Transcript Adult OI Guidelines Slides - Viral

Guidelines for Prevention and Treatment of Opportunistic
Infections in HIV-Infected Adults and Adolescents
Viral Infections Slide Set
Prepared by the AETC National Coordinating 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. Certain sections
have been updated to reflect changes in the published
guidelines.
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field of HIV care, this information could become out of date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 Coordinating Resource Center
http://www.aidsetc.org
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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Cytomegalovirus (CMV) Disease
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
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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
www.aidsetc.org
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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
www.aidsetc.org
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CMV Disease: Clinical Manifestations
 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
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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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
www.aidsetc.org
Credit: P. Volberding, MD; UCSF
Center for HIV Information
Image Library
May
2015
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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
www.aidsetc.org
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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
www.aidsetc.org
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CMV Disease: Clinical Manifestations (8)
Neurologic disease
 Dementia: lethargy, confusion, fever, but may mimic HIV1 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 Guillian-Barré
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
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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CMV Disease: Diagnosis (3)
 Pneumonitis:
 Neurologic disease:
interstitial infiltrates +
compatible clinical
presentation + multiple
CMV inclusion bodies in
lung tissue, and absence
of other likely pathogens
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)
www.aidsetc.org
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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
www.aidsetc.org
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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
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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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
www.aidsetc.org
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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 post-infusion hydration and probenecid)
(avoid in patients with sulfa allergy)
www.aidsetc.org
May 2015
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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 treatmentlimiting 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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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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 endorgan disease
 Use clinical judgment in case of neurologic disease
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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CMV Disease: Treatment Failure (2)
 Treatment options for first relapse:
 Reinduction with the same drug, followed by maintenance
therapy
 Ganciclovir + foscarnet: superior to monotherapy but greater
toxicity
 Changing to alternative drug at first relapse: usually not
more effective, unless drug resistance or significant side
effects
www.aidsetc.org
May 2015
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CMV Disease: Treatment Failure (3)
 Later relapse: often owing to drug resistance
 Resistance occurs in long-term therapy
(about 25% by 1 year of therapy, lower since widespread
use of ART)
 Similar rates for ganciclovir, foscarnet, cidofovir
 Consider resistance testing (blood sample)
 >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
www.aidsetc.org
May 2015
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CMV Disease: Treatment Failure (4)
 High-level ganciclovir resistance:
 Switch to alternative therapy
 Usually also resistant to cidofovir, sometimes
to foscarnet
 Consider series of intravitreal foscarnet injections
and/or systemic therapy
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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 pre- and postinfusion hydration and probenecid) (avoid in patients with
sulfa allergy)
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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Herpes Simplex Virus Disease
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Disease
Treatment
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
Credit: © I-TECH
May 2015
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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
www.aidsetc.org
Credit: HIV Web Study,
www.hivwebstudy.org; © 2006
University of Washington
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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)
www.aidsetc.org
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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 HSV-2 in all HIVinfected patients
 If infected with HSV-2: counsel about risk of transmission
to sex partners, means of preventing transmission
www.aidsetc.org
May 2015
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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)
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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HSV Disease: Treatment Failure
 Lesions should begin to resolve within 7-10 days of
therapy initiation
 Suspect drug resistance if no improvement
 Culture lesion, perform susceptibility testing
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
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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
www.aidsetc.org
May 2015
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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 HIVuninfected women; reduces need for cesarean delivery;
likely to have similar efficacy in HIV-infected women
 Efficacy in reducing incidence of neonatal herpes is
unknown
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
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Varicella-Zoster Virus
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Exposure & Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
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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
www.aidsetc.org
May 2015
68
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
Credit: HIV Web Study © 2006, U. of Washington
www.aidsetc.org
May 2015
69
VZV Disease: Clinical Manifestations (2)
 Varicella: chickenpox
 Illness may be severe in HIV infection
 Visceral dissemination, especially VZV pneumonitis, may
occur
www.aidsetc.org
May 2015
70
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
www.aidsetc.org
Credit: © I-TECH
May 2015
71
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 HIV-infected 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
www.aidsetc.org
May 2015
72
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
www.aidsetc.org
May 2015
73
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
www.aidsetc.org
May 2015
74
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)
www.aidsetc.org
May 2015
75
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 HIVinfected persons should be vaccinated
www.aidsetc.org
May 2015
76
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
www.aidsetc.org
May 2015
77
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
www.aidsetc.org
May 2015
78
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
www.aidsetc.org
May 2015
79
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
www.aidsetc.org
May 2015
80
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)
www.aidsetc.org
May 2015
81
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)
www.aidsetc.org
May 2015
82
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
www.aidsetc.org
May 2015
83
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
www.aidsetc.org
May 2015
84
VZV Disease: Starting ART
 Strongly consider ART initiation in patients with multiple
recurrences of herpes zoster or a complication of VZV
disease
www.aidsetc.org
May 2015
85
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
www.aidsetc.org
May 2015
86
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)
www.aidsetc.org
May 2015
87
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
www.aidsetc.org
May 2015
88
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
www.aidsetc.org
May 2015
89
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
www.aidsetc.org
May 2015
90
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
www.aidsetc.org
May 2015
91
Human Herpesvirus-8 Disease
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





Epidemiology
Clinical Manifestations
Diagnosis
Prevention
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
92
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 (20-77%)
 Higher in some Mediterranean countries (10-20%) and parts
of sub-Saharan Africa (30-80%)
www.aidsetc.org
May 2015
93
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
www.aidsetc.org
May 2015
94
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
www.aidsetc.org
May 2015
95
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
www.aidsetc.org
May 2015
96
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
www.aidsetc.org
May 2015
97
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
www.aidsetc.org
May 2015
98
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
www.aidsetc.org
May 2015
99
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
www.aidsetc.org
May 2015
100
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
www.aidsetc.org
May 2015
101
HHV-8 Disease: Preventing
Recurrence
 ART recommended for all with HHV-8 disease
 May prevent KS progression or recurrence
www.aidsetc.org
May 2015
102
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
www.aidsetc.org
May 2015
103
Progressive Multifocal
Leukoencephalopathy

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




Epidemiology
Clinical Manifestations
Diagnosis
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
104
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
www.aidsetc.org
May 2015
105
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 immuno-compromised
persons
 Reported in persons treated with immunomodulatory
humanized antibodies (eg, natalizumab, efalizumab,
infliximab, rituximab)
www.aidsetc.org
May 2015
106
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
www.aidsetc.org
May 2015
107
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
www.aidsetc.org
May 2015
108
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
www.aidsetc.org
May 2015
109
PML: Diagnosis (3)
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)
www.aidsetc.org
May 2015
110
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, lipid-laden macrophages
 Serologic testing generally not useful, but
newer approaches under investigation
www.aidsetc.org
May 2015
111
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
www.aidsetc.org
May 2015
112
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
www.aidsetc.org
May 2015
113
PML: Treatment (2)
 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
www.aidsetc.org
May 2015
114
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
www.aidsetc.org
May 2015
115
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
www.aidsetc.org
May 2015
116
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
www.aidsetc.org
May 2015
117
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
www.aidsetc.org
May 2015
118
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”)
www.aidsetc.org
May 2015
119
PML: Preventing Recurrence
 Effective ART regimen
www.aidsetc.org
May 2015
120
PML: Considerations in Pregnancy
 Diagnosis as in nonpregnant adults
 Treatment: optimal ART
www.aidsetc.org
May 2015
121
Human Papillomavirus
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Epidemiology
Clinical Manifestations & Diagnosis
Preventing Infection
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
122
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
www.aidsetc.org
May 2015
123
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 10-15% of cervical cancers
 Types 6 and 11 associated with 90% of genital warts
www.aidsetc.org
May 2015
124
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
www.aidsetc.org
May 2015
125
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
www.aidsetc.org
May 2015
126
HPV Disease: Epidemiology (5)
 Genital and anal warts:
 Incidence and prevalence are higher in HIV-infected
patients
www.aidsetc.org
May 2015
127
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
www.aidsetc.org
May 2015
128
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
www.aidsetc.org
May 2015
129
HPV Disease: Clinical Manifestations
and Diagnosis
Condyloma acuminata, perianal
Credit: P. Volberding, MD; UCSF Center
for HIV Information Image Library
www.aidsetc.org
 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
May 2015
130
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
www.aidsetc.org
May 2015
131
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
www.aidsetc.org
May 2015
132
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
www.aidsetc.org
May 2015
133
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
www.aidsetc.org
May 2015
134
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 HIVinfected boys aged 9-12 years
 Also recommended for HIV-infected males aged 13-26
years
www.aidsetc.org
May 2015
135
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
www.aidsetc.org
May 2015
136
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
www.aidsetc.org
May 2015
137
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
www.aidsetc.org
May 2015
138
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
www.aidsetc.org
May 2015
139
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
www.aidsetc.org
May 2015
140
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
www.aidsetc.org
May 2015
141
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
www.aidsetc.org
May 2015
142
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
www.aidsetc.org
May 2015
143
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
www.aidsetc.org
May 2015
144
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
www.aidsetc.org
May 2015
145
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
www.aidsetc.org
May 2015
146
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
www.aidsetc.org
May 2015
147
HPV Disease: Treatment – CIN and
Cervical Cancer
 Manage with a specialist
 Follow ASCCP guidelines, in general
www.aidsetc.org
May 2015
148
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 HIV-infected
women
www.aidsetc.org
May 2015
149
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
www.aidsetc.org
May 2015
150
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
www.aidsetc.org
May 2015
151
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 HIVinfected 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
www.aidsetc.org
May 2015
152
HPV Disease: Treatment – Other
HPV-Associated Cancers
 HPV-associated penile and oropharyngeal cancers: as in
HIV-uninfected patients
 Prognosis may be better with HPV-associated
oropharyngeal cancers than with non-HPV-associated
www.aidsetc.org
May 2015
153
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
www.aidsetc.org
May 2015
154
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
www.aidsetc.org
May 2015
155
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
www.aidsetc.org
May 2015
156
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
www.aidsetc.org
May 2015
157
HPV Disease: Preventing Recurrence
 Monitoring after therapy:
 CIN: follow ASCCP guidelines
 For high-grade CIN, low-dose intravaginal 5-FU reduced shortterm 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
www.aidsetc.org
May 2015
158
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
www.aidsetc.org
May 2015
159
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)
www.aidsetc.org
May 2015
160
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
www.aidsetc.org
May 2015
161
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
www.aidsetc.org
May 2015
162
HPV Disease: Considerations in
Pregnancy (5)
 HPV vaccines: not recommended during pregnancy,
though available data do not show negative effect on
pregnancy outcomes
www.aidsetc.org
May 2015
163
Hepatitis C Virus
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Exposure
Preventing Disease
Treatment
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
164
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
www.aidsetc.org
May 2015
165
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
www.aidsetc.org
www.aidsetc.org
May 2015
166
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
www.aidsetc.org
May 2015
167
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
www.aidsetc.org
May 2015
168
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 end-stage liver
disease (ESLD) and hepatocellular carcinoma (HCC)
www.aidsetc.org
May 2015
169
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
www.aidsetc.org
May 2015
170
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
www.aidsetc.org
May 2015
171
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
www.aidsetc.org
May 2015
172
HCV Disease: Diagnosis (2)
 False-negative HCV antibody results are possible in HIVinfected 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
www.aidsetc.org
May 2015
173
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
www.aidsetc.org
May 2015
174
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
www.aidsetc.org
May 2015
175
HCV Disease: Preventing Disease (2)
 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
www.aidsetc.org
May 2015
176
HCV Disease: Preventing Disease (3)
 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
www.aidsetc.org
May 2015
177
HCV Disease: Treatment
 Goals of treatment, therapy regimens, and monitoring
parameters generally are the same for HIV/HCVcoinfected patients as for HCV monoinfected
 HCV treatment is evolving rapidly and a number of new
drugs are now available, with more expected within the
next few years
 See most recent HCV treatment guidelines
(http://www.hcvguidelines.org) for current
recommendations
www.aidsetc.org
May 2015
178
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
www.aidsetc.org
May 2015
179
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
www.aidsetc.org
May 2015
180
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
www.aidsetc.org
May 2015
181
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
www.aidsetc.org
May 2015
182
Hepatitis B Virus
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Exposure
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
www.aidsetc.org
May 2015
183
HBV 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
www.aidsetc.org
May 2015
184
HBV 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
www.aidsetc.org
May 2015
185
HBV Disease: Epidemiology (3)
 Incubation period
 Exposure to onset of jaundice: 90 days (range 60-150 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
www.aidsetc.org
May 2015
186
HBV Disease: Clinical Manifestations
 Acute hepatitis B:
 May be asymptomatic
 Symptoms may include RUQ abdominal pain, nausea,
vomiting, fever, arthralgias, jaundice
www.aidsetc.org
May 2015
187
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
www.aidsetc.org
May 2015
188
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
www.aidsetc.org
May 2015
189
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
www.aidsetc.org
May 2015
190
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])
www.aidsetc.org
May 2015
191
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
www.aidsetc.org
May 2015
192
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
www.aidsetc.org
May 2015
193
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
www.aidsetc.org
May 2015
194
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 3-shot series
 If no response, consider revaccination
 Some experts might wait to revaccinate until sustained
CD4 increase with effective ART
www.aidsetc.org
May 2015
195
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
www.aidsetc.org
May 2015
196
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 3-dose
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-alfabased 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, hypoor 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 interferon- alfa:
 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
and updated in May 2015.
 See the AETC NRC website for the most current
version of this presentation:
http://www.aidsetc.org
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