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.
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.||Lok et al.12 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).||Izumi et al.14 Vierling et al.15 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.||Muir et al.16|
|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.||Thompson et al.17 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.||Feld et al.13 Jacobson et al.18 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 Gilead
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||Sulkowski et al.7 Gilead is developing an in-house co-formulation of sofosbuvir and GS 5885, their NS5a inhibitor rather than continuing co-development with BMS.|
|ELECTRON Phase 2
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.||Gane et al.4|
Drugs: sofosbuvir with ribavirin
Duration: 12 weeks
|Genotypes 2 and 3, treatment-experienced, non-cirrhotic (N=25)||SVR-1268% (17/25)||Gane et al.4 Regimen most effective with weight-based ribavirin dosing and 12-week vs. 8-week duration|
The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.
|What Would an HIV Cure Mean for You?|
|Condomless Anal Sex Rising in U.S. MSM With or Without HIV Infection|
|If We Act to Remove Structural, Behavioral and Social Barriers, We Can End the HIV Epidemic With the Medicines We Already Have|
|This Week in HIV Research: Immune System Differences Could Produce bNAbs; New HIV Infections Are No Longer Falling; and Zoledronic Acid May Prevent Bone Loss|
|What's the Next Game-Changer in HIV Treatment?|