Chronic Hepatitis Is Common and Often Untreated Among Children with Hepatitis B Infection in the United States and Canada

Abstract

Objective: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada.

Study design: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data.

Results: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations.

Conclusions: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated.

Keywords: alanine aminotransferase; clinical outcomes; entecavir; interferon; lamivudine; phenotype; platelet count; vertical transmission.

Figure 1.

Cumulative probability of (A) onset of ALT flare; (B) becoming HBeAg negative for patients who were HBeAg positive at baseline; (C) becoming HBsAg negative; (D) developing unquantifiable HBV DNA for patients who had quantifiable HBV DNA at baseline; and, (E) commencing standard of care anti-HBV treatment.

Figure 2.

Sequential lab plots in four example patients demonstrating four different patterns of HBeAg loss. (2A) A significant fall in DNA was seen in 20 participants in whom ALT was initially either normal or elevated and became normal or near normal after HBeAg loss. (2B) In 4 participants, HBV DNA remained high and ALT remained normal or elevated. (2C) In 16 participants, treatment with entecavir (n=15) or lamivudine (n=1) was associated with a significant fall in HBV DNA and an initially normal or high ALT fell to normal or near normal after HBeAg loss. (2D) Interferon treatment in 5 participants was associated with a significant reduction in HBV DNA and normalization or near normalization of initially elevated ALT.

Figure 2.

Sequential lab plots in four example patients demonstrating four different patterns of HBeAg loss. (2A) A significant fall in DNA was seen in 20 participants in whom ALT was initially either normal or elevated and became normal or near normal after HBeAg loss. (2B) In 4 participants, HBV DNA remained high and ALT remained normal or elevated. (2C) In 16 participants, treatment with entecavir (n=15) or lamivudine (n=1) was associated with a significant fall in HBV DNA and an initially normal or high ALT fell to normal or near normal after HBeAg loss. (2D) Interferon treatment in 5 participants was associated with a significant reduction in HBV DNA and normalization or near normalization of initially elevated ALT.

Figure 2.

Sequential lab plots in four example patients demonstrating four different patterns of HBeAg loss. (2A) A significant fall in DNA was seen in 20 participants in whom ALT was initially either normal or elevated and became normal or near normal after HBeAg loss. (2B) In 4 participants, HBV DNA remained high and ALT remained normal or elevated. (2C) In 16 participants, treatment with entecavir (n=15) or lamivudine (n=1) was associated with a significant fall in HBV DNA and an initially normal or high ALT fell to normal or near normal after HBeAg loss. (2D) Interferon treatment in 5 participants was associated with a significant reduction in HBV DNA and normalization or near normalization of initially elevated ALT.

Figure 2.

Sequential lab plots in four example patients demonstrating four different patterns of HBeAg loss. (2A) A significant fall in DNA was seen in 20 participants in whom ALT was initially either normal or elevated and became normal or near normal after HBeAg loss. (2B) In 4 participants, HBV DNA remained high and ALT remained normal or elevated. (2C) In 16 participants, treatment with entecavir (n=15) or lamivudine (n=1) was associated with a significant fall in HBV DNA and an initially normal or high ALT fell to normal or near normal after HBeAg loss. (2D) Interferon treatment in 5 participants was associated with a significant reduction in HBV DNA and normalization or near normalization of initially elevated ALT.

Figure 3.

Heatmap of phenotype by baseline phenotype included 312 participants who had first available phenotype at week 0 and had at least one additional follow-up phenotype result.

Figure 4.

Heatmap of ALT level during follow up of 346 participants who had at least two visits with ALT values.

Figure 5.

Platelet count (mean and 95% confidence intervals) by age in healthy children (CALIPER study) vs HBRN pediatric cohort at baseline (cross-sectional analysis). CALIPER data were obtained via personal communication from the CALIPER senior author (23)(Adeli 2015).

Figure 6.

Two case studies. Sequential platelet count and ALT measurements in two patients demonstrating different patterns of association between the two variables.

Figure 6.

Two case studies. Sequential platelet count and ALT measurements in two patients demonstrating different patterns of association between the two variables.