 12% of the telaprevir based regimens patients receiving Rbv compared with 32% in those treated with PegIFN and telaprevir only. Although the mechanisms behind this finding remain unknown, these results confirm previous data obtained in Phase II studies in naïve patients receiving telaprevir or boceprevir (N Engl J Med 2009;360:1839–1850; J Hepatol 2009;50S1:A4), another NS3 protease inhibitor currently being tested in Phase III studies, and reinforce the concept that Rbv is an essential partner for this first-generation of DAAs.


In the light of the higher SVR rates that can be achieved by the telaprevir-based regimens, it is easy to get carried away by such a scientific breakthrough and literally close an eye on the profound and worrisome clinical implications that the study by McHutchison et al carries. Undoubtedly, the management and treatment of patients with chronic HCV will become extremely more complicated, requiring increased scientific and clinical expertise to comply with the new challenges that this first generation of DAA agents will provide us with. Although the development of viral resistance to telaprevir was seen in only 12% of the patients receiving the triple therapy regimen, it is important to understand that these mutant viral strains will likely preclude other class-specific DAA agents based therapies to our patients (Gastroenterology 2007;132:1979–1998). Not only cross-resistance between telaprevir and boceprevir has already been demonstrated (Hepatology 2009;50:1709–1718), but it is highly likely that the antiviral activity of other NS3 protease inhibitors that are currently being developed will be negatively influenced by the presence of circulating HCV mutants as well (Gastroenterology 2010;138:447–462). Because alternative DAA agents such as nucleoside or nonnucleoside NS5B polymerase inhibitors are in the early stages of development, our resistant patients will be left waiting for future drugs to enter the market before an effective anti-HCV treatment can be started. Even more worrisome is the theoretical preclusion of DAA agents cocktails that might permit maintained HCV replication suppression, such as a preemptive therapy to avoid the often dramatic course of HCV recurrence in liver transplanted patients (Clin Liver Dis 2003;7:585–602). Although this might seem unrealistic, a proof-of-concept study investigating the antiviral effect of a combination of a NS3 protease inhibitor and a polymerase inhibitor has shown no viral breakthrough during 14 days of therapy and HCV RNA undetectability in 63% of the treated patients (J Hepatol 2009;50[Suppl 380]:A1046). Even if these data are preliminary, they need to be kept well in mind when a patient is considered for a treatment with DAAs, and a risk/benefit evaluation is conducted at the individual level. It is therefore clear that careful patient selection for DAAs-based therapies is mandatory. The PROVE3 study fortunately does provide us with some important insights into this key matter; the rate of viral breakthrough was extremely higher in previous nonresponders compared with relapsers (25% vs 2%) and in patients infected with the 1a genotype than the 1b (24% vs 11%). This has 2 important clinical implications: First, it implies that telaprevir needs some degree of viral response to PegIFN and Rbv to maximize its potent antiviral effect, suggesting to prioritize treatment in relapser patients. Second, a correct definition of the HCV genotype by our laboratories is mandatory. Although this second point might seem trivial, a recent study has shown that using 2 commercially available assays that analyze the 5′ noncoding region of HCV through sequence analysis or reverse hybridization failed to correctly HCV subtype 1a in 23%–30% of cases, whereas a second-generation reverse hybridization assay that targets both the 5′ noncoding and the core–core region was able to correctly identify subtype 1a in more than 99% of the cases (PLoS One 2009;4:e8209). All in all, telaprevir will certainly provide a major breakthrough in the treatment of HCV-1 patients who failed to eradicate HCV during a previous course of PegIFN and Rbv therapy, however at the cost of an increase in treatment related side effects and discontinuation rates.


The high rates of treatment discontinuation owing to adverse events reported in the telaprevir arms will provide us quite a challenge in the near future, especially considering that a Phase II study conducted on previous treatment failures by definition enrolls extremely motivated and well-prepared patients, which might not reflect well the everyday clinical practice. It seems highly likely that a dermatologist will become a constant presence in our clinics, as the skin side effects of telaprevir will affect roughly 50% of our patients, with ≥5% developing potentially severe rashes. Unfortunately, to date the exact mechanisms by which rash develops in some patients remain unknown, and although future efforts should concentrate on the genetic predisposition that might lead to skin and subcutaneous tissue disorders, currently the management of these side effect by experts is warranted. On top of this, the every-8-hour administration of telaprevir will not only add more practical problems, because patients will be taking a total of 11 or 12 capsules (Rbv and telaprevir) in 4 different moments of their day, but it might also increase the risk of viral resistance as a consequence of relatively high chance of incorrect assumption of the 2 drugs. In theory, an every-12-hour dosing would be extremely more practical, because it would permit intake of Rbv and telaprevir roughly at the same time; however, even if in a recent Phase II study the telaprevir 12-hour dosing achieved similar SVR rates compared with the every-8-hour dosing, the fear of an increased rate of viral breakthrough will probably preclude its further assessment in randomized, controlled studies (Hepatology 2008;48[Suppl]:1136A).


Although the next years will be an exciting period to be involved in research and treatment of chronic hepatitis, still our optimism should be cautioned by the possibly serious problems this first generation of DAAs might bring. Needless to say, we are all hopeful to replicate in HCV patients the successes that have followed the commercialization of nucleos(t)ide analogs in the treatment of hepatitis B virus infection (Hepatology 2009;50:227–242), however avoiding the mistakes that are intrinsic to the learning curve effect that follow every new drug. Indeed, we should not forget that, although lamivudine radically changed the clinical picture of hepatitis B virus infection, its broad and sometimes excessive use determined an equally impressive amount of problems owing to the high rates of viral resistance (Gastroenterology 2009;137:1593–1608) and to the lack of an available rescue therapy for some years (Hepatology 2005;42:1414–1149). It is our view that only through a dedicated continuing medical education program promoted by local and international scientific societies, and clustering of small hepatology centers around large-volume centers, with a dedicated laboratory facility and a multidisciplinary team of physicians, will this be achieved.