A series of additional PIs are in development and preliminary
studies confirm their superior antiviral effectiveness in
combined triple therapy over the SoC in treatment-naive
patients. Unlike telaprevir or boceprevir, which are active only
on genotypes 1 and 2 and have to be dosed three times a day,
investigational second-generation PIs, mainly non-covalent
inhibitors of the NS3/4A, seem to be active against different HCV
genotypes, as well as against resistant HCV variants previously
selected by other PIs. Also, they have a longer half-life which
enables more convenient once-daily dosing. In addition, they
may provide improved safety and efficacy as well as shortened
treatment duration for a higher proportion of patients. An
example is BI 201335, a once-daily HCV NS3/4A protease
inhibitor optimised to target genotype-1 HCV, with strong in
vitro activity also against GTs 4-6. Phase II studies showed
BI 201335 to have strong efficacy, with overall SVR rates
70 | Hepatitis C Treatment
reaching 83% in GT1 patients at once-daily dosages of 240 mg (in
combination with PegINF+RBV). BI 201335 is now in phase III
trials in combination with PegINF+RBV and in phase II as part of
the interferon-free combination with the polymerase inhibitor,
BI 207127, in genotype-1 HCV patients.
Other notable examples are MK-5172, a competitive inhibitor
of HCV NS3/4A protease that has demonstrated in vitro activity
against genotypes 1b, 2a, 2b, and 3a, and proved to be active in
vivo against genotypes 1 and 3; and TMC435 (that can also be
administered once-daily), active in therapy-naive patients with
HCV G4 infection. Moreover, TMC435 antiviral activity was
similar, irrespective of the IL28B genotype. Some compounds,
such as Danoprevir (formerly R7227/ITMN-191) are being
studied in combination with low-dose ritonavir (a pharmacologic
booster used for HIV protease inhibitors) in order to improve
pharmacokinetics, without increasing toxicity. Whether such
complex therapies have the potential to minimize the risk of
viral breakthrough and the selection of resistance mutations,
remains to be evaluated.
studies confirm their superior antiviral effectiveness in
combined triple therapy over the SoC in treatment-naive
patients. Unlike telaprevir or boceprevir, which are active only
on genotypes 1 and 2 and have to be dosed three times a day,
investigational second-generation PIs, mainly non-covalent
inhibitors of the NS3/4A, seem to be active against different HCV
genotypes, as well as against resistant HCV variants previously
selected by other PIs. Also, they have a longer half-life which
enables more convenient once-daily dosing. In addition, they
may provide improved safety and efficacy as well as shortened
treatment duration for a higher proportion of patients. An
example is BI 201335, a once-daily HCV NS3/4A protease
inhibitor optimised to target genotype-1 HCV, with strong in
vitro activity also against GTs 4-6. Phase II studies showed
BI 201335 to have strong efficacy, with overall SVR rates
70 | Hepatitis C Treatment
reaching 83% in GT1 patients at once-daily dosages of 240 mg (in
combination with PegINF+RBV). BI 201335 is now in phase III
trials in combination with PegINF+RBV and in phase II as part of
the interferon-free combination with the polymerase inhibitor,
BI 207127, in genotype-1 HCV patients.
Other notable examples are MK-5172, a competitive inhibitor
of HCV NS3/4A protease that has demonstrated in vitro activity
against genotypes 1b, 2a, 2b, and 3a, and proved to be active in
vivo against genotypes 1 and 3; and TMC435 (that can also be
administered once-daily), active in therapy-naive patients with
HCV G4 infection. Moreover, TMC435 antiviral activity was
similar, irrespective of the IL28B genotype. Some compounds,
such as Danoprevir (formerly R7227/ITMN-191) are being
studied in combination with low-dose ritonavir (a pharmacologic
booster used for HIV protease inhibitors) in order to improve
pharmacokinetics, without increasing toxicity. Whether such
complex therapies have the potential to minimize the risk of
viral breakthrough and the selection of resistance mutations,
remains to be evaluated.
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