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Hepatitis B Virus
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Epidemiology

Chronic hepatitis B infection is defined as persistence of hepatitis B surface antigen (HbsAg) for >6 months. Risk of developing chronic hepatitis B infection after acute infection correlates with age at time of hepatitis B virus (HBV) infection. Among HBV-infected persons, chronic hepatitis B infection develops in ≤90% of infants, 25%-50% of children aged 1-5 years, and 6%-10% of older children and adolescents (639Chu CM, Karayiannis P, Fowler MJ, et al. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 1985;5:431-4., 640Chang MH, Sung JL, Lee CY, et al. Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children. J Pediatr 1989;115:385-90., 641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48.).

Childhood HBV infection can be acquired parenterally, perinatally, or through sexual transmission. Horizontal transmission of HBV can occur secondary to frequent interpersonal contact of nonintact skin or mucus membranes with blood or body fluids that contain blood (e.g., saliva) or from sharing household objects, such as toothbrushes or razors. Universal hepatitis B vaccination of newborns has dramatically lowered chronic HBV infection among children and reduced the rates of HBV-related morbidity and mortality in the United States.

Adolescents are at risk for HBV infection through sexual activity or injection-drug use. In a study of HIV-infected adolescents at 43 PACTG centers, 19% had evidence of current or resolved HBV infection; the rate of current or resolved HBV infection in HIV-infected adolescent girls was twice the U.S. population-based rates for HIV-uninfected adolescent girls and, for adolescent boys, nearly seven times higher (642Rogers AS, Lindsey JC, Futterman DC, et al. Serologic examination of hepatitis B infection and immunization in HIV-positive youth and associated risks. The Pediatric AIDS Clinical Trials Group Protocol 220 Team. AIDS Patient Care STDS 2000;14:651-7.). Substance abuse and sexual activity increase the risk for HIV/ HBV coinfection in adolescents, particularly among males who have sex with other males (643Wang EE, King S, Goldberg E, et al. Hepatitis B and human immunodeficiency virus infection in street youths in Toronto, Canada. Pediatr Infect Dis J 1991;10:130-3.).

Most children who acquire HBV perinatally are immunotolerant to HBV. Although they have high HBV DNA levels, serum transaminase levels are usually normal, and necroinflammatory liver disease is minimal. Childhood-acquired HBV infection is characterized by lower HBV DNA levels, greater serum transaminase elevation, and higher necroinflammatory liver disease than in perinatally acquired HBV infection (644Mieli-Vergani G, Vergani D. Treatment of hepatitis B virus in children: why, whom, how? Indian J Gastroenterol 2006;25:121-4.).

Data from the National Health and Nutrition Examination Survey, 1999-2004, indicate that 0.51% (95% CI: 0.3% - 0.9%) of children aged 6-19 years had ever been infected with HBV (645Wasley A, Kruszon-Moran D, Kuhnert W, et al. Hepatitis B prevalence in the U.S. in the era of vaccination [abstract 723]. In: Abstracts of the Infectious Diseases Society of America 45th annual meeting; October 4-7, 2007; San Diego, CA. Arlington VA: Infectious Diseases Society of America; 2007:171.). Data are limited on the prevalence of chronic HBV infection in HIV-infected children in the United States. In a study of 228 HIV-infected children at an inner-city hospital, six HIV-infected children had chronic HBV infection (2.6% [95% CI: 1.1%-5.9%]) (646Toussi SS, Abadi J, Rosenberg M, et al. Prevalence of hepatitis B and C virus infections in children infected with HIV. Clin Infect Dis 2007;45:795-8.). The mean age of HIV/HBVcoinfected children was 17 years; 33% had acquired both HIV and HBV infection through blood transfusion; and 84% were HBV early antigen-positive (HBeAg), indicating infectiousness. Half of coinfected children had normal serum transaminase levels, and half had mild elevations of up to twofold above upper limit of normal.

Clinical Manifestations

Most acute HBV infections in children are asymptomatic. Prodromal symptoms of lethargy, malaise, fatigue, nausea, and anorexia can occur. Jaundice and right upper quadrant pain can follow and, less commonly, hepatomegaly and splenomegaly. Gianotti-Crosti syndrome (papular acrodermatitis), urticaria, macular rash, or purpuric lesions may be seen in acute HBV infection. Extrahepatic manifestations associated with circulating immune complexes that have been reported in HBV-infected children include arthralgias, arthritis, polyarteritis nodosa, thrombocytopenia, and glomerulonephritis. Most children with chronic HBV infection are asymptomatic. However, rare cases of fulminant hepatic failure have occurred during childhood HBV infection (647Tovo PA, Lazier L, Versace A. Hepatitis B virus and hepatitis C virus infections in children. Curr Opin Infect Dis 2005;18:261-6.).

Most children with chronic HBV infection are asymptomatic. One quarter of infants and children with chronic HBV eventually will develop cirrhosis or hepatocellular carcinoma (HCC) (648Bortolotti F, Calzia R, Cadrobbi P, et al. Liver cirrhosis associated with chronic hepatitis B virus infection in childhood. J Pediatr 1986;108:224-7., 649Chen CH, Chen YY, Chen GH, et al. Hepatitis B virus transmission and hepatocarcinogenesis: a 9 year retrospective cohort of 13676 relatives with hepatocellular carcinoma. J Hepatol 2004;40:653-9.). However, these sequelae usually develop over 2-3 decades and rarely occur during childhood (650Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology 2006;43:556-62.). Development of HCC correlates with HBV DNA levels and duration of HBV infection, with the highest risk in persons infected in early life (651Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73.). HIV/HBV-coinfected adults are at increased risk for cirrhosis, end-stage liver disease, and liver-related mortality (652Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356:1445-54.).

Diagnosis

Testing for HBV infection should be performed in any child whose mother is known to be infected with HBV. Adolescents and young adults with histories of injection-drug use or high-risk sexual contact also should undergo testing for HBV infection.

HBsAg is the first marker detectable in serum, appearing 30 days after infection; it precedes the elevation of serum aminotransferase levels and the onset of symptoms. Necroinflammatory liver disease then can occur, during which serum transaminase levels increase, along with high HBV DNA levels and HBeAg positivity. HBeAg correlates with viral replication, DNA polymerase activity, infectivity, and increased severity of liver disease. Antibody to hepatitis B core antigen (anti-HBc) appears 2 weeks after HBsAg and persists for life. Passively transferred maternal anti-HBc can be detectable in the infant up to age 12 months. In self-limited infections, HBsAg is usually eliminated in 1-2 months, and hepatitis B surface antibody (anti-HBs) develops during convalescence. Anti- HBs indicates immunity from HBV infection. After recovery from natural infection, both anti-HBs and anti-HBc usually are present. In persons who become chronically infected (i.e., persistently positive for HBsAg beyond 24 weeks), anti-HBs is not detectable. Persons who have been vaccinated may have detectable anti-HBs but not anti-HBc.

HBeAg seroconversion, defined as loss of HBeAg, followed by the production of antibodies to HBeAg (e.g., anti-HBe), heralds transition of the HBV-infected person to the inactive carrier state. HBeAg seroconversion is infrequent in children aged <3 years and may not occur until the third or fourth decade of HBV infection (653Chang MH, Hsu HY, Hsu HC, et al. The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age. Hepatology 1995;22:1387-92.). Less than 10% of children infected perinatally with HBV undergo HBeAg seroconversion. In contrast, higher rates of HBeAg seroconversion occur in childhood-acquired HBV infection, with 70%-80% of children acquiring anti-HBe by the second decade of life (650Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology 2006;43:556-62.). HBeAg seroconversion usually is followed by reduction of serum HBV DNA levels, an initial increase and then subsequent normalization of serum transaminase levels, followed by resolution of necroinflammatory liver disease (650Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology 2006;43:556-62.). Development of cirrhosis and HCC occur more commonly in patients with delayed HBeAg seroconversion (654Chu CM, Hung SJ, Lin J, et al. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004;116:829-34.). HBeAgnegative infection (precore mutant) occurs uncommonly in children (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48.).

HBV DNA is a marker for HBV replication. In the active phase of chronic hepatitis B, high HBV DNA levels have been associated with necroinflammatory liver disease. Children infected perinatally, however, may remain in an immunotolerant phase with high levels of HBV DNA without evidence of liver damage. Quantitative DNA assays may help determine the need for treatment and for evaluating treatment response. Although not necessary for diagnostic purposes, liver biopsy may be useful to assess the degree of liver damage and determine the need for treatment.

Prevention Recommendations
Prevention of Exposure

All pregnant women should be tested for HBsAg during an early prenatal visit in each pregnancy (AI). Testing should be repeated in late pregnancy for HBsAg-negative women at high risk for HBV infection (e.g., injection-drug users, women with intercurrent sexually transmitted infections, and women with multiple sex partners). Pregnancy is not a contraindication to hepatitis B vaccination for women who have not previously been vaccinated; current hepatitis B vaccines contain noninfectious HBsAg and should cause no risk to the fetus.

Preventing First Episode of Disease

All infants born to HBV-infected women, including HIVcoinfected women, should receive hepatitis B vaccine and hepatitis B immune globulin (HBIG) within 12 hours after birth, a second dose of hepatitis B vaccine at age 1-2 months, and a third dose at age 6 months (AI) (Figures 1 and 2) (38CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. MMWR 2005;54(No. RR-16).). For preterm infants weighing <2000 g, the initial vaccine dose (birth dose) should not be counted as part of the vaccine series because of the potentially reduced immunogenicity of hepatitis B vaccine in these infants; three additional doses of vaccine (for a total of four doses) should be administered beginning when the infant reaches age 1 month (AI) (38CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. MMWR 2005;54(No. RR-16).). A three-dose hepatitis B vaccine regimen is 95% effective in preventing HBV infection in HBV-exposed infants. Postvaccination testing for anti-HBs and HBsAg should be performed at age 9 - 18 months in infants born to HBsAg positive women. The level of anti-HBs that is considered protective is >10 mIU/ mL. Infants who are HBsAg negative and have anti-HBs levels <10 mIU/mL should be revaccinated with a second three-dose series of hepatitis B vaccine and retested 1-2 months after the final vaccine dose (38CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. MMWR 2005;54(No. RR-16).).

The three-dose series of hepatitis B vaccine also is recommended for all children and adolescents aged <19 years who were not previously vaccinated. However, antibody responses to hepatitis B vaccination may be diminished in HIV-infected children, especially in older children or children with CD4 counts <200 cells/mm3 (655Rutstein RM, Rudy B, Codispoti C, et al. Response to hepatitis B immunization by infants exposed to HIV. AIDS 1994;8:1281-4., 656Siriaksorn S, Puthanakit T, Sirisanthana T, et al. Prevalence of protective antibody against hepatitis B virus in HIV-infected children with immune recovery after highly active antiretroviral therapy. Vaccine 2006;24:3095-9.). For this reason, HIVinfected infants, children, and adolescents should be tested for anti-HBs 1-2 months after completing the vaccination series and, if anti-HBs levels are <10 mIU/mL, revaccinated with a second three-dose series of hepatitis B vaccine (AIII). Modified hepatitis B vaccine dosing regimens, including a doubling of the standard antigen dose, might increase response rates. However, although a current randomized trial is evaluating use of various hepatitis B vaccine preparations and doses in HIV-infected youth, no data are available yet.

The need for booster doses of hepatitis B vaccine in HIV-infected persons has not been determined. Annual anti-HBs testing and booster doses when the anti-HBs levels decline to <10 mIU/mL should be considered in persons with ongoing risk for hepatitis B exposure (CIII) (38CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children, and adolescents. MMWR 2005;54(No. RR-16).).

In addition to hepatitis B vaccine, hepatitis A vaccine can prevent hepatitis infection and its potential devastating longterm sequelae and thus all children should receive hepatitis A vaccination at age 12-23 months with the two doses in the series administered ≥ months apart (39CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR 2006;55(No. RR-7).). Children who are not fully vaccinated by age 2 years can be vaccinated at subsequent visits. Hepatitis A vaccine is also recommended for children aged ≥24 months who live in areas where vaccination programs target older children or those who are at increased risk for infection (Figures 1 and 2).

HBV-infected children should be advised not to share toothbrushes or other personal-care articles that might be contaminated with blood. Although efficiency of sexual transmission of HBV is relatively low, safe-sex practices should be encouraged for all HIV-infected adolescents and young adults; barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens, including HBV.

Treatment Recommendations
Treatment of Disease
General issues

Individualization of therapy is essential for any HBV-infected child and should be based on the child's age, age at acquisition of infection, HBV DNA levels, and serum transaminase levels. Antiviral therapy regimens for chronic hepatitis B are approved only for children aged >2 years who have compensated liver disease.

HIV-infected children who are not receiving anti-HBV therapy should be closely monitored with determination of serum aminotransferase levels every 6 months. If serum transaminase levels are persistently elevated (more than twofold the upper limit of normal for ≥6 months), HBeAg, anti- HBe, and HBV DNA levels should be obtained. Monitoring of serum transaminases and HBV DNA levels over time is important before the initiation of antiviral therapy to identify patients who may be in the process of spontaneous HBeAg seroconversion who would not require treatment. Liver biopsy is not required before treatment but may help to determine the severity of hepatic inflammation and fibrosis and to exclude other causes of liver disease.

No clear recommendations exist for treating chronic childhood HBV infection. HBV-infected children often have milder disease than adults and may show spontaneous HBeAg seroconversion. Few large randomized controlled trials exist of antiviral therapies for chronic hepatitis B infection in childhood. Moreover, the long-term safety of many of the agents used to treat chronic hepatitis B infection in adults is not known in children. However, a 2004 consensus meeting of pediatric liver experts recommended that antiviral treatment be considered in children with chronic HBV infection and a duration of necroinflammatory liver disease >6 months (657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54.).

Indications for treatment of chronic HBV infection in HIV-coinfected children are the same as in HBV-infected children without HIV infection: 1) evidence of ongoing HBV viral replication, as indicated by detectable serum HBV DNA, with or without HBeAg positivity, for >6 months and persistent elevation of serum transaminase levels (at least twice the upper limit of normal for >6 months); or 2) evidence of chronic hepatitis on liver biopsy (BII) (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48., 657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54.). Children without necroinflammatory liver disease usually do not warrant antiviral therapy (DIII). Treatment is not recommended for children with immunotolerant chronic HBV infection (i.e., normal serum transaminase levels despite detectable HBV DNA) (DIII). The goals of treatment for children with chronic hepatitis B infection are identical to those for adults: suppression of HBV replication; normalization of serum transaminase levels; acceleration of HBeAg seroconversion; preservation of liver architecture; and prevention of long-term sequelae, such as cirrhosis and HCC.

The optimal agent and duration of therapy for childhood hepatitis B infection remain unclear. Treatment of chronic hepatitis B infection is evolving; consultation with providers with expertise in treating chronic hepatitis B infection in children is recommended.

Treatment of chronic hepatitis B infection in adults and adolescents

Seven medications have been approved to treat chronic hepatitis B infection in adults: interferons (both standard and pegylated); nucleoside analogues (i.e., lamivudine; telbivudine; and entecavir); and the nucleotide analogues, adefovir and tenofovir. The FDA-approved HIV antiretroviral medication emtricitabine also has significant activity against HBV, although it is not approved for this indication. Preferred initial therapies for adults who have chronic hepatitis B without HIV infection include pegylated interferon-alfa, entecavir, or adefovir monotherapy. In adults who have chronic hepatitis B infection with or without HIV infection, treatment for hepatitis is considered in HBeAg-positive persons with HBV DNA ≥20,000 IU/mL (>105 copies/mL), HBeAg-negative persons with HBV DNA ≥2000 IU/mL (>104 copies/mL), patients with persistent serum transaminase elevation, or patients with evidence of cirrhosis or fibrosis (652Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356:1445-54.).

Treatment options for HBV in HIV-infected persons must account for the goals of therapy and the impact treatment might have on both HIV and HBV replication. In coinfected patients who require treatment for chronic hepatitis B, HIV, or both, many experts would initiate a fully suppressive regimen to treat HIV infection that includes a dual nucleoside analogue backbone with drugs active against both HIV and HBV plus a third agent active against HIV; this approach might reduce the risk for IRIS, particularly in patients with advanced immune deficiency. Tenofovir plus lamivudine or emtricitabine would be the first choice for the nucleoside backbone; the combination of tenofovir with lamivudine was demonstrated to be more effective in suppressing HBV than either drug alone and prevents development of lamivudine resistance (658Jain MK, Comanor L, White C, et al. Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response. J Viral Hepat 2007;14:176-82.). In instances in which HIV treatment is not an option but treatment of hepatitis B infection is needed, pegylated interferon-alfa can be used alone because it does not lead to development of drug-resistant HIV or HBV mutants. Use of tenofovir, lamivudine, or emtricitabine without a fully suppressive HAART regimen should be avoided because of the rapid development of drug-resistant HIV mutations.

Treatment of chronic hepatitis B infection in children without HIV infection

Only two drugs (monotherapy with interferon-alfa [standard] or lamivudine) are FDA-approved to treat chronic hepatitis B in children (AI). The limited pediatric trials of these agents show that although they are well-tolerated by children, response rates are low, and treatment does not fully eliminate HBV infection (659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60., 660Heller S, Valencia-Mayoral P. Treatment of viral hepatitis in children. Arch Med Res 2007;38:702-10.). In HIV-uninfected children, HBeAg seroconversion rates after 1 year of treatment are similar (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48.). Interferon-alfa treatment is administered for only 6 months but requires subcutaneous administration and has more frequent side effects, including growth impairment. Although lamivudine is administered orally and has a lower rate of side effects, it requires a longer duration of therapy and has a high rate of resistance if taken for an extended time (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48.).

Although various combination regimens involving sequential or concurrent lamivudine and standard or pegylated interferon-alfa have been studied in children or adults with chronic hepatitis B, the superiority of combination therapy over monotherapy with standard or pegylated interferon-alfa or lamivudine has not been demonstrated; however, lamivudine resistance rates may be lower (661Sokucu S, Gokçe S, Suoglu OD, et al. Comparison of interferon monotherapy with interferon-lamivudine combination treatment in children with chronic hepatitis B. Indian J Gastroenterol 2006;25:136-9., 662Kansu A, Doganci T, Akman SA, et al. Comparison of two different regimens of combined interferon-alpha2a and lamivudine therapy in children with chronic hepatitis B infection. Antivir Ther 2006;11:255-61., 663Yilmaz A, Akcam M, Gelen T, et al. Lamivudine and high-dose interferon alpha 2a combination treatment in nave HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterranean centers experience. Eur J Pediatr 2007;166:195-9.Yilmaz A, Akcam M, Gelen T, et al. Lamivudine and high-dose interferon alpha 2a combination treatment in naïve HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterranean center's experience. Eur J Pediatr 2007;166:195-9., 664DAntiga L, Aw M, Atkins M, et al. Combined lamivudine/interferonalpha treatment in immunotolerant children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148:228-33.D'Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferonalpha treatment in «immunotolerant» children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148:228-33., 665Saltik-Temizel IN, Kocak N, Demir H. Lamivudine and high-dose interferon-alpha combination therapy for naive children with chronic hepatitis B infection. J Clin Gastroenterol 2005;39:68-70.Saltik-Temizel IN, Koçak N, Demir H. Lamivudine and high-dose interferon-alpha combination therapy for naive children with chronic hepatitis B infection. J Clin Gastroenterol 2005;39:68-70., 666Ozgenc F, Dikici B, Targan S, et al. Comparison of antiviral effect of lamivudine with interferon-alpha2a versus -alpha2b in children with chronic hepatitis B infection. Antivir Ther 2004;9:23-6., 667Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAgnegative chronic hepatitis B. N Engl J Med 2004;351:1206-17., 668Dikici B, Bosnak M, Kara IH, et al. Lamivudine and interferon-alpha combination treatment of childhood patients with chronic hepatitis B infection. Pediatr Infect Dis J 2001;20:988-92., 669Dikici G, Ozgenc F, Kalayci AG, et al. Current therapeutic approaches in childhood chronic hepatitis B infection: a multicenter study. J Gastroenterol Hepatol 2004;19:127-33. 118 MMWR September 4, 2009, 670Kuloglu Z, Krsacloglu CT, Kansu A, et al. Liver histology of children with chronic hepatitis treated with interferon-a alone or in combination with lamivudine. J Pediatr Gastroenterol Nutr 2007;45:564-8.). A recent study of children with immunotolerant HBV infection suggested possible benefit from sequential lamivudine and interferon-alfa therapy, with 78% of patients clearing HBV DNA by the end of treatment (664DAntiga L, Aw M, Atkins M, et al. Combined lamivudine/interferonalpha treatment in immunotolerant children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148:228-33.D'Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferonalpha treatment in «immunotolerant» children perinatally infected with hepatitis B: a pilot study. J Pediatr 2006;148:228-33.). However, combination therapy cannot be recommended for pediatric HBV infection until more data are available (DII).

Treatment of HBV/HIV-coinfected children

None of the clinical studies of treatment of chronic hepatitis B infection have specifically studied children with HIV/HBV coinfection. As in coinfected adults, choice of antiviral therapy for the HIV/HBV-coinfected child involves consideration of whether concurrent HIV treatment is warranted.

• If treatment of chronic hepatitis B but not HIV infection is indicated, standard interferon-alfa is the preferred agent (BIII). Adefovir also could be considered in older children able to receive adult dosing (BIII). Antiviral drugs with activity against HIV (e.g., lamivudine, emtricitabine, tenofovir, and possibly entecavir) should be avoided to prevent future development of drug-resistant HIV mutations.

• If treatment of HIV infection but not chronic hepatitis B is indicated, use of a HAART regimen that avoids drugs with activity against HBV (e.g., lamivudine, emtricitabine, or tenofovir) is recommended to prevent future development of HBV drug resistance (BIII). Alternatively, in older coinfected children who can receive tenofovir, use of a HAART regimen with a nucleoside analogue backbone that contains two drugs effective against HBV (tenofovir plus lamivudine or emtricitabine) can be considered (BIII).

• If treatment for both HIV and chronic hepatitis B is indicated and the child is lamivudine-naïve, an antiretroviral regimen that includes lamivudine (or emtricitabine) is recommended (BIII). A regimen containing tenofovir and a nucleoside analogue (either lamivudine or emtricitabine) is preferred for HIV/HBV-coinfected adults, and should be considered for use in older HIV-infected children or adolescents who can receive adult dosage. However, tenofovir is not approved for use in HIV-infected children <18 years, and no pediatric formulations are available. Although pediatric studies with an investigational pediatric formulation of tenofovir are under way, data are not yet available.

• If treatment for HIV and chronic hepatitis B is indicated and the child is receiving antiretroviral therapy including lamivudine or emtricitabine with HIV suppression but detectable plasma HBV DNA, HBV lamivudine resistance can be assumed. However, HBV drug-resistant isolates may have lower replicative capacity, and some experts recommend continued use of lamivudine or emtricitabine, although this recommendation is controversial (CIII).

Treatment options for such children who require HBV therapy include the addition of interferon therapy to the antiretroviral regimen (BIII), or tenofovir (BIII), or adefovir if the child can receive adult dosing (BIII). Data are insufficient on other anti-HBV drugs in children to make recommendations.

Interferons

Standard interferon-alfa-2a or -2b has received the most study in children who have chronic hepatitis B (without HIV infection) and is recommended for treating chronic hepatitis B infection with compensated liver disease in HIV-uninfected children aged ≥2 years who warrant treatment (BII). In a review of six randomized clinical trials in 240 HBV-infected children aged >1.5 years, interferon-alfa therapy resulted in HBV DNA clearance in 35% of treated children, HBeAg clearance in 10%, and normalization of serum transaminase levels in 39% at treatment completion (671Torre D, Tambini R. Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis. Clin Infect Dis 1996;23:131-7.). Six to 18 months after therapy discontinuation, 29% of children had persistent HBV DNA, and 23% demonstrated HBeAg clearance. Children most likely to respond to interferon treatment are of younger age, higher baseline serum transaminase levels, and lower baseline HBV DNA levels (659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60., 672Gurakan F, Koçak N, Ozen H, et al. Comparison of standard and high dosage recombinant interferon alpha 2b for treatment of children with chronic hepatitis B infection. Pediatr Infect Dis J 2000;19:52-6., 673Yuce A, Koçak N, Ozen H, et al. Prolonged interferon alpha treatment in children with chronic hepatitis B. Ann Trop Paediatr 2001;21:77-80., 674Choe BH, Lee JH, Jang YC, et al. Long-term therapeutic efficacy of lamivudine compared with interferon-alpha in children with chronic hepatitis B: the younger the better. J Pediatr Gastroenterol Nutr 2007;44:92-8.). Response is less likely (10%) in those with normal serum transaminase levels, high HBV DNA levels, HBV genotypes C or D, or HBeAg-negative chronic HBV infection. Interferon-alfa therapy might be considered to treat chronic hepatitis B in HIV-coinfected children who do not require antiretroviral therapy for their HIV infection (BIII).

The standard course of interferon-alfa therapy for children without HIV infection is 24 weeks. Pegylated interferon-alfa, which results in more sustained plasma interferon concentrations and can be administered by injection once weekly for 48 weeks, has proven superior to standard interferon-alfa in treating HBV-infected adults (667Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAgnegative chronic hepatitis B. N Engl J Med 2004;351:1206-17., 675Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95.). However, the limited data on use of pegylated interferon-alfa in children come from treatment of hepatitis C infection, and appropriate dosing information is not available for use of pegylated interferon-alfa to treat chronic hepatitis B in children (DIII) (676Schwarz KB, Mohan P, Narkewicz MR, et al. Safety, efficacy and pharmacokinetics of peginterferon alpha2a (40 kd) in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2006;43:499-505., 677Wirth S, Pieper-Boustani H, Lang T, et al. Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatology 2005;415., 678Baker RD, Dee D, Baker SS. Response to pegylated interferon alpha-2b and ribavirin in children with chronic hepatitis C. J Clin Gastroenterol 2007;41:111-4.).

Lamivudine

Lamivudine (3TC) is an oral nucleoside analogue that inhibits HBV replication. It is approved for use in children aged 2-17 years who have compensated liver disease from chronic hepatitis B. In a placebo-controlled trial in children who have chronic hepatitis B without HIV infection, lamivudine was well tolerated, with virologic response (clearance of HBV DNA and HBeAg) in 23% of children receiving 52 weeks of lamivudine therapy, compared with 13% in placebo recipients (679Jonas MM, Mizerski J, Badia IB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706-13.). Response rates were higher (35%) for children with baseline serum transaminases more than two times normal (679Jonas MM, Mizerski J, Badia IB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706-13.). In a 2-year, open-label extension of this study, 213 children who remained HBeAg-positive after 1 year of therapy were continued on lamivudine treatment; virologic response was seen in 21% of the original lamivudine recipients, compared with 30% of prior placebo recipients, indicating that additional clinical response could occur over time with prolonged treatment (680Sokal EM, Kelly DA, Mizerski J, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology 2006;43:225-32.). However, longer duration of lamivudine therapy also was associated with progressive development of lamivudine-resistant HBV, with base pair substitutions at the tyrosine-methionine-aspartate-aspartate (YMDD) locus of HBV DNA polymerase.

Accordingly, lamivudine should not be used as a single agent for treatment of chronic hepatitis B in HIV-infected children because of the risk for HIV resistance to lamivudine (EIII); as discussed above, lamivudine should be used only in HIV/HBV-coinfected children in combination with other antiretroviral drugs in a HAART regimen (BIII). The dose of lamivudine required to treat HIV infection is higher than to treat pediatric chronic hepatitis B alone; therefore, the higher dose of lamivudine should be used in HIV/HBV-coinfected children to avoid development of lamivudine-resistant HIV (AIII). Lamivudine resistance should be suspected if HBV DNA levels increase during antiviral therapy. Such increases may precede increases in serum transaminase levels (hepatic flare) and liver decompensation (674Choe BH, Lee JH, Jang YC, et al. Long-term therapeutic efficacy of lamivudine compared with interferon-alpha in children with chronic hepatitis B: the younger the better. J Pediatr Gastroenterol Nutr 2007;44:92-8.).

Emtricitabine

Emtricitabine is structurally similar to lamivudine and is active against HBV and HIV, although not approved for treatment of chronic hepatitis B. Like lamivudine, emtricitabine also is associated with relatively rapid onset of HBV and HIV drug resistance, and patients with suspected lamivudine resistance should be assumed to have cross-resistance to emtricitabine. Lamivudine and emtricitabine should be considered interchangeable for treatment of chronic hepatitis B and not additive (BIII). As with lamivudine, emtricitabine should not be used to treat chronic hepatitis B in coinfected children who are not being treated with combination antiretroviral therapy for their HIV infection because of the risk for HIV-associated resistance mutations (EIII).

Adefovir

Adefovir dipivoxil is an oral nucleotide analogue active against HBV. Although active against HBV, adefovir has minimal anti-HIV activity, and HIV resistance has not been observed in patients receiving a 10-mg daily dose of adefovir for 48 weeks (681Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 2006;44:62-7.). HBV resistance to adefovir is much lower than in lamivudine, being reported as 2% after 2 years, 4% after 3 years, and 18% after 4 years of therapy in adults (682Locarnini S. Molecular virology and the development of resistant mutants: implications for therapy. Semin Liver Dis 2005;25 (Suppl 1): 9-19.). These adefovir-associated mutations in HBV Pol gene result in only a modest (threefold to eightfold) increase in the 50% inhibitory concentration and are partially cross-resistant with tenofovir. Adefovir is now FDA-approved for adults who require treatment for chronic hepatitis B but do not yet require treatment for their HIV infection. Adefovir has been studied in HIV/ HBV-coinfected adults with lamivudine-resistant HBV infection, and HBV suppression was demonstrated (681Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 2006;44:62-7.). Safety and effectiveness of adefovir for treating chronic hepatitis B in children has not yet been established, but an ongoing randomized clinical trial is evaluating its use in HIV-uninfected children aged 2-17 years who have chronic hepatitis B (659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60.).

Tenofovir

Tenofovir is a nucleotide analog structurally similar to adefovir that reduces HBV DNA levels in adults with lamivudineresistant and wild-type HBV infection. A study in HIV/ HBV-coinfected adults receiving stable antiretroviral therapy comparing treatment with tenofovir or adefovir found similar efficacy in suppression of HBV DNA without differences in toxicity (683Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006;44:1110-6.). Another study of HIV/HBV-coinfected adults receiving tenofovir in addition to lamivudine as part of their antiretroviral regimen found that HBV DNA became undetectable in 30% of HBeAg-positive and 82% of HBeAg-negative patients, most of whom had lamivudine-resistant HBV infection (681Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 2006;44:62-7.). As noted earlier, tenofovir is not approved for use in HIV-infected children aged <18 years, and no pediatric formulation is available. However, for HIV/HBV-coinfected adolescents who require treatment of both infections and who can receive adult doses, tenofovir in combination with an anti- HBV nucleoside (either lamivudine or emtricitabine) can be considered for treatment (BIII); a combined formulation of emtricitabine and tenofovir (Truvada) is available for adults. As with lamivudine and emtricitabine, tenofovir should not be used for treatment of chronic hepatitis B in HIV-coinfected patients who are not receiving combination antiretroviral therapy for their HIV infection because of the risk for HIV associated resistance mutations (EIII).

Entecavir

Entecavir is an oral nucleoside analogue that inhibits HBV DNA polymerase. Compared with lamivudine, entecavir therapy results in greater HBV viral suppression, increased normalization of serum transaminase levels, improved liver histology, and lower HBV resistance rates (684Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354: 1011-20.). HBV viral suppression also has been demonstrated in HIV/HBV-coinfected adults. Entecavir treatment is approved for treatment of chronic hepatitis B in adults and is preferred for lamivudine-resistant HBV infections. However, it recently was demonstrated to have suppressive activity against HIV (685McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir- effects on HIV-1 replication and resistance. N Engl J Med 2007; 356:2614-21.). Entecavir should not be used in HIV/HBV-coinfected patients who are not receiving combination antiretroviral therapy for their HIV infection. No data are available on safety and efficacy of entecavir in children.

Telbivudine

Telbivudine is a thymidine nucleoside analogue that was approved to treat chronic hepatitis B in adults. It is well tolerated, but like lamivudine, resistance emerges over time, and telbivudine is not active against lamivudine-resistant HBV. No data are available on telbivudine in HIV/HBV-coinfected adults. No data on children exist on safety and efficacy of telbivudine.

Duration of therapy

The optimal duration of therapy in HIV/HBV-coinfected children is not known. The duration of interferon-alfa treatment in HIV-uninfected children with chronic hepatitis B is 6 months. At least 1 year of lamivudine therapy is recommended for HIV-uninfected children who have chronic hepatitis B, with continuation of medication for ≥6 months after documented HBeAg seroconversion (659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60.). However, because lamivudine would be administered only to HIV/HBV-coinfected children who need HIV treatment and as part of a suppressive antiretroviral regimen, treatment with lamivudine (or other anti-HBV drugs with anti-HIV activity) should be continued indefinitely in children with HIV/HBV coinfection, even in the instance of HBeAg seroconversion (CIII).

Monitoring and Adverse Events, Including IRIS

The parameters of successful therapy for chronic hepatitis B are not well defined, but markers of improvement include decreased hepatic necroinflammatory disease, normalization of serum transaminase levels, reduction of HBV DNA levels, and HBeAg seroconversion. In children starting treatment for chronic hepatitis B, serum transaminase levels should be measured every 3-6 months. If the child also is beginning HAART, some experts would monitor transaminase levels more frequently during the first few months of therapy (e.g., monthly for 3 months) because of the risk for IRIS (see below). Monitoring of response to treatment for chronic hepatitis B is based on testing for HBV DNA and HBeAg and anti- HBe antibody on the same schedule as transaminase evaluations (every 3-6 months). Among HBeAg-positive persons, treatment for chronic hepatitis B should be continued until HBeAg seroconversion has been achieved and ≥6 months of additional treatment has been completed after the appearance of anti-HBe (BIII). Close monitoring for relapse is needed after withdrawal of therapy. Among persons who are HBeAg negative, treatment should be continued until HBsAg clearance has been achieved.

In HIV/HBV-coinfected persons starting HAART, serum transaminase elevations ("flares") can occur as part of IRIS or secondary to HAART-associated hepatotoxicity. HBVassociated liver injury is thought to be immune-mediated, and restoration of immunocompetence with antiretroviral treatment may reactivate liver inflammation and damage. Initiation of HAART without anti-HBV therapy can lead to reactivation of HBV. This does not represent a failure of HAART but rather a sign of immune reconstitution. IRIS manifests by an increase in serum transaminase levels as the CD4 count increases during the first 6-12 weeks of HAART. Thus, serum transaminase levels should be monitored closely after introduction of HAART. In such situtations, HAART should be continued and treatment for HBV initiated. The prognosis for most IRIS cases is favorable because a robust inflammatory response may predict an excellent response to HAART in terms of immune reconstitution and, perhaps, improved survival. In a patient experiencing a hepatic flare, differentiating between IRIS and drug-induced liver toxicity may be difficult, and no reliable clinical or laboratory predictor exists to distinguish between the two. Close collaboration of the HIV specialist with a specialist in hepatic disease is recommended for such patients; a hepatologist should be consulted promptly if elevated aminotransferases levels are associated with clinical jaundice or other evidence of liver dysfunction (e.g., low serum albumin).

Clinical and laboratory exacerbations of hepatitis and hepatic flare can occur in children receiving HAART if agents with anti-HBV activity are discontinued. Some experts recommend that once antiretroviral drugs with anti-HBV activity are begun, they should be continued unless contraindicated or until the child has been treated for >6 months after HBeAg seroconversion and can be closely monitored after discontinuation (BIII). If discontinuation of therapy for chronic hepatitis B results in hepatic flare, therapy for chronic hepatitis B should be reinstituted (BIII).

Some clinicians recommend monitoring HBV-infected children or adolescents for HCC with baseline screening and then yearly determinations of serum alpha fetoprotein levels and abdominal ultrasonography; however, no data support the benefit of such surveillance (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48., 657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54., 659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60., 660Heller S, Valencia-Mayoral P. Treatment of viral hepatitis in children. Arch Med Res 2007;38:702-10.).

Adverse effects of interferon-alfa use in children, although frequent, usually are not severe or permanent; however, approximately 5% of children require treatment discontinuation. The most common side effects include an influenza-like syndrome, cytopenias, and neuropsychiatric effects. Influenzalike symptoms comprising fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, and vomiting are seen in 80% of patients during the first month of treatment. These side effects decrease substantially during the first 4 months of therapy; premedication with acetaminophen or ibuprofen might reduce side effects. Subtle personality changes, which resolve when therapy is discontinued, have been reported in 42% of children (686Sokal EM, Conjeevaram HS, Roberts EA, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology 1998;114:988-95.). Depression and suicidal ideation have also been reported in clinical trials of children treated with interferon-alfa (687Gonzalez-Peralta R, Kelly DA, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42:1010-8.). Neutropenia, which resolves after discontinuation of therapy, is the most common laboratory abnormality; anemia and thrombocytopenia are less common. Abnormalities in thyroid function (hypothyroidism or hyperthyroidism) have been reported with interferon-alfa therapy (688Kuloglu Z, Kansu A, Berberoglu M, et al. The incidence and evolution of thyroid dysfunction during interferon-alpha therapy in children with chronic hepatitis B infection. J Pediatr Endocrinol Metab 2007;20:237-45.). Loss of appetite with transient weight loss and impaired height growth might occur but usually resolves after completion of therapy (689Comanor L, Minor J, Conjeevaram HS, et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat 2001;8:139-47.). Less commonly observed side effects of interferon-alfa include epistaxis and transient mild alopecia. Antinuclear autoantibodies have been detected in some children treated with interferon-alfa. Interferon-alfa therapy is contraindicated for children with decompensated liver disease; severe cytopenia; severe renal, cardiac, or neuropsychiatric disorders; and autoimmune disease (EII) (690Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999;29:163-70.). Elevation of serum transaminase levels has been reported during interferon-alfa therapy in children and adults but usually is not an indication to stop therapy; these flares may herald impending HBeAg seroconversion (659Jonas MM. Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2006;43(Suppl 1):S56-60.). Children receiving interferon-alfa therapy should be monitored with a complete blood count and serum level of thyroid stimulating hormone at baseline and periodically (e.g., at least every 3 months) for the duration of treatment.

Lamivudine usually is well-tolerated in children; rare cases of lactic acidosis and pancreatitis have been reported in HIV/ HBV-coinfected adults. Tenofovir and adefovir can cause renal tubular disease. Patients receiving either drug should have baseline urinalysis and periodic serum creatinine and phosphate monitoring. Administration of other nephrotoxic agents increases the risk for renal toxicity.

Management of Treatment Failure

Treatment failure is defined as ongoing HBV replication, persistent serum transaminase elevations, and the failure of HBeAg seroconversion in HBeAg-positive persons. Flares of liver disease with increasing HBV DNA levels can be seen with the development of resistance to lamivudine or emtricitabine. In some children who have received initial treatment for chronic hepatitis B with standard-dose interferon-alfa monotherapy, use of higher-dose interferon-alfa for retreatment improves response (665Saltik-Temizel IN, Kocak N, Demir H. Lamivudine and high-dose interferon-alpha combination therapy for naive children with chronic hepatitis B infection. J Clin Gastroenterol 2005;39:68-70.Saltik-Temizel IN, Koçak N, Demir H. Lamivudine and high-dose interferon-alpha combination therapy for naive children with chronic hepatitis B infection. J Clin Gastroenterol 2005;39:68-70., 691Vajro P, Migliaro F, Fontanella A, et al. Interferon: a meta-analysis of published studies in pediatric chronic hepatitis B. Acta Gastroenterol Belg 1998;61:219-23., 692Ozen H, Koçak N, Yüce A, et al. Retreatment with higher dose interferon alpha in children with chronic hepatitis B infection. Pediatr Infect Dis J 1999;18:694-7.). Lamivudine has also been used as secondary therapy for children without HIV infection who have not responded to standard interferon-alfa therapy (CII) (693Kocak N, Saltik IN, Ozen H, et al. Lamivudine treatment for children with interferon refractory chronic hepatitis B. Hepatology 2000;31:545., 694Sokal EM, Roberts EA, Mieli-Vergani G, et al. A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B. Antimicrob Agents Chemother 2000;44:590-7., 695Hartman C, Berkowitz D, Eshach-Adiv O, et al. Long-term lamivudine therapy for chronic hepatitis B infection in children unresponsive to interferon. J Pediatr Gastroenterol Nutr 2006;43:494-8.) ; in HIV-infected children, initiation of a lamivudine-based HAART regimen could be considered (CIII).

For HIV/HBV-coinfected children developing lamivudine resistance during therapy, treatment options are more limited because of the lack of data on use of adefovir, entecavir, and tenofovir in children. Because these HBV drug-resistant isolates may have lower replicative capacity than wild-type HBV, some experts recommend continuing lamivudine or emtricitabine therapy in such cases. Alternatively, the addition of interferonalfa therapy could be considered or, in children old enough to receive adult doses of tenofovir or adefovir, addition of tenofovir or adefovir to the regimen could be considered (CIII).

Prevention of Recurrence

Not applicable.

Discontinuing Secondary Prophylaxis

Not applicable.

Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†: Hepatitis B virus
Preferred therapies and durationAlternative therapiesOther options or issues

Excerpted from Table 4

* HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus

† Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box).

Treatment required only for HBV (HIV treatment not required; avoid TDF, 3TC, and FTC):

transparent gifgrey bulletInterferon-alfa, 3 million units/m2 body surface area subcutaneously 3 times weekly for 1 wk, followed by dose escalation to 6 million units/m2 (max 10 million units/ dose), to complete a 24-wk course (BII); OR
transparent gif
transparent gifgrey bulletAdefovir, 10 mg orally once daily for older children who can receive adult dosing for a minimum of 12 mos (BII)
transparent gif

Treatment required for both HIV and HBV:

transparent gifgrey bulletLamivudine (3TC), 4 mg/kg body weight orally (max 150 mg/dose) twice daily as part of a fully suppressive HAART regimen (BII)
transparent gif
transparent gifgrey bulletInclude tenofovir, 300 mg orally once daily,as part of a fully suppressive HAART regimen (BII)
transparent gif
transparent gifgrey bulletIf child is on HAART containing 3TC or emtricitabine (FTC) and has detectable HBV DNA (assume 3TC/FTC resistance):
transparent gif

—If child is old enough to receive adult dosing, continue 3TC (or FTC) (CIII); if child is old enough to receive adult dosing and not on tenofovir, add tenofovir, 300 mg orally once daily, as part of HAART regimen (BII); or add adefovir, 10 mg orally once daily, to HAART regimen (BII)

—If child is not old enough to receive adult dosing: administer 6-mo course of interferon-alfa as above in addition to HAART regimen (BII); continue 3TC (or FTC) (CIII)


Treatment for HIV alone:

transparent gifgrey bulletHAART regimen that avoids the use of 3TC, FTC, or tenofovir (BIII)
transparent gif

Interferon-alfa, 10 million units/m2 body surface area subcutaneously 3 times weekly for 6 mos (sometime used for retreatment of failed lower-dose interferon therapy) (CII)

Alternative for 3TC: FTC 6 mg/kg body weight (max 200 mg) once daily (BIII)

Indications for treatment include (BII):

transparent gifgrey bulletDetectable serum HBV DNA, with or without positive HBeAg, for >6 mos; and
transparent gif
transparent gifgrey bulletPersistent (>6 mos) elevation of serum transaminases (twice or more the upper limit of normal); or
transparent gif
transparent gifgrey bulletEvidence of chronic hepatitis on liver biopsy.
transparent gif

Interferon-alfa is contraindicated in children with decompensated liver disease, significant cytopenias, severe renal, neuropsychiatric, or cardiac disorders, and autoimmune disease (EII).

Choice of HBV treatment options for HBV/HCV coinfected children depends on whether concurrent HIV treatment is warranted.

3TC and FTC have similar activity (and have crossresistance) and should not be administered together.

Tenofovir is not approved for use in HIV-infected children aged <18 yrs, and no pediatric formulation exists; it can be used for older HIV-infected children who can receive adult dosage.

Adefovir is not approved for use in children but is under study in HIV-uninfected children for treatment of chronic hepatitis B; can be considered for older HIV-infected children who can receive adult dosage.

IRIS may be manifested by dramatic increase in transaminases as CD4 counts rise within the first 6-12 wks of HAART. Distinguishing between druginduced hepatotoxicity or other causes of hepatitis and IRIS may be difficult.

In children receiving 3TC, FTC, and/or tenofovir, clinical and laboratory exacerbations of hepatitis (flare) may occur if the drug is discontinued; thus, once anti-HBV/ HIV therapy has begun, it should be continued unless contraindicated or until the child has been treated for >6 mos after HBeAg seroconversion and can be closely monitored on discontinuation (BIII).

If anti-HBV therapy is discontinued and a flare occurs, reinstitution of therapy is recommended because a flare can be life threatening (BIII).

Entecavir and telbivudine have been approved for use in adults with HBV; no data exist on safety or efficacy of these medications in children.

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