Ledipasvir-Sofosbuvir for Children 6-11 years

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.

Key findings:

  • 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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Hepatitis B Reactivation with Direct-Acting Antiviral Hepatitis C Therapy

“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

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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 (:), 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.

Key findings:

  • 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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New HCV Treatment Effective in Adolescents –Important Study Now Published Online

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:

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.

TV sports analysts have tremendous  insight!

TV sports analysts have tremendous insight!  Virginia needs to score enough points to win.

NPR: Children Missing Out on Hepatitis C Treatment

From NPR: Children Missing Out on Hepatitis C Treatment

An excerpt:

study by the Philadelphia Department of Health points to what Wen and others in the medical profession see as a worrisome trend: Children with hepatitis C may be unaware of their diagnosis and the potential need for treatments down the road in order to prevent long-term liver damage.

Using city surveillance data, the study found that as many as 8 in 10 children at high risk for hepatitis C exposure in Philadelphia were never screened for the condition. More specifically, of the approximately 500 moms-to-be who were registered as having hepatitis C between 2011 and 2013, only 84 of their newborns, or about 16 percent, were tested for the virus by 20 months of age.

My take: As the article discusses, with the advent of better treatments, which will be available for children (?next 1-2 years), identifying Hepatitis C acquired prenatally is becoming important.

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Quick Take: How to Cure HCV in 99%!!

A new study shows an HCV sustained virological remission of 99% in a study of genotypes 1, 2, 4, 5, and 6.

ORIGINAL ARTICLE
Published Online: November 16, 2015

Here’s a terrific 2 minute summary from NEJM.