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New kids on the block [Merck]-step by step to an ideal HCV therapy
 
 
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New kids on the block [Merck]-step by step to an ideal HCV therapy
 
"Merck will also explore a nucleotide NS5B polymerase inhibitor, MK-3682, in combination with grazoprevir and elbasvir as a triplet regimen"
 
The Lancet
21 March 2015
*Markus Cornberg, Michael P Manns
Department of Gastroenterology, Hepatology, and Endocrinology,
Hannover Medical School, 30625 Hannover, Germany
 
There is an unmet need for highly effective, safe, short-term, and affordable antiviral regimens for all patients with hepatitis C virus (HCV) infection for overall eradication of this global health burden. Until recently, interferon alfa in combination with ribavirin was the mainstay of treatment. Yet eligibility for and safety of interferon-based therapies was low, and consequently overall effectiveness very limited.1, 2 Fortunately, the development of new direct-acting antiviral drugs against HCV has progressed enormously, allowing oral interferon-free therapies. HCV has three main therapeutic targets: the NS3/4A protease, NS5B polymerase, and NS5A replication complex. The first interferon-free regimens, including combinations of sofosbuvir plus ribavirin, sofosbuvir plus simeprevir,3 sofosbuvir plus daclatasvir,4 and daclatasvir plus asunaprevir,5 have already been approved and are available in some countries.
 
The costs for cure are high for these pioneering therapies, and therefore these drugs are currently mainly used in patients with the most urgent need for therapy. Sofosbuvir plus simeprevir and sofosbuvir plus daclatasvir are used on the basis of phase 2 studies,3, 4 with fairly low numbers of patients. Sofosbuvir plus daclatasvir is recommended for patients with cirrhosis, although cirrhosis was an exclusion criterion for the phase 2 study of this drug combination.4 However, new interferon-free regimens are arriving. A single-tablet regimen combining sofosbuvir and ledipasvir was approved on Oct 10, 2014 in the USA. Approval of the so-called 3D combination containing the ritonavir-boosted NS3/4A protease inhibitor paritaprevir, the NS5A inhibitor ombitasvir, and the non-nucleosidic NS5B inhibitor dasabuvir is expected early in 2015. However, are further anti-HCV drugs really needed when sustained virological response (SVR) rates of 96·4% have been reported in 3826 patients with HCV genotype 1 treated with sofosbuvir plus ledipasvir or 3D therapy in seven phase 3 trials?6, 7, 8, 9, 10, 11, 12 Certainly, research questions need to be addressed before we can consider hepatitis C conquered. The new compounds grazoprevir and elbasvir, which have been assessed in the phase 2 C-WORTHY trial reported by Mark Sulkowski and colleagues13 and Eric Lawitz and colleagues14 in The Lancet, tackle some of these issues.
 
The two C-WORTHY phase 2 studies had complex study designs that investigated the second-generation protease inhibitor grazoprevir in combination with the potent NS5A inhibitor elbasvir, with or without ribavirin. Both once-daily drugs were tested in 471 patients with HCV genotype 1 infection. Lawitz and colleagues14 assessed 12 and 18 weeks of treatment in 123 previously untreated patients with liver cirrhosis, and in 130 null responders to pegylated interferon plus ribavirin, with or without compensated cirrhosis. SVR at 12 weeks after the end of all study therapy (SVR12) ranged from 90% to 100% irrespective of ribavirin or the duration of therapy. Sulkowski and colleagues' study13 included 159 previously untreated patients with HCV monoinfection and 59 previously untreated, HIV-coinfected patients, all without cirrhosis. Except for 30 monoinfected HCV patients who had 8 weeks of therapy, all other patients received 12 weeks of treatment. SVR ranged from 87% to 98% in the 12-week groups. 8 weeks of treatment with grazoprevir plus elbasvir with ribavirin had a lower but still substantial SVR12 of 80% (95% CI 61-92).
 
How do these results differ from recently published data about interferon-free therapies? Grazoprevir plus elbasvir is the first single-tablet and once-daily regimen without interferon, ribavirin, or a nucleoside or nucleotide analogue that has shown more than 90% SVR in genotype 1a HCV as well as genotype 1b HCV. Other regimens sparing nucleoside or nucleotide analogues (eg, daclatasvir plus asunaprevir) have shown SVR of more than 90% in patients with genotype 1b infection only,5 whereas the 3D regimen still needs ribavirin in some patient groups and is dosed twice daily.9, 10, 11, 12 This is important because nucleoside or nucleotide analogues are mainly eliminated through renal clearance, with potential concerns about nephrotoxicity. Such toxic effects might be only a minor concern with short-term therapies for HCV, but so far sofosbuvir-based therapies are not used in renal insufficiency and at present dose recommendations cannot be made for patients with severe renal impairment. Both grazoprevir and elbasvir are mainly eliminated through hepatic pathways, and treatment of patients with renal insufficiency should be possible without dose adjustment. Phase 3 trials of this combination (eg, NCT02092350) also include patients with chronic kidney disease, including patients undergoing haemodialysis. Secondly, Sulkowski and colleagues' study13 is unique because it assessed both patients with HIV coinfection and those with HCV monoinfection. This presumably reflects the regulatory authorities' view that HIV/HCV coinfected patients are no longer a special patient group and can be adequately represented in trial populations.
 
Another important message of the C-WORTHY studies is that ribavirin is not required, at least in the assessed study populations. Furthermore, the single-tablet regimen of sofosbuvir plus ledipasvir has been developed without ribavirin.6, 7, 8 Ribavirin-free therapies are especially important in patients with advanced liver disease, comorbidities such as heart disorders, and chronic kidney disease. The C-WORTHY safety data underline that ribavirin is an important issue in current interferon-free regimens. Anaemia and hyperbilirubinaemia were only evident in patients treated with ribavirin in the C-WORTHY studies,13, 14 as already reported in COSMOS3exploring the combination of sofosbuvir plus simeprevir with or without ribavirin. Another interesting observation in C-WORTHY is that ribavirin was associated with a decrease in CD4 cell counts, certainly another argument for future ribavirin-free regimens.13 All but one of the phase 3 studies of grazoprevir plus elbasvir currently underway are ribavirin-free. In the various interferon-free regimens presently tested with or without ribavirin, the decrease in quality of life with treatment is almost exclusively due to ribavirin and, if ribavirin is omitted, quality of life seems to improve with therapy. However, valuable data about quality of life and patient-related outcomes are missing from the evidence base. Measures of patient-related outcomes, showing that quality of life improves with new interferon-free and ribavirin-free HCV therapies, are urgently needed. In the past, patients experienced a substantial decrease in quality of life with long-term therapies based on interferon and ribavirin, and only recovered slowly afterwards. Although nowadays therapy is prioritised by drug availability and cost, with selection of patients with advanced disease, in the future patients with HCV and no or little liver disease will receive treatment. Such patients could include patients with extrahepatic morbidity such as fatigue. Cure of HCV infection is already known to reduce not only liver-related mortality but also non-liver-related mortality.15
 
The final goal-one pill for all patients, with 100% cure, for all phenotypes of HCV infection-has not yet been reached. Many questions remain to be answered. Patients with decompensated cirrhosis have not been assessed sufficiently with new direct-acting antiviral drugs. Furthermore, substantial improvements are still needed for non-1 genotypes, especially genotype 3. Whether increased treatment duration or addition of ribavirin remain necessary for more difficult-to-treat patient populations is still unclear. Adherence to therapy will be very important in real-world settings to guarantee high SVR rates. So far, only data from well-controlled phase 2 and 3 trials, in which patients were highly selected and monitored at experienced centres, are available. Further, resistance has only been addressed superficially in the various phase 2 and 3 studies of direct-acting antiviral therapies. In C-WORTHY,13, 14 patients with resistance-associated variants (RAVs) for NS3 at baseline showed no impairment of SVR, although NS5A RAVs at baseline negatively affected treatment outcome. In both studies, 59 patients (13% of the tested cohort, n=459) had baseline NS5A RAVs and SVR was only 76%-a high response rate, but not ideal-in those patients.13, 14 Whether and which baseline RAV testing is necessary for new direct-acting antiviral regimens still needs to be defined.16 On the basis of these data, NS5A RAVs could become an issue in clinical practice, and a small number of patients might need intensive salvage therapies.
 
In conclusion, the new kid on the block of grazoprevir plus elbasvir provides promising SVR rates in HCV genotype 1 infection, adding an interferon-free, ribavirin-free, and nucleotide-free (or sparing) nail in the coffin of HCV.17 This new combination could offer some advantages for patient populations such as those with chronic kidney disease, and might become another ribavirin-free regimen to improve quality of life during treatment. Nevertheless, Merck will also explore a nucleotide NS5B polymerase inhibitor, MK-3682, in combination with grazoprevir and elbasvir as a triplet regimen.18 It is to be hoped that affordable and accessible oral regimens could achieve the ultimate vision-global eradication of hepatitis C-by pills alone.
 
 
 
 
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