HTB

Cure rates with pipeline HCV drugs: reports from AASLD

1 December 2012. Related: Conference reports, Hepatitis coinfection, .

Tracy Swan, TAG

It is difficult to be anything other than dazzled by astounding cure rates of up to 100% from a multitude of interferon-free hepatitis C virus (HCV) clinical trials presented at the American Association for the Study of Liver Diseases (AASLD) meeting in November of 2012.

Proof-of-concept has been established: hepatitis C, a disease that claims more than 350,000 lives annually, can be cured with three months of oral antiviral drugs.

These incredible advances bear scrutiny, since most of these interferon-free trials enrolled people with minimal liver disease – many of whom were being treated for the first time. Information about safety, efficacy and tolerability of interferon-free regimens is needed in other groups, including people coinfected with HIV, liver transplant candidates and recipients, and people with cirrhosis (especially those who are treatment-experienced). These are also the people with the greatest immediate need of a safe and effective cure.

Cure rates for interferon-containing and interferon-free regimens have skyrocketed in HCV genotype 1, although in treatment-naive people certain factors such as HCV subtype (1a versus 1b), IL-28B genotype (CC versus non-CC), and extent of liver damage (advanced versus mild-to-moderate) may impair response to treatment (see Table 2. Update: Interferon-free regimens in HCV genotype 1, treatment-naïve).

When is a cure really a cure?

The term sustained virologic response (SVR) is used when the hepatitis C viral load (also called HCV RNA) remains undetectable after completing HCV treatment; it indicates that hepatitis C has been cured. SVR has been proven to lower the risk for liver-related illness and death, although people with pre-treatment cirrhosis should be monitored regularly, since they are still at risk for liver cancer.

With pegylated interferon and ribavirin, a person was considered cured when HCV RNA became undetectable during treatment and remained undetectable for 24 weeks after completing therapy (known as SVR-24). Recently, the U.S. Food and Drug Administration (FDA) regulators revised this time point from SVR-24 to SVR-12, since most post-treatment relapses (when HCV RNA becomes detectable after treatment completion) occur within 12 weeks. Thus, SVR-12 became the new primary outcome for clinical trials studying peginterferon-based regimens.

The hunger for information about cure rates from interferon-free regimens has led to earlier reporting of results; SVR-4 (undetectable HCV RNA four weeks after finishing treatment) is now commonly used. But with interferon-free regimens, SVR-4 does not always predict SVR-12, and SVR-12 does not always predict SVR-24. In fact, there have been two late relapses, between 24 and 48 weeks after treatment with an interferon-free regimen: one in Abbott’s PILOT trial [1] and one in Boehringer Ingelheim’s SOUND-C2 trial [2]. In both cases, treatment consisted of an HCV protease inhibitor, a non-nucleoside polymerase inhibitor and ribavirin. Although SVR-12 and SVR-24 are primary outcomes for interferon-free trials, monitoring for late relapse will continue.

Results from trials in both treatment-naive and treatment experienced people with HCV genotypes 2 and 3 were presented at AASLD (see Table 5. Update: HCV genotypes 2 and 3, treatment-naive and treatment-experienced).

In late November 2012, Gilead Sciences issued the somewhat disappointing top-line results from POSITRON, a 278-person, interferon-free phase III trial in HCV genotypes 2 and 3. POSITRON compared 12 weeks of sofosbuvir (a nucleotide polymerase inhibitor) and ribavirin to placebo in treatment-naive, interferon ineligible, intolerant or unwilling participants. [3] In HCV genotype 2, SVR-12 was close to 100%, but in HCV genotype 3, SVR-12 was only 61% (see Table 1. SVR in genotypes 2 and 3 by population and regimen).

In treatment naive people with HCV genotypes 2 and 3, interferon-free regimens offer the advantage of improved tolerability and ease of administration. But high prices will make these drugs unappealing to payers without a clear demonstration of improved efficacy, and the potential to fill unmet therapeutic needs.

In genotypes 2 and 3, a retreatment regimen – especially for people with HCV genotype 3 who do not have any options – should be prioritised by pharmaceutical companies. Sponsors need to develop safe, effective, tolerable and affordable regimens when no alternatives exist, in addition to improving the existing standard of care.

AASLD also brought good news for treatment-experienced people with HCV genotype 1 (see Table 3. Update: Interferon-free regimens in HCV genotype 1, treatment experienced). Phase 3 trials of DAA combinations, in both treatment-naive and treatment-experienced people, with and without peginterferon and/or ribavirin are ongoing or soon to be launched.

Although people with hepatitis C and their medical providers want to dispense with interferon and ribavirin, some people – especially null responders with HCV genotype 1a and IL28B non-CC genotypes – may require one or both drugs plus a combination of direct-acting antivirals (DAAs) for a cure. Therefore, regimens that shorten duration of pegylated interferon and/or ribavirin or substitute peginterferon lambda (a potentially more tolerable type of interferon) for peginterferon alfa, are moving forward (see Table 4. Update on interferon-based regimens in HCV genotype 1, treatment-naive and treatment-experienced).

AASLD brought good news for treatment-experienced people with HCV genotypes 2 and 3, since there is currently no recommended retreatment option when peginterferon and ribavirin are unsuccessful.

For treatment-naïve people with HCV genotypes 2 and 3, interferon-free regimens combining sofosbuvir (a nucleotide polymerase inhibitor) and ribavirin yielded cure rates similar to those achieved with the current standard of care (which is 24 weeks of peginterferon and ribavirin), but duration was shortened to 8 weeks. When daclatasvir (an NS5a inhibitor) was added, SVR increased but duration doubled from 12 to 24 weeks (see Table 5. Update: HCV Genotypes 2 and 3, Treatment-Naive and Treatment-Experienced).

Table 1. SVR in genotypes 2 and 3 by population and regimen
Regimen Population SVR Comment
Current standard of care: 24 weeks of peginterferon/ ribavirin.* HCV genotype 2, treatment naive 74% (SVR-24)
Current standard of care: 24 weeks of peginterferon/ribavirin.* HCV genotype 3, treatment naïve 69% (SVR-24)
ELECTRON trial: 12 weeks of sofosbuvir/ribavirin. HCV genotypes 2 and 3, treatment naïve,(N=10). 100% (SVR-24) [4] Gane et al.
POSITRON trial: 12 weeks of sofosbuvir/ribavirin. HCV genotype 2 treatment naive plus interferon ineligible, intolerant and unwilling, (N=120). 93% (SVR-12) [3] Gilead PR.

* European Society for the Study of Liver Diseases (EASL). EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. June 2011.

http://www.easl.eu/assets/application/files/4a7bd873f9cccbf_file.pdf (PDF file)

For people with HCV genotypes 4 and 6, big news came in a small group of treatment naive, non-cirrhotic people in the ATOMIC study, treated with 24 weeks of sofosbuvir, peginterferon and ribavirin. Of the 11 people with HCV genotype 4, 82% had an SVR-12 (two participants, who were responding to treatment, did not return for follow-up visits). In genotype 6, 100% of 5 people had an SVR-12. No relapses were reported between weeks 12 and 24. [19]

Adding an HCV protease inhibitor to peginterferon and ribavirin boosted SVR and shortened treatment duration for 30 non-cirrhotic, treatment-naive people with HCV genotype 4. The DAUPHINE trial studied 50, 100 or 200 mg of danoprevir/r (a boosted protease inhibitor) plus peginterferon and ribavirin for 24 weeks (with the exception of one arm, where treatment was response-guided; early responders stopped treatment at 12 weeks). Regardless of the danoprevir/r dose, or treatment duration, 97% achieved SVR-24 (one person was lost to follow up). In the response-guided arm, all seven participants were eligible for 12 week of treatment, and SVR-24 was 100%. [20]

Peginterferon lambda may be a good option for people with HCV genotype 4, if phase III trials confirm the favourable side effect profile seen in phase 2. The EMERGE trial (which compared safety, efficacy and tolerability of peginterferon alfa and ribavirin versus peginterferon lambda and ribavirin) included a small group of people with HCV genotype 4 (approximately 18; 12 received peginterferon lambda). [21] Although overall efficacy was comparable, lambda was significantly less likely to cause flulike symptoms and laboratory abnormalities such as anemia and neutropenia than peginterferon alfa-2a. [16]

HIV/HCV coinfection

Final results from a Phase 2 trial of telaprevir plus peginterferon and ribavirin in HIV/HCV coinfected people were presented at AASLD.

In this trial, there were no relapses between 12 and 24 weeks post-treatment: 74% of people who received telaprevir-based triple therapy versus 45% of people given peginterferon and ribavirin plus placebo achieved SVR-24.

Telaprevir levels were similar in study participants in the no-ART arm as well as those taking a boosted atazanavir-or efavirenz-based regimen; in turn, antiretroviral concentrations were not significantly altered by telaprevir, confirming results of earlier drug-drug interaction studies. [22]

Sofosbuvir is already being studied in HIV/HCV coinfected people with HCV genotypes 2 and 3; a clinical trial is comparing 12 vs. 24 weeks of sofosbuvir and ribavirin is ongoing.[23]

Results from drug-drug interaction (DDI) studies of sofosbuvir and commonly used antiretroviral agents were presented at AASLD. There were no clinically significant interactions between sofosbuvir and efavirenz, rilpivirine, boosted darunavir, raltegravir, tenofovir and emtricitabine in healthy volunteers. [24]

Pharmacokinetics and DDIs may be different in people with hepatitis C – especially those with advanced liver damage – and HIV-positive people, compared with healthy volunteers. Nonetheless, these results suggest that these drugs can be co-administered with sofosbuvir, though careful monitoring in clinical trials is still warranted.

Hopefully, the near future will bring more interferon-free trials to HIV/HCV coinfected people.

Table 2. Update: Interferon-free regimens in HCV genotype 1,treatment-naïve
Study, sponsor & regimen Population and size SVR (at 4,12 or 24 weeks post-treatment) SVR: HCV Genotype 1a vs. 1b SVR: IL-28b CC vs. non-CC Comment
AVIATOR Phase 2b.
Abbott Laboratories
Drugs (3 or 4): ABT-450/r (boosted protease inhibitor) with or without ABT-267 (NS5a inhibitor) with or without ABT-333 (non-nucleoside polymerase inhibitor) with or without ribavirin.
Duration: 8, 12 or 24 weeks		 Non-cirrhotic (N=438; 358 were treatment-naïve; for null responder data see Table 3. Update: Interferon-Free Regimens in HCV Genotype 1, Treatment Experienced). SVR-1287.5% in the 8-week 4-drug arm (N=80) vs. 97.5% in the 12-week, 4 drug arm (N=79). 8-week, 4-drug arm:86% in G1a versus 96% in G1b.12-week, 4-drug arm: 98% in G1a vs. 100% for G1b. In all 12-week, 3-drug arms: 82% to 88% for G1a vs. 100% for G1b. 8-week, 4-drug arm:96% in IL28b-CC vs. 85% in non-CC.12-week, 4-drug arm: 100% in IL-28B CC vs. 97% in non-CC. In 12-week, 3-drug arms: 86% to 100% in IL-28B CC vs. 85% to 88% in non-CC. [5] Kowdley et al.
SOUND-C2 Phase 2b.
Boehringer-Ingelheim
Drugs: faldaprevir (protease inhibitor) with BI 207127 (non-nucleoside polymerase inhibitor) with or without ribavirin.
Duration: 16, 28 or 40 weeks.		 (N=362; 329 non-cirrhotic and 33 with compensated cirrhosis). SVR-12: 39% to 69%non-cirrhotic (highest SVR-12 in the 28-week, twice- daily 207127 arm; N=78). 33% to 67%(in cirrhotic participants; the highest SVR-12 in the 28-week, twice daily 207127 arm). In 28-week, twice-daily 207127 arm: 85% for G1b vs. 43% for G1a. In 28-week, twice-daily 207127 arm: 84% in IL28b CC vs. 64% in non-CC. [6] Zeuzem et al.
AI444-040 Phase 2a.
Bristol-Myers Squibb/ Gilead Sciences
Drugs: daclatasvir (NS5a inhibitor) with sofosbuvir (nucleotide polymerase inhibitor) with or without ribavirin.
Duration: 12 or 24 weeks.		 Non-cirrhotic(N=126). SVR-4:95% to 98% in 12-week treatment groups (N=82).SVR-12: 93% to 100% in 24-week treatment groups (N=44). No impact on SVR. No impact on SVR. [7] Sulkowski et al.Gilead is now only developing an in-house regimen.
AI443-014 Phase 2
Bristol-Myers Squibb
Drugs: daclatasvir (NS5a inhibitor) with asunaprevir (protease inhibitor) with BMS-791325 (non-nucleoside polymerase inhibitor).
Duration: 12 or 24 weeks.		 Non-cirrhotic(N=32) SVR-424-week dosing group (N=16): 94% SVR-24
12-week dosing group (N=16): 94%		 No impact on SVR. No impact on SVR. [8] Everson et al.
ELECTRON Phase 2
Gilead Sciences
Sofosbuvir (nucleotide polymerase inhibitor) with ribavirin with or without GS-5884 (NS5a inhibitor)
Duration: 12 weeks		 Non-cirrhotic(N=50) SVR-4100% (25/25) for triple therapy with sofosbuvir plus RBV and GS-5885. SVR-12 84% (21/25) for sofosbuvir plus RBV. No impact on SVR. No impact on SVR. [9] Gane et al.
SPARE Phase 2
Gilead Sciences/NIH
Drugs: sofosbuvir (nucleotide polymerase inhibitor) with weight-based ribavirin dosing (WBD) or low-dose ribavirin (600 mg).
Duration: 24 weeks.		 (N=60) Most were African American, IL-28B non-CC and non-cirrhotic (N=43); a small group had advanced fibrosis or compensated cirrhosis (N=13). SVR-12Part 1. Non-cirrhotic, WBD ribavirin: 90% (9/10). Part 2. WBD RBV (included 24% with advanced fibrosis): 72% (18/25). Part 2. Low-dose RBV (including 28% with advanced fibrosis): 56% (14/25). No impact on SVR. No impact on SVR. [10] Osinusi et al.
Vertex Pharmaceuticals
Drugs: telaprevir (protease inhibitor) with VX-222 (non-nucleoside polymerase inhibitor) with ribavirin.
Duration: response guided, either 12 weeks triple (N=11) or 12 weeks triple plus 24 weeks of PEG/RBV if HCV RNA detectable at week 2 or 8 (N=27).		 Non-cirrhotic (N=46). SVR-12Overall 72%33/46. 12-week group: 82% (9/11). 36-week group: 89% (24/27). 100% (5/5 for 12 weeks of triple in G1b vs. 67% (4/6) in G1a.85% (11/13) in 36-week group in G1b vs. 93% (13/14) in G1a. Data not broken out by IL-28b genotype. [11] Sulkowski et al.
Table 3. Update: Interferon-free regimens in HCV genotype 1, treatment experienced
Study, sponsor & regimen Population and size SVR (at 4,12 or 24 weeks post-treatment) SVR: HCV Genotype 1a vs. 1b SVR: IL-28b CC vs. non-CC Comment
AVIATOR Phase 2
Abbott
ABT-450/r (boosted protease inhibitor) with ABT-267 (NS5a inhibitor) with ribavirin with or without ABT-333 (non-nucleoside polymerase inhibitor)
Duration: 12 or 24 weeks.		 Null responders, non-cirrhotic (N=133). SVR-1293% (42/45) for 4-drug regimen.89% (40/45) for ABT 450/r, ABT-267 and ribavirin(12-week treatment group only; follow up of 24-week treatment group is ongoing). 100% in G1b vs. 81% to 89% in G1a. 100% in IL28B CC vs. 89% to 93% in non-CC. [5] Kowdley et al.Regimen slightly more effective in G1b vs. G1a, and for IL28b CC vs. non-CC.
AI447-011 Phase
Bristol-Myers Squib
Drugs: daclatasvir (NS5a inhibitor) with asunaprevir (protease inhibitor),once- or twice-daily.
Duration: 24 weeks.		 Null responders (N=101), HCV genotype 1b only (N=38; 16%, or 8 people had advanced fibrosis). SVR-12, 65% (13/20) to 78% (14/18) for once- versus twice-daily asunaprevir. Enrollment in asunaprevir/daclatasvir arms limited to G1b due to lack of efficacy in G1a. All but one person was IL28b non-CC. Lok et al. [12]In this trial, the same combination, plus ribavirin, was given to people with HCV genotypes 1a and 1b.Peginterferon was added in G1a due to high rates of viral, breakthrough; in HCV genotype 1b, SVR-4 was 100%.
ELECTRON Phase 2
Gilead Sciences
Drugs: GS-5885 (NS5a inhibitor) with sofosbuvir (nucleotide polymerase inhibitor) with ribavirin
Duration: 12 weeks		 Null responders, (N=9), non-cirrhotic SVR-4, 100% (3/3). [9] Gane et al.Only 3/9 null responders have completed treatment; the other 6 are being followed.
MATTERHORN Phase 2.
Hoffman-La Roche
Drugs: danoprevir/r (boosted protease inhibitor) with mericitabine (nucleoside polymerase inhibitor) with ribavirin
Duration: 24 weeks		 Partial (N=23) and null responders (N=32) HCV genotype 1b, non-cirrhotic. SVR-12Partial responders: 39% (9/23)Null responders: 55% (17/31) All G1a patients added peginterferon due to high rates of virologic breakthrough and are not included. >90% were IL28b non-CC. [13] Feld et al.Baseline viral load higher in partial vs. null responder.

Compensated cirrhosis and pre-and post-transplant

Reports of pre-transplant cures are encouraging but severe adverse events and poor tolerability of triple therapy with peginterferon, ribavirin and an HCV protease inhibitor significantly limit use in “real-life” situations in people with compensated cirrhosis, especially those with a platelet count of <100,000/mm3 or serum albumin level of <35 g/L. [25]

In fact, one study conducted at a transplant center reported discontinuation rates among people with compensated cirrhosis of >60%. [26] Clearly, DAA combination trials are needed in people with cirrhosis, to avert transplantation or treat post-transplant reinfection.

In CRUSH-C, a 103-person trial of protease-inhibitor-based triple therapy in post-transplant, treatment efficacy is promising: 57% of participants had an early response; HCV RNA was undetectable during treatment, at week 4 and week 12. But treatment safety and tolerability, as well as management of drug-drug interactions with immunosuppressants complicate treatment in the post-transplant setting. Only 14% discontinued treatment for adverse events, but most participants required dose reductions of peginterferon, ribavirin or both drugs and/or growth factors, and 48% required blood transfusions. After starting protease inhibitors (90% telaprevir; 10% boceprevir), immunosuppressant dosing was adjusted (cyclosporine was reduced by 75%; tacrolimus by 90%); nonetheless, a third of participants experienced worsening renal function, and graft rejection was noted (during transition off of the protease inhibitor). [27]

There is a single post-transplant case report of successful interferon-and ribavirin-free treatment of severe, recurrent hepatitis C infection, cured with 24 weeks of daclatasvir and sofosbuvir. [28]

Other drugs may be combined to create interferon-and ribavirin-free regimens in the post-transplant setting: drug-drug interaction studies with simeprevir (TMC-435, a protease inhibitor currently in phase III) and sofosbuvir did not report clinically significant interactions with immunosuppressants in healthy volunteers. [19, 20]

These glimmers of hope need to materialise into trials and programs providing access to lifesaving drugs, the sooner the better.

Table 4. Update on interferon-based regimens in HCV genotype 1, treatment-naive and treatment-experienced
Study, sponsor and regimen Population and size SVR (at 4,12 or 24 weeks post-treatment) SVR: HCV Genotype 1a vs. 1b SVR: IL-28b CC vs. non-CC Comment
AI447-011 Phase 2.
Bristol-Myers Squibb
Drugs: daclatasvir (NS5a inhibitor) with asunaprevir (protease inhibitor) once-or twice-daily with peginterferon and ribavirin (QUAD).		 Null responders (N=101), 41 treated with QUAD. 95% (20/21) for once-daily asunaprevir QUAD vs.90% (18/20) for twice-daily asunaprevir QUAD. Most participants were G1a: 85% (17/20) in the twice-daily asunaprevir QUAD arm and 91% (19/21)in the once-daily asunaprevir QUAD arm. All participants were IL28b non-CC. [12] Lok et al.This trial had a third arm, combining daclatasvir, twice-daily asunaprevir and ribavirin (N=22). Ten of 18 with G1a had viral breakthrough; 8/18 added peginterferon and are being followed (one achieved SVR-4; 100% (4/4) G1b achieved SVR-4).
D-LITE Phase 2b.
Bristol Myers Squib
Drugs: peginterferon lambda and ribavirin with asunaprevir (HCV protease inhibitor) or daclatasvir (NS5a inhibitor).
Duration: 24 weeks or 48 weeks (response-guided).		 Treatment-naive, non-cirrhotic, N=119; data from early responders treated for 24 weeks (N=69). SVR-1276% (26/37) of the daclatasvir group; 75% (22/32) of the asunaprevir group. Both regimens more effective in G1b: 93% (13/14) of G1b in the daclatasvir group vs. 65% (15/23 of G1a; 91% (10/11) of G1b in the asunaprevir group vs. 67% (14/21) of G1a. Daclatasvir group, no difference (between IL28b CC vs. non-CC; asunaprevir group 90% (9/10) IL 28b CC vs. 68% (15/22). [14] Izumi et al.[15] Vierling et al.Daclatasvir more tolerable than asunaprevir. Additional data from Japanese substudy (N=14) in HCV genotype 1b: SVR-12 100% (8/8) in daclatasvir arm; 5/5 in asunaprevir arm.
EMERGE Phase 2b
Bristol Myers Squib
Drugs: peginterferon alfa-2a and ribavirin or peginterferon lambda and ribavirin.
Duration: 48 weeks.		 Treatment naive, non-cirrhotic, (N=197). SVR-24, ~39% for both peginterferons. Not reported. Not reported. [16] Muir et al.
Gilead Sciences Phase 2.
Drugs: GS-5885 (NS5a inhibitor) with GS-9451 (protease inhibitor) with peginterferon and ribavirin.
Duration: 6 or 12 weeks.		 Treatment-naive, non-cirrhotic, (N=123). SVR-1281% (39/48) in 6-week treatment arm;100% (40/40) in 12-week treatment arm. More effective in G1b; of the 8 treatment failures reported,75% (6 of 8) had G1a. All participants were IL28b CC. [17] Thompson et al.Interim analysis; some participants are still in post-treatment follow-up and results from people who did not have an early response not yet available.
MATTERHORN Phase 2.Hoffman-La Roche
Drugs: danoprevir/r (boosted protease inhibitor) with peginterferon and ribavirin (triple therapy) with or without mericitabine (nucleoside polymerase inhibitor) (QUAD)
Duration: for partial responders 24 weeks; for null responders 24 or 48 weeks.		 Treatment-experienced non-cirrhotic partial (N=99) and null responders (N=151). SVR-1256% (27/48) for partial responders triple therapy vs. 86% (43/50) for QUAD.84% (62/74) in null responders, 24 weeks of quad therapy; 48-week treatment group ongoing. 91% (19/21) for triple therapy in partial responders with G1b vs. 30% with G1a.96% (25/26) for QUAD in partial responders with G1b vs. 75% (28/24) with G1a.100% for QUAD in null responders with G1b vs. 73% (32/44) with G1a. More than 90% were IL28b non-CC. [13] Feld et al.[18] Jacobson et al.Regimen more effective in genotype 1b versus 1a. Although numbers were small, efficacy of triple and QUAD did not differ between people with mild to moderate liver fibrosis.
Table 5. Update: HCV genotypes 2 and 3, treatment-naive and treatment-experienced
Study, sponsor & regimen Population and Size SVR (at 4,12 or 24 weeks post-treatment) Comment
AI444-040 Phase 2
Bristol Myers Squibb and Gilea
Drugs: daclatasvir (NS5a inhibitor) with sofosbuvir (nucleotide polymerase inhibitor) with or without ribavirin
Duration: 24 weeks		 Genotypes 2 and 3, treatment-naive, non-cirrhotic (N=44) SVR-2488% (14/16) (sofosbuvir lead-in + daclatasvir)100% (14/14) (daclatasvir and sofosbuvir) 93% (13/14) daclatasvir, sofosbuvir and ribavirin [7] Sulkowski et al.Gilead is developing an in-house co-forumlation of sofosbuvir and GS 5885, their NS5a inhibitor rather than continuing co-development with BMS.
ELECTRON Phase 2
Gilead Sciences
Drugs: sofosbuvir with ribavirin with or without peginterferon
Duration: 8 weeks		 Genotypes 2 and 3, treatment-naive, non-cirrhotic(N=35) SVR-24100% (10/10) in triple-therapy arm (sofosbuvir plus peginterferon and ribavirin) SVR-12 64% (16/25) for sofosbuvir and ribavirin. [4] Gane et al
ELECTRON Phase
Gilead Sciences
Drugs: sofosbuvir with ribavirin
Duration: 12 weeks		 Genotypes 2 and 3, treatment-experienced, non-cirrhotic(N=25) SVR-1268% (17/25) [ 4] Gane et al. Regimen most effective with weight-based ribavirin dosing and 12-week vs. 8-week duration

References:

Unless stated otherwise, all references are to the 63 Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9-13 November 2012, Boston, Massachusetts. Abstract can be viewed online using the itinerary planner on the conference website. Free login required.

http://www.aasld.org

  1. Lawitz E, Poordad F, Kowdley KV, et al. A 12-week interferon-free regimen of ABT-450/r, ABT-072 and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-naïve HCV IL28B CC genotype-1-infected subjects. 47th Annual Meeting of the European Association for the Study of the Liver (EASL). 18-22 April 2012, Barcelona, Spain. Abstract 13.
  2. Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor faldaprevir (BI 201335) and the non-nucleoside NS5B inhibitor BI 207127± ribavirin: final results of SOUND-C2 and predictors of response. 63rd AASLD, 2012, Boston. Abstract 232.
  3. Gilead Press release. Gilead announces sustained virologic response rate of 78% from phase 3 study of sofosbuvir for genotype 2/3 hepatitis C infected patients. (27 November 2012).
    http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&ID=1761988&highlight=
  4. Gane EJ, Stedman CJ, Hyland RH et al. Once daily sofosbuvir (GS-7977) regimens in HCV genotype 1-3: The ELECTRON trial. 63rd AASLD, 2012, Boston. Abstract 229.
  5. Kowdley KV, Lawitz E, Poordad F, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT 267, ABT-333, and ribavirin achieves SVR12 Rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection. 63rd AASLD, 2012, Boston. Abstract LB-1.
  6. Soriano V, Gane EJ, Angus P, et al. Efficacy and safety of the interferon-free combination of faldaprevir (BI 201335)+ BI 207127 ± ribavirin in treatment-naive patients with HCV GT-1 and compensated liver cirrhosis: results from the SOUND-C2 study. 63rd AASLD, 2012, Boston. Abstract 84.
  7. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatisvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor) with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3. 63rd AASLD, 2012, Boston. Abstract LB-2.
  8. Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naive Patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. 63rd AASLD, 2012, Boston. Abstract LB-3.
  9. Gane EJ, Stedman CJ, Hyland RH et al. Once daily sofosbuvir (GS-7977) regimens in HCV genotype 1-3: The ELECTRON trial. 63rd AASLD, 2012, Boston. Abstract 229.
  10. Osinusi A, Heytens L, Lee YJ, et al. High efficacy of GS-7977 in combination with low or full dose ribavirin for 24 weeks in difficult to treat HCV infected genotype 1 patients. 63rd AASLD, 2012, Boston. Abstract LB-4.
  11. Sulkowski MS, Jacobson IM, Gane EJ. The safety of telaprevir in the absence of interferon and/or ribavirin: analysis of on-treatment data from the ZENITH trial. 63rd AASLD, 2012, Boston. Abstract 786.
  12. Lok AS, Gardiner DF, Hézode C, et al. Sustained virologic response in chronic HCV genotype (GT)1-infected null responders with combination of daclatisvir (DCV; NS5a inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV). 63rd AASLD, 2012, Boston. Abstract 79.
  13. Feld JJ, Jacobson IM, Jensen DM, et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine and ribavirin with or without peginterferon alfa-2a (40KD) in genotype 1-infected partial and null responders: results from the MATTERHORN study. 63rd AASLD, 2012, Boston. Abstract 81.
  14. Izumi N, Lataillade M, Chayama K, et al; D-LITE Study Team. First report of peginterferon lambda/ribavirin in combination with either daclatasvir or asunaprevir in HCV genotype 1 Japanese patients: early sustained virologic response (SVR4) results from the D-LITE Japanese substudy. 63rd AASLD, 2012, Boston. Abstract 284.
  15. Vierling JM, Lataillade M, Gane EJ, et al; D-LITE Study Team. Sustained virologic response (SVR12) in HCV genotype 1 patients receiving peginterferon lambda in combination with ribavirin and either daclatasvir or asunaprevir: interim results from The D-LITE study. 63rd AASLD, 2012, Boston. Abstract LB-9.
  16. Muir A, Hilson J, Gray T, et al; EMERGE Study Group. Peginterferon lambda-1a (lamdba) compared with peginterferon alfa-2a (alfa) in treatment naive patients with HCV genotypes 1 or 4: SVR24 results from EMERGE phase 2b. 63rd AASLD, 2012, Boston. 214.
  17. Thompson A, Shiffman M, Rossaro L, et al. Six weeks of an NS5a inhibitor (GS-5885) and a protease inhibitor (GS-9451) plus peginterferon and ribavirin achieves high SVR4 rates in genotype 1 IL28B CC treatment naive hepatitis C virus patients: interim results of a prospective, randomized trial. 63rd AASLD, 2012, Boston. Abstract 759.
  18. Jacobson IM, Jensen DM, Pol S, et al. Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon alfa-2a (40KD) and ribavirin with or without mericitabine in genotype 1-infected treatment-experienced patients with advanced hepatic fibrosis: the MATTERHORN study. 63rd AASLD, 2012, Boston. Abstract 82.
  19. Hassanein T, Lawitz E, Crespo I, et al; the ATOMIC Investigators. Once-daily sofosbuvir (GS-7977) plus PEG/RBV in treatment-naive patients with HCV genotype 1, 4, and 6 infection: The ATOMIC study. 63rd AASLD, 2012, Boston. Abstract 230.
  20. Hézode C,Shiffman ML, Cooper C, et al. Ritonavir-boosted danoprevir plus PegIFN alfa-2a/ ribavirin (P/R) demonstrates up to 100% SVR24 with 12 or 24 weeks of total treatment in treatment-naive patients with HCV genotype 4 infection in the DAUPHINE study. 63rd AASLD, 2012, Boston. Abstract 760.
  21. Rodriguez-Torres M, Ishak L, Fontana D, et al; EMERGE Study Group. Peginterferon lambda-1a (LAMBDA) shows superior viral response with improved safety and tolerability versus peginterferon alfa-2a (alfa-2a) in patients with chronic HCV infection (G 1/2/3/4): EMERGE phase 2b through week 12 results. 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL 2012), 16-19 February 2012, Taipei, Taiwan.
  22. Sulkowski MS, Sherman KE, Soriano V, et al; Study 110 Team. Telaprevir in combination with peginterferon alfa-2a/ribavirin in HIV/HCV co-infected patients: SVR24 final study results. 63rd AASLD, 2012, Boston. Abstract 54.
  23. ClinicalTrials.gov. Study to Investigate the Efficacy and Safety of GS-7977 Plus Ribavirin for 12 Weeks in Chronic Genotype 2 and 3 Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Co-Infected Subjects.
    http://www.clinicaltrials.gov/ct2/show/NCT01667731
  24. Kirby B, Mathias A, Rossi S, et al. No clinically significant pharmacokinetic drug interactions between sofosbuvir (GS-7977) and HIV antiretrovirals atripla®, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers. 63rd AASLD, 2012, Boston. 1877.
  25. Hézode C, Dorival C, Zoulim F, et al. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 455 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO20-CUPIC) in real-life setting. 63rd AASLD, 2012, Boston. Abstract 51.
  26. Gallegos-Orozco JF, Chervenak AE, Carey EJ, et al. Liver transplant center focused experience with peginterferon alfa-2a, ribavirin and telaprevir therapy in patients with genotype 1 hepatitis C cirrhosis. 63rd AASLD, 2012, Boston. Abstract 53.
  27. Burton JR, O’Leary J, Verna EC, et al. A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: report from the CRUSH-C group. 63rd AASLD, 2012, Boston. Abstract 211.
  28. Fontana RJ, Bifano M, Hindes R, et al. First ever successful use of daclatasvir and GS-7977, an interferon-free oral regimen, in a liver transplant recipient with severe recurrent hepatitis. 63rd AASLD, 2012, Boston. Abstract 694.
  29. Mathias A, Cornpropst M, Clemons D, et al. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants, cyclosporine A or tacrolimus in healthy volunteers. 63rd AASLD, 2012, Boston. Abstract 1869.
  30. Ouwerkerk-Mahadevan S, Simion A, Mortier S, et al. No clinically significant interaction between the investigational HCV protease inhibitor TMC435 and the immunosuppressives cyclosporine and tacrolimus. 63rd AASLD, 2012, Boston. Abstract 80.

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