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International Liver Congress Offers Insight on the ‘Social Science’ of HCV

This month’s issue has a very nice summary of the data on therapeutic regimens presented at the International Liver Congress by Nancy S. Reau, MD. For me, the meeting highlighted how high is the summit to which we’ve climbed after years of a massive international effort to cure HCV, and how much the focus is shifting. We heard little about new HCV regimens and instead focused on real-world data sets on existing regimens and, equally important, the theme that HCV treatment has become as much of as social science as a medical one as we strive toward elimination. We saw an appropriate emphasis being placed on screening, linkage and access to care, including underprivileged and high-risk populations, on a national and global scale.

I encourage you to turn to Dr. Reau’s summary for specific data that emerged from real-world studies. I do heartily agree with her sentiment that despite the favorable data from one study of 8 weeks of therapy in genotype 3, this is not something crying out for a shortening of our regimens our currently recommended for 12 weeks for this genotype.

It also remains apparent that genotype 3-infected patients with certain baseline resistant variants or resistance associated substitutions (RASs) appear to benefit from the benefit of the addition of ribavirin, particularly treatment experienced cirrhotics, and we should remember that the AASLD guidelines still say we should add ribavirin in the case of baseline RASs for treatment-naive cirrhotics and even for treatment experienced non-cirrhotics.

Ira M. Jacobson

Although Vosevi (sofosbuvir/velpatasvir/voxilaprevir; SOF/VEL/VOX, Gilead Sciences) is not approved for patients other than DAA failures, the suggestion in the AASLD Guidance that the regimen can be considered instead of Epclusa (sofosbuvir/velpatasvir, Gilead Sciences) and ribavirin for these genotype 3 patients makes a lot of sense (it is actually preferred for the genotype 3 interferon-experienced cirrhotics even though not indicated in the package insert). The triple regimen is better tolerated and from an antiviral potency point of view, it is very tempting to think that voxilaprevir has to be a better choice than ribavirin as the third drug in the regimen.

Global View

I was impressed at the meeting with the national and global efforts to focus on needy populations such as intravenous drug users who clearly benefit from collaborations between HCV treaters and addiction medicine specialists, with very high SVR rates being attained in the presented models.

Such collaborations can ensure that recent or active drug users receive the opioid substitution therapy they need and that strategies geared toward harm reduction can continue to be implemented after the patient has finished with treatment to eliminate or minimize the risk for reinfection.

We also saw studies from places as diverse as the Punjab, Iceland and Georgia as well as several European countries which have implemented an EU funded project called HepCare Europe focusing on vulnerable patients, including the use of trained peers who can connect with underserved populations in effective ways.

Refinement, Benefits

One of the remaining important refinements of therapy that we need is strategies for how to treat patients who fail DAA regimens. The database from pivotal trials for SOF/VEL/VOX in DAA failures is larger than that for Mavyret (glecaprevir/pibrentasvir; GP, AbbVie), which is approved for 16 weeks only in genotype 1 DAA failures, accounting in part for the preferred status of 12 weeks of SOF/VEL/VOX in DAA failures accorded by the AASLD Guidance. From TARGET we saw an interim report presented by Anna S. Lok, MD, FAASLD, on more than 200 patients who achieved high levels of SVR4 with GP plus ribavirin for 12 or 16 weeks, with the best results so far with 16 weeks of GP without ribavirin. We’ll await final data in the future. We also saw some nice data from David L. Wyles, MD, on GP failures who did well when they received GP plus sofosbuvir, a regimen that might be difficult to access in many settings because of the expense and lack of an indication for this purpose in the package insert. Payers should recognize, though, that some sort of salvage therapy must be offered to the few patients who fail our current pangenotypic regimens. The overarching mantra should always be “no patient left behind.”

We also saw an abundance of follow-up data continuing to demonstrate the benefits that accrue to patients who had an SVR following DAA therapy. It is no surprise that the theme emerging from these studies mirrors what we saw in interferon therapy, which is that both liver-related and systemic benefits accrue. It was even suggested that DAA therapy is associated with a lower risk for subsequent non-hepatic cancers, a provocative notion that certainly deserves further attention.

As I read it, there continues to remain a preponderance of evidence suggesting that attainment of SVR in patients with a history of HCC treated with ablation or locoregional therapy do not have an increased risk for recurrence after the attainment of virologic cure, but there do remain proponents of the countervailing view.

On the other hand, the notion put forward a couple years ago that de novo HCC may also be sparked by attainment of virologic cure seems to be firmly disproven. There is consensus, however, reflected in the society guidance documents, that patients with advanced fibrosis or cirrhosis who achieve SVR on DAA therapy need ongoing HCC surveillance with no well-defined stopping point at this time.

Hepatitis B

As someone who has devoted most of his career to intensive immersion in the world of HCV, the EASL meeting represented an inflection point for me in terms of the greater amount of time I devoted to attending sessions on fatty liver disease and hepatitis B. Both of these fields are rapidly coming to dominate the investigative clinical trials arena and represent fascinating challenges and areas of major unmet need in the years to come.

The efforts in HBV center on the search for “functional cure,” interpreted by most observers as tantamount to clearance of HBsAg, since we have long since attained the capacity to effect long-term viral suppression. Unfortunately, we succeed in effecting HBsAg clearance in only a minority of patients, and long-term suppressive therapy is usually required.

At EASL we saw studies in several classes including capsid assembly modulators, or CAMs, of which there are two major classes. We are seeing data from agents in this class such as JNJ-56136379 (Janssen), and ABI-H0731 (Assembly Biosciences) and RO7049389 (Hoffman-La Roche) that show promising levels of viral suppression.

We are also seeing a resurgence of interest in siRNAs, such as ARC-520, ARO-HBV and ARB1467, which can be designed to suppress the expression of viral proteins, with several potential benefits including the triggering, with HBsAg suppression, of a hitherto virally suppressed host endogenous immune response that might contribute to the clearance of infected cells. There is increasing evidence in support of this hypothesis that needs further exploration.

We saw interesting data on an HBV RNA destabilizer in combination with other agents and on immunologic approaches including an oral RIG-I agonist, inarigivir, a RIG-I agonist. The latter agent may also have a separate direct antiviral effect.

Intriguingly, evidence recently emerged that in HBeAg-negative patients the surface antigen is expressed predominantly off the viral DNA integrated into human chromosomes, not the minichromosomal ccc DNA from which most HBsag expression appears to occur in HBeAg positive patients. The prospect of having functional cure reflected by HBsAg clearance when the origin of HBsAg is different in different patient populations, especially when expressed from integrated DNA, will be an interesting challenge in the coming years.

Finally, there were promising data from the final results of a study on an entry inhibitor – Myrcludex (MYR Pharma) – a hepatitis B entry inhibitor being studied for both chronic hepatitis B and hepatitis D.

The final results from Heiner Wedemeyer, MD, et al, of 6 months of treatment with this agent showed ongoing reduction of HDV RNA in the blood of infected patients at the 6-month time point and represents a new promise for these patients who have only interferon to rely upon with suboptimal results and considerable tolerability issues. It leaves us wondering if a more prolonged period of therapy will be able to suppress the virus completely, with the authors suggesting 2 to 3 years based on modeling.

NAFLD and NASH

The world of fatty liver disease continues to be characterized by an almost bewildering assortment of therapeutic targeting efforts and a plethora of clinical trials, a few of which are in phase 3 but most of which are phase 2 or earlier. Indeed, there was a host of studies on preclinical models in fatty liver presented at the EASL meeting.

What we are witnessing are pharmacologic attempts to target any one or more of the variety of pathways that cumulatively play a role in the pathogenesis of this complex disease. We are seeing a variety of approaches that support the further development of various drugs that can either improve or resolve the histologic features of steatohepatitis and/or have antifibrotic effects. Indeed, there is lively debate on whether steatohepatitis resolution or fibrosis regression should be our major endpoint; perhaps we should have the flexibility to allow for either or both, depending upon the putative mechanism of action of the agent being studied.

We saw data from a pipeline that contains several agents with different mechanisms of action where the agents were studied either singly or in dual combinations and it was clear that with the acetyl-CoA carboxylase inhibitor in the regimen we can inhibit de novo lipogenesis in the liver and steatosis with it. There were other interesting data from this study, and the agents in different combinations are progressing to a larger trial, but for the present discussion its major importance is that we are now seeing the advent of combination therapy, which is how many predict the field is likely to evolve, given the several different metabolic, inflammatory or antifibrotic pathways of which we should be able to take advantage. There was a wealth of data about other agents from diverse classes too numerous to recount in the space available for this commentary. Stay tuned for a rich landscape of new developments in the next several years in the NAFLD field.

Ira M. Jacobson, MD

Co-chief Medical Editor

HCV Next

• References
• Asselah T. GS-006. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Berg T, et al. GS-007. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Chokkalingam A. PS-155. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• D’Ambrosio R, et al. GS-013. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Harrison S, et al. FRI-487. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Lok AS, et al. LBO-008. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Mena de Cea A, et al. Abstract 418. Presented at: The International Liver Congress; April 11-15, 2018; Paris.
• Wedemeyer H, et al. GS-005. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
• Wyles DS, et al. PS-040. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.