Jerry O. Stern

A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients.

All classes of antiretroviral (ARV) therapy have been associated with asymptomatic elevations of alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels, and much less frequently with serious, and at times life threatening, clinical liver hepatotoxicity. The relationship between the risk of developing serious clinical liver injury and the rate and severity of elevated asymptomatic ALT/AST levels is poorly understood. Boehringer Ingelheim has recently completed the Viramune® Hepatic Safety Project; its primary objective was to identify risk factors for antiretroviral-associated hepatotoxicity. Data from 1731 nevirapine-treated patients and 1912 control patients who took part in Boehringer Ingelheim-controlled clinical trials as well as 814 nevirapine-treated patients in uncontrolled trials were analyzed. Risk factors for asymptomatic ALT/AST elevations during nevirapine therapy included baseline elevations of ALT/AST levels >2.5× upper limit of normal (RR = 4.3, p < .01) and co-infection with hepatitis B (RR = 2.3, p < .01) or hepatitis C (RR = 5.2, p < .01). An analysis of ALT/AST elevations >5× ULN for patients stratified by baseline CD4 cell count demonstrated that men with ≥400 CD4 cells/mm3 were at increased risk of asymptomatic transaminase elevations while taking nevirapine (RR = 1.6, p < .01). No consistent CD4 cell count cutoff could be identified in women that was associated with an increased risk of ALT/AST elevations. Analyses from five large observational cohorts (N = 8711) demonstrated no significant differences in the rate of serious hepatic events among antiretroviral regimens, including between the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Use of nevirapine was not associated with a significantly increased risk of clinical hepatotoxic events, including liver failure or liver related death, compared to therapy with other antiretroviral drugs.

Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

BACKGROUND Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.).

Drug-Induced Liver Injury Associated with the Use of Nonnucleoside Reverse-Transcriptase Inhibitors

Human immunodeficiency virus (HIV)-infected patients frequently present with elevated levels of serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). This has often been attributed to the hepatic effects of antiretroviral (ARV) drugs, including nonnucleoside reverse-transcriptase inhibitors (NNRTIs). A review of cohort studies investigating the incidence of hepatotoxicity among patients receiving ARV therapy suggests that the overall rate of ALT and/or AST elevations is similar among all ARVs. The rate of severe hepatotoxicity, ALT and/or ASTlevels >5 times the upper limit of normal (ULN), during therapy with NNRTIs is relatively low but may be significantly higher in patients with concurrent chronic viral hepatitis (hepatitis B or C). A comprehensive analysis of 17 randomized clinical trials of nevirapine demonstrated that 10% of all nevirapine-treated patients developed elevated levels of ALT and/or AST >5 times the ULN; however, almost two-thirds (6.3% of nevirapine-treated patients) of these elevations were asymptomatic. Symptomatic hepatic events were seen in 4.9% (3.2%-8.9%) of nevirapine-treated patients.

Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection

BACKGROUND & AIMS Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. METHODS Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy. RESULTS In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely. CONCLUSIONS The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.

Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

BACKGROUND & AIMS BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. METHODS Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. RESULTS In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing. CONCLUSIONS BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial†‡

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once‐daily (QD) dosing. Four hundred and twenty‐nine HCV genotype (GT)‐1 treatment‐naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa‐2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead‐in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8‐20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety‐two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty‐two percent of GT‐1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143–2154)

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

BACKGROUND & AIMS BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro. METHODS In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n=27 treatment-naïve [TN]; n=30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay. RESULTS HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log(10), TE 4.2 log(10)) and 800 mg (TN 5.4 log(10), TE 4.5 log(10)). Rapid virological response (RVR; HCV RNA <15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound >1 log(10) from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg. CONCLUSIONS BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg.

Faldaprevir (BI 201335), BI 207127 and ribavirin oral therapy for treatment-naive HCV genotype 1 : SOUND-C1 final results

BACKGROUND Faldaprevir (BI 201335) and deleobuvir (BI 207127) are direct-acting antiviral agents under development for the treatment of chronic HCV infection. This article describes the final results of the Phase Ib SOUND-C1 study that evaluated the interferon-free oral combination of faldaprevir, deleobuvir and ribavirin in 32 treatment-naive patients infected with HCV genotype 1. METHODS Patients were randomized to receive deleobuvir 400 mg (n=15) or 600 mg (n=17) three times daily plus faldaprevir 120 mg once daily and weight-based ribavirin for 4 weeks. Interferon-free therapy was followed by response-guided faldaprevir plus pegylated interferon-α2a/ribavirin to week 24 or 48. RESULTS At week 4, 73% (11/15) and 100% (17/17) of patients in the deleobuvir 400 mg and 600 mg groups achieved HCV RNA<25 IU/ml, respectively. During interferon-free treatment, virological breakthrough was reported in one patient and re-increase of HCV RNA in one patient. Both patients were successfully treated with interferon-containing therapy. The rate of sustained virological response 24 weeks after completion of treatment was 73% (11/15) in the deleobuvir 400 mg group and 94% (16/17) in the 600 mg group. During faldaprevir plus pegylated interferon-α2a/ribavirin treatment, the most common adverse events were pruritus (38% of patients), rash (31%) and asthenia (31%); these were severe in approximately 3% of patients. CONCLUSIONS Potent antiviral activity and favourable safety of the treatment regimen were demonstrated. Furthermore, the results suggest that patients with breakthrough at week 4 may be rescued with an interferon-containing regimen. Clinical trials.gov number NCT01132313.

Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

ABSTRACT A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P = 0.47) or treatment naive (62% compared to 66%; P = 0.72).

66 SILEN-C2: SUSTAINED VIROLOGIC RESPONSE (SVR) AND SAFETY OF BI201335 COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN (P/R) IN CHRONIC HCV GENOTYPE-1 PATIENTS WITH NON-RESPONSE TO P/R

66 SILEN-C2: SUSTAINED VIROLOGIC RESPONSE (SVR) AND SAFETY OF BI201335 COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN (P/R) IN CHRONIC HCV GENOTYPE-1 PATIENTS WITH NON-RESPONSE TO P/R M.S. Sulkowski, M. Bourliere, J.-P. Bronowicki, A. Streinu-Cercel, L. Preotescu, T. Asselah, J.-M. Pawlotsky, S. Shafran, S. Pol, F.A. Caruntu, S. Mauss, D. Larrey, C. Hafner, Y. Datsenko, J.O. Stern, R. Kubiak, W. Bocher, G. Steinmann. Johns Hopkins University, Baltimore, MD, USA; Hopital Saint Joseph, Marseille, Hopital de Brabois, Vandoeuvre Cedex, France; “Prof. Dr. Matei Bals” Institute of Infectious Diseases, Bucharest, Romania; Hopital Beaujon, Clichy Cedex, Hopital Henri Mondor, Creteil, France; University of Alberta, Edmonton, AB, Canada; Hopital Cochin, Paris, France; Center for HIV and Hepatogastroenterology, Dusseldorf, Germany; Hopital Saint-Eloi, Montpellier Cedex, France; Boehringer Ingelheim Pharma, Biberach, Germany; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA E-mail: msulkowski@jhmi.edu