Update on Hepatitis B & C -Postgraduate Course

Update on Hepatitis B –Jean Pappas Molleston

Hepatitis B: Who to Treat:

  • Immune active Hepatitis B with active disease: HBeAg+ (> 6 months), HBV DNA > 20,000 IU/ml, ALT > 1.5 x normal or > 60 IU/L, &  moderate/severe inflammation/fibrosis
  • Reactivated Hepatitis B with active disease: HBeAg‐ (> 12 months), HBV DNA > 2000 IU/ml, ALT > 1.5 x normal or > 60 IU/L

Hepatitis B: Who to Not Treat:

  • Immunotolerant Hepatitis B: HBeAg+, HBV DNA > 20,000 IU/ml, Normal ALT
  • Inactive carrier: HBe Ag, HBV DNA < 2000

What to Use to Treat Children with Hepatitis B and When:

  • Only children with active disease should be treated
  • Many would suggest IFN as a first line drug, especially for younger children
  • Nucleoside analogues can now be considered in older children: Tenofovir is licensed for over age 12,  Entecavir is licensed for over age 16

What’s Exciting?

  • NCT01519960 Peg‐IFN monotherapy for children with chronic active hepatitis B
  • NCT01368497 Peg‐IFN and Entecavir for treatment of Hepatitis B in immunotolerant children
  • New drugs
  • New ways to predict who will have worse disease and who will respond
  • Direct Acting Antivirals

Treating HCV: 2013 and Beyond… Regino P. González-Peralta, M.D.

Standard of Care HCV Therapy: Children

  1. IFN/PEG-IFN-α-2a (PEG-2a):  ‘‘Branched’’ 40-kDa PEG moiety, Dose: 104 μg/m2 SQ once weekly, Available: prefilled syringes or as vials
  2. PEG-IFN-α-2b (PEG-2b): ‘‘Linear’’ 12-kDa PEG, Dose: 60 μg/m2 SQ once weekly, Available: Measured vials/ready-use pens

Other pointers:

  • Discussed IL-28 B Polymorphism –No pediatric data yet
  • Close monitoring for those who are treated
  • PEG-RBV is standard of care for children though with suboptimal efficacy and significant toxicity
  • Warp-speed evolution of HCV therapies
  • All ORAL’ regimen on horizon
  • Yearly evaluation: CBC, liver tests, HCV RNA and PT/INR (cirrhosis)

HCV Rx in Children: to treat or not:

IN FAVOR…

  • Avoid disease progression
  • Remove social stigma
  • Decrease HCV burden
  • Children ‘better’ candidates

…AGAINST

  • Benign disease
  • Efficacy
  • Toxicity
  • Direct Acting Antivirals (in the pipeline)

Full slides available on postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Looking at the Tenofovir Data Another Way

In last Friday’s post, this blog reviewed 5-year data on tenofovir usage which showed that tenofovir could reverse fibrosis/cirrhosis.  Another study using the same cohort examined the efficacy of tenofovir in patients with high viral load (HVL) at baseline (Hepatology 2013; 58: 505-13).

From an initial total of 641 patients enrolled in GS-US-174-0102 (n=375) and GS-US-174-0103 (n=266), the authors identified 129 (20%) with HVL.  HVL was defined as having ≥9 log10 copies/mL.  After an initial 48 weeks of randomization between tenofovir (HVL n=82) or adefovir (HVL n=47), patients received an additional 192 weeks of therapy with tenofovir in an open label extension.

Results:

  • By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL
  • High HVL patients took longer to achieve undetectable HBV DNA, but by week 96 the results were similar in both groups
  • Patients who received tenofovir during the initial 48 weeks achieved undetectable HBV DNA quicker than those who had received adefovir initially
  • There were similar rates of histologic regression in both HVL and non-HVL patients

This study evaluated only patients in the ‘immune clearance’ phase of HBV and therefore cannot be extrapolated to those in the immune tolerant phase.

Changing the Outcome for Hepatitis B

Much of hepatology relies on surrogate markers to convey whether treatments are effective.  For hepatitis B virus (HBV), some of these markers include serology (eg. development of HBV e antibody), improvements in biochemistry (eg. transaminases) as well as histology.  Of these, improved histology is likely to have the most bearing on clinical outcomes like progression to end-stage liver disease and hepatocellular carcinoma.  A previous study of lamivudine has indicated that regression of fibrosis can reduce the rate of hepatocellular carcinoma (NEJM 2004; 351: 1521-31).

As such, the results of long-term use of agents like tenofovir have been awaited.  Since tenofovir along with entecavir are considered 1st line agents, their use has become commonplace for the treatment of HBV.  Now 5-year data are available in a large cohort (Lancet 2013; 381: 468-75).

The data from this study was derived from an open-label cohort that followed 48-week double-blind comparison trials. 489 patients completed 240 weeks of treatment.  348 patients had biopsy results available at baseline and at week 240.

Key findings:

  • 304 (87%) of those with biopsies at study completion had histologic improvement.
  • 176 (51%) had regression of fibrosis
  • 71 of 96 (74%) who had cirrhosis at baseline no longer had cirrhosis (≥1 unit decrease in Ishak fibrosis score)
  • 3 of 252 without cirrhosis at baseline progressed to cirrhosis at week 240
  • No evidence of resistance to tenofovir was evident.  Nearly all patients on tenofovir had undetectable HBV DNA
  • Adverse safery events were rare

As with all studies looking at liver histology, there were limiting factors including potential sampling errors and variable interpretation.  The authors sought to minimize this by using an independent pathologist.   Another strength of the study was the broad range of patients to make these findings broadly applicable.

Take-home message: Tenofovir treatment for 5 years is safe and effective.  Long-term suppression of HBV can lead to regression of fibrosis and reversal of cirrhosis.

Related blog posts:

HBV: translating advances from adults to pediatrics

Given the increased difficulties of conducting research in the pediatric population, it can take a long time for pediatric patients to benefit from the research advances demonstrated in adults.  Fortunately, with hepatitis B virus (HBV) the lag time has not been excessive.  A specific example has been a recent study demonstrating the effectiveness of tenofovir in the pediatric population (Hepatology 2012; 56: 2018-26).

In this double-blind, placebo-controlled study,  adolescents with chronic HBV were randomized into tenofovir 300 mg (n=52) or placebo (n=54) once daily for 72 weeks.  101 patients completed the 72 weeks of treatment.  In this population, 85% had received prior HBV therapy and 91% were HBeAg-positive at baseline.  Patients included in the study had to have ALT >2 x ULN or history of this w/in 24 months along with HBV DNA>10 to the 5th copies/mL.  The inclusion criteria required a weight of >35 kg.

Findings:

  • Virologic response (HBV DNA <400 copies/mL): 89% in tenofovir group and 0% in placebo group
  • No resistance noted through 72 weeks.  All cases of virologic breakthrough were associated with non-adherence but no genotypic or phenotypic resistance.
  • Normalization of ALT: among patients with baseline elevation, normalization occurred in 74% of tenofovir group compared with 31% of placebo group
  • Serologic response: 21% of tenofovir group and 15% of placebo group experienced loss of HBeAg by week 72
  • Adverse effects were more frequently noted in placebo group.  No patients met the safety endpoint of a 6% decrease in spine bone mineral density

Since suppression of HBV DNA is a limited surrogate endpoint for the development of long-term sequelae much longer followup is needed to determine the impact of this nucleotide analogue.  In adults, this agent has been associated with reversal of cirrhosis.

Across the globe, 350 million people live with chronic HBV infection and 600,000 die each year due to HBV infection.  About 25% of children with HBV develop cirrhosis or cancer of liver later in life.  Given the magnitude of the problem, the most promising approach remains prevention with vaccination.  Treatment to prevent complications in those already infected is likely to be offered to a tiny fraction of those who might benefit.

Related blog entries:

More on entecavir and tenofovir

In a previous post (Extended data with entecavir & annotated HBV management ) good news on the long term use of entecavir was reported.  Another large study indicates that  entecavir (ETV) monotherapy generally produces equivalent results to combination therapy with tenofovir (TDF) (Gastroenterol 2012; 143: 619-28).

The authors report their experience with a randomized open-label multi center study with 379 nucleos(t)ide-naive patients; 264 were HBeAg-positive and 115 were HBeAg-negative.  At week 96, among all patients, virology response defined as HBV DNA <50 IU/mL was 76.4% in the ETV group and 83.2% in the ETV-TDF group.

In multiple comparisons, the combination group tended to have better virological response  except in the HBeAg-negative group (91.1% ETV vs. 89.8% in ETV-TDF).  The other comparisons included the HBeAg-positive group (69.8% ETV vs. 80.4% ETV-TDF), low baseline HBV DNA (<10 to the 8th IU/mL) (83% in both groups), and the high baseline HBV DNA (62.0% ETV vs. 78.8% ETV-TDF).  Yet, the only group where this was statistically significant was those with high baseline HBV DNA, n= 164 (>10 to the 8th IU/mL).

Biological response was greater in the ETV monotherapy, 81.9% compared with 69% in the combination group.  Among HBeAg+ patients, loss of e antigen was comparable: 38.9% in ETV compared with 29.7% in ETV-TDF.  In this group, seroconversion to HBeAb+ occurred in 32.5% of ETV compared with 21.7% of combination patients.

Safety: five patients in combination group and two patients in ETV monotherapy group discontinued treatment due to adverse events.  Three deaths occurred in the combination group (either on treatment or during followup), with the following causes: cardiac arrest, bile duct tumor, and liver failure.  In the patient with liver failure, she had responded to therapy but experienced a breakthrough at week 48.  At week 100, she was switched to commercial treatment.  Five days later she was hospitalized and died within 1 week.  No resistance to either drug was identified.  Thus, the authors speculate that nonadherence was an important factor.  Also, during the course of the study, five malignancies were diagnosed, including 3 with HCC.