Download Treating Opportunistic Infections Among HIV

Guidelines for Prevention and Treatment of
Opportunistic Infections in HIV-Infected Adults
and Adolescents
Viral Infections Slide Set
Prepared by the AETC National Resource Center
based on recommendations from the CDC,
National Institutes of Health, and HIV Medicine
Association/Infectious Diseases Society of America
About This Presentation
These slides were developed using recommendations
published in July 2013. 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become out of date quickly.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.
– AETC National Resource Center
http://www.aidsetc.org
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Viral Infections
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Cytomegalovirus
Herpes Simplex Virus
Varicella-Zoster Virus
Human Herpesvirus-8
Progressive Multifocal Leukoencephalopathy
Human Papillomavirus
Hepatitis C
Hepatitis B
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Viral Infections
Cytomegalovirus Disease
CMV Disease: Epidemiology
 Double-stranded DNA virus, herpes virus family
 Disseminated or localized disease
 Occurs in patients with advanced
immunosuppression (CD4 count typically <50
cells/µL)
 Other risk factors: patient not on ART, previous
opportunistic infections, high level of CMV viremia,
high plasma HIV RNA (>100,000 copies/mL)
 Usually caused by reactivation of latent infection
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CMV Disease: Epidemiology (2)
 Before use of potent ART in the United States,
30% of AIDS patients developed CMV retinitis
 ART has decreased incidence by 75-80%
 In patients with established CMV retinitis,
recurrence rate much lower with ART, but may
occur even at high CD4 counts
 Regular ophthalmologic follow-up is needed
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CMV Disease: Clinical Manifestations
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Retinitis
Colitis, cholangiopathy
Esophagitis
Pneumonitis
Neurologic disease
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CMV Disease: Clinical Manifestations (2)
Retinitis
 Most common CMV end-organ disease
 Usually unilateral; if untreated, is likely to
progress to involve both eyes
 Symptoms:
 If peripheral: floaters, scotomata, visual field
defects, or may be asymptomatic
 If central or macular: decreased visual acuity,
central field defects
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CMV Disease: Clinical Manifestations (3)
Retinitis
 Examination: fluffy yellow-white retinal
infiltrates, with or without intraretinal
hemorrhage; little vitreous inflammation
unless immune recovery with ART
 Progresses unless treated; may cause
blindness
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CMV Disease: Clinical Manifestations (4)
CMV retinitis: funduscopic examinations showing hemorrhage and
retinal exudates
Credits: Left: P. Volberding, MD; UCSF Center for HIV Information Image Library
Right: D. Coats, MD; Pediatric AIDS Pictorial Atlas, Baylor International Pediatric
AIDS Initiative
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CMV Disease: Clinical Manifestations (5)
Colitis
 Second most common clinical
manifestation of CMV
 Occurs in 5-10% of persons
with CMV end-organ disease
 Weight loss, anorexia,
abdominal pain, severe
diarrhea, malaise, fever
 Mucosal hemorrhage and
perforation; can be life
threatening
 CT may show colonic
thickening
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Credit: P. Volberding, MD;
UCSF Center for HIV
Information Image Library
July 2013
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CMV Disease: Clinical Manifestations (6)
Esophagitis
 Infrequent in persons
with CMV end-organ
disease
 Odynophagia, nausea,
mid-epigastric or
retrosternal discomfort,
fever
Credit: P. Volberding, MD; UCSF
Center for HIV Information Image
Library
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CMV Disease: Clinical Manifestations (7)
Pneumonitis
 Uncommon
 CMV may be detected in bronchoalveolar lavage:
usually is not pathogenic; other causes should be
ruled out
 Shortness of breath, dyspnea on exertion,
nonproductive cough, hypoxemia
 CXR: interstitial infiltrates
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CMV Disease: Clinical Manifestations (8)
Neurologic disease
 Dementia: lethargy, confusion, fever, but may
mimic HIV-1 dementia
 CSF: lymphocytic pleocytosis, low-to-normal
glucose, normal-to-elevated protein
 Ventriculoencephalitis: more acute course;
cranial nerve palsies, nystagmus, other focal
neurologic signs, rapid progression to death
 CT or MRI: periventricular enhancement
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CMV Disease: Clinical Manifestations (9)
Neurologic disease
 Polyradiculomyelopathy: resembles GuillianBarré syndrome
 Urinary retention, progressive bilateral leg
weakness; progresses over weeks to loss of
bowel and bladder control, flaccid paraplegia
 Spastic myelopathy, sacral paresthesia possible
 CSF: neutrophilic pleocytosis, low glucose,
elevated protein
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CMV Disease: Diagnosis
 Blood tests (eg, PCR, antigen assays, blood
culture) not recommended for diagnosis of CMV
end-organ disease: poor positive and negative
predictive value
 CMV viremia usually present in end-organ
disease but may be present in absence of
end-organ disease
 Antibody levels not useful, though negative IgG
indicates CMV unlikely
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CMV Disease: Diagnosis (2)
 Retinitis: characteristic retinal changes on
funduscopy (by experienced ophthalmologist);
PCR of vitreous helpful if exam not diagnostic
 Colitis: mucosal ulcerations on endoscopy +
biopsy with characteristic intranuclear and
intracytoplasmic inclusions
 Esophagitis: ulceration of distal esophagus on
endoscopy + biopsy with intranuclear inclusion
bodies in endothelial cells
 CMV culture from biopsy or brushing of colon or
esophagus is not diagnostic
 In patients with low CD4 counts, viremia and positive
cultures may occur in absence of clinical disease
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CMV Disease: Diagnosis (3)
 Pneumonitis: interstitial infiltrates + compatible
clinical presentation + multiple CMV inclusion
bodies in lung tissue, and absence of other likely
pathogens
 Neurologic disease:
clinical syndrome +
CMV in CSF or brain
tissue; detection
enhanced by PCR
Brain biopsy with CMV inclusions
Credit: Images courtesy of AIDS Images
Library (www.aids-images.ch)
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CMV Disease: Preventing Exposure
 Patients from groups with low seroprevalence
rates for CMV exposure (no contact with MSM,
IDU, contact with children in day care) may be
tested for CMV IgG
 Counsel patients about exposure risks (semen,
cervical secretions, saliva) and prevention
(handwashing, latex gloves, condoms)
 CMV-seronegative patients needing
nonemergency blood transfusions should receive
CMV-negative blood products
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CMV Disease: Preventing Disease
 Use ART to suppress HIV VL and maintain CD4
count >100 cells/µL
 Primary prophylaxis with valganciclovir not
recommended (no preventive benefit in one
study)
 Recognition, treatment of early disease to prevent
progression
 Patient education: vigilance for increase in floaters,
decrease in visual acuity
 Some specialists recommend annual funduscopic
examinations by ophthalmologist if CD4 <50 cells/µL
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CMV Disease: Treatment
Retinitis
 Start or optimize ART for maximal viral
suppression and immune reconstitution
 Treat CMV retinitis in concert with ophthalmologist
experienced with diagnosis and management of
retinal disease
 Initial anti-CMV therapy followed by chronic
maintenance therapy
 Intravitreal therapy provides immediate high intraocular
drug levels and perhaps faster control of retinitis
 Systemic therapy important to prevent disease in
contralateral eye and improve survival
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CMV Disease: Treatment (2)
Retinitis (cont’d)
 Several effective treatments: few comparative
trials in recent years; no regimen proven to have
superior efficacy
 Individualize based on location and severity of
lesions, level of immunosuppression, other
factors
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CMV Disease: Treatment (3)
Retinitis (cont’d)
 Immediate sight-threatening lesions:
 Intravitreal injections of ganciclovir 2 mg/injection or
foscarnet 2.4 mg/injection for 1-4 doses over 7-10
days
 Ganciclovir ocular implant no longer available
PLUS systemic therapy:
 Preferred systemic therapy
 Valganciclovir 900 mg PO BID for 14-21 days, then QD
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CMV Disease: Treatment (4)
Retinitis (cont’d)
 Immediate sight-threatening lesions (cont’d):
 Alternative systemic therapy
 Ganciclovir 5 mg/kg IV Q12H for 14-21 days, then
5 mg/kg IV QD
 Ganciclovir 5 mg/kg IV Q12H for 14-21 days, then
valganciclovir 900 mg PO QD
 Foscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H
for 14-21 days, then 90-120 mg/kg Q24H
 Cidofovir 5 mg/kg/week IV for 2 weeks, then 5
mg/kg every other week (with pre- and postinfusion hydration and probenecid) (avoid in
patients with sulfa allergy)
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CMV Disease: Treatment (5)
Retinitis (cont’d)
 Small peripheral lesions:
 Preferred
 Systemic antiviral therapy as above
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CMV Disease: Treatment (6)
Colitis, esophagitis
 Preferred
 Ganciclovir 5 mg/kg IV Q12H, may switch to
valganciclovir 900 mg PO Q12H when patient can
absorb and tolerate PO therapy
 Alternative
 Foscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H – if
treatment-limiting toxicities or resistance to ganciclovir
 Oral valganciclovir if PO therapy can be absorbed
 For mild cases, if ART can be initiated or optimized
quickly, can consider withholding CMV therapy
 Duration: 21-42 days, or until signs and
symptoms have resolved
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CMV Disease: Treatment (7)
Pneumonitis
 Treat patients with histologic evidence of
CMV pneumonitis
 Limited experience: IV ganciclovir or
foscarnet is reasonable
 Oral valganciclovir not studied
 Duration of therapy not established
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CMV Disease: Treatment (8)
Neurologic disease
 Treatment not well studied
 Initiate treatment promptly
 Ganciclovir IV + foscarnet IV until symptoms
improve
 Combination treatment preferred as initial therapy,
to maximize response, but associated with high
rates of adverse effects
 Duration of therapy and role of oral
valganciclovir not established
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CMV Disease: Starting ART
 IRIS may cause retinal damage in patients with
active CMV retinitis, or recent or past CMV
retinitis
 Incidence or severity of IRIS may be reduced by
delaying ART until retinitis is controlled
 CMV replication usually controlled 1-2 weeks after
start of CMV therapy
 Weigh brief delay in ART initiation against risk of other
OIs
 Most experts would not delay ART for more than 2
weeks after starting CMV therapy for retinitis or other
CMV end-organ disease
 Use clinical judgment in case of neurologic disease
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CMV Disease: Monitoring
Retinitis
 Close monitoring by experienced
ophthalmologist
 Dilated exam at time of diagnosis, after induction
therapy, 1 month after initiation of therapy,
monthly thereafter while on treatment
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CMV Disease: Adverse Events
Immune recovery uveitis
 Inflammatory reaction to CMV after initiation of
ART and in setting of significant rise in CD4
counts 4-12 weeks after start of ART
 May cause macular edema and epiretinal
membranes, vision loss
 Treatment: periocular corticosteroids or short
course of systemic corticosteroids
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CMV Disease: Adverse Events (2)
 Ganciclovir: neutropenia, thrombocytopenia,
nausea, diarrhea, renal dysfunction, seizures
 Foscarnet: anemia, nephrotoxicity, electrolyte
abnormalities, neurologic symptoms including
seizures
 Monitor CBC, electrolytes, renal function twice
weekly during induction therapy, weekly
thereafter
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CMV Disease: Adverse Events (3)
 Cidofovir: nephrotoxicity, hypotony
 Check renal function, urinalysis before each
infusion
 Do not administer if renal dysfunction or proteinuria
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CMV Disease: Treatment Failure
 Retinitis: recurrence is likely unless immune
reconstitution with ART
 Early relapse: usually caused by limited
intraocular penetration of systemic treatments
 Drug resistance to ganciclovir, foscarnet, or
cidofovir can occur
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CMV Disease: Treatment Failure (2)
Treatment options for first relapse:
 Ganciclovir implant
 Reinduction with the same drug, followed by
maintenance therapy
 Changing to alternative drug at first relapse:
usually not more effective, unless drug
resistance or significant side effects
 Ganciclovir + foscarnet: superior to
monotherapy but greater toxicity
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CMV Disease: Treatment Failure (3)
Later relapse: often owing to drug resistance
 Resistance occurs in long-term therapy
(25-30% by 9 months of therapy)
 Similar rates for ganciclovir, foscarnet,
cidofovir
 Consider resistance testing in blood
 >90% correlation with virus in eye
 Can be done in <48 hours
 Most virus with high-level resistance to ganciclovir
(UL97 + UL54 mutations) respond to foscarnet
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CMV Disease: Treatment Failure (4)
Low-level ganciclovir resistance:
 Consider ganciclovir implant
(higher local levels of ganciclovir)
High-level ganciclovir resistance:
 Switch to alternative therapy
 Usually also resistant to cidofovir, sometimes
to foscarnet
 Consider repeated intravitreous fomivirsen
(combine with systemic therapy)
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CMV Disease: Preventing Recurrence
Retinitis:
 Chronic maintenance therapy (secondary
prophylaxis) for life, unless immune reconstitution
on ART
 Consult ophthalmologist regarding choice for
chronic maintenance therapy and the preferred
route (intravitreal, IV, oral, or combination),
consider anatomic location of retinal lesions,
vision in the contralateral eye, other factors
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CMV Disease: Preventing Recurrence (2)
Retinitis (cont’d):
 Preferred
 Valganciclovir 900 mg PO QD
 Alternative
 Ganciclovir 5 mg/kg IV 5-7 times weekly
 Foscarnet 90-120 mg/kg IV QD
 Cidofovir 5 mg/kg IV every other week (with preand post-infusion hydration and probenecid) (avoid
in patients with sulfa allergy)
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CMV Disease: Preventing Recurrence (3)
GI disease, pneumonitis, CNS disease:
 Chronic maintenance therapy not routinely
recommended, after resolution of acute CMV
syndrome and initiation of effective ART, unless
retinitis or relapses
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CMV Disease: Preventing Recurrence (4)
 Consider discontinuation of secondary
prophylaxis in patients with increase in CD4
count to >100-150 cells/µL for ≥6 months on ART
 For retinitis, consult with ophthalmologist;
consider location of retinal lesions, vision in
contralateral eye
 Close ophthalmologic monitoring
 Restart secondary prophylaxis if CD4 count decreases
to <100-150 cells/µL
 Relapses have occurred at high CD4 counts (≥1,250
cells/µL); relapse rate if secondary prophylaxis
discontinued for immune recovery is 3% per year
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CMV Disease: Considerations in Pregnancy
 Diagnosis as in nonpregnant women
 Treatment:
 For retinitis, consider retinal implants or
intravitreous therapy to limit fetal exposure to
systemic antivirals
 Ganciclovir: teratogenic in animals; limited data
in human pregnancy but is treatment of choice
during pregnancy
 No data on valganciclovir during pregnancy
 Monitor for hydrops fetalis after 20 weeks of
gestation
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CMV Disease: Considerations in Pregnancy (2)
 Foscarnet: skeletal abnormalities in animals;
no experience in early human pregnancy
 Monitor amniotic fluid volumes after 20 weeks of
gestation
 Cidofovir: embryotoxic and teratogenic in
animals; no experience in human pregnancy
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CMV Disease: Considerations in Pregnancy (3)
 In utero infection occurs most commonly among
infants born to mothers with primary CMV infection
during pregnancy
 >90% of HIV-infected women are CMV antibody
positive; no role for treatment of asymptomatic
women
 For pregnant women with primary CMV infection
or CMV end-organ disease, refer to maternal-fetal
specialist
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Viral Infections
Herpes Simplex Virus Disease
Herpes Simplex Virus (HSV) Disease:
Epidemiology
 HSV-1: seroprevalence 60% among adults in the
United States
 HSV-2: seroprevalence 17% among persons
aged ≥12 years in United States
 95% of HIV-infected persons are seropositive for
either HSV-1 or HSV-2
 Most infections are not clinically evident
 Reactivation occurs intermittently and can result
in transmission
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HSV Disease: Epidemiology (2)
 HSV-2 increases risk of HIV acquisition
2- to 3-fold
 HSV-2 reactivation increases HIV RNA
levels in blood and genital secretions of
HIV-infected patients
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HSV Disease: Clinical Manifestations
 Orolabial herpes: most
common in HSV-1 infection
 Local sensory prodrome
(pain, itching), then
papules progressing to
vesicles, then ulcers,
crusting
 Lasts 5-10 days if
untreated
 Recurs 1-12 times/year;
can be triggered by
sunlight, stress
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Credit: © I-TECH
May 2013
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HSV Disease: Clinical Manifestations (2)
 Genital herpes: most common in
HSV-2 infection
 Prodrome and lesions similar to
orolabial lesions
 With mucosal disease, dysuria,
vaginal or urethral discharge may
be present
 Perineal disease: may see inguinal
lymphadenopathy
 Lesions may be mild and atypical
 In advanced HIV (CD4 count <100
cells/µL), may see extensive, deep
nonhealing ulcerations
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Credit: HIV Web Study,
www.hivwebstudy.org; © 2006
University of Washington
May 2013
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HSV Disease: Clinical Manifestations (3)
 Genital HSV-1 episodes indistinguishable
from those of genital HSV-2 infection, but
HSV-1 recurs less frequently
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HSV Disease: Clinical Manifestations (4)
 Other manifestations: HSV keratitis, HSV
encephalitis, HSV hepatitis, herpetic whitlow are
similar in HIV infected and HIV uninfected
 HSV retinitis: acute retinal necrosis; can rapidly
cause vision loss
 Disseminated HSV is rare
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HSV Disease: Diagnosis
 Mucosal HSV cannot be diagnosed accurately
by clinical exam, especially in HIV infection:
laboratory diagnosis should be pursued
 Swab base of fresh vesicle:
 Viral culture
 HSV DNA PCR (most sensitive; not widely available)
 HSV antigen detection
 If HSV detected, obtain type (genital
HSV-1 recurs less frequently)
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HSV Disease: Diagnosis (2)
 Type-specific serologic assays: can use in
asymptomatic persons, or with atypical
lesions
 Consider routine serologic testing for HSV2 in all HIV-infected patients
 If infected with HSV-2: counsel about risk of
transmission to sex partners, means of
preventing transmission
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HSV Disease: Preventing Exposure
 Most HIV-infected persons have HSV-1 and HSV-2
 If HSV-2 seronegative
 Test partners for HSV-2 before initiating sexual activity
 Latex barriers reduce HSV-2 acquisition (at least in
heterosexual couples)
 Avoid sexual contact with partners who have evident
herpetic lesions
 Sexual transmission of HSV-2 usually occurs during
asymptomatic shedding
 Antiviral therapy (valacyclovir) can reduce HSV-2
transmission (not studied in HIV infection)
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HSV Disease: Preventing Disease
 Antiviral prophylaxis to prevent primary HSV is
not recommended
 Antiviral prophylaxis after exposure has not
been studied
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HSV Disease: Treatment
 Can treat episodically when lesions occur or
with daily therapy to prevent recurrences;
consider:
 Frequency and severity of recurrences
 Risk of HSV-2 transmission
 Potential for adverse HSV-2 effect on HIV viral
loads in plasma and genital secretions
 Treatment of individual episodes does not
reduce risk of HSV-2 transmission to sex
partners
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HSV Disease: Treatment (2)
 Orolabial HSV and genital HSV (initial or
recurrent)
 Valacyclovir 1 g PO BID, famciclovir 500 mg
PO BID, or acyclovir 400 mg PO TID
 Duration: 5-10 days (orolabial); 5-14 days
(genital)
 Severe mucocutaneous HSV
 Acyclovir 5 mg/kg IV Q8H until lesions begin
to regress, then PO therapy as above, until
lesions have completely healed
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HSV Disease: Starting ART
 Orolabial HSV usually should not influence
decision about when to start ART
 Prompt initiation of ART: chronic cutaneous or
mucosal HSV refractory to treatment, visceral or
disseminated HSV
 ART with immune reconstitution may improve
frequency and severity of genital HSV episodes
 ART does not reduce frequency of genital HSV
shedding
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HSV Disease: Monitoring and Adverse
Events
 No laboratory monitoring needed unless
advanced renal impairment
 Monitor renal function for patients on high-dose or
prolonged therapy with IV acyclovir
 High-dose (8 grams/day) valacyclovir may cause
thrombotic thrombocytopenic purpura/hemolytic
uremic syndrome; not reported at dosages used
for HSV treatment
 Atypical lesions reported in persons initiating ART
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HSV Disease: Treatment Failure
 Lesions should begin to resolve within 710 days of therapy initiation
 Suspect drug resistance if no improvement
 Culture lesion, perform susceptibility testing
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HSV Disease: Treatment Failure (2)
Acyclovir-resistant HSV
 Preferred:
 Foscarnet 80-120 mg/kg/day IV in 2-3 divided doses
until clinical response
 Alternatives (21-28 days or longer):
 Topical trifluridine, topical cidofovir, or topical
imiquimod for external lesions
 IV cidofovir
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HSV Disease: Preventing Recurrence
 Suppressive therapy recommended for patients
with frequent or severe recurrences; consider for
all with HSV-2
 Valacyclovir 500 mg PO BID
 Famciclovir 500 mg PO BID
 Acyclovir 400 mg PO BID
 Daily HSV suppressive therapy causes decrease
in HIV RNA in plasma and anal and genital
secretions, and lower risk of HIV progression
 Suppressive HSV therapy does not decrease risk of
HIV transmission
 Suppressive therapy is continued indefinitely,
regardless of CD4 cell count improvement
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HSV Disease: Considerations in
Pregnancy
 Diagnosis of mucocutaneous HSV as in
nonpregnant adults
 Visceral disease more likely during pregnancy
 May be transmitted to fetus or neonate
 Risk of neonatal HSV greatest if mother has
primary HSV infection during late pregnancy
 In utero transmission rare, but severe cutaneous,
ocular, and CNS damage
 Most neonatal infection occurs via exposure to
maternal genital fluids during birth
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HSV Disease: Considerations in
Pregnancy (2)
 Cesarean delivery lowers risk of transmission;
recommended for women with prodrome or
visible HSV genital lesions at onset of labor
 Acyclovir or valacyclovir during late pregnancy
suppresses genital HSV outbreaks and shedding
in HIV-uninfected women; reduces need for
cesarean delivery; likely to have similar efficacy
in HIV-infected women
 Efficacy in reducing incidence of neonatal herpes is
unknown
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HSV Disease: Considerations in
Pregnancy (3)
 Treatment
 Acyclovir: most experience in pregnancy
 Valacyclovir, famciclovir: appear to be safe
and well tolerated during pregnancy
 Suppressive therapy:
 Valacyclovir or acyclovir recommended
starting at 36 weeks, for pregnant women with
recurrences of genital HSV during pregnancy
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HSV Disease: Considerations in
Pregnancy (4)
 Maternal genital HSV increases risk of
perinatal HIV transmission in women not
on ART; unknown effect for women on
ART
 Whether HSV suppression reduces risk of
HIV transmission during pregnancy, birth,
or breast-feeding is unknown
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Viral Infections
Varicella-Zoster Virus
VZV Disease: Epidemiology
 Primary VZV = varicella (chickenpox)
 Reactivation of latent VZV results in herpes
zoster (shingles)
 Lifetime risk 15-20%; highest incidence in
immunocompromised and elderly
 Incidence >15-fold higher in HIV infected
compared with general population
 Can occur at any CD4 count; highest frequency
with CD4 count <200 cells/µL
 ART has not been shown to reduce incidence
of zoster in adults
 Rates higher in period immediately after ART
initiation
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VZV Disease: Clinical Manifestations
Varicella: chickenpox
 Lesions evolve rapidly
from macules, papules,
vesicles to pustules and
crusts; successive crops
of new lesions over 2-4
days
 First appears on head,
then trunk, extremities
 Pruritus, fever, headache,
malaise
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Credit: HIV Web Study
© 2006, U. of Washington
July 2013
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VZV Disease: Clinical Manifestations (2)
Varicella: chickenpox
 Illness may be severe in HIV infection
 Visceral dissemination, especially VZV
pneumonitis, may occur
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VZV Disease: Clinical Manifestations (3)
Herpes zoster (shingles):
 Characteristic painful
cutaneous eruption
(papules, then vesicles) in
dermatomal distribution;
often prodrome of pain
 New vesicle formation for
3-5 days, then pustulation
and scabbing; crusts may
peprsist 2-3 weeks
 Extensive skin involvement
and visceral involvement
are rare
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Credit: © I-TECH
July 2013
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VZV Disease: Clinical Manifestations (4)
Herpes zoster (shingles):
 Recurrence in 20-30% of HIV infected (same
or different dermatome)
 Postherpetic neuralgia in 10-15% of HIVinfected persons
 Complications more common if CD4 count
<200 cells/µL
 Neurologic syndromes: CNS vasculitis, multifocal
leukoencephalitis, ventriculitis, myelitis and
myeloradiculitis, optic neuritis, cranial nerve
palsies, aseptic meningitis
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VZV Disease: Clinical Manifestations (5)
 Progressive outer retinal necrosis may be
seen, almost exclusively with CD4 count
<100 cells/µL
 Acute retinal necrosis: may occur at any
CD4 count
 High rates of visual loss with both
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VZV Disease: Diagnosis
 Clinical diagnosis usually can be made, based
on appearance of lesions
 Retrospective diagnosis of varicella by
documenting seroconversion
 Atypical presentations may be seen in
immunocompromised persons, may be hard to
distinguish from disseminated zoster
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VZV Disease: Diagnosis (2)
 Definitive diagnosis:
 Viral culture, direct fluorescent antigen
testing, or PCR from swabs from fresh lesion,
or tissue biopsy, or scabs
 PCR is most sensitive and specific
 Histopathology and PCR of blood or fluids
(eg, CSF, vitreous humor)
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VZV Disease: Preventing Exposure
 If susceptible (no history of varicella or
zoster, not vaccinated, seronegative for
VZV): avoid exposure to persons with
varicella or zoster
 Susceptible household contacts of
susceptible HIV-infected persons should
be vaccinated
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VZV Disease: Preventing Disease
 Long-term prophylaxis with antiviral drugs is not
recommended
 Vaccination to prevent primary infection
 Live attenuated varicella vaccine may be considered
for HIV-infected, VZV-seronegative persons ≥8 years
of age with CD4 count ≥200 cells/µL (2 doses, 3
months apart)
 No efficacy data in HIV-infected adults and adolescents, but
safe and immunogenic in HIV-infected children with CD4
percentage ≥15%
 If vaccination results in disease caused by vaccine virus, treat
with acyclovir
 Vaccination not recommended if CD4 <200 cells/µL
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VZV Disease: Preventing Disease (2)
 Postexposure prophylaxis to prevent primary
infection:
 Varicella-zoster immune globulin (VariZIG) for VZVsusceptible HIV-infected children and adults
 Give as soon as possible (but ≤10 days) after close
contact with person with active varicella or herpes zoster
 May consider short-term postexposure acyclovir or
valacyclovir beginning 7-10 days after exposure
(not studied in HIV infection)
 Acyclovir 800 mg PO 5 times/day for 5-7 days
 Valacyclovir 1 g PO TID for 5-7 days
 Postexposure varicella vaccination reduces risk of
varicella in immunocompetent children; not studied
in HIV infection
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VZV Disease: Preventing Disease (3)
 Vaccination after exposure
 If postexposure VariZIG has been given, wait
≥5 months before varicella vaccination
 If postexposure acyclovir has been given, wait
≥3 days before varicella vaccination
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VZV Disease: Treatment
Varicella (chickenpox)
 Uncomplicated:
 Preferred
 Valacyclovir 1 g PO TID
 Famciclovir 500 mg PO TID
 Alternative
 Acyclovir 20 mg/kg up to maximum 800 mg PO 5 times
daily
 Duration: 5-7 days
 Severe or complicated:
 Acyclovir 10-15 mg/kg IV Q8H for 7-10 days
 May switch to PO treatment as above after fever
resolves, if no visceral involvement
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VZV Disease: Treatment (2)
Herpes zoster
 Start treatment promptly if diagnosed within 1
week of rash onset, or any time before full
crusting of lesions
 Local dermatomal zoster:
 Preferred
 Valacyclovir 1,000 mg TID
 Famciclovir 500 mg TID
 Alternative
 Acyclovir 800 mg PO 5 times per day
 Duration: 7-10 days (longer if lesions slow to
resolve)
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VZV Disease: Treatment (3)
 Extensive cutaneous lesions or visceral
involvement:
 Acyclovir 10-15 mg/kg IV Q8H, until clinical
improvement
 After clinical improvement and no new cutaneous
lesions, switch to PO therapy as above
 Duration: 10-14 days
 Adjunctive corticosteroid therapy not
recommended (limited data in HIV infection)
 ART optimization is recommended for all VZV
infections that are difficult to treat (eg, retinitis,
encephalitis)
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VZV Disease: Treatment (4)
 Progressive outer retinal necrosis:
 Optimal therapy not defined; poor prognosis for vision
preservation despite antiviral therapy
 Treatment should include at least one IV drug and at
least one intravitreal anti-VZV drug, plus effective ART
 Ganciclovir 5 mg/kg IV Q12H and/or foscarnet 90 mg/kg IV
Q12H PLUS ganciclovir 2 mg/0.05 mL intravitreal twice weekly
and/or foscarnet 1.2 mg/0.05 mL intravitreal twice weekly
 Optimize ART
 Manage in conjunction with an experienced
ophthalmologist
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VZV Disease: Treatment (5)
 Acute retinal necrosis:
 More responsive to antiviral therapy
 Acyclovir 10-15 mg/kg IV Q8H for 10-14 days, followed
by valacyclovir 1 g PO TID for 6 weeks, PLUS
ganciclovir 2 mg/0.05 mL intravitreal twice weekly x 1-2
doses
 Manage in conjunction with an experienced
ophthalmologist
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VZV Disease: Starting ART
 Strongly consider ART initiation in patients with
multiple recurrences of herpes zoster or a
complication of VZV disease
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VZV Disease: Monitoring and Adverse
Events
 IRIS: increased frequency of herpes zoster after
initiation of ART, but clinical presentation and
natural history are not different
 Valacyclovir, acyclovir: renal toxicity at high
dosage
 Monitor renal function for patients on high-dose or
prolonged therapy with IV acyclovir
 High-dose (8 grams/day) valacyclovir may cause
thrombotic thrombocytopenic purpura/hemolytic
uremic syndrome; not reported at lower dosages
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VZV Disease: Treatment Failure
 Suspect drug resistance if lesions do not
start to resolve within 7-10 days of
treatment initiation, or if they evolve to
verrucous or atypical appearance
 Virus culture with susceptibility testing if virus
is isolated
 If proven or suspected acyclovir resistance,
treat with IV foscarnet (alternative: IV
cidofovir)
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VZV Disease: Preventing Recurrence
 Efficacy of long-term antiviral prophylaxis
to prevent recurrence of zoster not
evaluated in HIV infection, not routinely
recommended
 Herpes zoster vaccine: FDA approved for
immunocompetent persons ≥50 years of
age
 Contraindicated if CD4 count <200 cells/µL
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VZV Disease: Considerations in
Pregnancy
 Postexposure prophylaxis:
 Recommended for VZV-susceptible HIV-infected
pregnant women if close contact to person with active
varicella or herpes zoster:
 Varicella-zoster immune globulin (VariZIG)
 Give as soon as possible (but ≤10 days) after exposure
 If acyclovir is used, obtain VZV serology and
discontinue drug if patient is seropositive
 Varicella vaccine and herpes zoster vaccine should
not be given during pregnancy
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VZV Disease: Considerations in
Pregnancy (2)
 Diagnosis as in nonpregnant adults
 Treatment of varicella:
 Uncomplicated: PO acyclovir or valacyclovir
 Severe disease or VZV pneumonitis: hospitalize, IV
acyclovir
 Treatment of zoster:
 PO acyclovir or valacyclovir
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VZV Disease: Considerations in
Pregnancy (3)
 Risk of transmission to fetus if woman has
primary VZV during first half of pregnancy
 Offer detailed ultrasound surveillance for signs of
fetal congenital varicella
 VariZIG recommended to prevent complications in
the mother (not known whether it prevents congenital
varicella syndrome)
 Infants born to women with peripartum varicella
(from 5 days before delivery until 2 days after)
 VariZIG to infant reduces severity and mortality of
neonatal infection
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Viral Infections
Human Herpesvirus-8 Disease
HHV-8 Disease: Epidemiology
 Associated with Kaposi sarcoma (KS) (all
forms) and certain neoplastic and
lymphoproliferative disorders (primary effusion
lymphoma [PEL]), multicentric Castleman
disease)
 HHV-8 seroprevalence in United States: 1-5%
 Higher in MSM regardless of HIV serostatus (2077%)
 Higher in some Mediterranean countries (10-20%)
and parts of sub-Saharan Africa (30-80%)
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HHV-8 Disease: Epidemiology (2)
 Pathogenesis of HHV-8 disease is unclear
 KS and PEL usually seen in advanced
immunosuppression (CD4 count <200 cells/µL),
but can occur at any CD4 count
 KS incidence up to 30% among AIDS patients in
United States before use of effective ART
 Dramatically lower incidence in recent years
 ART prevents and may regress KS lesions
 Ganciclovir, foscarnet, and cidofovir given for CMV
treatment may prevent or suppress KS
 Castleman disease and PEL remain rare
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HHV-8 Disease: Clinical Manifestations
 Most with chronic HHV-8 infection are
asymptomatic
 Acute infection may cause fever, rash,
lymphadenopathy, bone marrow failure,
occasional rapid progression to KS
 Castleman disease: generalized adenopathy,
fever; may progress to multiorgan failure
 PEL: pleural, pericardial, or abdominal effusions;
mass lesions are less common
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HHV-8 Disease: Clinical Manifestations (2)
 KS presentation varies
widely
 Most have nontender,
purplish, indurated skin
lesions
 Intraoral lesions are
common
 Visceral dissemination
may occur
Credit: P. Volberding, MD;
UCSF Center for HIV
Information Image Library
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HHV-8 Disease: Diagnosis
 Routine screening for HHV-8 is not
indicated
 Quantitation of HHV-8 by PCR has no
established role in diagnosis
 KS: biopsy
 Consult with specialist for diagnosis of
other suspected HHV-8 disease
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HHV-8 Disease: Prevention
 Preventing Exposure
 HHV-8 shedding in saliva and genital secretions
may transmit HHV-8 to uninfected partners
 Interventions to prevent exposure to HHV-8 not
likely to be highly effective, have not been
validated; are not recommended
 Preventing Disease
 Toxicity of anti-HHV-8 therapy outweighs
potential benefits
 Early initiation of ART likely to be most
effective prevention measure
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HHV-8 Disease: Treatment
 ART for all: initiate or optimize
 Limited studies of HHV-8-specific agents
 KS:
 Ganciclovir, foscarnet may regress lesions; cidofovir ineffective
in 1 study
 Chemotherapy if visceral KS; consider if widely disseminated
cutaneous KS
 Castleman disease:
 Preferred: valganciclovir 900 mg PO BID for 3 weeks or
ganciclovir 5 mg/kg IV Q12H for 3 weeks or valganciclovir 900
mg PO BID + zidovudine 600 mg PO Q6H for 7-12 days
 Alternative: rituximab for 4-8 weeks (effective as alternative or
adjunctive therapy; associated with subsequent exacerbation or
emergence of KS)
 PEL:
 Chemotherapy
 IV ganciclovir or PO valganciclovir may be useful adjunct
 Consult with specialist
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HHV-8 Disease: Starting ART
 Early ART initiation is likely to prevent KS and
PEL
 ART should be given to all with KS, muticentric
Castleman disease, or PEL
 Insufficient evidence to support specific ARV
regimens
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HHV-8 Disease: Monitoring and
Adverse Events
 IRIS reported in HHV-8-infected patients
who initiate ART
 KS: new onset KS or exacerbations of
previously stable disease
 Castleman disease: clinical decompensation
 PEL: no data
 ART is key component of therapy and
should not be delayed
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HHV-8 Disease: Preventing Recurrence
 ART recommended for all with HHV-8
disease
 May prevent KS progression or recurrence
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HHV-8 Disease: Considerations in
Pregnancy
 HHV-8 seropositivity does not appear to affect
pregnancy outcome; screening for HHV-8 not
indicated
 Antiviral therapy for HHV-8 infection during
pregnancy is not recommended
 Diagnosis as in nonpregnant women
 For treatment, consult with specialist
 Perinatal transmission occurs infrequently,
higher risk with higher maternal antibody titer;
may be associated with increased infant
mortality
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Viral Infections
Progressive Multifocal
Leukoencephalopathy
PML: Epidemiology
 Opportunistic infection, caused by the polyoma
virus JC virus
 Characterized by focal demyelination in the CNS
 Worldwide distribution, seroprevalence of 39-69%
in adults
 Primary infection usually in childhood
 No recognized acute JC virus infection
 Likely asymptomatic chronic carrier state
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PML: Epidemiology (2)
 Before use of potent ART, PML developed in 3-7%
of persons with AIDS
 Substantially lower incidence in countries with wide
access to ART
 High mortality rate
 Usually occurs with low CD4 count, but may occur
with CD4 count >200 cells/μL and in those on ART
 Rarely occurs in HIV-uninfected immunocompromised persons
 Reported in persons treated with immunomodulatory
humanized antibodies (eg, natalizumab, efalizumab,
infliximab, rituximab)
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PML: Clinical Manifestations
 Focal neurologic deficits, usually with insidious onset, steady
progression over several weeks/months
 Demyelinating lesions may involve any region of the brain
 Common: occipital lobes (hemianopsia), frontal and parietal lobes
(aphasia, hemiparesis, hemisensory deficits), cerebellar peduncles
and deep white matter (dysmetria, ataxia)
 Spinal cord involvement is rare
 Lesions often multiple, though one may predominate
 Headache and fever not characteristic (except in severe
IRIS)
 Seizures in 20%
 Cognitive dysfunction may occur but diffuse encephalopathy
or dementia is rare
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PML: Diagnosis
 Compatible clinical syndrome and
radiographic findings allow presumptive
diagnosis in most cases
 Clinical: steady progression of focal
neurological deficits
 Imaging: MRI is preferred
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PML: Diagnosis (2)
 MRI distinct white matter lesions in brain areas
corresponding to clinical deficits
 Usually hyperintense on T2 and FLAIR, hypointense
on T1
 Usually no mass effect
 Contrast enhancement in 10-15% but usually sparse
 IRIS PMN may have different appearance
 Diffusion-weighted imaging and MR spectroscopy
may give additional diagnositic information
 CT scan: single or multiple hypodense,
nonenhancing white matter lesions
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PML: Diagnosis (3)
PML, CT scan
PML, MRI scan
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)
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PML: Diagnosis (4)
 Definitive diagnosis: valuable, especially for
atypical cases
 CSF evaluation for JC virus DNA (by PCR):
helpful if positive; 70-90% sensitive in patients
who are not on ART (lower in those on ART)
 Brain biopsy: identification of JC virus;
visualization of oligodendrocytes with
intranuclear inclusions, bizarre astrocytes, lipidladen macrophages
 Serologic testing generally not useful, but
newer approaches under investigation
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PML: Prevention
 Preventing exposure
 No known way to prevent exposure
 Preventing disease
 ART is the only effective way to prevent PML
 Prevention of progressive immunosuppression
caused by HIV
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PML: Treatment
 No specific therapy
 Main approach: ART to reverse immune
suppression
 Start ART immediately for those not on ART; optimize
ART in all on ART without suppression of HIV viremia
 Effectiveness of ARVs with better CNS penetration is not
established – likely that systemic efficacy is most important,
via restoration of anti-JCV immunity
 Effective ART stops PML progression in approximately
50%
 Neurologic deficits often persist
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PML: Treatment
 Targeted treatments: no proven effective
therapies
 Cytarabine, cidofovir: studies show no clinical benefit;
not recommended
 5HT2a receptor inhibitors: clinical trial data lacking;
cannot be recommended
 Interferon-alfa: no clinical benefit; cannot be
recommended
 Topotecan: limited data; not recommended
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PML: Starting ART
 ART should be started immediately upon
diagnosis of PML
 For persons on ART with HIV viremia, optimize
ART to achieve HIV suppression
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PML: Monitoring and Adverse Events
 Monitor treatment response with clinical exam and
MRI
 If detectable JCV DNA in CSF before ART, may
repeat quantitation of CSF JCV to assess treatment
response (no clear guidelines)
 If stable or improving, repeat MRI 6-8 weeks after
ART initiation
 If clinical worsening, repeat MRI promptly
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PML: Monitoring and Adverse Events (2)
PML IRIS (inflammatory PML)
 PML may present within first weeks/months after
ART initiation, associated with immune
reconstitution
 Both unmasking of cryptic PML and paradoxical worsening of
known PML may occur
 Features may be atypical, may include mass
effect, edema, contrast enhancement on MRI,
more rapid clinical course; perivascular
mononuclear inflammatory infiltration on
histopathology
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PML: Monitoring and Adverse Events (3)
 IRIS management:
 Corticosteroids may be helpful if substantial
inflammation, edema or mass effect, or clinical
deterioration
 Dosage not established; consider starting with 3- to
5-day course of methylprednisolone 1 g IV QD,
followed by prednisone 60 mg PO QD tapered over
1-6 weeks, according to clinical response
 Contrast-enhanced MRI at 2-6 weeks –
document status of inflammation and edema
 ART should be continued
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PML: Treatment Failure
 Clinical worsening and detection of JCV
(without significant decrease) at 3 months
 Optimize ART, if detectable HIV RNA and
poor CD4 response
 Consider unproven therapies (see
“Treatment”)
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PML: Preventing Recurrence
 Effective ART regimen
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PML: Considerations in Pregnancy
 Diagnosis as in nonpregnant adults
 Treatment: optimal ART
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Viral Infections
Human Papillomavirus
HPV Disease: Epidemiology
 HPV causes spectrum of anogenital disease, from
warts and condyloma acuminata to squamous cell
cancer
 HPV is the main cause of cervical cancer, also
most anal cancer and some tumors of vulva,
vagina, penis, oral cavity, and oropharynx
 Most HPV infections resolve or become latent
and undetectable
 Tumorigenesis requires persistent infection with
oncogenic HPV type
 Transmitted by sexual contact
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HPV Disease: Epidemiology (2)
 Oncogenic HPV types: 16, 18, 31, 35, at
least 8 others
 Type 16 accounts for ~50% of cervical
cancers and most noncervical cancers in the
general population; HPV18 accounts for 1015% of cervical cancers
 Types 6 and 11 associated with 90% of
genital warts
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HPV Disease: Epidemiology (3)
Cervical dysplasia and cancer:
 In women with HIV infection
 Higher rates of cervical cancer
 Higher rates of:
 HPV infection
 Oncogenic HPV types
 Cervical intraepithelial neoplasia (CIN)
(low grade and high grade)
 Increased risk with lower CD4 cell counts
 Vulvar and vaginal intraepithelial neoplasia
also more common
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HPV Disease: Epidemiology (4)
Anal dysplasia and cancer:
 In women and men with HIV infection
 Higher incidence of anal cancer
 Higher rates of anal intraepithelial neoplasia
(AIN)
 Higher risk of anal cancer with lower CD4
counts
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HPV Disease: Epidemiology (5)
Genital and anal warts:
 Incidence and prevalence are higher in
HIV-infected patients
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HPV Disease: Epidemiology (6)
 Impact of ART on incidence of HPV-associated
cancers is not clear; may differ by tumor type
 Limited evidence that ART may decrease progression
of CIN
 No overall change in incidence of cervical cancer
since introduction of ART, and anal cancer rates are
increasing
 Incidence of low-grade VIN lesions and anogenital
warts lower with ART, though rate of high-grade VIN
unchanged
 Conflicting data re impact of ART on oral warts –
some, but not all, studies report increased rates
after ART initiation
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HPV Disease: Epidemiology (7)
 HPV vaccine:
 Use in adolescents and young adults may
reduce risk of cancers caused by HPB 16 and
18 in HIV-infected people later in life
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HPV Disease: Clinical Manifestations
and Diagnosis
Warts: genital, anal, and oral
 Usually flat, papular, or
pedunculated growths on
mucosa or epithelium, 2 mm to
2 cm, may occur in clusters
 Often asymptomatic; may
cause itching or discomfort
 Diagnosis: visual inspection;
biopsy if uncertain diagnosis
 HPV DNA: no data support use for
routine diagnosis or management
Condyloma acuminata, perianal
Credit: P. Volberding, MD; UCSF Center
for HIV Information Image Library
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HPV Disease: Clinical Manifestations
and Diagnosis (2)
Cervical and vaginal intraepithelial neoplasia (CIN,
VIN) and squamous cell cancers
 No characteristic symptoms; often asymptomatic,
may present with bleeding or mass
 Screening:
 Visual inspection of entire anogenital area
 Pap test
 Cytology (Pap) and colposcopy techniques as in HIVuninfected women
 Digital examination of vaginal, vulvar, perianal regions,
and anal canal to feel for masses
 High-resolution colposcopy and biopsy as needed
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HPV Disease: Clinical Manifestations
and Diagnosis (3)
Anal, vulvar, and vaginal intraepithelial neoplasia;
oral HPV disease
 No characteristic symptoms; often asymptomatic,
may present with bleeding or itching; external
lesions may be visible or palpable
 Screening:





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Visual inspection
Anal cytology
Digital examination to feel for masses
High resolution anoscopy as needed
Biopsy of suspicious lesions
May 2013
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HPV Disease: Clinical Manifestations
and Diagnosis (4)
Role of HPV testing
 Role of cervical HPV testing for HIV-infected
women has not been established
 Some specialists recommend HPV testing for triage
of women with ASC-US, as in HIV-uninfected women
 Utility uncertain, given high prevalence of oncogenic HPV in
HIV-infected women
 Anal and other noncervical specimens: no
recommendation
 Prior to HPV vaccination: no recommendation
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HPV Disease: Preventing Infection
Vaccination
 HPV vaccines (quadrivalent and bivalent), prevent
HPV 16 and 18 cervical, vaginal, and vulvar
infections, precancers, and cancers in females
 Quadrivalent vaccine also prevents
 HPV 16 and 18 anal infections and precancers
 HPV 6 and 11 infections
 No efficacy data in HIV-infected individuals (studies
ongoing), though quadrivalent vaccine shown to be
safe and immunogenic
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HPV Disease: Preventing Infection (2)
 HPV vaccine (bivalent or quadrivalent) is strongly
recommended for HIV-infected girls aged 9-12 years
 Also recommended for HIV-infected females aged 13-26
years
 Quadrivalent vaccine is strongly recommended for
HIV-infected boys aged 9-12 years
 Also recommended for HIV-infected males aged 13-26
years
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HPV Disease: Preventing Infection (3)
 Vaccination ideally should precede sexual exposure
to HPV; likely to be less effective in persons aged
19-26 because they already may have acquired
HBV 6, 11, 16, or 18
 Data insufficient to recommend vaccination for those
aged >26; HPV vaccines not approved for age >26
 HIV-infected women who have been vaccinated
should have routine cervical cancer screening
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HPV Disease: Preventing Infection (4)
Condom use
 Use of male latex condoms is strongly
recommended for preventing transmission
or acquisition of HPV
 Associated with lower rates of HPV infection
 If male condoms cannot be used properly, a female
condom should be considered
137
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HPV Disease: Preventing Infection (5)
Male circumcision
 Lower rates of oncogenic HPV infection of the penis
 In the general population, lower risk of penile cancer
and of cervical cancer in sex partners (data from
observational studies)
 In HIV-infected men, limited data suggest effect is
protective but to lesser degree
 Effect on genital, anal, or oral HPV-related cancer or
precancer in HIV-infected men or their sex partners not
known
 In the U.S., insufficient evidence to recommend adult male
circumcision for the purpose of reducing risk of
oncogenic HPV infection
138
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HPV Disease: Preventing Disease –
Cervical Cancer
 For all HIV-infected women who have initiated sexual
activity: screening Pap at 6-month intervals in first year
after HIV diagnosis; annually thereafter if results are
normal
 Consider screening within 1 year of sexual activity,
regardless of age or mode of HIV infection
 High rate of progression of abnormal cytology in HIVinfected adolescents and young women who were infected
via sex; high rate of cervical abnormalities in perinatally
infected adolescents
 Annual screening should continue for life: HIV-infected
women remain at risk of development of cervical
cancer
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HPV Disease: Preventing Disease –
Cervical Cancer
(2)
 If abnormal Pap result, care generally should be
provided according to American Society for
Colposcopy and Cervical Pathology (ASCCP)
guidelines
 Exception: in HIV-infected women, HPV testing alone
is not recommended for follow-up of an abnormal Pap
test
140
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HPV Disease: Preventing Disease –
Cervical Cancer (3)
Management of abnormal results
 ASC-US
 Immediate referral for colposcopy or repeat cytology in
6-12 months
 Greater than ASC-US (ASC-H, LSIL, or HSIL)
 Refer for colposcopy
141
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HPV Disease: Preventing Disease –
Vaginal and Vulvar Cancer
 Women with history of high-grade CIN or cervical
cancer: regular vaginal cuff Pap test
 Routine screening not recommended after hysterectomy
for benign disease in absence of prior CIN 2-3 or cancer
 Abnormal vaginal Pap results: vaginal colposcopy
with Lugol iodine solution
 Concomitant cervical and vulvar lesions: vaginal
colposcopy
 No available screening procedure for vulvar
cancer; biopsy or refer if suspected lesions
142
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HPV Disease: Preventing Disease –
Anal Cancer
 No national recommendations for routine
screening; some specialists recommend anal
cytologic screening of all HIV-infected men and
women:
 Annual digital rectal exam for masses
 Management of abnormal anal Pap results
 ASC-US, ASC-H, LSIL, or HSIL: high-resolution
anoscopy
 Biopsy of visible lesions
143
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HPV Disease: Treatment – Genital and
Oral Warts
 In HIV infection, warts may be larger or more
numerous, may not respond well to therapy,
and may recur more frequently
 No uniformly effective or preferred
 For intra-anal, vaginal, or cervical warts, refer
to a specialist
144
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HPV Disease: Treatment – Genital and
Oral Warts (2)
 Patient-applied treatment
 For uncomplicated external warts
 Podophyllotoxin (e.g., podofilox 0.5% solution or
0.5% gel) applied to lesions BID for 3 days,
followed by 4 days of no therapy, repeated weekly
for up to 4 weeks
 Imiquimod 5% cream applied to lesions at bedtime
and washed off in morning, 3 nonconsecutive
nights per week for up to 16 weeks
 Sinecatechins 15% ointment applied to area TID
for up to 16 weeks
145
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HPV Disease: Treatment – Genital and
Oral Warts (3)
 Provider-applied treatment
 For complex or multicentric lesions, or lesions
inaccessible to patient
 Cryotherapy (liquid nitrogen or cryoprobe),
repeat every 1-2 weeks for up to 4 weeks
 Trichloroacetic or bichloroacetic acid 80-90%
aqueous solution to lesions, repeat weekly for up
to 6 weeks
146
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HPV Disease: Treatment – Genital and
Oral Warts (4)
 Provider-applied treatment (cont’d)
 Surgical excision or laser surgery
 Podophyllin resin 10-25% in tincture of benzoin;
weekly for up to 6 weeks
 Other treatments: consider if above are not
effective:
 Topical cidofovir (not available commercially)
 Intralesional interferon not recommended
 Oral warts: surgical treatment is most common;
many topicals cannot be used on oral mucosa
147
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HPV Disease: Treatment – CIN and
Cervical Cancer
 Manage with a specialist
 Follow ASCCP guidelines, in general
148
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HPV Disease: Treatment – CIN and
Cervical Cancer (2)
 High-grade CIN:
 Satisfactory colposcopy: ablation or excision
 Unsatisfactory colposcopy: excision
 Recurrent high-grade CIN: diagnostic excisional
methods; hysterectomy is acceptable
 Invasive cervical, vaginal, vulvar cancer
 Follow National Comprehensive Cancer Network
guidelines
 Standard treatment appears safe and effective
 Complication and failure rates may be higher in HIVinfected women
149
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HPV Disease: Treatment – CIN and
Cervical Cancer (3)
 HIV-infected adolescents
 Follow ASCCP guidelines for adolescents and
young women
 Progression and recurrence of lesions is more
common
 For CIN 1 and CIN 2, consider close observation
(per guidelines recommendations)
 If compliance is questionable, may be preferable to
follow the treatment arm of management for CIN 2
150
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HPV Disease: Treatment – VIN, VAIN, Vulvar
and Vaginal Cancers
 Consult with specialists; individualize care
 Low-grade VIN/VAIN: can observe or manage
as for vulvovaginal warts
 VIN: local excision, laser vaporization, ablation,
imiquimod
 VAIN: topical 5-fluorouracil (5-FU), laser
vaporization, excision
 Vulvar and vaginal cancer: individualize care,
follow National Comprehensive Cancer
Network guidelines
151
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HPV Disease: Treatment – AIN and Anal
Cancer
 Insufficient data to recommend specific
treatment approaches
 Choice of treatment based on size and location
of lesion, histologic grade
 Options for AIN:
 Infrared coagulation has moderate efficacy for AIN 2
or 3 in HIV-infected patients
 Others: topical 5-FU, cryotherapy, laser therapy,
surgical excision
 Local TCA has been used for AIN; intra-anal imiquimod
shows moderate efficacy for intra-anal AIN
 Anal cancer: consult with specialist; combination
radiation and chemotherapy used most
commonly
152
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HPV Disease: Treatment – Other HPVAssociated Cancers
 HPV-associated penile and oropharyngeal
cancers: as in HIV-uninfected patients
 Prognosis may be better with HPV-associated
oropharyngeal cancers than with non-HPVassociated
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HPV Disease: Starting ART
 To date, no data show that ART initiation should
be influenced by presence of HPV-related
disease
 Some studies found decreased persistence and
progression of CIN during ART, but no change
in incidence of cervical cancer, and anal cancer
incidence has increased
 No data show that treatment for CIN or AIN
should be modified for patients on ART or that
ART should be started or modified for treatment
of CIN or AIN
154
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HPV Disease: Monitoring and Adverse
Events
 Increased risk of recurrence of CIN and
cervical cancer in HIV-infected patients
 Frequent cytologic screening and
colposcopy according to guidelines
 No IRIS has been described in
association with HPV infections
155
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HPV Disease: Monitoring and Adverse
Events (2)
 All treatment modalities have risk of adverse
effects: monitor by physical exam and symptom
review during and after treatment
 Ablative and excisional modalities: pain,
discomfort, intraoperative or postoperative
bleeding, infection, cervical stenosis
 AIN treatments may cause pain, bleeding,
ulceration; rarely abscesses, fissures, or fistulas
 Anal cancer treatment (radiation + chemotherapy)
associated with high rate of morbidity, including
proctitis
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HPV Disease: Treatment Failure
 Persistence or recurrence of lesions after
appropriate therapy
 For genital warts, consider retreatment with
any modality listed above; >1 course of therapy
often needed
 Consider biopsy to rule out VIN
 For persistent or recurrent CIN, manage
according to ASCCP guidelines
 VIN: no consensus; consider surgical excision
157
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HPV Disease: Preventing Recurrence
 Monitoring after therapy:
 CIN: follow ASCCP guidelines
 For high-grade CIN, low-dose intravaginal 5-FU
reduced short-term risk of recurrence in one
study; no recommendation for use
 VIN: no guidelines; twice-yearly vulvar
inspection appears reasonable
 High-grade VIN: manage as with CIN 2 (cytology
at 6 and 12 months after treatment, annually
thereafter)
 No indication for secondary prophylaxis
158
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HPV Disease: Considerations in
Pregnancy
 Genital warts or anogenital HPV-related
neoplasia: manage with team of specialists (eg,
OB/GYN and infectious disease)
 Warts: frequency and rate of growth may be
greater during pregnancy
 Podophyllin and podofilox should not be used: risk of
fetal death
 Imiquimod: insufficient data to recommend during
pregnancy
 Other topical treatments (eg, BCA, TCA) and ablation
can be used
159
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HPV Disease: Considerations in
Pregnancy (2)
 Transmission of genital HPV 6 and 11 at delivery
may cause recurrent laryngeal papillomatosis in
infants, but no change in obstetrical management
is indicated for women with HPV infection (unless
extensive lesions that may impede vaginal
delivery or cause extensive bleeding)
160
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HPV Disease: Considerations in
Pregnancy (3)
 All pregnant women should have Pap screen at
initial prenatal visit (unless normal Pap within 1 year)
 Abnormal cervical cytology: colposcopy with biopsy of
suspicious lesions
 Cytobrush sampling can be done; endocervical curettage
should not be done
 ASC-US: manage as in nonpregnant women, except
may defer colposcopy until ≥6 weeks postpartum
 CIN: treatment not recommended during pregnancy,
unless invasive disease; reevaluate with cytology
and colposcopy after 6 weeks postpartum
 Vaginal delivery appropriate, if no contraindications
161
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HPV Disease: Considerations in
Pregnancy (4)
 Suspected cervical cancer: refer to
gynecological oncologist for definitive
diagnosis, treatment, delivery plan
 AIN: effects of treatment on pregnancy are
not known
 Most experts recommend deferral of diagnosis
and treatment until after delivery, unless strong
suspicion of anal cancer
162
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HPV Disease: Considerations in
Pregnancy (5)
 HPV vaccines: not recommended during
pregnancy, though available data do not
show negative effect on pregnancy
outcomes
163
May 2013
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Viral Infections
Hepatitis C Virus
HCV Disease: Epidemiology
 HCV disease is a leading non-AIDS cause of death
in HIV-infected persons
 20-30% of HIV-infected U.S. patients have HCV
coinfection
 HCV is a single-stranded RNA virus
 7 genotypes
 Genotype 1: ~75% of HCV infections in United States; ~90% of
HCV infections in U.S. blacks
165
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HCV Disease: Epidemiology (2)
 Transmission: percutaneous exposure, sexual
exposure, perinatal, contaminated blood products
or medical equipment
 Percutaneous transmission:
 HCV is 10 times more infectious than HIV through
percutaneous blood exposures
 Injection drug use is most common risk in the U.S. (via
syringes or injection paraphernalia)
 HCV can survive for weeks in syringes
 Other risks: intranasal cocaine use, tattoo placement
166
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HCV Disease: Epidemiology (3)
 Sexual transmission
 HIV appears to increase risk of sexual transmission of
HCV
 In HIV-infected MSM, multiple outbreaks of acute HCV
 Risk factors: unprotected receptive anal sex, sex toys,
recreational drug use, concurrent STD
 In HIV-uninfected MSM, HCV transmission inefficient
 Heterosexual transmission uncommon; increased risk if
partner is HIV/HCV coinfected
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HCV Disease: Epidemiology (4)
 Perinatal transmission
 HIV appears to increase transmission risk
 HCV incidence:
 1-3% if HCV-infected mothers had detectable plasma HCV
 4-7% if mothers had detectable plasma HCV RNA
 10-20% if mothers had HIV/HCV coinfection
168
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HCV Disease: Epidemiology (5)
 HIV infection speeds progression of HCV to
cirrhosis, especially if CD4 count is <200 cells/µL
 HIV speeds progression from cirrhosis to endstage liver disease (ESLD) and hepatocellular
carcinoma (HCC)
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HCV Disease: Clinical Manifestations
Acute hepatitis C:
 Usually asymptomatic or mildly symptomatic;
usually not recognized
 <20% have symptoms of acute hepatitis (eg,
fever, right upper quadrant pain, nausea,
vomiting, anorexia, jaundice)
 Liver transaminases may be elevated
 Recognizing possible acute HCV is important, given
greater efficacy of treatment in early HCV
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HCV Disease: Clinical Manifestations (2)
Chronic hepatitis C:
 Often asymptomatic
 Fatigue is common
 With progression, stigmata of portal
hypertension (eg, spider angiomata, temporal
wasting, splenomegaly, caput medusa, ascites,
jaundice, pruritus, encephalopathy)
 May see skin abnormalities (leukocytoclastic
vasculitis, porphyria cutanea tarda), renal
disease
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HCV Disease: Diagnosis
 Screen all HIV-infected patients for HCV at
entry into care: sensitive immunoassay
 For at-risk HCV uninfected, retest annually or as
indicated by risk exposure
 To confirm infection: HCV RNA by sensitive
quantitative assay
 HCV RNA does not correlate with HCV disease;
should not be monitored serially unless on HCV
treatment
 HCV RNA correlated with likelihood of response to
HCV treatment
172
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HCV Disease: Diagnosis (2)
 False-negative HCV antibody results are possible
in HIV- infected persons with advanced
immunosuppression (<1%)
 Negative HCV antibody result can occur during
acute infection
 Window period before seroconversion is 2-12 weeks
 Test for HCV RNA if risk of HCV, high ALT, but negative
or indeterminate serologic test
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HCV Disease: Preventing Exposure
 Encourage injection drug users to enter substance
abuse treatment program
 Advise IDUs not to share needles or drug
preparation equipment if unable to stop using
 Needle exchange may facilitate access to sterile
equipment
 Inform patients of risks associated with nonsterile
body piercing, tattooing
 Encourage safer sex, especially condom use, to
reduce sexual transmission of HCV
174
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HCV Disease: Preventing Disease
 No vaccine or recommended postexposure
prophylaxis
 After acute HCV, treatment within 6-12 months
may prevent chronic infection; high rates of HCV
clearance
 Acutely infected patients should be offered treatment,
unless contraindications
 Peginterferon (PegIFN) +/– ribavirin (RBV)
 Some experts recommend observation for ~3-6
months to see if HCV will clear spontaneously
175
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HCV Disease: Preventing Disease
Prevent liver damage:
 Avoid alcohol consumption
 Avoid hepatotoxins; limit acetaminophen intake
(<2 g/day)
 Avoid iron supplementation unless iron
deficiency
 Vaccinate against HAV, HBV if nonimmune
 If cirrhosis, consult with specialist
 Serial screening for HCC:
 Optimal strategy unknown; some recommend ultrasound
every 6-12 months
 AFP has poor specificity and sensitivity; should not be used
as the only screening method
176
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HCV Disease: Preventing Disease (2)
 Liver transplant is not absolutely contraindicated in
HIV/HCV coinfection
 May refer coinfected patients with well-controlled HIV
and liver decompensation or early HCC
 ART associated with reduced risk of liver disease
progression
 Treat with ART in accordance with usual ART guidelines
 Dosage adjustment of some ARVs may be needed for
patients with decompensated cirrhosis
177
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HCV Disease: Treatment
 Goals of treatment, therapy regimens, and
monitoring parameters generally are the same
for HIV/HCV-coinfected patients as for HCV
monoinfected
 HCV treatment is evolving rapidly and a
number of new drugs are expected within the
next few years
 See most recent HCV treatment guidelines
(http://www.hcvguidelines.org) for current
recommendations
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HCV Disease: Preventing Recurrence
 No protective immunity after infection; reinfection
possible if new exposure to HCV (eg, via injection
drug use or unprotected sex)
 Patients who achieve SVR should be counseled
to avoid reinfection
 Methods that prevent sexual transmission of HIV
should prevent sexual transmission of HCV
179
May 2013
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HCV Disease: Considerations in
Pregnancy
 All HIV-infected pregnant women should be
tested for HCV
 Evaluation, including liver biopsy, can be
delayed ≥3 months after delivery
(pregnancy-related changes in HCV activity
should resolve)
 Hepatitis A and hepatitis B vaccination can
be given; should be given if not immune
180
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HCV Disease: Considerations
in Pregnancy (2)
 HCV treatment with PegIFN and ribavirin is
contraindicated during pregnancy
 IFN: has antigrowth and antiproliferative effects; is
abortifacient in monkeys
 Ribavirin: FDA category X; teratogenic at low dosages
in many animal species
 Both women and men must be counseled about risks and
need for consistent and effective contraception during
ribavirin therapy and for 6 months after completion of therapy
 BOC, TPV: pregnancy category B, but must be used
with IFN and ribavirin, which are contraindicated
181
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HCV Disease: Considerations in
Pregnancy (3)
 Perinatal HCV transmission: higher risk for HIVcoinfected women
 Limited data on efficacy of medical or surgical
preventive measures
 Cesarean delivery does not decrease risk of perinatal
HCV transmission, and may increase risk of maternal
morbidity in HIV-infected women
 Cesarean delivery in HIV/HCV-coinfected women can
be considered based on HIV-related indications; data
insufficient to support routine use for prevention of HCV
transmission
182
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Viral Infections
Hepatitis B Virus
Hepatitis B Virus Disease:
Epidemiology
 HBV is leading cause of chronic liver disease
worldwide
 Approximately 10% of HIV-infected patients had
chronic HBV infection (globally and in North
America)
 In low-prevalence countries, transmitted primarily
through sexual contact and injection drug use
 More efficient transmission than HIV-1
 In higher-prevalence countries, perinatal
transmission is most common
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Hepatitis B Virus Disease:
Epidemiology (2)
 HIV infection increases risk of chronic hepatitis
B after HBV exposure
 HIV/HBV-coinfected patients have higher HBV
DNA levels, greater likelihood of HBe
antigenemia, and increased risk of liver-related
morbidity and mortality
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HBV Disease: Epidemiology (3)
 Incubation period
 Exposure to onset of jaundice: 90 days (range 60150 days)
 Exposure to onset of abnormal liver enzymes: 60
days (range 40-90 days)
 Genotypes A-H; GT A is most common in North
America and Western Europe
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HBV Disease: Clinical Manifestations
 Acute hepatitis B:
 May be asymptomatic
 Symptoms may include RUQ abdominal pain,
nausea, vomiting, fever, arthralgias, jaundice
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HBV Disease: Clinical Manifestations (2)
 Chronic hepatitis B:
 Most have no symptoms or nonspecific
symptoms (eg, fatigue) until development of
cirrhosis and signs of portal hypertension (eg,
ascites, variceal bleeding, coagulopathy,
jaundice, hepatic encephalopathy)
 Hepatocellular carcinoma (HCC) is
asymptomatic in early stages
 Other manifestations: polyarteritis nodosa,
glomerulonephritis, vasculitis
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HBV Disease: Diagnosis
 All HIV-infected persons should be tested for
HBV
 Test for HBsAg, HBcAb, and HBsAb
 HBsAb can be detected 4 weeks (range 1-9 weeks)
after exposure anti-HBc IgM usually detectable at
onset of symptoms
 Chronic hepatitis B: HBsAg detected on 2
occasions ≥6 months apart
 Test for HBeAg, anti-HBe, HBV DNA
 HBV DNA and ALT elevation distinguish active from
inactive HBV
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HBV Disease: Diagnosis (2)
 Isolated positive anti-HBc:
 May reflect a false-positive result, distant exposure
with loss of anti-HBs, or “occult” chronic HBV infection
 More common in HIV-infected patients, especially if
underlying HCV infection
 Test for HBV DNA: if positive, treat as chronically
infected, if negative, consider susceptible to HBV and
vaccinate accordingly
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HBV Disease: Diagnosis (3)
Additional evaluation
 To assess severity and progression of disease,
check ALT, AST, albumin, bilirubin, PT, and
CBC at diagnosis and every 6 months
thereafter
 Transient or persistent elevated ALT levels
caused by many factors, including:
 Discontinuation of HBV therapy, resistance to HBV
therapy, before loss of HBeAg, hepatotoxicity from
HIV or other medications, immune reconstitution,
infection with a new hepatitis virus (HAV, HCV,
delta virus [HDV])
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HBV Disease: Diagnosis (4)
Additional evaluation
 Screening for HCC:
 Chronic HBV increases risk of HCC
 Risk and natural history of HBV-related HCC
in HIV-coinfected patents has not been
determined
 Liver imaging recommended every 6 months
if cirrhotic, Asian male > age 40, Asian
female >age 50, sub-Saharan African male
>age 20
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HBV Disease: Diagnosis (5)
Additional evaluation
 Assessment of liver fibrosis:
 Important for guiding when to start screening
for esophageal varices and HCC in cirrhotic
patients
 Liver biopsy or noninvasive methods
 Individualize decisions to perform biopsy, especially
as treatment of both HIV and HBV is recommended
for all coinfected patients, using anti-HBV ARVs in
the ART regimen
 Noninvasive methods (eg, transient elastography,
serum biochemical indices): increasing evidence
and experience in HBV
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HBV Disease: Preventing Exposure
 Counsel all HIV-infected patients about
reducing risk of exposure to HBV
 Emphasize transmission risks of sharing
needles and syringes, tattooing, body
piercing, unprotected sex
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HBV Disease: Preventing Disease
 Vaccinate all HIV-infected patients without
evidence of prior immunity
 Vaccine efficacy higher at CD4 count >350
cells/μL, but do not defer for lower counts
 Decreased response to vaccination in coinfected
patients: check anti-HBs titers 1 month after 3shot series
 If no response, consider revaccination
 Some experts might wait to revaccinate until
sustained CD4 increase with effective ART
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HBV Disease: Preventing Disease (2)
 Optimum vaccination strategy not entirely clear,
especially for patients with advanced
immunosuppression
 Schedule of 4 double-dose vaccines yielded higher
anti-HBs titers in 2 studies, and higher overall response
rate in 1
 In 1 study, increased response rate in patients with
CD4 count >350 cells/µL
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HBV Disease: Preventing Disease (3)
 Vaccination Schedule
 HBV vaccine IM (Engerix-B 20 mcg/mL or Recombivax
HB 20 mcg/mL) at 0,1, and 6 months, or
 HBV vaccine IM (Engerix-B 40 mcg/mL or Recombivax
HB 20 mcg/mL) at 0, 1, 2, and 6 months, or
 Combined HAV and HBV vaccine (Twinrix) 1 mL as 3dose series at 0,1, and 6 months or as 4-dose series at
days 0, 7, and 21, and at 12 months
 Vaccine non-responders
 Revaccinate with 2nd vaccine series
 If low CD4 count at time of first series, consider
revaccination until sustained increase in CD4 with ART
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HBV Disease: Preventing Disease (4)
 HAV-susceptible HIV-infected patients should
receive HAV vaccine
 Check HAV IgG 1 month after vaccination; if negative,
revaccinate when CD4 >200 cells/µL
 All HBV patients should avoid alcohol
consumption
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HBV Disease: Treatment
 Goals of anti-HBV therapy: reduce morbidity and
mortality
 Treatment indicated for all with HIV/HBV
coinfection, regardless of CD4 count or HBV
treatment status
 Treat with ART that includes 2 drugs active
against both HIV and HBV (ie, tenofovir plus
emtricitabine or lamivudine)
 Regimen should fully suppress both HIV and
HBV
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HBV Disease: Treatment (2)
 Most drugs active against HBV are also active
against HIV: lamivudine, emtricitabine,
tenofovir, entecavir, probably telbivudine,
adefovir (at full dose)
 HIV may develop resistance to these agents if
they are not coadministered in fully suppressive
ART regimens
 Avoid HBV monotherapy with emtricitabine or
lamivudine – high rates of HBV resistance
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HBV Disease: Treatment (3)
 Preferred
 ART regimen should include tenofovir 300 mg PO
QD + [emtricitabine 200 mg PO QD or lamivudine
300 mg PO QD] or 2 other drugs active against HBV
(+ additional therapy active against HIV)
 Continue treatment indefinitely
 Alternative
 If patients do not want ART or are unable to take it:
 Treatment indicated when presence of active liver disease,
elevated transaminases, and HBV DNA >2,000 IU/mL, or
significant fibrosis
 Peginterferon-alfa 2a or 2b for 48 weeks
 If tenofovir cannot be used:
 Fully suppressive ART regimen (without tenofovir), plus
entecavir
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HBV Disease: Treatment (4)
 When changing ART, continue agents active
against HBV to avoid HBV flare, IRIS
 If anti-HBV therapy is discontinued and disease
flares, reintroducing anti-HBV therapy can be
life-saving
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HBV Disease: Treatment (5)
 HBV/HCV/HIV triple infection:
 Faster progression of liver fibrosis, higher
risk of HCC, increased mortality
 Try to treat both hepatitis viruses, if feasible
 Include anti-HBV therapy with ART;
introduce HCV therapy as needed
 If ART is not desired, consider treatment
with interferon-alfa-based therapy for both
HBV and HCV
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HBV Disease: Starting ART
 ART strongly recommended for all with
HIV/HBV coinfection, regardless of ART
 ART that includes agents with activity against
both viruses is recommended
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HBV Disease: Monitoring
Monitoring treatment response:
 HBV DNA every 12 weeks
 Complete virologic response: undetectable HBV
DNA at 24-48 weeks
 Nonresponse: <1 log10 copies/mL decrease in
HBV DNA at 12 weeks
 Sustained virologic response: undetectable HBV
DNA 6 months after stopping therapy
 HBeAg every 6 months (if HBeAg positive)
 HBeAg loss, development of HBeAb (uncommon)
 Liver histology, transaminases
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HBV Disease: Adverse Events
 Tenofovir
 Renal toxicity; more frequent if underlying renal
disease or prolonged treatment
 Check electrolytes and serum creatinine at
baseline and every 3-6 months; urinalysis every 6
months
 Change to alternative therapy if renal toxicity
occurs
 Dosage adjustment required if used in patients
with baseline renal insufficiency
 Entecavir
 Lactic acidosis reported in patients with cirrhosis
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HBV Disease: Adverse Events (2)
 Telbivudine
 CPK elevations and myopathy reported; check CPK
at baseline and every 3-6 months, and if symptoms
occur
 Discontinue if CPK elevation
 Adefovir
 Renal tubular disease at higher dosages;
uncommon at HBV treatment dosage
 Interferon-alfa
 “Flulike” symptoms (fever, myalgia, headache,
fatigue), depression (may be severe), cognitive
dysfunction, cytopenias including CD4 decrease,
retinopathy, neuropathy, autoimmune disorders,
hypo- or hyperthyroidism (monitor TSH)
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HBV Disease: Adverse Events (3)
Discontinuation flares
 Discontinuation of nucleos(t)ide analogues
active against HBV (eg, lamivudine, adefovir,
tenofovir, or emtricitabine) associated with
HBV flare in ~30% of cases; may cause
decompensation
 If anti-HBV therapy is discontinued, monitor
transaminases every 6 weeks for 3 months,
then every 3 months
 In case of flare, reinstitute HBV treatment
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HBV Disease: IRIS
 Immune reconstitution in HIV/HBV-coinfected
patients can cause rise in transaminases and
symptoms of acute hepatitis flare, usually in first
6-12 weeks after starting ART
 Monitor transaminases monthly for first 3-6
months, then every 3 months
 Flares can be deadly; treat HBV when treating
HIV
 Continue anti-HBV drugs to prevent flares when
switching to ART regimens not containing
lamivudine, emtricitabine, or tenofovir
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HBV Disease: IRIS (2)
 If severe flare or suspected HBV drug resistance,
consult with hepatologist
 Distinguishing IRIS and other causes of
transaminase elevation (eg, hepatotoxicity, acute
HCV or HAV, HBV drug resistance, HBeAg
seroconversion) is difficult
 Test HBV DNA, HBeAg, HIV RNA, CD4
 Consider liver histology
 Test for other viral hepatitis as appropriate (hepatitis A,
C, D, E)
 Review medication list
 Review drug and alcohol use
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HBV Disease: IRIS (3)
 Hepatotoxicity is associated with all classes of
ARVs, but is uncommon
 Discontinuation of ART usually not necessary unless
symptoms of hypersensitivity are present (fever,
lymphadenopathy, rash), symptomatic hepatitis, or
transaminase elevations >10 times upper limit of
normal
 Jaundice is associated with severe morbidity and
mortality: discontinue offending drug(s)
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HBV Disease: Treatment Failure
 Treatment failure on nucleos(t)ide analogues:
<1 log10 copies/mL decrease in HBV DNA at
12 weeks in adherent patient, or increase in
HBV DNA >1 log10 above nadir
 Usually attributable to drug resistant HBV;
change in treatment is needed
 Many experts suggest HBV resistance testing
 May help distinguish noncompliance and resistance,
evaluate patients with unclear treatment history,
assess different adefovir resistance pathways, and
predict level of resistance to entecavir
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HBV Disease: Treatment Failure (2)
 HBV monotherapy should not be used: risk of
resistance mutations to both HBV and HIV
 Lamivudine resistance:
 ~20% per year in HIV/HBV patients treated with
lamivudine alone
 Cross-resistance to emtricitabine, telbivudine,
perhaps entecavir
 If lamivudine-resistant HBV is suspected or
documented, add tenofovir to lamivudine
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HBV Disease: Treatment Failure (3)
 Treatment failure with tenofovir:
 Consider entecavir (especially if experienced with
lamivudine or emtricitabine)
 In vivo resistance to tenofovir not yet reported
 Treatment failure with entecavir:
 Cross-resistance with lamivudine, emtricitabine,
telbivudine
 Replace entecavir with tenofovir (+/– emtricitabine)
 Failure of response to pegylated interferonalfa:
 Nucleos(t)ide analogues
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HBV Disease: Treatment Failure (4)
 HBV DNA may decline slowly over
months/years (especially when high before
treatment)
 Patients on adefovir or L-nucleosides with <2
log10 copies/mL decrease in HBV DNA should
be switched to more potent regimen (eg,
tenofovir + emtricitabine or entecavir) because
of risk of resistance
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HBV Disease: Treatment Failure (5)
 ESLD management as in HIV-uninfected
patients
 Refer to hepatologist
 IFN contraindicated
 Nucleos(t)ide analogues safe and effective
 HCC screening:
 Imaging every 6-12 months if cirrhosis (ultrasound,
CT, MRI, depending on expertise of the imaging
center and whether patient has cirrhosis)
 Liver transplantation
 Not contraindicated in HIV infection, if on effective
ART
 HBV treatment is needed after transplant
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HBV Disease: Preventing Recurrence
 Most patients should continue HBV therapy
(except interferon) indefinitely
 Relapses may occur on therapy, particularly if CD4
count is low
 Hepatitis flare may occur if treatment is stopped
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HBV Disease: Considerations in Pregnancy
 All pregnant women should be screened for
HBsAg, HBcAb, and HBsAb and vaccinated
against HBV if sAg negative and sAb negative
 Hepatitis A vaccination can be given
 Acute HBV: treatment is supportive (including
maintaining normal blood glucose levels and
clotting status); higher risk of preterm labor
and delivery
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HBV Disease: Considerations in Pregnancy (2)
 Perinatal HBV transmission (including failure of
prophylaxis) correlated with high maternal HBV
DNA levels
 ART including HBV-active drugs recommended
for all coinfected pregnant women
 Drugs with anti-HBV activity will lower HBV levels and
may decrease risk that HBV immune globulin and
vaccine will fail to prevent perinatal HBV transmission
 HBV treatment may lower risk of IRIS-related HBV
flare on ART
 Indefinite treatment is recommended; if ARVs are
discontinued postpartum, monitor LFTs frequently
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HBV Disease: Considerations in Pregnancy (3)
 Tenofovir/emtricitabine or tenofovir/lamivudine is
recommended as NRTI backbone for ART in
pregnant HIV/HBV-coinfected women
 More experience in pregnancy with lamivudine
 Entecavir, adefovir, telbivudine: not teratogenic
in animals; limited experience in human
pregnancy
 Consider whether other options are inappropriate; use
only with a fully suppressive ARV regimen
 Interferon should not be use during pregnancy:
antigrowth and antiproliferative effects
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HBV Disease: Considerations in Pregnancy (4)
 Infants born to HBsAg+ women: hepatitis B
immune globulin and hepatitis B vaccine within
12 hours of birth
 2nd and 3rd doses of vaccine at 1 and 6 months
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Websites to Access the Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
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About This Slide Set
 This presentation was prepared by Susa Coffey,
MD, for the AETC National Resource Center in
July 2013
 See the AETC NRC website for the most current
version of this presentation:
http://www.aidsetc.org
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