Dramatic advances at CROI for HCV treatment: telaprevir, boceprevir, faldaprevir, sofosbuvir, ABT-450, ABT-267, ABT-333 and ledipasvir

Sanjay Bhagani, Royal Free Hospital

The wealth of hepatitis C studies at CROI 2013 included two oral abstract sessions, a symposium, a young investigator session and numerous poster sessions.

These featured new drugs in co-infected patients and interferon-free combinations in mono-infected patients highlighting the clinical decisions for optimal management and timing of treatment. Several studies were also presented on drug-drug interactions.

New and pipeline treatments

The three new groups of drugs with direct activity against hepatitis C are NS3/4 protease inhibitors (first generation of which, telaprevir and boceprevir are already approved), nucleoside/tide and non-nucleoside NS5B polymerase inhibitors (generally furthest along in pipeline development) and NS5A inhibitors. Although the study design differs between studies the top line results in this report highlights the vibrant optimism for approaching therapies.

NS3/4 protease inhibitors

There were several studies using NS3/4 protease inhibitors with pegylated interferon plus ribavirin (pegIFN/RBV) in coinfected patients with HCV genotype 1 infection.

Results from two ANRS studies using telaprevir and boceprevir in HCV treatment-experienced patients were included as oral presentations. These two recently approved drugs that are already standard of care but require dosing three times a day. Approximately 30-35% of patients in both studies had F3/4 cirrhosis although, as with most of the studies at CROI, decompensated cirrhosis was an exclusion criteria. Treatment duration was 48 weeks although this was extended to 72 weeks for patients without early treatment responses.

An interim analysis at 16 weeks reported approximately 90% of patients using telaprevir and 50-70% using boceprevir had early treatment responses (ETR) defined as undetectable HCV RNA. This has a strong correlation to sustained virological response (SVR), irrespective of previous non-response to pegIFN/RBV. This included 70% patients with F4 cirrhosis in the telaprevir study.

However, side effects were significant. Approximately 10% patients on telaprevir discontinued before week 16, about 30% of participants had grade 3/4 side effects and 58% required erythropoietin. There were 67 grade 3/4 side effects reported by the 39 patients in the boceprevir study, including 21 serious adverse events.

Once-daily NS3/4 PIs: faldaprevir and simeprevir

Interim 12-week data in 308 HIV/HCV coinfected patients (239 naïve, 69 previous relapsers) was also presented for faldaprevir. This is a once-daily NS3/4 protease inhibitor in development with Boehringer Ingelheim. All patients also used pegIFN plus ribavirin and the majority were also on ART. [3]

This late-breaker oral presentation reported greater than 90% ETR in HCV treatment-experienced patients and 85% in those using HCV treatment for the first time. These results were equivalent to those seen in HCV monoinfection. Approximately 10% of patients reported serious side effects with 6% of patients discontinuing the study early due to tolerability.

Another two oral late-breakers presented interim 24-week results with simeprevir (TMC435). This is a once-daily NS3/4 protease inhibitor in development with Tibotec/Janssen. [4, 5]

One study included 50 HCV treatment-naïve patients and 14 prior non-responders. All patients used pegIFN plus ribavirin. Rapid viral response (RVR) rates were approximately 90% at week 4 but was lower in previous null responders. Overall, 15% of patients experienced HCV treatment failure (approximate breakdown: naïve 9%, previous relapsers 0%, previous partial responders 10%, previous null responders 36%). Approximately 30% of patients reported grade 3/4 with serious adverse events in 5% of patients and 4 discontinuations.

Interim results from a second study, combined simeprevir with the investigational nucleotide NS5B polymerase inhibitor sofosbuvir which is being developed by Gilead. This study was in prior non-responders, with some patients randomised to additional ribavirin but without using pegIFN. In the very small numbers of patients with longer follow-up data, sustained viral response (SVR) rates at week 4 and 24 were greater than 85%. The suggestion from this dataset was that when two effective DAAS are combined, even for previous IFN null-responders, ribavirin may not be required.

Shorter treatment duration: 12 weeks in acute HCV

Telaprevir with pegIFN plus ribavirin was also associated with higher response rates from shorter duration of treatment (compared to historical results using only pegIFN plus ribavirin) in a US study of acute HCV genotype-1 infection. The results were from a small single-arm open-label study in 18 men with HCV genotype 1 and health insurance that would cover telaprevir treatment. [6]

Patients with RVR at week-4 stopped treatment at week 12, with an additional 12 weeks of pegIFN plus ribavirin for two patents without RVR.

The SVR rate at 4 weeks after end of treatment was 83% (15/18 patients). Over 75% of these men had IL28B CC genotypes. Interpretation of these results is thus complicated by the difficulty of knowing whether some of these people may have spontaneously cleared HCV without treatment and whether the shorter duration of therapy may only be applicable to sub-set of patients with IL28B CC genotypes, as is already becoming apparent in chronic genotype 1 HCV monoinfection.

Drug interactions

The complexity of drug interactions with new HCV treatments was highlighted in several studies.

An interaction between telaprevir and ribavirin (RBV) in monoinfected patients appears to increase plasma levels of ribavirin by 1.5 fold and intracellular levels of RBV mono-, di- and tri-phosphates (by 2-3 fold). The mechanism for this is not yet unexplained, but this could explain the high rates of anaemia seen in the ANRS studies reported above. [7]

A poster reported that boceprevir increased plasma levels of the HIV NNRTI rilpivirine [GMR (90%CI) for AUC, Cmax and C24h levels was 1.39 (1.27, 1.52), 1.15 (1.04, 1.28), and 1.51(1.36, 1.68) respectively] but that this was not considered clinically significant and that no dose adjustment was necessary. [8]

CYP-mediated interactions between faldaprevir (FDV) and some ARVs in a study in uninfected volunteers reported that FDV exposure increased by 130% with darunavir/ritonavir (requiring an FDV dose reduction) and decreased with tenofovir, and efavirenz (by 22% and 35% respectively, both requiring FDV dose increase). FDV has no clinically significant affect on levels of darunavir or tenofovir [9]

The best source for this growing complex field is the HCV drug interaction website developed by Liverpool University. [10]

Interferon-free treatment in HCV monoinfection

Several studies in HCV monoinfected patients provided early results from other exciting pipeline HCV drugs often in interferon-free oral combinations.

A US NIH-sponsored phase II study in difficult to treat (mostly African-American patients with genotype 1, non-CC monoinfection) using sofosbuvir (NS5B nucleotide) plus high/low dose ribavirin, reported high week 4 and week 12 early response rates (>95% and 90%) but that significantly lower SVR rates 24-weeks post-treatment (48-70%) suggesting that full weight-base ribavirin dosing is still required. [11] This is different to the sofosbuvir/simeprevir combination (Cosmos study reported above).

An interferon free combination from Abbott used three new compounds: ABT450/ritonavir (PI), ABT 267 (NS5A inhibitor) and ABT-333 (non-nuceloside polymerase inhibitor), with and without ribavirin, reported SVR rates of around 90% or higher at 12 week post-treatment in treatment naïve patients and around 90% in prior null responders. They also reported very low rates of relapse in the 4-drug arm in prior null responders after 8 and 12 weeks of treatment (~12% and 1% respectively, with little or no association with high HCV viral load or IL28B HCV genotype. In a logistic regression analysis of the quadruple therapy arms, length of therapy less than 12 weeks was the only statistically significant factor associated with risk of relapse, but note that this study excluded cirrhotic patients. [12]

Simeprevir (TMC-435) plus sobosfuvir (GS-7977), with and without ribavirin, with both 12 week and 24 week treatment arms in genotype 1 prior null responders showed significantly reduced rates of rapid virologial responses (RVR week 4) in the two-drug arms, suggesting that ribavirin may affect viral kinetics.. However, early results (SVR4) showed little difference between the 12 and 24 week treatment groups, suggesting that 12 weeks may be possible even for prior null responders. [13]

Final results from another interferon-free combination using two Gilead compounds: sofosbuvir (NS5B nucleotide) plus ledipasvir (GS-5885; NS5A inhibitor), plus ribavirin, in patients with genotype1 monoinfection (25 treatment-naive and 9 previous non-reponders) reported 100% end of treatment responses and 100% 4-week post-treatment responses. [14]

The challenge in the current management of HCV/HIV coinfected patients is assessing who should use currently available, more difficult, but still successful treatments, and who may be able to wait for the treatment in development that are likely to be easier to tolerate.

This issue was the focus of a retrospective Spanish study looking at the risk of liver decompensation in 102 patients (86% were men) with HCV/HIV coinfection and with F3/F4 (57/43%) fibrosis over 12 years (median 5.6 years follow-up). [15]

Baseline characteristics included median (IQR) age was 39 (37-44) years, CD4 cell count 497 cells/mm3 (331-666) and 71% had undetectable HIV viral load.

The incidence of decompensation events per 100 patient years was 0.12 (95% CI: 0.05-0.28) cases vs 0.45 (0.26-0.78) for patients with F3 vs. F4 stage respectively at baseline. The probability of remaining free of decompenstation for patients with F3 vs F4 was: at 1, 3 and 5 years was 98% (88%-100%) vs 86% (71%-93%); 94% (82%-98%) vs 75% (59%-86%) and 84% (62%-94%) vs 59% (38%-75%) respectively (p=0.007).

Although baseline fibrosis F4 vs F3 only showed a borderline association [HR 2.7; 95%CI: 0.93-7.95; p=0.067), baseline platelet count <100 x 103 was significant associated with the risk of decompensation (HR 3.9: 95%CI 1.4-11.2; p=0.011). Predictors for progression also included F4 stage on biopsy or liver stiffness >14.6 KPa with Fibroscan.

Although the study concluded that patients with F3 fibrosis are at significant risk of decompensation over three years – the expected time needed for need drugs to become available – monitoring may help identify patients who have the lowest risks and where waiting may be appropriate.

Note: This article is based on a BHIVA feedback lecture that is posted online as a webcast. [16]

comment

This is a very exciting time for HCV coinfection.

While both telaprevir and boceprevir plus pegIFN and ribavirin continue to be standard of care and dramatically improve response rates in genotype 1 infection, treatment involves complex daily regimens, careful management of interactions with ARVs and other medications and side effects are difficult.

Although ribavirin is likely to continue to be needed with other oral HCV drugs that are furthest in the pipeline, treatment may be able to be shortened to 12 weeks with some combinations. These are generally once-daily drugs with fewer side effects, in all-oral combinations with very high rates of viral efficacy.

While results look impressive and encouraging these were generally interim analyses at early time points, and that patients with decompensated cirrhosis were not included.

Close monitoring is needed to determine the risks of deferring treatment for patients with the lowest risk for liver decompensation.

References:

Unless stated otherwise, references are to the Programme and Abstracts of the 20th Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2013, Atlanta.

http://www.retroconference.org

Cotte L et al. High early virological response with telaprevir-pegylated-interferon-ribavirin in treatment-experienced hepatitis C virus genotype 1/HIV co-infected patients: ANRS HC26 TelapreVIH study. 20th CROI, 2013. Oral abstract 36.
http://www.retroconference.org/2013b/Abstracts/46245.htm
Poizot-Martin I et al. ANRS-HC27 BocepreVIH interim analysis: high early virologic response with boceprevir + pegylated interferon + ribivirin in hepatitis C virus/HIV co-infected patients with previous failure to pegylated interferon + ribivirin. 20th CROI, 2013. Oral abstract 37.
http://www.retroconference.org/2013b/Abstracts/46522.htm
Dieterich D et al. STARTVerso 4: high rates of early virologic response in hepatitis C virus genotype 1/HIV co-infected patients treated with faldaprevir + pegylated interferon and ribavirin. 20th CROI, 2013. Late breaker oral abstract 40LB.
http://www.retroconference.org/2013b/Abstracts/47927.htm
Dieterich D et al. Simeprevir with pegylated interferon/ribavirin in patients co-infected with chronic hepatitis C virus and HIV-1: week-24 interim analysis of the TMC435-C212 study. 20th CROI, 2013. Late breaker oral abstract 154LB.
http://www.retroconference.org/2013b/Abstracts/47929.htm
Lawitz E et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders. 20th CROI, 2013. Late breaker oral abstract 155LB.
http://www.retroconference.org/2013b/Abstracts/47930.htm
Fierer D et al. Telaprevir for acute hepatitis C virus in HIV+ men both shortens treatment and improves outcome. 20th CROI, 2013. Late breaker oral abstract 156LB.
http://www.retroconference.org/2013b/Abstracts/48077.htm
Hammond K et al. Increased plasma and intracellular ribavirin concentrations associated with telaprevir use. 20th CROI, 2013. Oral abstract 34.
http://www.retroconference.org/2013b/Abstracts/47368.htm
Rhee E et al. Absence of a significant pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and HIV-1 NNRTI rilpivirine.20th CROI, 2013. Poster abstract 537.
http://www.retroconference.org/2013b/Abstracts/46133.htm
Sabo J et al. Pharmacokinetic interactions of darunavir/ritonavir, efavirenz, and tenofovir with the hepatitis C virus protease inhibitor faldaprevir in healthy volunteers. 20th CROI, 2013. Oral abstract 35.
http://www.retroconference.org/2013b/Abstracts/46357.htm
Liverpool University Drug Interractions website.
http://www.hiv-druginteractions.org/
Osinusi A et al. High efficacy of sofosbuvir with weight-based ribavirin for 24 weeks in difficult-to-treat patients. 20th CROI, 2013. Oral late breaker abstract 157LB.
http://www.retroconference.org/2013b/Abstracts/47966.htm
Lawitz E et al. 12 weeks of ABT-450/ritonavir, non-nucleoside inhibitor and ribavirin achieved SVR24 in >90% of treatment-naïve hepatitis C virus GT1 patients and 47% of prior non-responders. 20th CROI, 2013. Oral abstract 38.
http://www.retroconference.org/2013b/Abstracts/46137.htm
Lawitz E et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders. 20th CROI, 2013. Oral late breaker abstract 155LB.
http://www.retroconference.org/2013b/Abstracts/47930.htm
Gane E et al. ELECTRON: 100% suppression of viral load through 4 weeks’ post-treatment for sofosbuvir + ledipasvir (GS-5885) + ribavirin for 12 weeks in treatment-naïve and -experienced hepatitis C virus GT 1 patients. Oral late breaker abstract 41LB.
http://www.retroconference.org/2013b/Abstracts/47869.htm
Macias J et al. Risk of decompensation of cirrhosis among HIV/Hepatitis C virus Co-infected individuals with advanced fibrosis: implications for the timing of therapy against hepatitis C virus. 20th CROI, 2013. Poster abstract 727.
http://www.retroconference.org/2013b/Abstracts/46929.htm
Bhagani S. CROI 2013: hepatitis/TB and opportunistic infections and malignancies. BHIVA feedback workshop.
http://www.bhiva.org/CROI2013-Bhagani.aspx