HCV: 4 Weeks Too Short for Treatment With New Drugs

Medscape Medical News

HCV: 4 Weeks Too Short for Treatment With New Drugs
Veronica Hackethal, MD
November 24, 2015

Four weeks of triple or quadruple combination therapy using new drugs for hepatitis C virus (HCV) results in only limited cure rates in patients with early-stage liver fibrosis, according to a study published online November 23 in the Annals of Internal Medicine.

"In this proof-of-concept study involving treatment-naive noncirrhotic patients with chronic HCV genotype 1 infection, 4 weeks of treatment with ledipasvir, sofosbuvir, and GS-9451 with or without GS-9669 was well-tolerated; however, only 30% (15 of 50) of patients achieved [a sustained viral response at 12 weeks]," write Anita Kohli, MD, from the University of Maryland, Baltimore, and colleagues "Thus, a treatment duration of 4 weeks with 3 or 4 potent [direct-acting antivirals] is not sufficient to cure HCV infection in most patients."

Current treatment regimens for HCV require 12 or more weeks of therapy. Shorter-term regimens have the potential to simplify therapy, increase adherence, reduce toxicity, and increase cost-effectiveness.

A previous study with the investigational drugs GS-9451 (a protease inhibitor) and GS-9669 (a nonnucleoside polymerase inhibitor), combined with ledipasvir and sofosbuvir, showed a sustained viral response rate of 95% (39 of 40 patients) in just 6 weeks.

To try to abbreviate therapy further, Dr Kohli and colleagues designed the current trial. The open-label nonrandomized phase 2a trial took place at the National Institutes of Health Clinical Center in Bethesda, Maryland, from January 2014 to May 2015. It included mostly African Americans (76%; 38/50), who are disproportionately affected by the HCV epidemic. Participants had not been previously treated and had early-stage liver fibrosis. Most were male (72%; 36/50) and had HCV 1a genotype (68%; 34/50).

Researchers divided participants sequentially into two groups. Twenty-five participants received a triple drug regimen of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks. The second group of 25 participants received the four-drug regimen of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. Dosages included ledipasvir 400 mg and sofosbuvir 90 mg as a single combination tablet taken once daily, GS-9451 80 mg once daily, and GS-9669 250 mg once daily. All but one patient completed the trial.

Among participants in the triple-drug group, 10 patients (40%; 95% confidence interval [CI], 21% - 61%) reached a sustained viral response at 12 weeks, defined as unquantifiable HCV RNA levels at week 12, as did five patients (20%; 95% CI, 7% - 41%) in the four-drug group.

At baseline, 10 participants had HCV variants that increased resistance to at least one of the antivirals in the study. All these participants experienced viral relapse.

Adverse events, mostly mild, occurred among 48% (12/25) of patients in the triple-drug group and 72% (18/25) in the four-drug group. None of the patients discontinued therapy because of adverse events.

Lower baseline viral load, younger age, HCV genotype 1b, and absence of resistance mutations were linked to increased likelihood of a sustained viral response at 12 weeks. This subgroup may achieve acceptable response rates using a 4-week regimen, the authors suggest, and the possibility warrants further investigation.


"Our data suggest that for most patients, a treatment duration longer than 4 weeks is required to achieve [a sustained viral response]," they conclude. "However, some patients are capable of achieving [a sustained viral response] with 4 weeks of therapy, which could be attributable to the presence of several favorable factors, such as early fibrosis, low viral burden, and absence of [resistance-associated variables]."

The nonrandomized nature of the study and small sample size could have limited the study.

One or more coauthors reports research agreements, grants, personal fees, and/or stock ownership in one or more of the following: National Institutes of Health, Gilead Sciences, Merck, Pfizer, Johnson & Johnson, and Bristol-Myers Squibb. Two coauthors were employees of Gilead Sciences.

Ann Intern Med. Published online November 24, 2015. Abstract

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Advances in the Treatment of Hepatitis C

Advances in the Treatment of Hepatitis C as seen at CROI 2014

March 28, 2014
By Mariel Selbovitz
Source

The opening day of the 21st Conference on Rtroviruses and Opportuistic Infections (CROI 2014) featured a press conference on advances in the treatment of hepatitis C, with a focus on how new drugs may be used in the real world, given barriers such as high cost and a shortage of experienced medical providers.

As new Hepatitis C drugs are approved, more clinical trial options become available and interferon-free regimens near FDA approval, Hepatitis C treatment is changing rapidly. Several presentations at CROI 2014 focused on what has become the ever-evolving face of Hepatitis C treatment.

Anita Kohli presented data from the first three arms of the eight arm SYNERGY study1. The objective of the SYNERGY study is to use multiple drugs to target various stages of the HCV life cycle with the goal of shortening the duration of therapy.

Twenty treatment-naive patients were enrolled in each of the study arms for a total of 60 study participants. Four different drugs were used (2 as a co-formulated fixed dose tablet) to target different stages of the Hepatitis C life cycle.

Sofosbuvir is a nucleotide NS5B polymerase inhibitor and Ledipasvir is an NS5A inhibitor, both of which were used in all three arms as a fixed dose tablet. In the first arm, this regimen was given for 12 weeks. In the second arm, GS-9669, a non-nucleoside NS5B polymerase inhibitor (which works at a different site in the NS5B region than Sofosbuvir), was added. The third arm consisted of Sofosbuvir/Ledipasvir and GS-9451. GS-9451 is a protease NS3/4 inhibitor.

The study population reflected what researchers felt was an accurate representation of the HCV patient population in the U.S. and was a difficult to treat cohort. Across the three arms of the trial the average age of participants were 54- 57; 65- 80% were male, 80-95% were black, 55- 85% had Genotype 1a and 15-45% had genotype 1b. 75-90% maintained an unfavorable Il-28B genotype of CC or TT, 65- 75% had a viral load of greater than 800, 000 IU/mL and 25-40% had stage 3 or 4 liver disease.

Study results showed that 59 of the 60 patients across all 3 arms achieved SVR 12, and that 39 of the 40 patients in the two 6 week arms achieved SVR 12 after 6 weeks of therapy.

In the Sofosbuvir/Ledipasvir group all patients were virally suppressed below the level of quantification by week 4 and remained suppressed at SVR12. In the Sofosbuvir/Ledipasvir and GS-9669 group all patients were virally suppressed by week 4 and remained suppressed at end of treatment. One African American male with stage 3 liver disease, a high viral load and genotype 1a relapsed at week 4. All other patients achieved SVR12 in this arm. In the Sofosbuvir/Ledipasvir and GS-9451 arm, all patients were virally suppressed at week 4 and remained suppressed at SVR12.

Blood draws were taken over the initial 36 hours following the first medication dose on a subset of patients (n=29). Viral kinetic analysis was performed to determine if the addition of a third agent could enhance viral clearance of HCV and to develop a future model of treatment with combination regimens that could possibly shorten therapy even further.

Researchers found the 3 drug regimen of Sofosbuvir/Ledipasvir and GS-9451 led to a significantly faster decline of virus than the other 2 regimens, at day 7, day 14 and day 21.

Rapid normalization was seen of ALT and AST across all arms with 90-100% normalization by day 14.

No deaths or discontinuations occurred. All regimens were well tolerated. The highest percentages of adverse events were headache, which was seen in 25% of the Sofosbuvir/Ledipasvir group and 25% of the Sofosbuvir/Ledipasvir and GS-9669 group, and diarrhea at 5% in the Sofosbuvir/Ledipasvir group, 25% in the Sofosbuvir/Ledipasvir and GS-9669 group and 15% in the Sofosbuvir/Ledipasvir and GS-9451 group. Two grade 3 adverse events occurred but were not related to study drugs. One was site pain from a liver biopsy and the second was vertigo in a patient with a history of severe vertigo reported at baseline.

There were 11 grade 3 laboratory abnormalities in 9 patients:
In the Sofosbuvir/Ledipasvir arm there was one case each of elevated ALT, elevated AST, elevated LDL, hyperglycemia and hypoglycemia
In the Sofosbuvir/Ledipasvir and GS-9669 arm, 2 patients experienced a-symptomatic Hypophosphatemia
In the Sofosbuvir/Ledipasvir and GS-9451 one patient who had a history of anemia experienced decreased hemoglobin and three patients experienced elevated serum creatine but 2 had been elevated at baseline and the third developed renal insufficience after initiating 1600 mg/daily ibuprofen; all three returned to normal.

While most clinical trials of next-generation hepatitis C drugs are sponsored by pharmaceutical companies, the National Institutes of Allergy and Infectious Diseases (NIAID) is conducting parallel studies in underserved populations, looking for simple, well-tolerated treatments for people prone to difficulties with poor adherence and side effects. In the NIAID SYNERGY study, Anita Kohlifrom the National Institutes of Health and colleagues evaluated brief interferon- and ribavirin-free oral DAA regimens using a fixed-dose coformulation of Gilead Science’s recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885).

The SYNERGY studied found overall that 6 weeks of treatment with 3 Hepatitis C drugs that targeted different steps of the Hepatitis C viral life cycle was safe and efficacious, had a very high rate of viral clearance and offered a shorter course of treatment with fewer side effects then the currently available treatment.

Several new drugs and drug combinations are proving to be safe and efficacious for use in HCV patients. Trevor Hawkins of Southwest CARE Center in Sante Fe, New Mexico presented data on all-oral combination Daclatasvir, Asunaprevir and BMS-791325 for the treatment of HCV Genotype 12.

Daclatasvir (DCV) is a once- daily NS5A replication complex inhibitor that has been studied in over 5,500 patients and has been found to have a potent pan-genotypic activity in vitro. Asunaprevir (ASV) is a twice-daily, NS3 protease inhibitor that has been studied in over 2,000 patients and is active against genotypes 1,4,5, and 6 in vitro. BMS-791325 is a twice-daily, non-nucleoside NS5B polymerase inhibitor that is active against genotypes 1,3,4,5 and 6 in vitro. Various dose and drug-to-drug interactions have been seen with all three drugs.

A1443-014 is a randomized, phase IIb, 2 arm, 166 patient, open label study where patients received study drug for 12 weeks with follow-up to SVR 48. Patients were stratified by genotype 1a or 1b and whether or not they had biopsy-confirmed cirrhosis, receiving either DCV 30 mg BID +ASV 200 mg BID + BMS-791325 75 mg BID or DCV 30 mg BID+ ASV 200 mg BID+ BMS-791325 150 mg BID.

Researchers felt the study participant demographics were common for HCV clinical trials with an average 67% of the two arms being male; average age was 54, 83% were white and 16% African American. 82% had genotype 1a and 18% had genotype 1b and 38% had either FIB-3 or FIB-4 as determined by FibroSure/FibroTest. Those with FIB-4 received biopsies and an average 9% of the two arms had cirrhosis. Two/thirds were non-CC.

Study results found 92% of study participants achieved SVR. All treatment failures occurred in Genotype 1a. There were no predictors of failure other than Genotype.

In the DCV+ASV+BMS-791325 75 mg arm, 71/77 achieved SVR-12. The most frequent adverse events in this group were headache at 21.3%, diarrhea at 15%, fatigue at 15% and nausea at 12.5%. Grade 3/4 lab abnormalities included high AST in 1 patient and high glucose fasting serum in 1 patient.

In the DCV+ASV+ BMS-791325 150mg., 77/84 patients achieved SVR-12. In this arm the most frequent adverse events were headache in 27.9%, diarrhea in 15.1% and fatigue and nausea in 8.7% each. Grade 3/4 lab abnormalities included high glucose fasting serum in 1 patient and high bilirubin in 1 patient. There was 1 discontinuation due to adverse events and one patient discontinued BMS-791325 only and added peg/IFNa/RBV for 12 weeks.

Both regimens were found to be safe and effective and researchers recommend the continuation of clinical trials into Phase III trials.

Vincent LoRe from the University of Pennsylvania reported on a multi-site Veterans Administration (VA) study3, which analyzed predicting risk of end-stage liver disease (ESLD) in HIV/HCV co-infected patients for individualized HCV therapy decisions. The study evaluated the efficacy of utilizing laboratory and clinical variables to predict end-stage liver disease in HIV/HCV patients.

Researchers utilized data from the Veterans Aging Cohort Study (VACS) to identify 4,280 co-infected patients in the VA, all of who had been on HIV antiretroviral therapy for at least one year. Data was gathered of baseline predictors that included diabetes, Hepatitis B, race, obesity, a viral load greater than 400 c/mL, CD4 count below 200 cells/mm3 and a class 4 Fibrosis rating, from the initial year on therapy.

Study participants were followed for a total of 6.8 years where researchers found 8% of patients had developed ESLD as defined by hepatic liver decomposition, hepatocellular carcinoma or liver-related death.

Researchers discovered that utilizing Fibrosis 4 rating may be an effective means of means of predicting ESLD over time and could help to inform HCV treatment decisions. Additional predictors that were measured with FIB-4 were insufficient in adding greater predictability. Ongoing analysis continues for additional predictors.

REFERENCES
Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Results from the SYNERGY Trial A Kohil et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22048?mediaType=slideVideo&)
All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection GT Everson et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22046?mediaType=slideVideo&)
Predicting Risk of ESLD in HIV/HCV Patients for Individualized HCV Therapy Decisions V Lo Re et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
(http://www.croiwebcasts.org/console/player/22196?mediaType=slideVideo&)