We know that antiviral therapy reduces HCC risk but is there a difference risk between TDF and ETV? This issue was raised in several studies from Asia suggesting that TDF was associated with a lower risk of HCC compared to ETV but this finding is controversial. Shown here are two European studies suggesting that is not the case. The first study was from the French ANRS cohort comparing HCC risk among 1960 HBeAg+/- patients with CHB who received tenofovir (1075) or entecavir (885) and followed-up for a mean of 4 years. As you can see there was no difference in incidence of HCC rate between those treated with entecavir and TDF. The second study included only Caucasians demonstrated similar results. With no difference in the 8-year cumulative incidence of HCC between in patients treated with TDF or entecavir. These two large studies provide robust data suggesting that there is no difference in HCC risk between tenofovir and entecavir and we can put this issue to rest.

Turning to therapy, the goals of treatment are changing from not just HBV DNA suppression but functional cure defined as HBsAg loss so that we can have finite therapy. To look at durability of this endpoint comparing incidence of HBsAg sero-reversion and HCC in patients who stopped or continued treatment. The cumulative incidence of HBsAg-reversion and HCC at 5 years were not different in both groups under 10%. This study confirms that HBsAg loss is a durable and safe endpoint for stopping therapy.

Unfortunately, the rate of HBsAg loss is low with existing therapies but can we refine how we use these agents to increase HBsAg loss. This study looked at whether add-on pegIFN to ongoing NUC treatment  or switching to pegIFN would lead to higher rates of HBsAg loss compared to continuing NA therapy. Adding or switching to pegIFN led to HBsAg loss in 7-10%. A similar rate of HBsAg loss was observed in another controlled study from a Canadian/European trial evaluating an add-on approach. Based on these data there is little benefit to add-on or switch approach to induce HBsAg loss. Because PegIFN can reduce HBsAg levels it may stlll have a role to play in combination with other novel agents.

Although we have many agents conceptually there are only a few pathways to achieving functional cure. To inhibit viral replication to target not detected, lower viral antigen burden with the hope of restoring immune response and to boost the immune response. So let’s have a look at a few of these approaches.

Here is an example of an antiviral approach using a CAM. CAMs are small molecules that work by either inhibiting encapsidation of pregenomic RNA or nucleocapsid assembly, leading to inhibition of viral replication. A CAM administered at different dosing schedules for 28 days resulted in potent inhibition of viral replication and reduction in HBV RNA but had minimal effects on HBeAg or HBsAg levels. No safety issues were noted. Potent inhibition of viral replication was demonstrated but we await studies to see if functional cure can be achieved.

Yet another approach is enhancement of the innate immune response using a TRL8 agonist. This was administered at different doses once weekly for 24 weeks in virally suppressed HBeAg+/- patients and compared to placebo. Changes in HBsAg levels from baseline were minimal however, 2 HBeAg- patients cleared HBsAg and one HbeAg positive patient cleared HBeAg. Dose-dependent increases in serum cytokines observed in TLR88 treatment groups.

Therapeutic vaccination has been tried for many years as a therapeutic modality for HBV but has been largely unsuccessful perhaps because current vaccines use a single antigen. NASVAC is a therapeutic vaccine containing HBsAg and HBcAgs. It was administered intranasally in patients with CHB and inactive carriers and ¾ of patients had a 20% decline in HBsAg levels from baseline and induced anti-HBs in a 1/3 of patients. 2 patients in each group lost HBsAg. This data suggests that it may be possible to break immune tolerance to achieve functional cure in HBV infected patients with a therapeutic vaccine. Further studies awaited.

Lessons from HIV and HCV have taught us that we need combination therapy to achieve viral suppression. This study evaluating a a dual therapy with a CAM and a NUC compared to NUC in HBeAg+ treatment naïve and nuc suppressed patients for 24 weeks. In the untreated cohort combination therapy resulted in greater DNA and RNA suppression compared to NA. In the nuc –suppressed patients, addition of a CAM resulted in a higher proportion of patients achieving HBV DNA target not detected using a research assay with a limit of detection of 5 IU/mL and greater RNA suppression. Deeper HBV DNA suppression can be achieved with a combination antiviral approach. We await data if this translates into HBeAg and HBsAg loss.

Finally very interesting data was presented on triple therapy regimen consisting of a RNAi plus a CAM plus a NUC in HBeAg+/- treatment naïve and nuc suppressed patients. The siRNA was administered monthly for three months in combination with daily CAM plus a NUC for 12 weeks. HBsAg levels declined in all patients and potent suppression of HBV DNA  was achieved in treatment-naïve patients .Triple therapy resulted in marked decline in HBsAg levels …?Functional cure 

Results were also presented on the impact of screening to reduce cancer mortality. This was an analysis of data from the National Health Insurance Service in Korea looking at outcome of patients who complied with regular screening compared to those that did not. Compliant patients had significantly lower risk of death from HCC compared to those who were not compliant and were more likely to receive curative therapy. These data reinforce the need to screen our patients with CHB.

Moving to delta virus There are no approved therapies for this virus. Myrcludex B is an inhibitor of the HBV entry receptor. This study evaluated a high dose of myrcludex in combination with either peginterferon or TDF for 48 weeks. Compared to pegIFN and myrcludex respectively. Combination treatment resulted in greater HDV RNA suppression and undetectable HDV RNA compared to monotherapy. Additionally greater viral inhibition of mycludex in combination with peginterferon than TDF. Minimal changes were observed in HBsAg levels. These are promising results but minimal changes in HBsAg suggest that long-term administration may be needed.

Another agent evaluated for delta hepatitis was a prenylation inhibitor lonafarnib. Prenylation of the HDAg is critical to virion assembly. This study evaluated ritonavir boosted lonafarnib in combination with peginterferon lambda for 24 weeks. At end of dosing, HDV RNA levels declined by a median  of 3.4 log IU/ml and ~half of patients achieved suppression of HDV RNA to undetectable or below the LLOQ. No patient cleared HBsAg. These are promising results and we await off-treatment follow-up.

Now that we have effective treatment for HCV, efforts have focused on elimination. Treatment of PWIDs will be critical if we are going to eliminate HCV but they are a challenging population to treat. This project examined the feasibility of treating PWIDs in a public health setting by training PCPs to deliver care using a defined algorithm and provide support if necessary. Over 3000 PWIDs initiated treatment 2/3 of whom completed treatment with an impressive SVR rate of 91%. However, non-adherence was common 16%, and reduced the SVR rate to 78%. Several studies looked at strategies to improve adherence in this population including direct observation therapy 1561 digital medical program 1554 and integrate Internist- addiction medicine-hepatology clinics with varying levels of success.

One of the barriers to treating PWIDs is the concern for reinfection. As you can see in this population based cohort study that estimated HCV reinfection rates among all DAA-treated individuals in British Columbia, Canada that the overall reinfection rates were low but were three times higher among PWID (n=36, 2.36/100 PYs) than non-PWIDs (n=26, 0.79/100 PYs). Reinfection typically occurred the first 2 years following SVR was higher among younger males. Notably, uninterrupted use of Opioid agonist therapy was protective against reinfection. Similar findings were reported in the co-Star study. So opioid agonist therapy should be considered before and after HCV treatment.

A HCV vaccine would greatly improve efforts to eliminate HCV. A candidate prime (chimpanzee derived Adenovirus: ChAd3) /boost (MVA modified vaccinia virus Ankara virus) HCV vaccine was compared to placebo among actively using PWIDs. Unfortunately, the incidence of infection was the same between the vaccinated and unvaccinated groups. However, vacinnees had significant blunting of peak HCV RNA levels and >3/4 of vaccine recipients demonstrated an immune response. Although the study was negative, the feasibility of vaccine studies among PWIDs was demonstrated. More efforts are needed on vaccine development

The second study evaluated Sof/Vel in those 6-18 years of age. Children less than 12 received half the standard dose whereas those 12 and older received standard adult dosing. The SVR12 rate among children <12 years old was 92% and 12 or > was 95%). one patient in each age group had virologic failure. Therapy was well tolerated. In the near future we should have have a safe and effective, pangenotypic regimen for children 3 and older. This will enhance efforts to eliminate HCV in the pediatric population

We know that HCV treatment lowers overall mortality. However, less in known of the effect of treatment upon liver-related mortality. Investigators analyzed a VA database to examined the impact of SVR on liver-related mortality using propensity score matched untreated controls. Among treated persons those achieving a SVR had a significantly lower rate of liver-related mortality compared to those not achieving SVR and DAA treatment was associated with a significantly lower rate of liver-related deaths compared to interferon treated patients. These data provide further evidence of the benefits of SVR

While we tend to focus on the hepatic benefits of SVR it is important to remember that may be extrahepatic benefits to SVR. This was an analysis of incidence of acute coronary syndromes, ESRD and ischemic stroke in untreated and treated patients who achieved SVR in a large cohort of HCV patients. As you can see here compared with no treatment, SVR was associated with significantly reduced risk of ACS, ESRD, and IS. Suggesting that there are important extrahepatic benefits to SVR

The availability of curative therapy opens the possibility of using HCV+ donors to bridge the shortfall of donor organs. There is limited data on this approach in liver transplants. This was a retrospective analysis of liver transplantation among 14 NAT+ donor to HCV- recipients. Viremia was documented within 5 days after LT. Mean pre-treatment viral laod was high ~25 million IU/mL. Treatment was initiated a mean of one month post-transplant and all achieved SVR12. LT using grafts from HCV-viremic donors to HCV-non-viremic recipients had excellent short-term outcomes. While encouraging we need longer term follow-up on graft and patient outcomes and effects on wait-list times.

Iatrogenic infection is high after transplantation using organs from HCV positive donors to HCV negative recipients. The optimal timing of treatment is unknown. This study evaluated a short duration prophylactic approach in 10 D+R- renal transplants. 50% of patients viremia was never detected. Of those with detectable virmeia, levels were low suggestive of transfer of donor virus. Thus far all 9 have achieved SVR. Short course prophylactic therapy appears effective at preventing post-transplant infection from HCV Donor+ to recipients-.

If we use a pre-emptive approach can we get away with even shorter treatment duration. This study took a rather clever approach to prevent infection combining DAA therapy with an entry blocker. Ezetimibe + Glecaprevir/Pibrentasvir was given peri-operatively and for 7 days post-transplant. Viremia was detected in 3/4 but levels were low and correlated with donor viral load suggesting that that it was donor virus. To date 18 have achieved SVR12 and there have been no treatment failures. Pre-emptive Ezetimibe + glecaprevir/pibrentasvir for 7 days, prevented or rapidly cured post-transplant HCV infection