NRC Peds Oi July09 Viral

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
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become out of date quickly.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 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

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)

 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

 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

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

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

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

Cytomegalovirus: Diagnosis
 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 (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

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

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

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
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

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 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

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: 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

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

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

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

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

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

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

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

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

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

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

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

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)

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

 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

 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)

 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)

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

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

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)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

Hepatitis C: Treatment (2)
HIV/HCV-coinfected adults and adolescents
 Consider treatment of any nonpregnant HCV-
infected adult with abnormal liver enzymes or a liver
biopsy showing chronic hepatitis or significant
fibrosis
 Recommended treatment is pegylated interferon-
alfa 2a or 2b or daily oral ribavirin for 48 weeks
 Note: HCV treatment generally is not recommended
during pregnancy because ribavirin is teratogenic

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 2b 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

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

Adults and children with HIV disease
 Combination therapy with interferon and ribavirin
(A I)
 Pegylated interferon-alfa 2a: subcutaneously
180 mcg/kg weekly or alfa 2b subcutaneously 1.5
mcg/kg weekly (adults)
 Ribavirin: 400 mg orally BID (adults)
 Limited data on use of interferon with children

 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

Interferon-alfa 2a and alfa 2b
 Pediatric dosage in studies ranged from 1.75 to 5
million units/m2 (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

Ribavirin oral solution

 Dosage: oral solution 40 mg/mL – 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.

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
 Personality changes
 Abnormalities of thyroid function

Hepatitis C: Adverse Events (2)
Ribavirin
 Flulike syndrome consisting of fever, chills,
headache, myalgia, arthralgia, abdominal
pain, nausea, vomiting
 Hemolytic anemia, lymphopenia
 Depression and suicidal ideation
 Do not use in combination with ddI

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

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

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

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

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

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

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

Human Herpes Virus-8:
Epidemiology (2)
 Transmitted through oral and 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 HIV-
uninfected 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

Human Herpes Virus 8:
 Primary infection is associated with fever, mild
expiratory symptoms, and a maculopapular rash
 Some evidence suggests there may be a more
severe clinical presentation in immunodeficient HIV-
infected 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

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 HIV-

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

Treatment
 Effective suppression of HIV replication with ART
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 anti-
herpesvirus drugs (ganciclovir or oral valganciclovir),
leading to substantial clinical improvement

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 1/2,000-
5,000 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

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

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

Herpes Simplex Virus:
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%)

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)

 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 HIV-
infected 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

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

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

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

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

Herpes Simplex Virus: Adverse 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)

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)

Human Papillomavirus: 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

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

Human Papillomavirus:
 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 “cauliflower-
like” sessile growths

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

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

Human Papillomavirus: Prevention (2)
 Data on safety, immunogenicity and duration of
immunity of HPV vaccine is not available in HIV-
 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

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)

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

Genital warts
 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)
 Podophyllin resin 10-25% in a compound of tincture
of benzoin

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)

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

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

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

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

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

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

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

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

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

Varicella-Zoster Virus:
 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

Varicella-Zoster Virus:
 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

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; IgM indicates acute infection or
recurrent infection

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 CD4
percentage >15% should be considered for
immunization
 Limited data indicate that varicella vaccine in HIV-
infected children is well tolerated and that >80% of
subjects have detectable antibody

Varicella-Zoster Virus: Prevention (2)
 HIV-infected children with low CD4 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 HIV-
infected 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

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 Q8H as 1-hour
infusion for 7-10 days
 >1 year of age: dosage as above or 500 mg/m2/dose
IV Q8H as 1-hour infusion for 7-10 days

Varicella-Zoster Virus: Treatment (2)
Children with HIV coinfection and normal or
minimal decrease in CD4 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

 Oral acyclovir data limited in children <2 years of age;
infants who receive long-term suppressive therapy (300
mg/kg/m2/dose administered TID) frequently develop
neutropenia (usually self-limited)
 Acute retinal necrosis: high-dose acyclovir (10-15 mg/kg
IV Q8H for 10-14 days
 Progressive retinal necrosis: combination of ganciclovir
(5 mg/kg Q12H) and foscarnet (90 mg/kg IV Q12H plus
twice weekly intravitreal ganciclovir (2 mg/0.5 mL or
foscarnet 1.2 mg/0.5 mL)

 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

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

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

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Guidelines for Prevention and

Treatment of Opportunistic Infections

These slides were developed using the April 2008

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 CMV may be transmitted intrapartum or

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Treatments for adults (inadequate pediatric data)

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 Majority of children are asymptomatic

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Ribavirin oral solution

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