Tx Options for HCV GT 1 or 4 Non-responders

Posted on August 9, 2015

New study shows that genotype 1- or 4-infected non-responders, including patients with cirrhosis, achieve high SVR12 rates on the 24 week, quad treatment regimen of daclatasvir plus asunaprevir and peginterferon/ribavirin. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens. A combination of Direct Acting Antivirals (DAAs) and peginterferon/ribavirin may provide a viable treatment option for those patients who experience virologic failure on all-oral, DAA regimens.

Some of the more difficult chronically-infected HCV patients to treat are those with a prior null or partial response to peginterferon/ribavirin therapy. Daclatasvir is a potent, pan-genotypic inhibitor of the HCV NS5A protein with activity against genotypes 1 to 6 in vitro. Asunaprevir is an NS3 protease inhibitor with activity against genotypes 1 and 4. Positive results of HALLMARK-QUAD, a global, single-arm, open-label, phase 3 study evaluating the efficacy and safety of daclatasvir plus asunaprevir combined with peginterferon/ribavirin in patients (≥18 years) infected with HCV genotype 1 or 4 who were null or partial responders to peginterferon alfa-2a or -2b plus ribavirin (Study AI447029; ClinicalTrials.gov number NCT01573351), were recently published in Journal of Hepatology (Jensen D, et al. J Hepatol. 2015 Jul;63(1):30-7).

  • Patients received daclatasvir 60 mg once-daily, asunaprevir 100 mg softgel capsule twice-daily and 180 μg peginterferon alfa-2a weekly and twice-daily ribavirin dosed according to bodyweight (<75 kg, 1000 mg daily; ≥75 kg, 1200 mg daily) for 24 weeks and were subsequently followed for 24 weeks post-treatment
  • Null response to peginterferon/ribavirin was defined as a <2 log10 decline in HCV RNA after ≥12 weeks of therapy, or a <1 log10 decline after ≥4 weeks of therapy
  • Partial responders had achieved a ≥2 log10 decline, but never achieved undetectable HCV-RNA after ≥12 weeks of peginterferon/ribavirin therapy, or became undetectable and subsequently had detectable HCV-RNA on-treatment
  • Patients with compensated cirrhosis were eligible but were capped at a maximum of 25% of the treated population

Of the 496 patients who were screened for the study, 354 with HCV genotype 1, and 44 with HCV genotype 4 treated between May 2012 and December 2013. The majority of patients (379/398; 95.2%) completed the 24- week treatment period.

  • The majority of patients were male (68.6%) and white (76.4%) with a median age of 52.7 years
  • Approximately two-thirds of the study population were null responders and as expected, a high proportion had a non- CC IL28B genotype
  • Overall, 23.4% of patients enrolled in the study had compensated cirrhosis; 45.5% of genotype 4-infected patients had compensated cirrhosis compared with 20.6% of genotype 1-infected patients

Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated rapid early antiviral activity among genotype 1- and 4-infected patients. SVR12 rates of 92.9% (329/354) were achieved in genotype 1-infected patients. Among genotype 4-infected patients, the SVR12 rate was 97.7% (43/44).

  • One patient had a missing post-treatment week 12 HCV-RNA value, but subsequently achieved SVR24, yielding a 100% SVR rate in genotype 4-infected patients. Study authors noted that this supports the ongoing development of the all-oral triple DAA regimen of daclatasvir and asunaprevir plus beclabuvir (BMS-791325), which has achieved high SVR rates in both genotype 1 (89–94%) and genotype 4 (100%) patients (Everson GT, et al. Gastroenterology. 2014;146:420-429. Hassanein T, et al. J Hepatol. 2014;60(suppl1):S472). Other potential treatment options in development for this population include the combination of ABT-450/ritonavir plus ombitasvir, which achieved high SVR rates in a small cohort of 50 genotype 4-infected null and partial responders (Hezode C, et al. J Hepatol. 2014;60(suppl1):S24).
  • SVR12 rate 94.9% in genotype 1-infected patients who achieved RVR (82.5% [292/354]), compared with 83.1% among those who did not achieve RVR
  • A large number of cirrhotic null and partial responders were treated in this study (23%). Daclatasvir plus asunaprevir and peginterferon/ribavirin resulted in high SVR12 rates in both cirrhotic (90.4%; 66/73) and non-cirrhotic genotype 1 patients (93.6%; 263/281).
  • Baseline factors previously associated with a suboptimal response to peginterferon/ribavirin-based regimens, such as sex, age, body mass index, and baseline HCV-RNA did not appear to affect response, as SVR12 rates were high across all groups
  • SVR12 rates were slightly lower among the small number of black patients (87.9%; 29/33) compared with white patients (92.6%; 251/271)
  • SVR12 was higher among patients infected with subtype 1b (98.9%; 176/178) compared with subtype 1a (86.9%; 153/176)

Virological failure was observed infrequently among genotype 1-infected patients: 3.1% (11/354) experienced virological breakthrough, 0.6% (2/354) had detectable HCV-RNA at the end of treatment, and 2.4% (8/337) experienced relapse post-treatment.

  • Three patients with baseline asunaprevir resistance polymorphisms did experience virological breakthrough. Multiple linked resistance variants were present in two of these patients, which are unusual in protease inhibitor-naive patients, suggesting these patients may have been previously exposed to protease inhibitor-based therapy, but this could not be verified after further investigation.
  • No association between the presence of baseline daclatasvir resistance polymorphisms and virological failure was observed
  • No genotype 4-infected patients experienced virological failure

Daclatasvir plus asunaprevir and peginterferon/ribavirin was well tolerated in this patient population. The most frequent AEs and laboratory abnormalities observed during treatment were those typically associated with peginterferon/ribavirin therapy.

  • AEs occurring at a frequency >20% were fatigue, headache, pruritus, asthenia, influenza-like illness, insomnia, and rash
  • Serious AEs were reported in 5.5% (22/398) of patients during treatment, with nine events considered by the investigator to be related to study therapy: anemia, anemia/dehydration, encephalopathy, pneumonia, traumatic ulcer, lymphadenopathy, sepsis, hepatic enzymes increased, and dry skin in one patient each
  • No clinically relevant differences in hepatic laboratory abnormalities or AEs were noted between patients with or without cirrhosis
  • Grade 3/4 ALT and aspartate aminotransferase (AST) elevations occurred in 3.0% and 3.3% of patients, respectively.

Infrequent viral breakthrough and relapse, combined with a low rate of AE-related discontinuations, led to a high number of patients completing treatment in this study, compared with historical peginterferon/ribavirin-based studies.

  • Discontinuations due to AEs occurred in 4.5% (18/398) of patients; the most frequent events leading to discontinuation were rash, malaise, neutropenia, and vertigo, occurring in two patients each

Study authors noted that future therapeutic options for patients with a partial or null response to peginterferon/ribavirin are likely to focus on all-oral regimens such as daclatasvir in combination with other DAAs including asunaprevir and sofosbuvir, and simeprevir plus sofosbuvir, which are well tolerated and provide SVR rates comparable to those observed in this study. However, study authors also note that a combination of DAAs and peginterferon/ribavirin may provide a viable treatment option for those patients who experience virologic failure on all-oral regimens.

 


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