Interferon-free hepatitis treatment is highly effective for people with HIV and HCV co-infection in three studies

David Wyles at IAS 2015. Photo by Liz Highleyman, hivandhepatitis.com

Three different interferon-free regimens – sofosbuvir/ledipasvir, AbbVie's 3D regimen and grazoprevir/elbasvir – were well-tolerated and cured more than 90% of participants with HIV and HCV co-infection in three clinical trials, confirming that HIV-positive people can respond as well as HIV-negative people to modern hepatitis C treatment, according to a set of reports presented at the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) last week in Vancouver, Canada.

It is estimated that about a third of people with HIV worldwide have hepatitis C virus (HCV) co-infection. Over years or decades, chronic hepatitis C can progress to serious liver disease including cirrhosis and liver cancer. People with HIV and HCV co-infection have faster disease progression than those with HCV alone, and liver disease is a leading cause of illness and death among people living with HIV. People with HIV do not respond as well to interferon-based hepatitis C treatment, but there is growing evidence that this is not the case for the new interferon-free direct-acting antiviral (DAA) regimens.

Sofosbuvir/ledipasvir

Curtis Cooper of the University of Ottawa presented findings from ION-4, a phase 3 trial evaluating the safety and efficacy of Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir – the drugs in the Harvoni coformulation – for people with HIV and HCV co-infection.

The study results were previously presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI) and are published in the July 21 advance edition of the New England Journal of Medicine.

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

subtype

In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

open-label

A clinical trial where both the researcher and participants know who is taking the experimental treatment. 

ION-4 enrolled 335 participants with HIV and HCV co-infection living in the US, Canada and New Zealand. Most (82%) were men, 61% were white, 34% were black and the mean age was 52 years. Almost all (98%) had HCV genotype 1 (75% 1a and 23% 1b), with a small number having genotype 4; the mean baseline HCV viral load was 6.7 log10. More than half were treatment-experienced, three-quarters had unfavourable IL28B gene variants and 20% had liver cirrhosis (Metavir stage F4).

Participants had a median CD4 cell count of 628 cells/mm3 and most had undetectable HIV viral load on antiretroviral regimens that included efavirenz (Sustiva; 48%), raltegravir (Isentress; 44%) or rilpivirine (Edurant; 9%), all with tenofovir/emtricitabine (the drugs in Truvada).

Everyone in this open-label study was treated with sofosbuvir plus ledipasvir taken as a once-daily single-tablet regimen for 12 weeks, without ribavirin. They were followed for an additional 12 weeks after treatment to assess sustained virological response (SVR12).

The overall SVR12 rate was 96% – similar to response rates seen in the other ION trials of HIV-negative people. Rates were similar for previously untreated and treatment-experienced participants (95% and 97%) and for people with and without cirrhosis (94% and 96%). Non-responders included 10 relapsers and two people with viral breakthrough while on therapy.

Surprisingly, being black was a significant predictor of poorer response (90% SVR12). People of African descent are known to respond less well to interferon, but so far this has not been seen in studies of people with HCV mono-infection treated with interferon-free DAA regimens. Drug levels were similar across racial/ethnic groups and the reason for the disparity remains unknown.

Sofosbuvir/ledipasvir was generally safe and well-tolerated with no treatment discontinuations due to adverse events. The most common side-effects were headache (25%), fatigue (21%), diarrhoea (11%) and nausea (10%). Participants maintained stable CD4 counts and none had confirmed HIV rebound.

Viekirax/Exviera

David Wyles from the University of California at San Diego presented results from an analysis of response predictors for people with HIV and HCV co-infection treated with AbbVie's 3D regimen in the phase 2/3 TURQUOISE-I trial. The main study results were previously reported at the 2014 AASLD (American Association for the Study of Liver Diseases) Liver Meeting.

The regimen consists of the HCV NS3/4 protease inhibitor paritaprevir, a ritonavir booster and the NS5A inhibitor ombitasvir in a once-daily fixed-dose coformulation (Viekirax), taken with the twice-daily non-nucleoside NS5B polymerase inhibitor dasabuvir (Exviera); in the US the complete regimen is sold together as Viekira Pak.

TURQUOISE-I enrolled 63 people with genotype 1 chronic hepatitis, living in the US. More than 90% were men, three-quarters were white, about 25% were black and the mean age was approximately 50 years. About 90% had harder-to-treat HCV subtype 1a and the mean baseline HCV viral load was approximately 6.0 log10. Two-thirds had not previously taken treatment while a third had previously tried interferon-based therapy (a mix of relapsers, partial responders and null responders). About 80% had unfavourable IL28B gene variants and 19% had cirrhosis.

The median CD4 count was approximately 630 cells/mm3 and they were on suppressive antiretroviral therapy (ART) containing atazanavir (Reyataz) or raltegravir (Isentress) plus Truvada – drugs found to have no clinically relevant interactions with the HCV regimen.

Participants in this open-label study were randomly assigned to receive the 3D regimen plus weight-based ribavirin for either 12 or 24 weeks.

Overall, 94% of participants in the 12-week arm and 91% in the 24-week arm achieved SVR12. Two people experienced virological failure: one post-treatment relapse in the 12-week group and one on-treatment viral breakthrough in the 24-week group. Again, treatment was generally safe and well-tolerated.

The current analysis looked at response rates across a variety of demographic and disease characteristics. However, given that there were just 63 participants in the trial, breaking them down into subgroups often yielded very small numbers.

There were no notable differences in the likelihood of response – with SVR12 rates exceeding 90% – based on sex, race/ethnicity, HCV subtype 1a or 1b, baseline HCV viral load, body mass index, diabetes status, history of injecting drugs, depression or bipolar disorder, baseline CD4 cell count or use of atazanavir vs raltegravir.

People over age 55 had a slightly lower response rate than younger people using the 12-week regimen (88% vs 100%), but this evened out when treatment was extended to 24 weeks.

The only groups with poorer response regardless of treatment duration were people with the least favourable 'TT' IL28B gene variant (89% in the 12-week arm and 80% in the 24-week arm), prior null responders (80% with either duration) and people with cirrhosis (83% with either duration). In fact, both participants with virological failure were people with cirrhosis, categorised as previous null responders with HCV subtype 1a and IL28B 'TT'.

In people with HIV and HCV genotype 1 co-infection, the 3D regimen plus ribavirin "achieved high rates of SVR12 regardless of baseline host, viral and disease characteristics whether treated with 12 or 24 weeks of therapy," the investigators concluded.

Grazoprevir/elbasvir

Finally, Jürgen Rockstroh from the University of Bonn in Germany presented final results from the phase 3 C-EDGE Co-infection study, which tested Merck's NS3/4 protease inhibitor grazoprevir and NS5A inhibitor elbasvir. This regimen is under review by the US Food and Drug Administration (FDA) with a decision expected in January 2016; Merck has said it plans to file for European approval by the end of 2015.

Results from this study were previously presented at this year's EASL (European Association for the Study of the Liver) International Liver Congress and published in the July 9 advance edition of The Lancet.

This trial included 218 previously untreated people with HIV and HCV co-infection in Europe, the US and Australia. More than 80% were men, three-quarters were white, 17% were black and the mean age was 49 years. Two-thirds had HCV subtype 1a, 20% had subtype 1b, 13% had genotype 4 and 1% (two people) had genotype 6. Nearly 60% had high baseline HCV viral load, which Prof. Rockstroh noted is characteristic of HIV and HCV co-infection. About two-thirds had unfavourable IL28B variants and 16% had cirrhosis.

Participants were either untreated for HIV with a CD4 count above 500 cells/mm3 (3%) or were on stable ART with more than 200 cells/mm3 (mean 613 cells/mm3) and undetectable HIV viral load. Antiretrovirals permitted in this study were raltegravir (52%), dolutegravir (Tivicay; 27%) or rilpivirine (17%), paired with a tenofovir (75%) or abacavir (21%) NRTI ‘backbone’.

Participants in this open-label trial received grazoprevir/elbasvir in a once-daily single-tablet regimen, without ribavirin, for 12 weeks.

The overall SVR12 rate was 96%, close to the rate for treatment-naive HIV-negative people in another C-EDGE trial. Response rates were similar for HCV 1a, 1b and 4 (97%, 96% and 96%, respectively), and both people with genotype 6 were cured. There were no significant differences in response according to sex, race/ethnicity, IL28B, baseline HCV viral load, antiretroviral regimen or cirrhosis (all 35 people with cirrhosis were cured). Five people – all but one with subtype 1a – relapsed after completing treatment; two of these had pre-existing NS5A resistance-associated viral variants at baseline.

Here too, treatment with grazoprevir/elbasvir was generally safe and well-tolerated, with no drug-related serious adverse events or discontinuations for this reason. The most common side-effects were fatigue (13%), headache (12%) and nausea (9%), which occurred at about the same frequency seen in studies of grazoprevir/elbasvir for HIV-negative people.

"Low rates of adverse events, once-daily administration and suitability for use in patients also receiving antiretroviral therapy suggest grazoprevir/elbasvir may represent a highly effective treatment option for patients with HCV/HIV co-infection," the researchers summarised.

Conclusion

Taken together, these studies add to the evidence that people with HIV and HCV co-infection can respond as well as HIV-negative people to interferon-free hepatitis C treatment.

Dr Cooper explained that historically, when using interferon, unless a person had a CD4 count over 500 cells/mm3 it was considered best to treat HIV first and get that virus under control and CD4 cell count up before starting hepatitis C treatment. But these days, with well-tolerated short-duration hepatitis C therapy, "there's a lot to be said for offering [hepatitis C] treatment to people with lower CD4 counts," he said. "If hepatitis C is cured, then we don't need to worry about drug-drug interactions and there may be superior CD4 recovery and fewer drug adverse events."

At the Second International HIV/Viral Hepatitis Co-infection Meeting preceding the IAS conference, Prof. Rockstroh, Jordan Feld of the University of Toronto and others discussed whether HIV-positive and HIV-negative people are really the same when it comes to hepatitis C treatment.

Current European and US hepatitis C treatment guidelines recommend the same regimens for people with or without HIV, save for taking into account potential drug-drug interactions with antiretrovirals

Prof. Rockstroh argued that people with HIV and HCV co-infection no longer need to be considered a 'special population'. Dr Feld, however, was more cautious, suggesting there are still some "subtle differences" between HIV-positive and HIV-negative people with HCV.

HIV may still be a factor when treating people with multiple predictors of poor response, such as genotype 1a prior null responders with cirrhosis. This may be a concern especially when pushing a regimen to its limits, for example shortening treatment to 8 weeks or less. In addition, most industry-sponsored hepatitis C treatment trials which have included people with co-infection, have enrolled people on ART with suppressed HIV and high CD4 counts, and those with less well-controlled HIV may not fare as well.

References

Naggie S et al. (Cooper C presenting) Ledipasvir/sofosbuvir for 12 weeks in patients co-infected with HCV and HIV-1. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0202, 2015.

You can download the slides of this presentation from the conference website.

A webcast of this presentation is available on the conference YouTube channel.

Naggie S et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. New England Journal of Medicine, July 21, 2015 (epub).

Wyles D et al. High SVR rates in HCV/HIV-1 co-infected patients regardless of baseline characteristics. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0203, 2015.

You can download the slides of this presentation from the conference website.

A webcast of this presentation is available on the conference YouTube channel.

Rockstroh J et al. High efficacy of grazoprevir/elbasvir in HCV genotype 1, 4, and 6-infected patients with HIV co-infection: the phase 3 C-EDGE co-infection study. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0206, 2015.

You can download the slides of this presentation from the conference website.

A webcast of this presentation is available on the conference YouTube channel.

Rockstroh J et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. The Lancet, July 9, 2015 (epub).

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