Guidelines for Prevention and Treatment of Opportunistic Infections

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Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Viral Infections Recommendations

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 the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics July 2009 www. aideetc. org

About This Presentation These slides were developed using the April 2008 Guidelines. The intended

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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 2 July 2009 www. aideetc. org

Cytomegalovirus: Epidemiology § Infection with CMV common and often inapparent § 50 -80% of

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 3 July 2009 www. aideetc. org

Cytomegalovirus: Epidemiology (2) § In utero infection occurs most commonly among infants born to

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) 4 July 2009 www. aideetc. org

Cytomegalovirus: Epidemiology (3) § CMV may be transmitted intrapartum or postpartum § 57% of

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 5 July 2009 www. aideetc. org

Cytomegalovirus: Epidemiology (4) § HIV-coinfected women have a higher rate of CMV shedding §

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 6 July 2009 www. aideetc. org

Cytomegalovirus: Clinical Manifestations § 10% of infants infected in utero are symptomatic at birth

Cytomegalovirus: Clinical Manifestations § 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 7 July 2009 www. aideetc. org

Cytomegalovirus: Clinical Manifestations (2) § HIV-infected children with CMV coinfection have accelerated HIV progression

Cytomegalovirus: Clinical Manifestations (2) § 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 8 July 2009 www. aideetc. org

Cytomegalovirus: Clinical Manifestations (3) § End organ disease reported in liver, lung, GI tract,

Cytomegalovirus: Clinical Manifestations (3) § 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 9 July 2009 www. aideetc. org

Cytomegalovirus: Diagnosis § Antibody assays indicative of maternal transfer of Ig. G in children

Cytomegalovirus: Diagnosis § Antibody assays indicative of maternal transfer of Ig. G 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 10 July 2009 www. aideetc. org

Cytomegalovirus: Diagnosis (2) Recommendations include: § Testing all HIV-infected infants with urine culture for

Cytomegalovirus: Diagnosis (2) 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 11 July 2009 www. aideetc. org

Cytomegalovirus: Prevention § Administer CMV antibody-negative blood and blood products if transfusion is required

Cytomegalovirus: Prevention § 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 12 July 2009 www. aideetc. org

Cytomegalovirus: Treatment Symptomatic congenital CMV § Ganciclovir: 6 mg/kg IV Q 12 H for

Cytomegalovirus: Treatment Symptomatic congenital CMV § Ganciclovir: 6 mg/kg IV Q 12 H for 6 weeks (B I) § Alternative treatment for ganciclovir-resistant CMV is foscarnet 13 July 2009 www. aideetc. org

Cytomegalovirus: Treatment (2) Initial and maintenance treatment of disseminated CMV and CMV retinitis §

Cytomegalovirus: Treatment (2) Initial and maintenance treatment of disseminated CMV and CMV retinitis § Ganciclovir: 5 mg/kg/dose IV over period of 1 -2 hours BID for 1421 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 14 July 2009 www. aideetc. org

Cytomegalovirus: Treatment (3) Alternative treatment for ganciclovir resistance § Foscarnet (A I) at 60

Cytomegalovirus: Treatment (3) Alternative treatment for ganciclovir resistance § Foscarnet (A I) at 60 mg/kg/dose IV (infused at 1 mg/kg/minute) over period of 1 -2 hours Q 8 H for 1421 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 15 July 2009 www. aideetc. org

Cytomegalovirus: Treatment (4) Treatments for adults (inadequate pediatric data) § Valganciclovir: prodrug of ganciclovir,

Cytomegalovirus: Treatment (4) Treatments for adults (inadequate pediatric data) § Valganciclovir: prodrug of ganciclovir, given orally, effective in retinitis in adults § Oral ganciclovir (or valganciclovir) plus ganciclovir sustainedrelease intraocular implant used for retinitis § Cidofovir for retinitis § Fomivirsen: antisense nucleotide used as intravitreous injection 16 July 2009 www. aideetc. org

Cytomegalovirus: Adverse Events Ganciclovir and valganciclovir § Neutropenia may occur and may require dosage

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 17 July 2009 www. aideetc. org

Cytomegalovirus: Discontinuing Secondary Prophylaxis § Multiple studies indicate that maintenance therapy can be discontinued

Cytomegalovirus: Discontinuing Secondary Prophylaxis § Multiple studies indicate that maintenance therapy can be discontinued in adults with CMV retinitis whose CD 4 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 CD 4 percentage of >15% or CD 4 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 18 July 2009 www. aideetc. org

Hepatitis B: Epidemiology § Acquired by perinatal or mother-to-infant transmission § Unknown whethere is

Hepatitis B: Epidemiology § Acquired by perinatal or mother-to-infant transmission § Unknown whethere is a greater risk of HBV transmission to infants from HIVcoinfected mothers § Chronic hepatitis B infection is defined as persistence of hepatitis B surface antigen (Hbs. Ag) for >6 months 19 July 2009 www. aideetc. org

Hepatitis B: Epidemiology (2) § HBV-infected household members may pose risk of infection §

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 20 July 2009 www. aideetc. org

Hepatitis B: Epidemiology (3) § HBV infection risk increased through sexual activity in adolescents

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 610% of older children and adolescents 21 July 2009 www. aideetc. org

Hepatitis B: Clinical Manifestations § Majority of children are asymptomatic § Children who are

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 22 July 2009 www. aideetc. org

Hepatitis B: Clinical Manifestations (2) § Young children may experience a serum sickness-like illness

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 23 July 2009 www. aideetc. org

Hepatitis B: Diagnosis § HBs. Ag is the first detectible marker and it precedes

Hepatitis B: Diagnosis § HBs. Ag is the first detectible marker and it precedes an increase in liver enzymes § Anti-HBV core antibody (anti-HBc) appears 2 weeks after HBs. Ag and persists for life § Passively transferred anti-HBc present in infants up to 12 months of age § Ig. M anti-HBc highly specific for acute infection 24 July 2009 www. aideetc. org

Hepatitis B: Diagnosis (2) § In self-limited infections, HBs. Ag is eliminated in 1

Hepatitis B: Diagnosis (2) § In self-limited infections, HBs. Ag is eliminated in 1 -2 months § Anti-HBs. Ag during convalescence, indicating immunity to HBV § After recovery, both anti-HBs and anti-HBc usually are present § Following immunization, only anti-HBs develops 25 July 2009 www. aideetc. org

Hepatitis B: Diagnosis (3) § Chronically infected individuals are persistently positive for HBs. Ag

Hepatitis B: Diagnosis (3) § Chronically infected individuals are persistently positive for HBs. Ag and anti-HBc beyond 24 weeks; anti-HBs not detectible § HBe antigen (HBe. Ag) 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 26 July 2009 www. aideetc. org

Hepatitis B: Prevention § All pregnant women should be tested for HBV surface antigen

Hepatitis B: Prevention § All pregnant women should be tested for HBV surface antigen (HBs. Ag) § Repeat test late in pregnancy for women at high risk for HBV infection § Pregnancy is not a contraindication for hepatitis B immunization 27 July 2009 www. aideetc. org

Hepatitis B: Prevention (2) § All infants born to HBV-infected mothers should receive HBV

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 HBs. Ag 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 28 July 2009 www. aideetc. org

Hepatitis B: Treatment § Indications for treatment are the same as those for children

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 HBe. Ag 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) 29 July 2009 www. aideetc. org

Hepatitis B: Treatment (2) § Correlates of successful treatment not well defined § Current

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 30 July 2009 www. aideetc. org

Hepatitis B: Treatment (3) § 6 drugs have been approved for the treatment of

Hepatitis B: Treatment (3) § 6 drugs have been approved for the treatment of HBV § IFN-alfa (standard and pegylated), lamivudine (3 TC), telbivudine, entecavir, and adefovir approved for treatment of HBV in adults § IFN-alfa and 3 TC 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 31 July 2009 www. aideetc. org

Hepatitis B: Treatment (4) § If treatment of chronic HBV, but not HIV, is

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 3 TC, use an ARV regimen that includes 3 TC (or emtricitabine) (B III) 32 July 2009 www. aideetc. org

Hepatitis B: Treatment (5) § If treatment for HIV and chronic HBV is indicated

Hepatitis B: Treatment (5) § If treatment for HIV and chronic HBV is indicated and the child is receiving ART including 3 TC or emtricitabine with HIV suppression but detectable plasma HBV DNA, HBV 3 TC 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) 33 July 2009 www. aideetc. org

Hepatitis B: Treatment (6) IFN-alfa § Most widely studied for treatment of compensated HBV

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 2 a or 2 b: 3 -10 million units/m 2 subcutaneously 3 times weekly for 3 -12 months § Commonly used regimen is 5 million units/m 2 3 times weekly for 6 months § Prolonged and higher dosages improve responses 34 July 2009 www. aideetc. org

Hepatitis B: Treatment (7) 3 TC § Results in rapid decline in HBV DNA

Hepatitis B: Treatment (7) 3 TC § 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 35 July 2009 www. aideetc. org

Hepatitis B: Treatment (8) 3 TC (cont’d) § Do not use 3 TC monotherapy

Hepatitis B: Treatment (8) 3 TC (cont’d) § Do not use 3 TC monotherapy in HIV/HBVcoinfected children (3 TC resistance develops) § Dosage: 3 mg/kg once daily (lower than dosage required for HIV treatment) § If 3 TC is used to treat HBV/HIV-coinfected children, treat with 4 mg/kg BID in the context of ART (A III) 36 July 2009 www. aideetc. org

Hepatitis B: Treatment (9) Adefovir § Some experts recommend combined adefovir or TDF in

Hepatitis B: Treatment (9) Adefovir § Some experts recommend combined adefovir or TDF in addition to 3 TC as part of suppressive ART to reduce development of resistance § Development of resistance is less common with adefovir than with 3 TC § Adefovir dipivoxil (10 mg once daily in adults) active against HBV with minimal anti-HIV effect (insufficient data in children) 37 July 2009 www. aideetc. org

Hepatitis B: Treatment (10) Tenofovir § Shown to reduce HBV DNA levels in adult

Hepatitis B: Treatment (10) Tenofovir § Shown to reduce HBV DNA levels in adult patients with 3 TC-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 38 July 2009 www. aideetc. org

Hepatitis B: Treatment (11) Entecavir § Compared with 3 TC, treatment results in a

Hepatitis B: Treatment (11) Entecavir § Compared with 3 TC, treatment results in a greater effect on indicators of chronic HBV infection § Preferred for 3 TC-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 39 July 2009 www. aideetc. org

Hepatitis B: Adverse Events IFN-alfa § Flulike syndrome most severe during first month of

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 40 July 2009 www. aideetc. org

Hepatitis B: Adverse Events (2) Adverse effects: IFN-alfa § § Neutropenia, anemia, thrombocytopenia Personality

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 41 July 2009 www. aideetc. org

Hepatitis C: Epidemiology § Low seroprevalence among children in United States: 0. 1 -0.

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 42 July 2009 www. aideetc. org

Hepatitis C: Epidemiology (2) § Higher risk of MTCT if mother is HIV coinfected,

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 43 July 2009 www. aideetc. org

Hepatitis C: Epidemiology (3) § Viremia in HCV-infected, HIV-uninfected children: persistent 52%; intermittent 42%;

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 44 July 2009 www. aideetc. org

Hepatitis C: Clinical Manifestations § Most children are asymptomatic with minor abnormalities including hepatomegaly,

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 45 July 2009 www. aideetc. org

Hepatitis C: Clinical Manifestations (2) § Histologic changes can be present in the absence

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 46 July 2009 www. aideetc. org

Hepatitis C: Diagnosis § Testing is recommended for all children whose mothers are known

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 47 July 2009 www. aideetc. org

Hepatitis C: Diagnosis (2) § A positive anti-HCV antibody test result in a child

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 48 July 2009 www. aideetc. org

Hepatitis C: Prevention § All HIV-infected individuals, including HIV-infected pregnant women, should be screened

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 49 July 2009 www. aideetc. org

Hepatitis C: Treatment § Limited studies on the treatment of HCV-infected children § Consideration

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 50 July 2009 www. aideetc. org

Hepatitis C: Treatment (2) HIV/HCV-coinfected adults and adolescents § Consider treatment of any nonpregnant

Hepatitis C: Treatment (2) HIV/HCV-coinfected adults and adolescents § Consider treatment of any nonpregnant HCVinfected adult with abnormal liver enzymes or a liver biopsy showing chronic hepatitis or significant fibrosis § Recommended treatment is pegylated interferonalfa 2 a or 2 b or daily oral ribavirin for 48 weeks § Note: HCV treatment generally is not recommended during pregnancy because ribavirin is teratogenic 51 July 2009 www. aideetc. org

Hepatitis C: Treatment (3) HCV-infected children without HIV infection § Treatment of HIV-uninfected children

Hepatitis C: Treatment (3) HCV-infected children without HIV infection § Treatment of HIV-uninfected children with HCV infection who are <3 years of age is not recommended § Only interferon-alfa 2 b and ribavirin are approved by the FDA for treatment of children 3 -17 years of age § A 24 -week course of treatment is recommended for genotypes 2 and 3; 48 -week course for other HCV genotypes 52 July 2009 www. aideetc. org

Hepatitis C: Treatment (4) HIV/HCV-coinfected children § Recommendations for treatment are based primarily on

Hepatitis C: Treatment (4) HIV/HCV-coinfected children § Recommendations for treatment are based primarily on adult data § Consider treatment for all HIV/HCV-coinfected individuals including children >3 years of age who have no contraindication to treatment (B III) § Treatment of HCV-infected children regardless of HIV status should include combination therapy with interferon-alfa and ribavirin (B III) § Based on adult studies, 48 weeks of treatment is recommended for coinfected children 53 July 2009 www. aideetc. org

Hepatitis C: Treatment (5) Adults and children with HIV disease § Combination therapy with

Hepatitis C: Treatment (5) Adults and children with HIV disease § Combination therapy with interferon and ribavirin (A I) § Pegylated interferon-alfa 2 a: subcutaneously 180 mcg/kg weekly or alfa 2 b subcutaneously 1. 5 mcg/kg weekly (adults) § Ribavirin: 400 mg orally BID (adults) § Limited data on use of interferon with children 54 July 2009 www. aideetc. org

Hepatitis C: Treatment (6) § HCV RNA levels in serum transaminase should be monitored

Hepatitis C: Treatment (6) § HCV RNA levels in serum transaminase should be monitored every 6 -12 months alone with an annual hemogram and serum AFP § Patients who are on treatment should be monitored at baseline, and after 12 and 24 weeks of antiviral therapy § Individuals with undetectable levels of HCV RNA following treatment should be retested after 24 weeks § In HIV-coinfected patients, testing can be continued for an additional 1 -5 years 55 July 2009 www. aideetc. org

Hepatitis C: Treatment (7) Interferon-alfa 2 a and alfa 2 b § Pediatric dosage

Hepatitis C: Treatment (7) Interferon-alfa 2 a and alfa 2 b § Pediatric dosage in studies ranged from 1. 75 to 5 million units/m 2 (maximum dosage 3 -5 million units) administered subcutaneously or intramuscularly 3 times weekly for 4 -12 months § Treatment contraindicated in decompensated liver disease, cytopenia, cardiac disease or autoimmune disease 56 July 2009 www. aideetc. org

Hepatitis C: Treatment (8) Ribavirin oral solution § Dosage: oral solution 40 mg/m. L

Hepatitis C: Treatment (8) Ribavirin oral solution § Dosage: oral solution 40 mg/m. L – 15 mg/kg/day divided into 2 doses given BID § 25 -36 kg: 1 capsule (200 mg) in a. m. , 1 in p. m. 37 -49 kg: 1 capsule (200 mg) in a. m. , 2 in p. m. 50 -61 kg: 2 capsules (200 mg each) in a. m. , 2 in p. m. 57 July 2009 www. aideetc. org

Hepatitis C: Adverse Events § Initiation of ART in HIV/HCV coinfection may worsen hepatitis

Hepatitis C: Adverse Events § Initiation of ART in HIV/HCV coinfection may worsen hepatitis as evidenced by increased serum transaminase levels and clinical signs of liver disease (IRIS) § Adverse effects: interferon-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 § Neutropenia, anemia, thrombocytopenia § Personality changes § Abnormalities of thyroid function 58 July 2009 www. aideetc. org

Hepatitis C: Adverse Events (2) Ribavirin § Flulike syndrome consisting of fever, chills, headache,

Hepatitis C: Adverse Events (2) Ribavirin § Flulike syndrome consisting of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, vomiting § Hemolytic anemia, lymphopenia § Neutropenia, anemia, thrombocytopenia § Depression and suicidal ideation § Do not use in combination with dd. I 59 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: Epidemiology § Human herpes virus 6 (HHV-6) and

Human Herpes Virus 6 and 7: Epidemiology § Human herpes virus 6 (HHV-6) and 7 (HHV-7) are closely related members of the Roseolovirus genus of herpes viruses § Humans are the only known host § Infection is believed to be transmitted through saliva; sexual transmission may occur and presumptive in utero infection has been described § Children become infected early in childhood with 100% infected by 3 years of age 60 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: Epidemiology (2) § HHV-6 has been transmitted from

Human Herpes Virus 6 and 7: Epidemiology (2) § HHV-6 has been transmitted from mother to child § Congenital HHV-6 infection has been documented in <2% of newborns § HHV-7 is acquired later in life than is HHV-6 § Seropositivity for HHV-7 is approximately 50% by 2 years of age § Salivary shedding of HHV-7 is common and viral DNA has been found in breast milk 61 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: Clinical Manifestations § HHV-6 primary infection may be

Human Herpes Virus 6 and 7: Clinical Manifestations § HHV-6 primary infection may be asymptomatic or accompanied by mild nonspecific symptoms § Common symptoms are fever, irritability, and rhinitis § HHV-6 is the causative agent of most cases of exanthem subitum (also known as roseola infantum) § Primary infection and reactivation associated with severe central nervous system syndromes in immunodeficient individuals § Reactivation of infection may include pneumonia, encephalitis, bone marrow suppression, fever, skin rash, and leukopenia § Reactivation of HHV-7 also occurs in immunodeficient individuals 62 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: Diagnosis § Most often, the diagnosis is based

Human Herpes Virus 6 and 7: Diagnosis § Most often, the diagnosis is based on clinical features and presence of a distinctive rash § Laboratory confirmation of the infection includes antibody testing, culture, antigen detection, PCR, immunohistochemistry § Detection of HHV-6 -specific antibodies, seroconversion, or changing antibody titer indicate infection § Many of the laboratory tests for the diagnosis of HHV infection are available only on the research basis 63 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: Prevention § HHV-6 and HHV-7 infections are ubiquitous,

Human Herpes Virus 6 and 7: Prevention § HHV-6 and HHV-7 infections are ubiquitous, making prevention difficult § Prophylactic ganciclovir may decrease the number of episodes and severity of HHV-6 reactivation and transplantations § There is no vaccine to prevent HHV-6 or HHV-7 infections 64 July 2009 www. aideetc. org

Human Herpes Virus 6 and 7: § Treatment The majority of HHV-6 primary infections

Human Herpes Virus 6 and 7: § Treatment The majority of HHV-6 primary infections are mild and self-limited § There are no clear indications for treatment although treatment might be considered for severe encephalitis § There are no proven therapies, but based on in vitro data, there is a suggestion that ganciclovir and foscarnet are active against HHV-6 § Other treatments that have been reported are based on individual or small numbers of patients 65 July 2009 www. aideetc. org

Human Herpes Virus 8: § Human herpes virus-8 (HHV-8) is a transmissible DNA Epidemiology

Human Herpes Virus 8: § Human herpes virus-8 (HHV-8) is a transmissible DNA Epidemiology virus similar in DNA structure to Epstein-Barr virus § Causally linked to all forms of Kaposi sarcoma (KS) § Also linked to cavity-based lymphoma and multicentric Castleman disease § In the United States, 1 -3% of the general population is seropositive, with higher rates among homosexual men § Seropositivity rate in some parts of Africa >80% 66 July 2009 www. aideetc. org

Human Herpes Virus 8: § Transmitted through oral and Epidemiology (2) genital secretions §

Human Herpes Virus 8: § Transmitted through oral and Epidemiology (2) genital secretions § Immunocompetent HHV-8 -infected adults shed HHV-8 in their oropharyngeal secretions § Seroprevalence increases in endemic areas during the first 5 years of life § Seropositivity in the United States among HIVuninfected adolescents equals 11% § Seropositivity in the United States among homosexual males equals 23% § In the United States, KS accounts for <1% of pediatric AIDS-defining illnesses 67 July 2009 www. aideetc. org

Human Herpes Virus 8: § Primary infection is associated with fever, mild Clinical Manifestations

Human Herpes Virus 8: § Primary infection is associated with fever, mild Clinical Manifestations expiratory symptoms, and a maculopapular rash § Some evidence suggests there may be a more severe clinical presentation in immunodeficient HIVinfected individuals § KS presentation varies widely and includes nontender, purplish, indurated skin lesions; intraoral lesions; visceral dissemination § Multicentric Castleman disease presents with generalized adenopathy and fever 68 July 2009 www. aideetc. org

Human Herpes Virus 8: Diagnosis § Diagnosis based on serologic assays including immunofluorescence, ELISA,

Human Herpes Virus 8: Diagnosis § Diagnosis based on serologic assays including immunofluorescence, ELISA, and Western blot § Sensitivity varies from 80% to 90% § DNA hybridization and PCR are important for diagnosis on biologic specimens § Routine screening for HHV-8 by PCR or serologic testing is not indicated for HIVinfected individuals 69 July 2009 www. aideetc. org

Human Herpes Virus 8: Prevention § Exposure to HHV-8 places HIV-infected individuals at risk

Human Herpes Virus 8: Prevention § Exposure to HHV-8 places HIV-infected individuals at risk of KS § HIV-infected individuals should be counseled concerning transmission risk of HHV-8 to sexual partners § Safe sexual practices are warranted to reduce the risk of transmission § There is no effective way to prevent childhood acquisition of HHV-8 70 July 2009 www. aideetc. org

Human Herpes Virus 8: § Effective suppression of HIV replication with ART Treatment may

Human Herpes Virus 8: § Effective suppression of HIV replication with ART Treatment may prevent KS progression or returns of new lesions § KS requires treatment with cytotoxic chemotherapy § Chemotherapy in combination with potent ART should be considered for patients with visceral KS or primary effusion lymphoma (B II) § Castleman disease has been treated with antiherpesvirus drugs (ganciclovir or oral valganciclovir), leading to substantial clinical improvement 71 July 2009 www. aideetc. org

Herpes Simplex Virus: Epidemiology § HSV-1 and HSV-2 affect all populations § HSV-1 is

Herpes Simplex Virus: Epidemiology § HSV-1 and HSV-2 affect all populations § HSV-1 is transmitted primarily through contact with infected oral secretions § HSV-2 is acquired primarily through contact with infected genital secretions § Neonatal HSV infection occurs at a rate of 1/2, 0005, 000 deliveries § Transmitted from infected mother to infant primarily through exposure to maternal genital fluids during birth, by ascending infection, or by invasive procedures (eg, fetal scalp electrodes) § Congenital (in utero) rare, but severe cutaneous, ocular, and CNS damage 72 July 2009 www. aideetc. org

Herpes Simplex Virus: Epidemiology (2) § Maternal antibody to HSV predicts likelihood and severity

Herpes Simplex Virus: Epidemiology (2) § Maternal antibody to HSV predicts likelihood and severity of transmission to infant § Risk of neonatal HSV greatest in infant born to mother with primary HSV infection (30 -40%) § Genital shedding of HSV and prolonged rupture of membranes increases risk of HSV transmission § Cesarean section lowers risk of transmission 73 July 2009 www. aideetc. org

Herpes Simplex Virus: Epidemiology (3) § In the United States, 75% of neonatal HSV

Herpes Simplex Virus: Epidemiology (3) § In the United States, 75% of neonatal HSV is caused by genital herpes (HSV-2) § HSV-2 seroprevalence in women of childbearing age is 26%; rates may be higher in HIV-infected women § HIV-infected women shed HSV from genital area more frequently than HIV-uninfected women (may be asymptomatic) § No evidence that in utero HSV infection is more frequent in HIV-infected pregnant women § HSV infection may increase the risk of MTCT 74 July 2009 www. aideetc. org

Herpes Simplex Virus: Clinical Manifestations Neonatal HSV may appear as: § Disseminated multiorgan disease

Herpes Simplex Virus: Clinical Manifestations Neonatal HSV may appear as: § Disseminated multiorgan disease (occurring in about 25% of neonates with infection) § Localized CNS disease (about 35%) § Localized infection of skin, eyes, mouth (about 40%) 75 July 2009 www. aideetc. org

Herpes Simplex Virus: Clinical Manifestations (2) § Disseminated disease usually manifests at 9 -11

Herpes Simplex Virus: Clinical Manifestations (2) § Disseminated disease usually manifests at 9 -11 days with encephalitis in 60 -70% and vesicular rash in 60% § Localized disease usually appears at 10 -11 days § Even with treatment, neonates with skin lesions may have recurrences for first 6 months of life § Outside neonatal period, most common presentation is orolabial disease with fever, irritability, submandibular lymphadenopathy, painful ulcers in gingival and oral mucosa (gingivostomatitis) 76 July 2009 www. aideetc. org

Herpes Simplex Virus: Clinical Manifestations (3) § HSV-2 infection presents as painful, ulcerative lesions

Herpes Simplex Virus: Clinical Manifestations (3) § HSV-2 infection presents as painful, ulcerative lesions on the perineum as well as on the vaginal and urethral mucosa § HSV keratitis, neonatal HSV, HSV encephalitis, and herpetic whitlow have similar presentations in HIVinfected and HIV-uninfected patients but may be more severe among HIV-infected patients § When severely immunocompromised, may develop disseminated HIV infection including infection of esophagus, CNS, liver, lung, kidney, spleen, adrenal 77 July 2009 www. aideetc. org

Herpes Simplex Virus: Diagnosis § Appearance of typical ulcers and vesicles § Isolation of

Herpes Simplex Virus: Diagnosis § Appearance of typical ulcers and vesicles § Isolation of HSV from lesions following culture § Diagnosis of neonatal HSV based on cultures from blood, skin vesicles, mouth, eyes, urine, and stool § CSF using DNA PCR sequence common to HSV-1 and HSV-2 § Direct immunofluorescence for HSV antigen in samples § HSV DNA PCR has replaced brain biopsy § Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy 78 July 2009 www. aideetc. org

Herpes Simplex Virus: Prevention § Effective ART regimens may decrease but not prevent the

Herpes Simplex Virus: Prevention § Effective ART regimens may decrease but not prevent the frequency of maternal genital HSV shedding § Use of acyclovir or valacyclovir in late pregnancy in HIV-uninfected pregnant women may reduce the need for cesarean section; not recommended for HIV-infected women who should have cesarean section § Avoid sexual contact when herpetic lesions are present § Use condoms to reduce transmission of HSV and other sexually transmitted infections § Chronic suppressive therapy with valacyclovir may reduce HSV-2 transmission 79 July 2009 www. aideetc. org

Herpes Simplex Virus: Treatment § Acyclovir is the drug of choice regardless of infection

Herpes Simplex Virus: Treatment § Acyclovir is the drug of choice regardless of infection status (AI) (oral and IV formulations available) § Treat neonatal HSV with 20 mg/kg/dose IV TID for 21 days for CNS and disseminated diseases § For skin, eye, mouth disease, treat for 14 days § Do not discontinue acyclovir in neonates with CNS disease unless CSF DNA PCR is negative at days 19 -21 of treatment (B III) § Acyclovir is the drug of choice for disseminated HSV encephalitis: treat for 21 days § Trifluridine is the treatment of choice for herpes keratoconjunctivitis 80 July 2009 www. aideetc. org

Herpes Simplex Virus: Treatment (2) § Alternatives to acyclovir in older children include valacyclovir

Herpes Simplex Virus: Treatment (2) § Alternatives to acyclovir in older children include valacyclovir and famciclovir (A I) § No pediatric formulation available for valacyclovir § Data on the use of famciclovir in children are not available 81 July 2009 www. aideetc. org

Herpes Simplex Virus: Adverse § § 82 Events Acyclovir toxicity effects primarily renal function

Herpes Simplex Virus: Adverse § § 82 Events Acyclovir toxicity effects primarily renal function Valacyclovir toxicity is similar to acyclovir Neutropenia may occur in contents Treatment failure should be managed with IV foscarnet (A I) July 2009 www. aideetc. org

Human Papillomavirus: Epidemiology § HPV infects cutaneous and mucosal squamous epithelium § Approximately 100

Human Papillomavirus: Epidemiology § HPV infects cutaneous and mucosal squamous epithelium § Approximately 100 distinct types § HPV 16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59 are considered high risk § Genital HPV types can cause conjunctiva, nasal, oral, and laryngeal warts § Transmission occurs by direct contact or sexual contact (genital warts in young children may be a sign of sexual abuse) 83 July 2009 www. aideetc. org

Human Papillomavirus: § § 84 Epidemiology (2) Latent HPV seen in 5 -42% of

Human Papillomavirus: § § 84 Epidemiology (2) Latent HPV seen in 5 -42% of pregnant women without HIV infection HPV infection rates higher among HIV-infected women (up to 95%) Mother-to-child HPV transmission occurs and can result in infant laryngeal and juvenile laryngeal papillomatosis In general, no neonatal abnormalities are associated with detection of HPV in neonates July 2009 www. aideetc. org

Human Papillomavirus: Epidemiology (3) § HPV detected in 13 -60% of sexually active adolescent

Human Papillomavirus: Epidemiology (3) § HPV detected in 13 -60% of sexually active adolescent girls § 40 -80% of infections in HIV uninfected are transient § Persistent infection with HPV 16, 81, 31, and 33 associated with high risk of developing cervical, vulvovaginal, and anal carcinoma; cervical and anal intraepithelial neoplasia § Increased risk if HIV infected 85 July 2009 www. aideetc. org

Human Papillomavirus: Clinical Manifestations § Hyperplastic, papillomatosis and verrucous squamous epithelial lesions on the

Human Papillomavirus: Clinical Manifestations § Hyperplastic, papillomatosis and verrucous squamous epithelial lesions on the skin and mucous membranes including anal, genital, oral, nasal, conjunctiva, GI, and respiratory tract mucosa § Lesions are soft, pink or white “cauliflowerlike” sessile growths 86 July 2009 www. aideetc. org

Human Papillomavirus: Diagnosis § Most cutaneous and anogenital warts diagnosable on physical examination §

Human Papillomavirus: Diagnosis § Most cutaneous and anogenital warts diagnosable on physical examination § Diagnosis of laryngeal papillomatosis requires laryngoscopy § DNA PCR can be used for detection of HPV types but is not necessary for diagnosis or management of anogenital or cutaneous warts or papillomas 87 July 2009 www. aideetc. org

Human Papillomavirus: Prevention § A vaccine to prevent HPV types 6, 11, 16, and

Human Papillomavirus: Prevention § A vaccine to prevent HPV types 6, 11, 16, and 18 has been approved § HPV 6 and 11 cause 90% of the external genital warts § HPV 16 and 18 cause 70% of invasive cervical cancers § To be fully effective, the HPV vaccine should be administered before the onset of sexual activity 88 July 2009 www. aideetc. org

Human Papillomavirus: Prevention (2) § Data on safety, immunogenicity and duration of immunity of

Human Papillomavirus: Prevention (2) § Data on safety, immunogenicity and duration of immunity of HPV vaccine is not available in HIVinfected individuals § Current recommendations are to immunize all females aged 11 -12 years: a secondary should be given 2 months after the first dose; a third dose should be administered 6 months after the first dose § The HPV vaccine has not been shown to have a therapeutic benefit 89 July 2009 www. aideetc. org

Human Papillomavirus: Treatment Topical Treatment (B III) § Standard topical treatment often ineffective in

Human Papillomavirus: Treatment Topical Treatment (B III) § Standard topical treatment often ineffective in HIV-infected children as underlying infection persists and results in recurrence § Podofilox 0. 5% (antimitotic agent) § Imiquimod cream 5% (immune enhancer) § Trichloroacetic or bichloracetic acid 80 -90% aqueous solution (caustic agent) 90 July 2009 www. aideetc. org

Human Papillomavirus: Treatment (2) § Cidofovir topical gel 1% evaluated primarily in adults; used

Human Papillomavirus: Treatment (2) § Cidofovir topical gel 1% evaluated primarily in adults; used successfully for molluscum contagiosum in children with HIV infection § Cryotherapy and electrodessication applied to each lesion; treatment can be repeated every 1 -2 weeks § Treatment of laryngeal papillomatosis directed primarily to removal of obstructions § ART not consistently associated with reduced risk of HPV-related cervical abnormalities 91 July 2009 www. aideetc. org

Human Papillomavirus: Treatment (3) Genital warts § Standard topical treatment often ineffective in HIVinfected

Human Papillomavirus: Treatment (3) Genital warts § Standard topical treatment often ineffective in HIVinfected children as underlying infection persists and results in recurrence § Podofilox 0. 5% (antimitotic agent) § Imiquimod cream 5% (immune enhancer) § Trichloroacetic or bichloracetic acid 80 -90% aqueous solution (caustic agent) § Podophyllin resin 10 -25% in a compound of tincture of benzoin 92 July 2009 www. aideetc. org

Human Papillomavirus: Treatment (4) Respiratory papillomatosis § Should be managed by a specialist §

Human Papillomavirus: Treatment (4) Respiratory papillomatosis § Should be managed by a specialist § Treatment is directed toward removing lesions constructing the airway rather than eliminating the disease § Lesions are removed by debridement or laser treatment § Systemic interferon-alfa therapy or intralesional cidofovir has been used with limited success (C III) 93 July 2009 www. aideetc. org

Human Papillomavirus: Treatment (5) Treatment of histologic CIN § Follow-up with annual cytologic assessment

Human Papillomavirus: Treatment (5) Treatment of histologic CIN § Follow-up with annual cytologic assessment is recommended for adolescents with CIN 1 (A II) § Either treatment or observation should be implemented for up to 24 months using both colposcopy and cytology for CIN 2 or 3 not otherwise specified § Treatment recommended for histologic diagnosis of CIN 3 § Persistent CIN 1, 2, and 3 lesions in HIV-infected women should be treated as in HIV-uninfected women § Treatment includes cryotherapy, laser therapy, cone biopsy, and loop electrosurgical excision 94 July 2009 www. aideetc. org

Human Papillomavirus: Role of ART, IRIS, and Adverse Events § ART has not been

Human Papillomavirus: Role of ART, IRIS, and Adverse Events § ART has not been consistently associated with a reduced risk of HPV-related cervical abnormalities in HIV-infected women § Major toxicities are associated with local skin irritation from topical therapy § Pain is a frequent side effect of surgical procedures § Interferon treatment may induce fever, fatigue, myalgia, and depression § IRIS associated with oral warts has been observed in adults 95 July 2009 www. aideetc. org

PML: Epidemiology § Rare demyelinating disease of the CNS in immunocompromised patients § First

PML: Epidemiology § Rare demyelinating disease of the CNS in immunocompromised patients § First described in association with chronic lymphocytic leukemia and Hodgkin disease § Caused by the Jamestown Canyon polyoma virus (JCV) § 50% of children are seropositive by 9 -11 years of age § Infection results in chronic asymptomatic carriage of the virus in kidneys, lymphoid tissue, bone marrow, and lymphocytes § Reactivation of the virus in immunocompromised individuals results; virus is spread to the brain by lymphocytes 96 July 2009 www. aideetc. org

PML: Clinical Manifestations § No known symptoms of acute infection exist § PML may

PML: Clinical Manifestations § No known symptoms of acute infection exist § PML may initially present with focal neurologic deficits involving different regions of the brain § Steady progression over course of weeks or months characterized by ataxia, aphasia, cranial nerve deficits, visual abnormalities, hemiparesis or quadriparesis, and eventually coma § Survival has improved with ART 97 July 2009 www. aideetc. org

PML: Diagnosis § Criteria for a clinical diagnosis include signs and symptoms on neurologic

PML: Diagnosis § Criteria for a clinical diagnosis include signs and symptoms on neurologic examination, focal white matter lesions on MRI or CT, and exclusion of other causes § Brain biopsy with characteristic pathologic findings § JCV may be demonstrated by in situ hybridization or by electron microscopy 98 July 2009 www. aideetc. org

PML: Prevention § There is no known means of preventing exposure to JCV §

PML: Prevention § There is no known means of preventing exposure to JCV § The use of ART can prevent or reverse the development of severe immunosuppression, which may stabilize the disease 99 July 2009 www. aideetc. org

PML: Treatment and Adverse Events § There is no effective treatment for JCV or

PML: Treatment and Adverse Events § There is no effective treatment for JCV or PML § Survival of HIV-infected adults has been substantially improved with ART in adults but there are no data in children § A number of studies have evaluated various forms of treatment, including cytosine arabinoside, cidofovir, and interferon-alfa, but none have been reported to be successful § Following ART, patients may have improvement in their neurologic symptoms, remain stable, or have worsening of symptoms attributed to IRIS 100 July 2009 www. aideetc. org

Varicella-Zoster Virus: Epidemiology § 9% of children <10 years of age experience varicella infection

Varicella-Zoster Virus: Epidemiology § 9% of children <10 years of age experience varicella infection (before vaccine use) § 95% of adults have antibody to VZV § Rare perinatal VZV transmission § Congenital VZV occurs in 2% of infants whose mothers have primary VZV in first trimester § Zoster occurs only when previously VZV infected § Rate of zoster as high as 70% in HIV-infected children who are immunocompromised at time of primary VZV infection 101 July 2009 www. aideetc. org

Varicella-Zoster Virus: Epidemiology (2) § VZV is transmitted primarily from skin lesions during illness

Varicella-Zoster Virus: Epidemiology (2) § VZV is transmitted primarily from skin lesions during illness and is highly contagious § Mother-to-child transmission can occur but is unusual § Congenital varicella occurs in <1% of infants born to women who have VZV before 13 weeks’ gestation and in approximately 2% of infants born to women who have VZV between 13 and 20 weeks’ gestation § VZV can be transmitted to the fetus in later gestation, resulting in acute neonatal infection § Zoster was common in HIV-infected children prior to the widespread use of ART 102 July 2009 www. aideetc. org

Varicella-Zoster Virus: Clinical Manifestations § Prodrome of malaise and fever, followed by the appearance

Varicella-Zoster Virus: Clinical Manifestations § Prodrome of malaise and fever, followed by the appearance of a pruritic vesicle papular lesion § Complications include superinfection of the skin, neurologic manifestations, transverse myelitis, and on occasion, vascular stroke, hepatitis, and pneumonia § Uncommonly, HIV-infected children may experience persistent chronic infection with continued lesions for >1 month § Zoster presents with painful pruritic unilateral vesicular eruptions in a dermatomal distribution 103 July 2009 www. aideetc. org

Varicella-Zoster Virus: Clinical Manifestations (2) § Congenital infection characterized by cicatricial skin scarring, limb

Varicella-Zoster Virus: Clinical Manifestations (2) § Congenital infection characterized by cicatricial skin scarring, limb hypoplasia, microcephaly, seizures, mental retardation, chorioretinitis, cataracts, microphthalmia, neurogenic bladder, hydroureter, abnormalities of swallowing § Duration of disease longer and complications more frequent in HIV-infected children § May develop VZV retinitis § Acute in retinal necrosis occurs as a peripheral necrotizing retinitis 104 July 2009 www. aideetc. org

Varicella-Zoster Virus: Diagnosis § Clinical diagnosis based on typical generalized pruritic vesicular rash and

Varicella-Zoster Virus: Diagnosis § Clinical diagnosis based on typical generalized pruritic vesicular rash and fever § Direct immunofluorescence for VZV antigen on cells from skin, conjunctiva, mucosal lesions § VZV PCR sensitive and specific, can differentiate wild-type and vaccine-type virus § VZV antibody response positive 2 -3 weeks after onset of illness; Ig. M indicates acute infection or recurrent infection 105 July 2009 www. aideetc. org

Varicella-Zoster Virus: Prevention § HIV-infected individuals who have no history or laboratory evidence of

Varicella-Zoster Virus: Prevention § HIV-infected individuals who have no history or laboratory evidence of VZV should avoid exposure to individuals with varicella or zoster § Household contacts without evidence of previous varicella should be immunized with varicella vaccine § HIV-infected children 1 -8 years of age with CD 4 percentage >15% should be considered for immunization § Limited data indicate that varicella vaccine in HIVinfected children is well tolerated and that >80% of subjects have detectable antibody 106 July 2009 www. aideetc. org

Varicella-Zoster Virus: Prevention (2) § HIV-infected children with low CD 4 counts may develop

Varicella-Zoster Virus: Prevention (2) § HIV-infected children with low CD 4 counts may develop pneumonia and neurologic manifestations following immunization § Immunization of such children may be considered following treatment with ART and evidence of immune restoration § Postexposure prophylaxis against varicella in HIVinfected children should be provided within 96 hours after close contact using varicella zoster immunoglobulin § Data are lacking regarding the effectiveness of acyclovir for preventing varicella in HIV-infected susceptible children 107 July 2009 www. aideetc. org

Varicella-Zoster Virus: Treatment § Acyclovir is the drug of choice for HIV-infected children; should

Varicella-Zoster Virus: Treatment § Acyclovir is the drug of choice for HIV-infected children; should be initiated as soon as possible after diagnosis (A I) § New lesions may continue to appear several days after initiation of treatment § Dosing § <1 year of age: 10 mg/kg/dose IV Q 8 H as 1 -hour infusion for 7 -10 days § >1 year of age: dosage as above or 500 mg/m 2/dose IV Q 8 H as 1 -hour infusion for 7 -10 days 108 July 2009 www. aideetc. org

Varicella-Zoster Virus: Treatment (2) Children with HIV coinfection and normal or minimal decrease in

Varicella-Zoster Virus: Treatment (2) Children with HIV coinfection and normal or minimal decrease in CD 4 T-cell counts § Acyclovir: 20 mg/kg per dose orally 4 times daily; maximum dose 800 mg (B III) Children with zoster and HIV infection § Oral acyclovir § Use IV if severely immunocompromised, trigeminal nerve involvement, or extensive multidermatomal zoster 109 July 2009 www. aideetc. org

Varicella-Zoster Virus: Treatment (3) § Oral acyclovir data limited in children <2 years of

Varicella-Zoster Virus: Treatment (3) § Oral acyclovir data limited in children <2 years of age; infants who receive long-term suppressive therapy (300 mg/kg/m 2/dose administered TID) frequently develop neutropenia (usually self-limited) § Acute retinal necrosis: high-dose acyclovir (10 -15 mg/kg IV Q 8 H for 10 -14 days § Progressive retinal necrosis: combination of ganciclovir (5 mg/kg Q 12 H) and foscarnet (90 mg/kg IV Q 12 H plus twice weekly intravitreal ganciclovir (2 mg/0. 5 m. L or foscarnet 1. 2 mg/0. 5 m. L) 110 July 2009 www. aideetc. org

Varicella-Zoster Virus: Treatment (4) § Use IV foscarnet for treatment of children with acyclovir-resistant

Varicella-Zoster Virus: Treatment (4) § Use IV foscarnet for treatment of children with acyclovir-resistant VZV (B II) § Dosage: 40 -60 mg/kg/dose IV over period of 1 -2 hours administered TID for 7 days or until no new lesions appear § Modify dosage in patients with renal insufficiency § Valacyclovir and famciclovir are alternative treatments (not active against acyclovir-resistant VZV) but data in children are limited 111 July 2009 www. aideetc. org

Varicella-Zoster Virus: Adverse Events § Acyclovir toxicities include phlebitis, nausea, vomiting, rash, impaired renal

Varicella-Zoster Virus: Adverse Events § Acyclovir toxicities include phlebitis, nausea, vomiting, rash, impaired renal function, neutropenia § Foscarnet toxicities include decreased renal function § IRIS has been described in adults and children following initiation of ART 112 July 2009 www. aideetc. org

About This Slide Set § This presentation was prepared by Arthur Ammann, MD, Clinical

About This Slide Set § This presentation was prepared by Arthur Ammann, MD, Clinical Professor of Pediatrics University of California and President of Global Strategies for HIV Prevention for the AETC National Resource Center, in July 2009 § See the AETC NRC website for the most current version of this presentation: http: //www. aidsetc. org 113 July 2009 www. aideetc. org