Hepatitis C -Can We Really Accomplish Widespread Screening?

A pessimist sees the difficulty in every opportunity; an optimist sees the opportunity in every difficulty.  -Winston Churchill

The aforementioned quote leads a recent editorial (Lutchman G, Kim WR, Hepatology 2015; 1455-8) which discusses the challenges of widespread Hepatitis C virus (HCV) screening and avoiding late diagnosis/missed opportunity for timely treatment.  The associated article (Moorman AC et al. Hepatology 2015; 1479-84) reviewed a large cohort of 14,717 patients with HCV and noted that 17% (n=1056) had a ‘late diagnosis’ which resulted in high rates of hospitalization and mortality.  Late diagnosis was defined as having cirrhosis at time of diagnosis or hepatic decompensation within 12 months of initial diagnosis.

The editorialists note that the related article presents data from 2006-11 which models ‘real-life’ practice settings.  Late diagnosis was more common in African-Americans and in patients with Medicare insurance.

With regard to widespread screening, pessimists argue that “we do not have coherent strategies and resources” to implement.

  • there are too few health care providers who are qualified and interested
  • the ‘treat-all” strategy is too expensive.  “For example, in the first 3 months after the release of sofosbuvir, a large commercial health insurance carrier announced that it had spent over $100 million on hepatitis C prescriptions…cause[d] a substantial drop in its stock price”
  • “while prioritizing treatment to patients who are at risk of future problems seems the optimal solution to deliver the most benefits at the lowest costs, the problems lies in the identification of those patients.”

Optimists see the opportunity for early intervention and improved outcomes.

Bottomline: While more effective treatment is available, there are still many questions, especially who should receive treatment and how to identify those most in need.  If/when costs of therapy are reduced, some of the difficult questions will resolve.

Related blog posts:

Briefly noted:

  • “Adding Pegylated Interferon to Entecavir for Hepatitis e Antigen-Positive Chronic Hepatitis B: A Multicenter Randomized Trial (ARES Study)” Brouwer WP et al. Hepatology 2015; 1512-22). “Peg-IFN add-on therapy may facilitate the discontinuation of nucleus(t)ice analogs.”
  • “The Impact of Phlebotomy in Nonalcoholic Fatty Liver Disease: A prospective, randomized, controlled trial.” Adams LA et al. Hepatology 2015; 1555-64).  “Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD”
  • “Nonalcoholic Steatohepatitis is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States.” Wong RJ et al. Gastroenterol 2015; 148: 547-55.
Chattahoochee River

Chattahoochee River

Don’t Give Up Too Soon (with Hepatitis B treatment)

A recent study shows that ongoing treatment with entecavir is usually effective in “primary nonresponders” (Hepatology 2014; 59: 1303-10).

This study retrospectively reviewed a study with 1254 treatment-naive patients who received entecavir (ETV) 0.5 mg/day for >6 months. Only 16 (1.28%) patients were considered “primary nonresponders.”  The latter was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD or <1 log drop after 3 months by EASL.

Key findings:

  • The probability of achieving a virologic response (HBV DNA <15 IU/mL) was 95.8% at 54 months among these “nonresponders”
  • Primary nonresponders did not have ETV resistance; however, 13 (1%) of the entire cohort developed ETV resistance.
  • In this treatment cohort, the 5-year cumulative risk of hepatocellular carcinoma (HCC) was 2.5%.  Previous studies have shown that HBV suppression lowers the risk of HCC.

Take-home message: 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

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.

Do antivirals lower the risk of Hepatocellular Carcinoma in HBV?

Meaningful endpoints of therapy are often difficult to demonstrate in clinical studies due to the length of followup that may be needed.  For patients infected with hepatitis B virus (HBV), most clinical studies use surrogate biologic, virologic and histologic markers rather than endpoints like hepatocellular carcinoma (HCC) and death.  In addition, long-term randomized trials with untreated controls are difficult to justify given the success of current treatments in improving these surrogate markers.

A recent Japanese study (Hepatology 2013; 58: 98-107 and editorial pg 18) reports data on a large entecavir-treated cohort (n=472) which was matched with a historical control (retrospective control group, n=1143).  The authors used propensity score matching to eliminate any baseline differences.

Findings:

  • Cumulative incidence of HCC rate at 5 years was 3.7% (for entecavir group) and 13.7% (for controls)
  • Using regression analysis and adjusting for known HCC risk factors, patients treated with entecavir had a hazard ratio of 0.37 for developing HCC.
  • Patients with more risk factors for HCC (eg. older, more active disease, cirrhosis) obtained greater benefit from entecavir treatment (shown in Figure 4 in manuscript)
  • The authors also showed that entecavir-treated patients also had less risk of developing HCC than lamivudine-treated patients
  • Entecavir-treated patients had low rates of resistance (0.8%) at 3.2 years of treatment

Take-home message: suppression of viral replication in HBV cirrhosis patients reduces but does not eliminate the risk of HCC.  In noncirrhotic patients, the magnitude of risk reduction is less.  Thus, patients with active disease should be treated.

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.

Extended data with entecavir & annotated HBV management references

Long-term data for entecavir continue to look good (Clin Gastroenterol Hepatol 2012; 10: 1047-1050).

With this study, the authors performed a post hoc analysis of 94 Asian patients with hepatitis B e antigen-positve (HBeAg+) nucleus(t)ice analogue-naive patients who received 5 years of entecavir therapy.  By five years, 66 patients remained in the study; of the other 28: 11 withdrew consent, 4 completed treatment, 5 died, 2 were lost to followup, 2 had minimal virologic response, and 4 had other reasons.

Results:

  • 63 of 66 (95%) patients who completed 5 years of therapy had HBV DNA < 300 copies/mL
  • 50 of 66 (76%) had normalized levels of alanine aminotransferase
  • 26 of 65 (40%) had HBeAg loss
  • 12 of 65 (18%) had HBeAg seroconversion
  • No resistance to entecavir was detected

Related blog entries:

References on Hepatitis B Management:

  • Chronic Hepatitis B: Update_2009 AASLD Practice Guidelines
  • -Clin Gastroenterol Hepatol 2011; 9: 85. Mgt recommendations.
  • -Hepatology 2010; 52: 2192. Consensus guidelines suggest that IFN is treatment of choice in pediatric pts (<16yrs) due to resistance among nucleosides and lack of pediatric studies with these agents along with PEG-IFN. Does not recommend Rx for immune tolerant (NL ALT, HBeAg+, HBV >20K), inactive dz (NL ALT, HBeAg-Neg, HBV <2K), mild disease. Reactivation (HBeAg-Neg, HBV>2K IU/mL & +ALT1.5ULN or >60) & Immune active (+ALT1.5ULN or >60, HBeAg+, HBV >20K) can be treated if mod-severe dz.
  • -JPGN 2009; 48: 399-404. For children, IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT>2 x ULN, Rx post 3months (sooner if decompensating). IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT<2 x ULN or if inactive replication, then monitor. Consider: Follow yearly U/S, q6mo AFP.  IF HBV DNA <20K U/mL & NL ALT: no Rx, monitor q6-12mo. IF HBV DNA >20K U/mL & NL ALT, low rate of HBeAg conversion, young pts often immunotolerant, consider biopsy, esp if >35yrs.  IF HBV DNA >20K U/mL & incr ALT, then Rx options entecavir, tenofovir, PEG interferon alfa-2a preferred.
  • Hepatology 2009; 49: May 2009 supplement -Entirely on management of HBV: S1-S199. NIH Consensus conference. S8: “Reasonable to monitor this group ((younger than 40/HBeAg+) without therapy unless evidence of progressive liver disease is found” S10 Table 1 -Criteria for determining Rx. Generally not indicated: immune-tolerant phase (High HBV DNA but normal ALT or little activity on Bx).S119: “almost all of the oral agents are superior to interferon-based therapy in achieving other clinical endpoints…and in achieving biochemical and histological improvement…in addition, with longer use, oral agents can equal and exceed the level of pegIFN-associated HBeAg & HBsAg serologic responses w/o the need for injections, side effects…”
  • -Hepatology 2009; 49: 699. German Rx guidelines: IF HBV DNA+ & Cirrhosis –>Rx. IF HBV DNA >10 to 4th and any of the following: ALT >2X, F2 + inflammation, Risk HCC/extrahep dz—>Rx. If none of these reeval q6-12mo

Additional entecavir/tenofovir references:

  • -Gastroenterol 2011; 141: 1212. Entecavir effective as monotherapy post OLT.
  • -Hepatology 2010; 53: 763. No resistance with tenofovir over 2yrs. n=641 (HBe+ & HBe-neg)
  • -Gastroenterol 2011; 140: 132. n=365. Excellent efficacy of tenofovir over 3 yr Rx for HBV. 87% of HBeAg-neg with undetectable HBV & 74% of HBeAg-pos. 8% of HBeAg-pos lost HBsAg & 34% lost HBeAg.
  • -Hepatology 2009; 51: 73. n=131. Tenofovir Rx.
  • -Clin Gastroenterol Hepatol 2010; 9: 274. Use of entecavir (long term) reverses fibrosis in HBV
  • -Hepatology 2010; 52: 886. Long term entecavir Rx (>6yrs) with good efficacy & improved histology (96%), n=69.
  • -Hepatology 2009; 49: 1503. Long term entecavir Rx with LOW resistance. n=608 @ yr1, 108 @ yr5. Resistance ~1%
  • -Hepatology 2009; 50: 1064. Entecavir less effective in pts with combined LAM/ADV resistance.
  • -Hepatology 2008; 48: 99. Entecavir for lamivudine-refractory HBV thru 96 weeks. n=141 entecavir, n=145 lam. Entecavir fairly effective (81% had NL Alt, 10% HBeAg seroconversion) 6/77 in 2nd yr developed resistance much higher than those in studies who never rec’d lamivudine
  • -NEJM 2007; 356: 2614. Use entecavir with caution in pts coinfected w HIV -may select for resistant organisms in those not on fully sppressive antiretroviral regimens.
  • -NEJM 2006; 354: 1001, 1011, 1074. Hepatitis B patients: At 48 weeks, Entecavir-Rx’d HBeAg+ had 72% histologic response, 67% c undetectable HBV DNA, and 68% normalized ALT (n=314/314 entecavir/lamivudine pts). At 48 weeeks among HBeAG-neg, 90% in entecavir group (n=296 vs. 287 lamivudine pts) w/o detectable HBV DNA, 78% c Nl ALT, 70% c histologic improvement. Entecavir has caused cancer in mice.
  • -Hepatology 2006; 44: 1656. Entecavir had highly potent efficacy in reducing HBV DNA levels to <300 copies/mL. Study of 673 Rx’d pts. In HBeAg+, 69% were HBV DNA-neg at 48 weeks, & 82% at 96 weeks; in HBeAg-neg, 93% at 48 weeks & 96% at 96 weeks were HBV DNA neg. Low level of resistance due potent HBV DNA levels.