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Recommendations from Centers for Disease Control and Prevention,

Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Viral Infections. Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of

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Recommendations from Centers for Disease Control and Prevention,

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  1. Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected ChildrenViral Infections Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

  2. About This Presentation These slides were developed using the April 2008 Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. Expert opinion should be sought for complex treatment regimens. – AETC NRC www.aideetc.org

  3. Cytomegalovirus:Epidemiology Infection with CMV common and often inapparent 50-80% of women of childbearing age in United States are CMV antibody positive 90% of HIV-infected women are CMV antibody positive Infection occurs: During infancy, early childhood, adolescence Via contact with virus-containing salvia, urine, sexual fluid, blood, transplanted organ Perinatally – most common www.aideetc.org

  4. Cytomegalovirus:Epidemiology (2) In utero infection occurs most commonly among infants born to mothers with primary infection during pregnancy 30-40% rate of CMV transmission to fetus following primary infection during pregnancy 0.2-1% rate of CMV transmission to fetus following recurrent infection during pregnancy (reactivation of infection or reinfection with a different strain of CMV) www.aideetc.org

  5. Cytomegalovirus:Epidemiology (3) CMV may be transmitted intrapartum or postpartum 57% of infants whose mothers shed CMV become infected 53% of infants who are breast-fed with milk that contains CMV become infected www.aideetc.org

  6. Cytomegalovirus:Epidemiology (4) HIV-coinfected women have a higher rate of CMV shedding HIV-coinfected women have a higher rate of HIV transmission HIV-infected children at greater risk of acquiring CMV during early childhood CMV causes 8-10% of AIDS-defining illnesses Children with positive CMV urine cultures have lower survival rates A higher percentage of HIV/CMV-coinfected children shed CMV than do CMV-infected, HIV-uninfected children www.aideetc.org

  7. 10% of infants infected in utero are symptomatic at birth with congenital CMV syndrome Infants with congenital infection: small for gestational age, purpura/petechiae, jaundice, hepatosplenomegaly, chorioretinitis, microcephaly, intracranial calcification,hearing loss Delayed manifestations of congenital infections include developmental abnormalities, sensorineural hearing loss, chorioretinitis, neurologic defects Cytomegalovirus: Clinical Manifestations www.aideetc.org

  8. HIV-infected children with CMV coinfection have accelerated HIV progression Coinfected children more likely to develop HIV CNS disease CMV retinitis most frequent severe manifestation of CMV disease, accounting for 25% of CMV AIDS-defining illnesses CMV retinitis is frequently asymptomatic Older children may have floaters or loss of peripheral central vision Cytomegalovirus: Clinical Manifestations (2) www.aideetc.org

  9. End organ disease reported in liver, lung, GI tract, pancreas, kidney, sinuses, CNS Nonspecific symptoms include weight loss, loss of developmental milestones, fever, anemia, thrombocytopenia Also observed: oral and esophageal ulcers, ascending cholangiopathy, CMV colitis, CMV pneumonia with shortness of breath and dry nonproductive cough CNS manifestations include encephalopathy, myelitis, polyradiculopathy with nonspecific or normal CSF Cytomegalovirus: Clinical Manifestations (3) www.aideetc.org

  10. Antibody assays indicative of maternal transfer of IgG in children <12 months; indicative of previous infection in children >12 months Positive cell culture from urine, tissues, blood leukocytes DNA PCR assays more sensitive than buffy coat or urine culture Quantitative DNA PCR can be used to monitor disease and treatment Other methods include monoclonal antibody staining and immunostaining for antigen Cytomegalovirus:Diagnosis www.aideetc.org

  11. Recommendations include: Testing all HIV-infected infants with urine culture for CMV in the first months of life to identify congenital, perinatal, or early postnatal infection Testing annually for CMV antibody in infants previously negative by culture and antibody to identify occult CMV infections permitting appropriate screening for retinitis Dilated retinal examinations for coinfected children every 4-6 months; older children should report floaters and visual changes Cytomegalovirus: Diagnosis (2) www.aideetc.org

  12. Administer CMV antibody-negative blood and blood products if transfusion is required Begin CMV antibody testing at 1 year of age in seronegative HIV-infected infants and children who are severely immunosuppressed Inform parents and care providers that HIV-infected children are at risk of CMV in daycare settings Minimize risk of acquiring CMV infection with optimal hygienic practices Cytomegalovirus: Prevention www.aideetc.org

  13. Symptomatic congenital CMV Ganciclovir: 6 mg/kg IV Q12H for 6 weeks (B I) Alternative treatment for ganciclovir-resistant CMV is foscarnet Cytomegalovirus: Treatment www.aideetc.org

  14. Initial and maintenance treatment of disseminated CMV and CMV retinitis Ganciclovir: 5 mg/kg/dose IV over period of 1-2 hours BID for 14-21 days, followed by lifelong maintenance therapy (A I) Combination treatment with ganciclovir and foscarnet delays progression of retinitis inpatients failing monotherapy (B III) Maintenance treatment with oral valganciclovir with a ganciclovir sustained-release ocular implant can be considered for chronic suppression of CMV retinitis in older children and adults Cytomegalovirus: Treatment (2) www.aideetc.org

  15. Alternative treatment for ganciclovir resistance Foscarnet (A I) at 60 mg/kg/dose IV (infused at1 mg/kg/minute) over period of 1-2 hours Q8H for 14-21 days, followed by lifelong therapy Foscarnet plus ganciclovir delays progression of retinitis in certain patients failing monotherapy Toxicity: decreased renal function, metabolic abnormalities, electrolyte imbalances with secondary seizures, cardiac dysrhythmia, abnormal liver enzymes, and CNS symptoms Cytomegalovirus:Treatment (3) www.aideetc.org

  16. Treatments for adults (inadequate pediatric data) Valganciclovir: prodrug of ganciclovir, given orally, effective in retinitis in adults Oral ganciclovir (or valganciclovir) plus ganciclovir sustained-release intraocular implant used for retinitis Cidofovir for retinitis Fomivirsen: antisense nucleotide used as intravitreous injection Cytomegalovirus:Treatment (4) www.aideetc.org

  17. Cytomegalovirus: Adverse Events Ganciclovir and valganciclovir Neutropenia may occur and may require dosage modification Resistance and myelosuppression can occur Other toxic effects include renal impairment, CNS effects, GI dysfunction, increased liver enzymes Metabolic disturbances can be minimized by slow infusion rates Immune recovery uveitis, and immunologic reaction to CMV, is related to the occurrence of IRIS and other coinfections following initiation of ART www.aideetc.org

  18. Cytomegalovirus: Discontinuing Secondary Prophylaxis Multiple studies indicate that maintenance therapy can be discontinued in adults with CMV retinitis whose CD4 counts have increased and who are on ART Safety of discontinuing maintenance therapy in children has not been well studied Discontinuing prophylaxis and children 1-6 years of age receiving ART and with CD4 percentage of >15% or CD4 count >500 cells/L can be considered (C III) Patients who have had CMV maintenance therapy discontinued should undergo ophthalmologic monitoring at 3-6 month intervals www.aideetc.org

  19. Hepatitis B:Epidemiology Acquired by perinatal or mother-to-infant transmission Unknown whether there is a greater risk of HBV transmission to infants from HIV-coinfected mothers Chronic hepatitis B infection is defined as persistence of hepatitis B surface antigen (HbsAg) for >6 months www.aideetc.org

  20. Hepatitis B:Epidemiology (2) HBV-infected household members may pose risk of infection Infection occurs through contact with infected blood or body fluids and through sharing of objects such as toothbrushes Adolescents are at risk of HBV infection through sexual activity or injection drug use All infants previously unimmunized should receive routine childhood HBV vaccine www.aideetc.org

  21. Hepatitis B:Epidemiology (3) HBV infection risk increased through sexual activity in adolescents who are HIV coinfected Immunize HBV-susceptible adolescents Limited data on the prevalence of HBV infection in HIV-infected children Risk of chronic HBV infection in children without HIV infection is inversely related to age at time of infection Chronic hepatitis B infection develops in less than 90% of infants, 25-50% children 1-5 years of age and 6-10% of older children and adolescents www.aideetc.org

  22. Hepatitis B: Clinical Manifestations Majority of children are asymptomatic Children who are coinfected with HIV may have smoldering chronic infection along with lethargy, malaise, fatigue, and anorexia Jaundice is sometimes present with hepatosplenomegaly www.aideetc.org

  23. Hepatitis B:Clinical Manifestations (2) Young children may experience a serum sickness-like illness consisting of asymmetrical arthropathy and skin lesions Papular acrodermatitis and urticarial or purpuric skin lesions may occur Aplastic anemia, polyarteritis nodosa, glomerulonephritis are occasionally seen Rarely, fulminant hepatic failure may occur during childhood 25% of infants and children with chronic HBV will eventually develop cirrhosis or hepatocellular carcinoma www.aideetc.org

  24. Hepatitis B:Diagnosis HBsAg is the first detectible marker and it precedes an increase in liver enzymes Anti-HBV core antibody (anti-HBc) appears 2 weeks after HBsAg and persists for life Passively transferred anti-HBc present in infants up to 12 months of age IgM anti-HBc highly specific for acute infection www.aideetc.org

  25. Hepatitis B:Diagnosis (2) In self-limited infections, HBsAg is eliminated in 1-2 months Anti-HBsAg during convalescence, indicating immunity to HBV After recovery, both anti-HBs and anti-HBc usually are present Following immunization, only anti-HBs develops www.aideetc.org

  26. Hepatitis B:Diagnosis (3) Chronically infected individuals are persistently positive for HBsAg and anti-HBc beyond 24 weeks; anti-HBs not detectible HBe antigen (HBeAg) correlates with viral replication, DNA polymerase activity, increased infectivity, increased severity of liver disease HBV DNA can be detected in serum and blood mononuclear cells by PCR or branched DNA Quantitative DNA assays may be useful for evaluating responses to treatment www.aideetc.org

  27. Hepatitis B:Prevention All pregnant women should be tested for HBV surface antigen (HBsAg) Repeat test late in pregnancy for women at high risk for HBV infection Pregnancy is not a contraindication for hepatitis B immunization www.aideetc.org

  28. Hepatitis B: Prevention (2) All infants born to HBV-infected mothers should receive HBV vaccine and HBV immune globulin (HBIG) within 12 hours of birth Second dose of vaccine at 1-2 months of age; third dose at 6 months of age Test for antibody to HBsAg at 9-15 months of age; if negative, reimmunize Immunize HBV-susceptible adolescents All children, including HIV-infected children and those with HBV coinfection, should receive hepatitis A immunization HBV-infected children should not share toothbrushes or other personal items www.aideetc.org

  29. Hepatitis B:Treatment Indications for treatment are the same as those for children coinfected with HBV and HIV: Evidence of ongoing viral replication as indicated by presence of detectible HBV DNA with or without HBeAg positivity for at least 6 months Persistent elevation of transaminases(2 times upper limit of normal) Evidence of chronic hepatitis on liver biopsy(B II) www.aideetc.org

  30. Hepatitis B:Treatment (2) Correlates of successful treatment not well defined Current correlates: improved liver histology, normalization of hepatic transaminases, decrease in HBV DNA levels, loss of e antigen with development of anti-HBe No target HBV DNA level has been defined www.aideetc.org

  31. Hepatitis B:Treatment (3) 6 drugs have been approved for the treatment of HBV IFN-alfa (standard and pegylated), lamivudine (3TC), telbivudine, entecavir, and adefovir approved for treatment of HBV in adults IFN-alfa and 3TC approved for children Preferred initial treatment for adults for chronic hepatitis B infection without HIV infection include pegylated interferon-alfa, adefovir, or entecavir monotherapy Some experts would initiate fully suppressive treatment for HIV/HBV coinfection with 2 drugs that have activity against both HIV and HBV plus a third agent with activity against HIV www.aideetc.org

  32. Hepatitis B:Treatment (4) If treatment of chronic HBV, but not HIV, is indicated, standard interferon-alfa is preferred (B III) Adefovir should be considered in older children If treatment of HIV, but not chronic HBV, is indicated, use of ART that avoids drugs with activity against HBV is suggested If treatment of both HIV and chronic HBV is indicated and the patient is naive to 3TC, use an ARV regimen that includes 3TC (or emtricitabine) (B III) www.aideetc.org

  33. Hepatitis B:Treatment (5) If treatment for HIV and chronic HBV is indicated and the child is receiving ART including 3TC or emtricitabine with HIV suppression but detectable plasma HBV DNA, HBV 3TC resistance can be assumed Treatment options for children who require HBV therapy include the addition of interferon therapy to the ARV regimen (B III), tenofovir, or adefovir if the child can receive adult dosing (B III) www.aideetc.org

  34. Hepatitis B:Treatment (6) IFN-alfa Most widely studied for treatment of compensated HBV liver disease Studies of HBV/HIV coinfection in children have not been performed Dosage range in children for IFN-alfa 2a or 2b: 3-10 million units/m2 subcutaneously 3 times weekly for 3-12 months Commonly used regimen is 5 million units/m2 3 times weekly for 6 months Prolonged and higher dosages improve responses www.aideetc.org

  35. Hepatitis B:Treatment (7) 3TC Results in rapid decline in HBV DNA levels Used for HBV-infected, HIV-uninfected children but sustained virologic response rates are low Used as both primary and secondary treatment in HBV-infected, HIV-uninfected children Extended monotherapy treatment can lead to resistance www.aideetc.org

  36. Hepatitis B:Treatment (8) 3TC (cont’d) Do not use 3TC monotherapy in HIV/HBV-coinfected children (3TC resistance develops) Dosage: 3 mg/kg once daily(lower than dosage required for HIV treatment) If 3TC is used to treat HBV/HIV-coinfected children, treat with 4 mg/kg BID in the context of ART (A III) www.aideetc.org

  37. Hepatitis B:Treatment (9) Adefovir Some experts recommend combined adefovir or TDF in addition to 3TC as part of suppressive ART to reduce development of resistance Development of resistance is less common with adefovir than with 3TC Adefovir dipivoxil (10 mg once daily in adults) active against HBV with minimal anti-HIV effect (insufficient data in children) www.aideetc.org

  38. Hepatitis B: Treatment (10) Tenofovir Shown to reduce HBV DNA levels in adult patients with 3TC-resistant virus as well as wild-type HBV infection Not approved for use in treatment of chronic HBV infection or for use in HIV-infected children <18 years of age Should not be used for HBV/HIV-coinfected patients who are not receiving ART www.aideetc.org

  39. Hepatitis B: Treatment (11) Entecavir Compared with 3TC, treatment results in a greater effect on indicators of chronic HBV infection Preferred for 3TC-resistant HBV infection Use only in patients receiving ART in HIV/HBV coinfection Telbivudine Approved for treatment of chronic HBV and adults Emergence of resistance over time No data available on HIV/HBV-coinfected adults and no data on children www.aideetc.org

  40. Hepatitis B:Adverse Events IFN-alfa Flulike syndrome most severe during first month of therapy, consisting of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, vomiting Epistaxis associated with thrombocytopenia or prolonged prothrombin time www.aideetc.org

  41. Hepatitis B:Adverse Events (2) Adverse effects: IFN-alfa Neutropenia, anemia, thrombocytopenia Personality changes Abnormalities of thyroid function Treatment contraindicated in decompensated liver disease, cytopenias, cardiac disease, and autoimmune disease Monitor patients with complete blood count and serum TSH level every 3 months www.aideetc.org

  42. Hepatitis C:Epidemiology Low seroprevalence among children in United States: 0.1-0.2% Seroprevalence higher among HIV-infected children: 1.5% in one study Risk of MTCT about 6% Mother-to-child transmission is the dominant mode of HCV infection HCV infection in older children results from injection drug use, body piercing, tattoos, accidental needlestick injury, household contacts, and sexual exposure Most infections occur at or near time of delivery www.aideetc.org

  43. Hepatitis C:Epidemiology (2) Higher risk of MTCT if mother is HIV coinfected, IV drug user, or viremic; and with intrapartum exposure to infected blood, perineal or vaginal laceration, and fetal hypoxia No reduction of transmission with cesarean section No increased risk from breast-feeding Transmission risk of HIV may be increased with HCV coinfection Chronic HCV infection, defined as the presence of HCV RNA for >6 months, resolves spontaneously in 15-40% of adults There are more than 6 HCV genotypes, with genotype 1 being most common in the United States www.aideetc.org

  44. Hepatitis C:Epidemiology (3) Viremia in HCV-infected, HIV-uninfected children: persistent 52%; intermittent 42%; not detectable 6% Spontaneous clearing has been reported in MTCT of HCV >40% of those who are viremic have persistent features of hepatitis www.aideetc.org

  45. Hepatitis C:Clinical Manifestations Most children are asymptomatic with minor abnormalities including hepatomegaly, fatigue, myalgia, and poor weight gain Children have less frequent and slower progression than adults In a study of posttransfusion HCV, 55% of antibody-positive children had detectable HCV in blood www.aideetc.org

  46. Hepatitis C:Clinical Manifestations (2) Histologic changes can be present in the absence of symptoms No correlation between persistent viremia or elevated liver enzymes and liver disease No evidence of clinical differences between HIV-coinfected and HIV-uninfected children www.aideetc.org

  47. Hepatitis C:Diagnosis Testing is recommended for all children whose mothers are known to have HCV and for all HIV-infected adults and adolescents Serologic and nucleic acid tests are used to diagnose HCV infection HCV antibody passively transferred; not useful for diagnosis of infection until >18 months of age A third-generation anti-HCV EIA is available for detection of antibody HCV RNA first becomes detectable 1-3 weeks following infection A single HCV RNA test is not sufficient for diagnosis; testing should be repeated on 2 separate occasions between 2-6 months of age www.aideetc.org

  48. Hepatitis C: Diagnosis (2) A positive anti-HCV antibody test result in a child >18 months of age is indicative of infection A positive HCV RNA test confirms the presence of infection, and if positive for >6 months, suggests chronic infection Liver biopsy best for evaluation of hepatic disease; should be considered before initiating treatment www.aideetc.org

  49. Hepatitis C: Prevention All HIV-infected individuals, including HIV-infected pregnant women, should be screened for HCV There is no reliable method for preventing perinatal HCV transmission; cesarean delivery is not associated with decreased HCV transmission Adolescents should be warned about the risks of tattooing, body piercing, and intravenous drug use HCV-infected individuals should not share toothbrushes, razors, and other personal items www.aideetc.org

  50. Hepatitis C: Treatment Limited studies on the treatment of HCV-infected children Consideration for treatment includes: symptomatic disease, advanced pathologic features (bridging necrosis, active cirrhosis) (B I) Response to treatment better with HCV 2 and HCV 3 than with HCV 1 Use quantitative HCV RNA to access treatment response www.aideetc.org

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