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Hepatitis Debrief
The Liver Meeting 2019
AASLD 2019 Nov 8-11Boston
Marc Ghany, MD, MHSc, FAASLD Liver Diseases Branch, NIDDK, NIH Bethesda, Maryland
NAFLDand HBV are two common liver disease so it is highly likely they would occurtogether. This analysis looked at whether NAFLD worsens HBV liver disease usingliver biopsies from a large North American cohort of HBV. Presence ofsteatohepatitis was associated with more severe perisinusoidal fibrosis whichis not surprising but it was alsThis was confirmed on multivariate analysis.So, forour patients with CHB it is important to screen for and manage metabolicabnormalities to prevent liver disease progression.
Weknow that antiviral therapy reduces HCC risk but is there a difference riskbetween TDF and ETV? This issue was raised in several studies from Asiasuggesting that TDF was associated with a lower risk of HCC compared to ETV butthis finding is controversial. Shown here are two European studies suggestingthat is not the case. The first study was from the French ANRScohort comparing HCC risk among 1960 HBeAg+/-patients with CHB who received tenofovir (1075) or entecavir (885) andfollowed-up for a mean of 4 years. As you can see there was no difference inincidence of HCC rate between those treated with entecavir and TDF. Thesecond study included only Caucasians demonstratedsimilar results. With no difference in the 8-year cumulative incidence of HCCbetween in patients treated with TDF or entecavir. These two large studiesprovide robust data suggesting that there is no difference in HCC risk betweentenofovir and entecavir and we can put this issue to rest.
Weknow that antiviral therapy reduces HCC risk but is there a difference riskbetween TDF and ETV? This issue was raised in several studies from Asiasuggesting that TDF was associated with a lower risk of HCC compared to ETV butthis finding is controversial. Shown here are two European studies suggestingthat is not the case. The first study was from the French ANRScohort comparing HCC risk among 1960 HBeAg+/-patients with CHB who received tenofovir (1075) or entecavir (885) andfollowed-up for a mean of 4 years. As you can see there was no difference inincidence of HCC rate between those treated with entecavir and TDF. Thesecond study included only Caucasians demonstratedsimilar results. With no difference in the 8-year cumulative incidence of HCCbetween in patients treated with TDF or entecavir. These two large studiesprovide robust data suggesting that there is no difference in HCC risk betweentenofovir and entecavir and we can put this issue to rest.
Turningto therapy, the goals of treatment are changing from not just HBV DNAsuppression but functional cure defined as HBsAg loss so that we can havefinite therapy. To look at durability of this endpoint comparing incidence ofHBsAg sero-reversionand HCC in patients who stopped or continued treatment. Thecumulative incidence of HBsAg-reversion and HCC at 5 years were not differentin both groups under 10%. This study confirms that HBsAgloss is a durable and safe endpoint for stopping therapy.
Unfortunately, the rate of HBsAgloss is low with existing therapies but can we refine how we use these agentsto increase HBsAg loss. This study looked at whether add-on pegIFNto ongoing NUC treatment or switching topegIFNwould lead to higher rates of HBsAg loss compared to continuing NA therapy.Adding or switching to pegIFNled to HBsAg loss in 7-10%. A similar rate of HBsAg loss was observed inanother controlled study from a Canadian/European trial evaluating an add-onapproach. Based on these data there is little benefitto add-on or switch approach to induce HBsAg loss. Because PegIFNcan reduce HBsAg levels it may stlllhave a role to play in combination with other novel agents.
Althoughwe have many agents conceptually there are only a few pathways to achievingfunctional cure. To inhibit viral replication to target not detected, lowerviral antigen burden with the hope of restoring immune response and to boostthe immune response. So let’s have a look at a few of these approaches.
Hereis an example of an antiviral approach using a CAM. CAMs are small moleculesthat work by either inhibiting encapsidation of pregenomic RNAor nucleocapsid assembly, leading to inhibition
of viral replication. A CAM administeredat different dosing schedules for 28 days resulted in potent inhibition ofviral replication and reduction in HBV RNA but had minimal effects on HBeAg orHBsAg levels. No safety issues were noted. Potentinhibition of viral replication was demonstrated but we await studies to see iffunctional cure can be achieved.
Anotherapproach is to reduce antigen burden by targeting viral transcripts usinga livertargeted antisense oligonucleotide. In this study, HBeAg-positiveand -negative patients received weekly or bi-weekly injections of differentdoses for 12 weeks. There was a dose dependent decline in HBsAg level and closeto 1 log reduction was observed in highest dosing arm compared to placebo.These agents do not target the cccDNA andconsequently rebound of HBsAg was observed when the drug was stopped. Thuscontinued administration or use in combination with other agents will berequired.
Yetanother approach is enhancement of the innate immune response using a TRL8agonist. This was administered at different doses once weekly for 24 weeks invirally suppressed HBeAg+/-patients and compared to placebo. Changes in HBsAg levels from baseline wereminimal however, 2 HBeAg-patients cleared HBsAg and one HbeAg positive patient cleared HBeAg. Dose-dependentincreases in serum cytokines observed in TLR88 treatment groups.
Therapeutic vaccination has beentried for many years as a therapeutic modality for HBV but has been largelyunsuccessful perhaps because current vaccines use a single antigen. NASVAC is atherapeutic vaccine containing HBsAg and HBcAgs.It was administered intranasally in patients with CHB and inactive carriers and¾ of patients had a 20% decline in HBsAg levels from baseline and inducedanti-HBs in a 1/3 of patients. 2 patients in each group lost HBsAg. This datasuggests that it may be possible to break immune tolerance to achievefunctional cure in HBV infected patients with a therapeutic vaccine. Furtherstudies awaited.
Lessonsfrom HIV and HCV have taught us that we need combination therapy to achieveviral suppression. This study evaluating a a dual therapy with a CAM and a NUCcompared to NUC in HBeAg+treatment naïve and nucsuppressed patients for 24 weeks. In the untreated cohort combination therapyresulted in greater DNA and RNA suppression compared to NA. In the nuc–suppressed patients, addition of a CAM resulted in a higher proportion ofpatients achieving HBV DNA target not detected using a research assay with alimit of detection of 5 IU/mL and greater RNA suppression. Deeper HBV DNAsuppression can be achieved with a combination antiviral approach. We awaitdata if this translates into HBeAg and HBsAg loss.
Finallyvery interesting data was presented on triple therapy regimen consisting of aRNAi plus a CAM plus a NUC in HBeAg+/- treatment naïve and nucsuppressed patients. The siRNA was administered monthly for three months incombination with daily CAM plus a NUC for 12 weeks. HBsAg levels declined inall patients and potent suppression of HBV DNA was achieved in treatment-naïve patients .Tripletherapy resulted in marked decline in HBsAg levels …?Functional cure
Movingfrom treatment to prevention, data was presented on a new trivalent vaccinecontaining pres1,pres2 and s antigens that was compared to a monovalent vaccine engerix.Overall the trivalent vaccine induced high rates of seroprotectioncompared to the monovalent vaccine but more impressive was its greater efficacyin difficult to vaccinate populationsmen, diabetics, obese and smokers.
Resultswere also presented on the impact of screening to reduce cancer mortality. Thiswas an analysis of data from the National Health Insurance Service in Korealooking at outcome of patients who complied with regular screening compared tothose that did not. Compliant patients had significantly lower risk of deathfrom HCC compared to those who were not compliant and were more likely toreceive curative therapy. These data reinforce the need to screen our patientswith CHB.
Movingto delta virus There are no approved therapies for this virus. Myrcludex B isan inhibitor of the HBV entry receptor. This study evaluated a high dose of myrcludex incombination with either peginterferon or TDF for 48 weeks. Compared to pegIFN and myrcludexrespectively. Combination treatment resulted in greater HDV RNA suppression andundetectable HDV RNA compared to monotherapy. Additionally greater viralinhibition of mycludex incombination with peginterferon than TDF. Minimal changes were observed in HBsAglevels. Theseare promising results but minimal changes in HBsAg suggest that long-termadministration may be needed.
Anotheragent evaluated for delta hepatitis was a prenylation inhibitor lonafarnib. Prenylationof the HDAg iscritical to virion assembly. This study evaluated ritonavir boosted lonafarnibin combination with peginterferon lambda for 24 weeks. At end of dosing, HDVRNA levels declined by a median of 3.4log IU/ml and ~half of patients achieved suppression of HDV RNA to undetectableor below the LLOQ. No patient cleared HBsAg. Theseare promising results and we await off-treatment follow-up.
Nowthat 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 theyare a challenging population to treat. This project examined the feasibility oftreating PWIDs in a public health setting by training PCPs to deliver careusing a defined algorithm and provide support if necessary. Over 3000 PWIDsinitiated treatment 2/3 of whom completed treatment with an impressive SVR rateof 91%. However, non-adherence was common 16%, and reduced the SVR rate to 78%.Several studies looked at strategies to improve adherence in this populationincluding direct observation therapy 1561 digital medical program 1554 andintegrate Internist-addiction medicine-hepatology clinics with varying levels of success.
One of the barriers to treatingPWIDs is the concern for reinfection. As you can see in this population based cohortstudy that estimated HCV reinfection rates among all DAA-treated individuals inBritish Columbia, Canada that the overall reinfection rates were low but werethree 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 SVRwas higher among younger males. Notably, uninterrupted use of Opioid agonisttherapy was protective against reinfection. Similar findings were reported inthe co-Star study. So opioid agonist therapy should be considered before andafter HCV treatment.
AHCV vaccine would greatly improve efforts to eliminate HCV. Acandidate prime (chimpanzeederived Adenovirus: ChAd3) /boost(MVAmodified vaccinia virus Ankara virus) HCVvaccine was compared to placebo among actively using PWIDs. Unfortunately, theincidence of infection was the same between the vaccinated and unvaccinatedgroups. However, vacinnees had significant blunting of peakHCV RNA levels and >3/4 of vaccine recipients demonstrated animmune response. Although the study was negative, the feasibility of vaccinestudies among PWIDs was demonstrated. Moreefforts are needed on vaccine development
DAAs have not yet been approved forchildren under the age of 12. Two studies now provide important information onthe safety and efficacy of pangenotyicregimens in this population. In the first study GP was dosed was based on ageand weight for 8 weeks. Overall, 96% achieved SVR12 and efficacy was highacross all age groups. One GT3 patient experienced relapse by post-treatmentweek 4. The safety profile was comparable to those in adolescents and adults.
The second study evaluated Sof/Velin those 6-18 years of age. Children less than 12 received half the standarddose whereas those 12 and older received standard adult dosing. The SVR12 rateamong children <12 years old was 92% and 12 or > was 95%). one patient ineach age group had virologic failure. Therapy was well tolerated. Inthe near future we should have have a safe and effective, pangenotypicregimen for children 3 and older. This will enhance efforts to eliminateHCV in the pediatric population
Lastyear we learned that treatment-naïve patients with compensated cirrhosis couldbe effectively treated with a 8 week regimen of G/P but data was not presentedon genotype 3, the most difficulttotreat GT. As you can see here SVR12rates were high 98% in the per-protocol population. One patient relapsed atpost-treatment Week 4. Importantlybaseline RASs had no impact on treatment outcome. Basedon the results of this study, the US Food and Drug Administration has approvedthe use of G/P for 8 weeks in treatment-naïve patients with compensatedcirrhosis in all GTs.
Weknow that HCV treatment lowers overall mortality. However, less in known of theeffect of treatment upon liver-related mortality. Investigators analyzed a VAdatabase to examined the impactof SVR onliver-related mortality using propensity score matched untreated controls.Among treated persons those achieving a SVR had a significantly lower rate ofliver-related mortality compared to those not achieving SVR and DAA treatmentwas associated with a significantly lower rate of liver-related deaths comparedto interferon treated patients. Thesedata provide further evidence of the benefits of SVR
Whilewe tend to focus on the hepatic benefits of SVR it is important to rememberthat may be extrahepatic benefits to SVR. This was an analysis of incidence ofacute coronary syndromes, ESRD and ischemic stroke in untreated and treatedpatients who achieved SVR in a large cohort of HCV patients. Asyou can see here compared with no treatment, SVR was associated withsignificantly reduced risk of ACS, ESRD, and IS. Suggesting that there areimportant extrahepatic benefits to SVR
SVRmay also improve HCC survival. This was a multi-national propensity scorematched analysis looking at the impact of HCV eradication on HCC survival. Asyou can see both all cause and liver-related mortality were reduced ~65% inpatients who achieved SVR compared to those who were untreated. So HCC patientswho are candidates for HCC therapy should be considered for DAA therapy
Theavailability of curative therapy opens the possibility of using HCV+ donors tobridge the shortfall of donor organs. There is limited data on this approach inliver transplants. This was a retrospective analysis of liver transplantationamong 14 NAT+ donor to HCV- recipients. Viremia was documented within 5 daysafter LT. Mean pre-treatment viral laod was high ~25 million IU/mL.Treatment was initiated a mean of one month post-transplant and all achievedSVR12. LT using grafts from HCV-viremic donors toHCV-non-viremic recipients had excellent short-term outcomes. While encouragingwe need longer term follow-up on graft and patient outcomes and effects onwait-list times.
Iatrogenicinfection is high after transplantation using organs from HCV positive donorsto HCV negative recipients. The optimal timing of treatment is unknown. Thisstudy evaluated a short duration prophylactic approach in 10 D+R- renaltransplants. 50% of patients viremia was never detected. Of those withdetectable virmeia,levels were low suggestive of transfer of donor virus. Thus far all 9 haveachieved SVR. Short course prophylactic therapyappears effective at preventing post-transplant infection from HCV Donor+ torecipients-.
Ifwe use a pre-emptive approach can we get away with even shorter treatmentduration. This study took a rather clever approach to prevent infectioncombining DAA therapy with an entry blocker. Ezetimibe+ Glecaprevir/Pibrentasvirwas given peri-operatively and for 7 days post-transplant. Viremia was detectedin 3/4 but levels were low and correlated with donor viral load suggesting thatthat it was donor virus. To date 18 have achieved SVR12 and there have been notreatment failures. Pre-emptive Ezetimibe + glecaprevir/pibrentasvirfor 7 days, prevented or rapidly cured post-transplant HCV infection.
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发表于 2019-11-14 11:33
