Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes. There is some terrific content. Here are some of the slides (borrowed with permission from NASPGHAN).
Link to complete NASPGHAN Chronic Liver Disease Symposium 2019
SESSION II – FRONTIERS IN LIVER THERAPEUTICS
Keynote Speaker: Outcomes for the future: How do we improve on the status quo? Ronald J. Sokol, MD, FAASLD, Children’s Hospital Colorado (SLIDES NOT AVAILABLE in onliine handout)
Recognition and stabilization of the pediatric patient with acute liver failure Robert Squires MD Children’s Hospital of Pittsburgh at UPMC
Should I offer treatment for my patients with Hepatitis B or Hepatitis C? Regino P. Gonzalez-Peralta MD, AdventHealth for Children
Are there any medical therapies for NASH? Marialena Mouzaki, MD, Cincinnati Children’s Hospital Medical Center
This lecture describes a lot of the emerging pharmacologic treatments; none of these are currently recommended.
P Rosenthal et al. Hepatology 2019; 69: 2326-37. This study examined the efficacy and safety of combined entecavir and Peginterferon for immune-tolerant chronic hepatitis B-infected children (n=60). 48 weeks after completing treatment (week 96), 2 children (3%) achieved the primary outcome of undetectable HBeAg with HBV DNA levels <1000 IU/mL. These two children were also HBsAg negative/anti-HBs positive. In the other children (55 completed study), the ALT and HBV DNA levels were similar to baseline. 37 children experienced adverse events. My take: Entecavir/peginterferon is not very effective in immune-tolerant children infected with chronic HBV.
DL Thomas. NEJM 2019; 380: 2041-50. This article reviews the pathway to the global elimination of chronic hepatitis. Currently, it is estimated that hepatitis C virus (HCV) and hepatitis B virus (HBV) kill more than 1 million persons each year. “In fact, by 2040, deaths from chronic hepatitis are projected to exceed the combined mortality associated with HIV infection, tuberculosis, and malaria.”
JR Dillman et al. J Pediatr 2019; 212: 60-5. This study with 41 patients and 13 patients with biliary atresia prospectively assessed ultrasound shear wave elastography (SWE). The authors found that SWE with a cut-off value of >1.84 m/s had 92% sensitivity and 79% specificity. Also, in their cohort, GGT >320 had a sensitivity of 100% and specificity of 78%.
Z Younossi et al. Hepatology 2019; 69: 2672-82. This review provides a global perspective of NAFLD. 25% of the world’s population is currently thought to have NAFLD with highest prevalence in South America at 30.45% and lowest in Africa at 13.5%. This article usggest North America to have 24.1% prevalence rate.
Almost two years ago, the FDA approved Ledipasvir-Sofosbuvir (aka Harvoni) for pediatric patients 12-17 years of age with hepatitis C virus (HCV) infection. Now, a recent study (KF Murray, WF Balistreri, S Bansal et al. Hepatology 2018; 68: 2158-66) is likely to expedite approval for children ages 6-11 years of age.
In this open-label study with 92 patients, 88 had genotype 1, 89 received treatment with ledipasvir-sofosbuvir without ribavirin for 12 weeks, 97% were perinatally-infected, and 78% were treatment naive. The median age was 9 years. The dose (determined by intense pharmacokinetics) was 45 mg-200 mg (half the adult dosage). Two patients with genotype 3 HCV received ledipasvir-sofosbuvir for 24 weeks along with ribavirin.
- SVR12 was 99% (91/91). The single patient without SVR12 had relapsed 4 weeks after completing a 12 week treatment course.
- Ledipasvir-sofosbuvir was well-tolerated; the common adverse events reported were headache and pyrexia.
The authors note that while most children are considered to have mild symptoms or are asymptomatic, some progress to have significant fibrosis or cirrhosis, a small minority develop hepatocellular carcinoma, and HCV infection can impact both cognitive development and overall health.
My take: This study confirms that effectiveness of DAA therapy with ledipasvir/sofosbuvir in children as young as 6 years of age.
Related study: F Tucci et al. Hepatology 2018; 68: 2434-37. The authors report the successful treatment with ledipasvir/sofosbuvir of an infant with both SCID and HCV infection.
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“I refuse to accept the view that mankind is so tragically bound to the starless midnight of racism and war that the bright daybreak of peace and brotherhood can never become a reality.” Martin Luther King, Jr
More information on hepatitis B virus (HBV) reactivation with direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy has been published:
- PS Belperio et al. Hepatology 2017; 66: 27-36
- G Chen et al Hepatology 2017; 66: 13-26
- Editorial: RP Perrillo. G Chen et al Hepatology 2017; 66: 4-6.
In a previous post on this topic (Word of Caution with New Hepatitis C Medications:), it was noted that physicians need to be aware of HBV reactivation with DAAs. It appears that HCV can suppress HBV replication and that successful HCV therapy allows for HBV reactivation.
Belperio et al reviewed data from an observational study on more than 62,000 HCV-infected veterans, including 377 who had HBsAg-positivity and 7295 who had anti-HBc-positivity.
- 8 of 377 HBsAg-positive had reactivation (defined as HBV DNA increase of >1000 IU/mL) of HBV during DAA treatment of HCV. Only one of these eight had a severe hepatitis (ALT 154o IU)
- 1 of 7295 HBc-positive had HBV reactivation. This rate of reactivation is actually lower than HBV reactivation reported with ‘inactive’ disease (1-2% per year).
- For HBV screening, the authors recommend HBsAg and anti-HBc testing
Chen et al performed a systematic review (of 28 studies included) and meta-analysis had identified overt HBV reactivation in 12.2% of those receiving DAAs. This was a lower rate of HBV reactivation than with interferon (14.5%); however, reactivation during DAA therapy occurred earlier (typically 4-12 weeks into treatment) and was more clinically significant. There was significant variation in the virologic and ALT criteria used to define HBV reactivation. The authors conclude that it is “important to have HBV serology (HBsAg, anti-HBc) in all HCV patients prior to therapy.
Perillo recommends that in addition to screening, “it is my belief that anti-HBV prophylaxis be given to all HBsAg-positive patients, ” regardless of HBV DNA level.
My take: These articles help quantitate the risk of HBV reactivation during HCV therapy.
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A soon-to-be-published study (available online Hepatology) from WF Balistreri et al shows that the combination of Ledipasvir-Sofosbuvir is highly effective in pediatric patients aged 12-17 years.
Here is the abstract:
No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a Phase 2, multi-center, open-label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients ages 12 to 17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the 10th day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks posttreatment (SVR12). Median age of patients was 15 years (range, 12-17 years). A majority (80%) were HCV treatment naïve, and 84% were infected through perinatal transmission. One patient had cirrhosis and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% CI, 93% to 100%) of patients reached SVR12. No patient had virologic failure. The 2 patients who did not achieve SVR12 were lost to follow-up either during or after treatment. The 3 most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. AUCtau and Cmax values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50% to 200% when compared with adults from Phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective in treating adolescents with chronic HCV genotype 1 infection. The dose of ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile.
My take: This is great news for pediatric patients. This study indicates that this breakthrough therapy (and likely others) for adults will become more widely available for pediatric patients soon.
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