Guidelines for Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents Viral Infections Slide Set 2 May 2015 wwwaidsetcorg These slides were developed using recommendations published in July 2013 The intended audience is clinicians involved in the care of ID: 700797
Download Presentation The PPT/PDF document "Prepared by the AETC National Coordinati..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
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
Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Viral Infections Slide SetSlide2
2
May 2015
www.aidsetc.org
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Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 Centerhttp://www.aidsetc.org
About This PresentationSlide3
3
May 2015
www.aidsetc.org
Cytomegalovirus
Herpes Simplex Virus
Varicella-Zoster Virus
Human Herpesvirus-8
Progressive Multifocal Leukoencephalopathy
Human Papillomavirus
Hepatitis C
Hepatitis B
Viral InfectionsSlide4
4
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
Cytomegalovirus (CMV) DiseaseSlide5
5
May 2015
www.aidsetc.org
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 infectionCMV Disease: EpidemiologySlide6
6
May 2015
www.aidsetc.org
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 neededCMV Disease: Epidemiology (2)Slide7
7
May 2015
www.aidsetc.org
Retinitis
Colitis,
cholangiopathyEsophagitisPneumonitisNeurologic diseaseCMV Disease: Clinical ManifestationsSlide8
8
May 2015
www.aidsetc.org
Retinitis
Most common CMV end-organ disease
Usually unilateral; if untreated, is likely to progress to involve both eyesSymptoms: If peripheral: floaters, scotomata, visual field defects, or may be asymptomaticIf central or macular: decreased visual acuity, central field defectsCMV Disease: Clinical Manifestations (2)Slide9
9
May 2015
www.aidsetc.org
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 blindnessCMV Disease: Clinical Manifestations (3)Slide10
10
May 2015
www.aidsetc.org
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
InitiativeSlide11
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 threateningCT may show colonic thickening
11
May 2015
www.aidsetc.org
Credit: P. Volberding, MD; UCSF Center for HIV Information Image LibrarySlide12
CMV Disease: Clinical Manifestations (6)
Esophagitis
Infrequent in persons with CMV end-organ disease
Odynophagia, nausea, mid-epigastric or retrosternal discomfort, fever
12
May 2015
www.aidsetc.org
Credit: P. Volberding, MD;
UCSF Center
for HIV
Information Image LibrarySlide13
13
May 2015
www.aidsetc.org
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, hypoxemiaCXR: interstitial infiltratesCMV Disease: Clinical Manifestations (7)Slide14
14
May 2015
www.aidsetc.org
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 deathCT or MRI: periventricular enhancement
CMV Disease: Clinical Manifestations (8)Slide15
15
May 2015
www.aidsetc.org
Neurologic disease
Polyradiculomyelopathy
: resembles Guillian-Barré syndromeUrinary retention, progressive bilateral leg weakness; progresses over weeks to loss of bowel and bladder control, flaccid paraplegiaSpastic myelopathy, sacral paresthesia possibleCSF: neutrophilic pleocytosis
, low glucose, elevated protein
CMV Disease: Clinical Manifestations (9)Slide16
16
May 2015
www.aidsetc.org
Blood tests (
eg
, PCR, antigen assays, blood culture) not recommended for diagnosis of CMV end-organ disease: poor positive and negative predictive valueCMV viremia usually present in end-organ disease but may be present in absence of end-organ diseaseAntibody levels not useful, though negative IgG indicates CMV unlikelyCMV Disease: DiagnosisSlide17
17
May 2015
www.aidsetc.org
Retinitis
: characteristic retinal changes on
funduscopy (by experienced ophthalmologist); PCR of vitreous helpful if exam not diagnosticColitis: mucosal ulcerations on endoscopy + biopsy with characteristic intranuclear and intracytoplasmic inclusionsEsophagitis: 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
CMV Disease: Diagnosis (2)Slide18
18
May 2015
www.aidsetc.org
Neurologic disease
:
clinical syndrome + CMV in CSF or brain tissue; detection enhanced by PCRPneumonitis: interstitial infiltrates + compatible clinical presentation + multiple CMV inclusion bodies in lung tissue, and absence of other likely pathogens
CMV Disease: Diagnosis (3)
Brain biopsy with CMV inclusions
Credit: Images courtesy of AIDS
Images Library
(www.aids-images.ch)Slide19
19
May 2015
www.aidsetc.org
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 IgGCounsel 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 productsCMV Disease: Preventing ExposureSlide20
20
May 2015
www.aidsetc.org
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 progressionPatient education: vigilance for increase in floaters, decrease in visual acuitySome specialists recommend annual funduscopic examinations by ophthalmologist if CD4 <50 cells/µL
CMV Disease: Preventing DiseaseSlide21
21
May 2015
www.aidsetc.org
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 diseaseInitial anti-CMV therapy followed by chronic maintenance therapy Intravitreal therapy provides immediate high intraocular drug levels and perhaps faster control of retinitisSystemic therapy important to prevent disease in contralateral eye and improve survival
CMV Disease: TreatmentSlide22
22
May 2015
www.aidsetc.org
Retinitis
(cont’d)
Several effective treatments: few comparative trials in recent years; no regimen proven to have superior efficacyIndividualize based on location and severity of lesions, level of immunosuppression, other factorsCMV Disease: Treatment (2)Slide23
23
May 2015
www.aidsetc.org
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 daysGanciclovir ocular implant no longer availablePLUS systemic therapy:Preferred systemic therapyValganciclovir
900 mg PO BID for 14-21 days, then QD
CMV Disease: Treatment (3)Slide24
24
May 2015
www.aidsetc.org
Retinitis
(cont’d)
Immediate sight-threatening lesions (cont’d): Alternative systemic therapyGanciclovir 5 mg/kg IV Q12H for 14-21 days, then 5 mg/kg IV QDGanciclovir 5 mg/kg IV Q12H for 14-21 days, then valganciclovir 900 mg PO QDFoscarnet 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)
CMV Disease: Treatment (4)Slide25
25
May 2015
www.aidsetc.org
Retinitis
(cont’d)
Small peripheral lesions: PreferredSystemic antiviral therapy as aboveCMV Disease: Treatment (5)Slide26
26
May 2015
www.aidsetc.org
Colitis, esophagitis
Preferred
Ganciclovir 5 mg/kg IV Q12H, may switch to valganciclovir 900 mg PO Q12H when patient can absorb and tolerate PO therapyAlternativeFoscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H – if treatment-limiting toxicities or resistance to ganciclovirOral 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
CMV Disease: Treatment (6)Slide27
27
May 2015
www.aidsetc.org
Pneumonitis
Treat patients with histologic evidence of CMV pneumonitis
Limited experience: IV ganciclovir or foscarnet is reasonableOral valganciclovir not studiedDuration of therapy not established
CMV Disease: Treatment (7)Slide28
28
May 2015
www.aidsetc.org
Neurologic disease
Treatment not well studied
Initiate treatment promptlyGanciclovir IV + foscarnet IV until symptoms improveCombination treatment preferred as initial therapy, to maximize response, but associated with high rates of adverse effectsDuration of therapy and role of oral valganciclovir not established
CMV Disease: Treatment (8)Slide29
29
May 2015
www.aidsetc.org
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 therapyWeigh 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 diseaseUse clinical judgment in case of neurologic disease
CMV Disease: Starting ARTSlide30
30
May 2015
www.aidsetc.org
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 treatmentCMV Disease: MonitoringSlide31
31
May 2015
www.aidsetc.org
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 lossTreatment: periocular corticosteroids or short course of systemic corticosteroidsCMV Disease: Adverse Events Slide32
32
May 2015
www.aidsetc.org
Ganciclovir
: neutropenia, thrombocytopenia, nausea, diarrhea, renal dysfunction, seizures
Foscarnet: anemia, nephrotoxicity, electrolyte abnormalities, neurologic symptoms including seizuresMonitor CBC, electrolytes, renal function twice weekly during induction therapy, weekly thereafterCMV Disease: Adverse Events (2)Slide33
33
May 2015
www.aidsetc.org
Cidofovir
: nephrotoxicity,
hypotonyCheck renal function, urinalysis before each infusionDo not administer if renal dysfunction or proteinuriaCMV Disease: Adverse Events (3)Slide34
34
May 2015
www.aidsetc.org
Retinitis
: recurrence is likely unless immune reconstitution with ART
Early relapse: usually caused by limited intraocular penetration of systemic treatmentsDrug resistance to ganciclovir, foscarnet, or cidofovir can occurCMV Disease: Treatment FailureSlide35
35
May 2015
www.aidsetc.org
Treatment options for first relapse:
Reinduction
with the same drug, followed by maintenance therapyGanciclovir + foscarnet: superior to monotherapy but greater toxicityChanging to alternative drug at first relapse: usually not more effective, unless drug resistance or significant side effects CMV Disease: Treatment Failure (2)Slide36
36
May 2015
www.aidsetc.org
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, cidofovirConsider resistance testing (blood sample)>90% correlation with virus in eyeCan be done in <48 hoursMost virus with high-level resistance to ganciclovir (UL97 + UL54 mutations) respond to foscarnet
CMV Disease: Treatment Failure (3)Slide37
37
May 2015
www.aidsetc.org
High-level ganciclovir resistance:
Switch to alternative therapy
Usually also resistant to cidofovir, sometimesto foscarnetConsider series of intravitreal foscarnet injectionsand/or systemic therapyCMV Disease: Treatment Failure (4)Slide38
38
May 2015
www.aidsetc.org
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 factorsCMV Disease: Preventing Recurrence Slide39
39
May 2015
www.aidsetc.org
Retinitis
(cont’d):
PreferredValganciclovir 900 mg PO QD AlternativeGanciclovir 5 mg/kg IV 5-7 times weeklyFoscarnet 90-120 mg/kg IV QDCidofovir 5 mg/kg IV every other week (with pre- and post-infusion hydration and probenecid) (avoid in patients with sulfa allergy)
CMV Disease: Preventing Recurrence (2)Slide40
40
May 2015
www.aidsetc.org
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
CMV Disease: Preventing Recurrence (3)Slide41
41
May 2015
www.aidsetc.org
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 monitoringRestart 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 yearCMV Disease: Preventing Recurrence (4)Slide42
42
May 2015
www.aidsetc.org
Diagnosis as in
nonpregnant
womenTreatment:For retinitis, consider retinal implants or intravitreous therapy to limit fetal exposure to systemic antiviralsGanciclovir: teratogenic in animals; limited data in human pregnancy but is treatment of choice during pregnancyNo data on valganciclovir during pregnancy
Monitor for hydrops
fetalis
after 20 weeks of gestation
CMV Disease: Considerations in PregnancySlide43
43
May 2015
www.aidsetc.org
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 pregnancyCMV Disease: Considerations in Pregnancy (2)Slide44
44
May 2015
www.aidsetc.org
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 specialistCMV Disease: Considerations in Pregnancy (3)Slide45
45
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Disease
Treatment
Preventing
Recurrence
Considerations in
PregnancyHerpes Simplex Virus DiseaseSlide46
46
May 2015
www.aidsetc.org
HSV-1:
seroprevalence
60% among adults in the United StatesHSV-2: seroprevalence 17% among persons aged ≥12 years in United States95% of HIV-infected persons are seropositive for either HSV-1 or HSV-2 Most infections are not clinically evidentReactivation occurs intermittently and can result in transmission
Herpes Simplex Virus (HSV) Disease: EpidemiologySlide47
47
May 2015
www.aidsetc.org
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
HSV Disease: Epidemiology (2)Slide48
HSV Disease: Clinical Manifestations
Orolabial
herpes: most common in HSV-1 infection
Local sensory
prodrome
(pain, itching), then papules progressing to vesicles, then ulcers, crustingLasts 5-10 days if untreatedRecurs 1-12 times/year; can be triggered by sunlight, stress48
May 2015
www.aidsetc.org
Credit: © I-TECHSlide49
HSV Disease: Clinical Manifestations (2)
Genital herpes: most common in HSV-2 infection
Prodrome
and lesions similar to
orolabial
lesionsWith mucosal disease, dysuria, vaginal or urethral discharge may be presentPerineal disease: may see inguinal lymphadenopathyLesions may be mild and atypicalIn advanced HIV (CD4 count <100 cells/µL), may see extensive, deep nonhealing ulcerations49
May 2015
www.aidsetc.org
Credit: HIV Web Study, www.hivwebstudy.org; © 2006 University of Washington Slide50
50
May 2015
www.aidsetc.org
Genital HSV-1 episodes indistinguishable from those of genital HSV-2 infection, but HSV-1 recurs less frequently
HSV Disease: Clinical Manifestations (3)Slide51
51
May 2015
www.aidsetc.org
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 rareHSV Disease: Clinical Manifestations (4)Slide52
52
May 2015
www.aidsetc.org
Mucosal HSV cannot be diagnosed accurately by clinical exam, especially in HIV infection: laboratory diagnosis should be pursued
Swab base of fresh vesicle:
Viral cultureHSV DNA PCR (most sensitive; not widely available)HSV antigen detectionIf HSV detected, obtain type (genitalHSV-1 recurs less frequently)
HSV Disease: DiagnosisSlide53
53
May 2015
www.aidsetc.org
Type-specific serologic assays: can use in asymptomatic persons, or with atypical lesions
Consider routine serologic testing for HSV-2 in all HIV-infected patients
If infected with HSV-2: counsel about risk of transmission to sex partners, means of preventing transmissionHSV Disease: Diagnosis (2)Slide54
54
May 2015
www.aidsetc.org
Most HIV-infected persons have HSV-1 and HSV-2
If HSV-2 seronegative
Test partners for HSV-2 before initiating sexual activityLatex 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 sheddingAntiviral therapy (valacyclovir) can reduce HSV-2 transmission (not studied in HIV infection)
HSV Disease: Preventing ExposureSlide55
55
May 2015
www.aidsetc.org
Antiviral prophylaxis to prevent primary HSV is not recommended
Antiviral prophylaxis after exposure has not
been studiedHSV Disease: Preventing DiseaseSlide56
56
May 2015
www.aidsetc.org
Can treat episodically when lesions occur or with daily therapy to prevent recurrences; consider:
Frequency and severity of recurrences
Risk of HSV-2 transmissionPotential for adverse HSV-2 effect on HIV viral loads in plasma and genital secretionsTreatment of individual episodes does not reduce risk of HSV-2 transmission to sex partnersHSV Disease: TreatmentSlide57
57
May 2015
www.aidsetc.org
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
HSV Disease: Treatment (2)Slide58
58
May 2015
www.aidsetc.org
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 HSVART with immune reconstitution may improve frequency and severity of genital HSV episodesART does not reduce frequency of genital HSV sheddingHSV Disease: Starting ARTSlide59
59
May 2015
www.aidsetc.org
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 treatmentAtypical lesions reported in persons initiating ARTHSV Disease: Monitoring and Adverse EventsSlide60
60
May 2015
www.aidsetc.org
Lesions should begin to resolve within 7-10 days of therapy initiation
Suspect drug resistance if no improvement
Culture lesion, perform susceptibility testingHSV Disease: Treatment FailureSlide61
61
May 2015
www.aidsetc.org
Acyclovir-resistant HSV
Preferred:
Foscarnet 80-120 mg/kg/day IV in 2-3 divided doses until clinical responseAlternatives (21-28 days or longer):Topical trifluridine, topical cidofovir, or topical imiquimod for external lesionsIV cidofovir
HSV Disease: Treatment Failure (2)Slide62
62
May 2015
www.aidsetc.org
Suppressive therapy recommended for patients with frequent or severe recurrences; consider for all with HSV-2
Valacyclovir
500 mg PO BIDFamciclovir 500 mg PO BIDAcyclovir 400 mg PO BIDDaily HSV suppressive therapy causes decrease in HIV RNA in plasma and anal and genital secretions, and lower risk of HIV progressionSuppressive HSV therapy does not decrease risk of HIV transmission
Suppressive therapy is continued indefinitely, regardless of CD4 cell count improvement
HSV Disease: Preventing RecurrenceSlide63
63
May 2015
www.aidsetc.org
Diagnosis of
mucocutaneous
HSV as in nonpregnant adultsVisceral disease more likely during pregnancyMay be transmitted to fetus or neonateRisk of neonatal HSV greatest if mother has primary HSV infection during late pregnancyIn utero transmission rare, but severe cutaneous, ocular, and CNS damageMost neonatal infection occurs via exposure to maternal genital fluids during birth
HSV Disease: Considerations in PregnancySlide64
64
May 2015
www.aidsetc.org
Cesarean delivery lowers risk of transmission; recommended for women with
prodrome
or visible HSV genital lesions at onset of laborAcyclovir 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 womenEfficacy in reducing incidence of neonatal herpes is unknown
HSV Disease: Considerations in Pregnancy (2)Slide65
65
May 2015
www.aidsetc.org
Treatment
Acyclovir: most experience in pregnancy
Valacyclovir, famciclovir: appear to be safe and well tolerated during pregnancySuppressive therapy: Valacyclovir or acyclovir recommended starting at 36 weeks, for pregnant women with recurrences of genital HSV during pregnancy
HSV Disease: Considerations in Pregnancy (3)Slide66
66
May 2015
www.aidsetc.org
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
HSV Disease: Considerations in Pregnancy (4)Slide67
67
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Exposure & Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in
Pregnancy
Varicella-Zoster VirusSlide68
68
May 2015
www.aidsetc.org
Primary VZV = varicella (chickenpox)
Reactivation of latent VZV results in herpes zoster (shingles)
Lifetime risk 15-20%; highest incidence in immunocompromised and elderlyIncidence >15-fold higher in HIV infected compared with general populationCan occur at any CD4 count; highest frequency with CD4 count <200 cells/µL ART has not been shown to reduce incidence of zoster in adultsRates higher in period immediately after ART initiation
VZV Disease: EpidemiologySlide69
VZV Disease: Clinical ManifestationsVaricella: 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
69
May 2015
www.aidsetc.org
Credit: HIV Web
Study ©
2006, U. of Washington Slide70
70
May 2015
www.aidsetc.org
Varicella: chickenpox
Illness may be severe in HIV infection
Visceral dissemination, especially VZV pneumonitis, may occurVZV Disease: Clinical Manifestations (2)Slide71
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 weeksExtensive skin involvement and visceral involvement are rare71
May 2015
www.aidsetc.org
Credit: © I-TECHSlide72
72
May 2015
www.aidsetc.org
Herpes zoster (shingles):
Recurrence in 20-30% of HIV infected (same or different dermatome)
Postherpetic neuralgia in 10-15% of HIV-infected personsComplications more common if CD4 count <200 cells/µLNeurologic syndromes: CNS vasculitis, multifocal leukoencephalitis, ventriculitis, myelitis and myeloradiculitis, optic neuritis, cranial nerve palsies, aseptic meningitis
VZV Disease: Clinical Manifestations (4)Slide73
73
May 2015
www.aidsetc.org
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 VZV Disease: Clinical Manifestations (5)Slide74
74
May 2015
www.aidsetc.org
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 zosterVZV Disease: DiagnosisSlide75
75
May 2015
www.aidsetc.org
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 specificHistopathology and PCR of blood or fluids (eg, CSF, vitreous humor)VZV Disease: Diagnosis (2)Slide76
76
May 2015
www.aidsetc.org
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
VZV Disease: Preventing ExposureSlide77
77
May 2015
www.aidsetc.org
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 acyclovirVaccination not recommended if CD4 <200 cells/µL
VZV Disease: Preventing DiseaseSlide78
78
May 2015
www.aidsetc.org
Postexposure
prophylaxis to prevent primary infection:
Varicella-zoster immune globulin (VariZIG) for VZV-susceptible HIV-infected children and adultsGive 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 infectionVZV Disease: Preventing Disease (2)Slide79
79
May 2015
www.aidsetc.org
Vaccination after exposure
If
postexposure VariZIG has been given, wait ≥5 months before varicella vaccinationIf postexposure acyclovir has been given, wait ≥3 days before varicella vaccination VZV Disease: Preventing Disease (3)Slide80
80
May 2015
www.aidsetc.org
Varicella (chickenpox)
Uncomplicated:
PreferredValacyclovir 1 g PO TID Famciclovir 500 mg PO TIDAlternativeAcyclovir 20 mg/kg up to maximum 800 mg PO 5 times dailyDuration: 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
VZV Disease: TreatmentSlide81
81
May 2015
www.aidsetc.org
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)
VZV Disease: Treatment (2)Slide82
82
May 2015
www.aidsetc.org
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 aboveDuration: 10-14 daysAdjunctive 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)
VZV Disease: Treatment (3)Slide83
83
May 2015
www.aidsetc.org
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 ARTGanciclovir 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 weeklyOptimize ART
Manage in conjunction with an experienced ophthalmologist
VZV Disease: Treatment (4)Slide84
84
May 2015
www.aidsetc.org
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 dosesManage in conjunction with an experienced ophthalmologistVZV Disease: Treatment (5)Slide85
85
May 2015
www.aidsetc.org
Strongly consider ART initiation in patients with multiple recurrences of herpes zoster or a complication of VZV disease
VZV Disease: Starting ARTSlide86
86
May 2015
www.aidsetc.org
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 dosageMonitor renal function for patients on high-dose or prolonged therapy with IV acyclovirHigh-dose (8 grams/day) valacyclovir may cause thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; not reported at lower dosages
VZV Disease: Monitoring and Adverse EventsSlide87
87
May 2015
www.aidsetc.org
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 appearanceVirus culture with susceptibility testing if virus is isolatedIf proven or suspected acyclovir resistance, treat with IV foscarnet (alternative: IV cidofovir)VZV Disease: Treatment FailureSlide88
88
May 2015
www.aidsetc.org
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/µLVZV Disease: Preventing RecurrenceSlide89
89
May 2015
www.aidsetc.org
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 exposureIf acyclovir is used, obtain VZV serology and discontinue drug if patient is seropositiveVaricella vaccine and herpes zoster vaccine should not be given during pregnancy
VZV Disease: Considerations in PregnancySlide90
90
May 2015
www.aidsetc.org
Diagnosis as in
nonpregnant
adultsTreatment of varicella: Uncomplicated: PO acyclovir or valacyclovirSevere disease or VZV pneumonitis: hospitalize, IV acyclovir Treatment of zoster: PO acyclovir or valacyclovir
VZV Disease: Considerations in Pregnancy (2)Slide91
91
May 2015
www.aidsetc.org
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
VZV Disease: Considerations in Pregnancy (3)Slide92
92
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPrevention
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
Human Herpesvirus-8 DiseaseSlide93
93
May 2015
www.aidsetc.org
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%)
HHV-8 Disease: EpidemiologySlide94
94
May 2015
www.aidsetc.org
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 ARTDramatically lower incidence in recent yearsART prevents and may regress KS lesionsGanciclovir, foscarnet, and cidofovir given for CMV treatment may prevent or suppress KSCastleman disease and PEL remain rare
HHV-8 Disease: Epidemiology (2)Slide95
95
May 2015
www.aidsetc.org
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 failurePEL: pleural, pericardial, or abdominal effusions; mass lesions are less commonHHV-8 Disease: Clinical ManifestationsSlide96
HHV-8 Disease: Clinical Manifestations (2)KS presentation varies widely
Most have
nontender
, purplish, indurated skin lesions
Intraoral lesions are common
Visceral dissemination may occur96
May 2015
www.aidsetc.org
Credit: P. Volberding, MD; UCSF Center for HIV Information Image LibrarySlide97
97
May 2015
www.aidsetc.org
Routine screening for HHV-8 is not indicated
Quantitation of HHV-8 by PCR has no established role in diagnosis
KS: biopsyConsult with specialist for diagnosis of other suspected HHV-8 diseaseHHV-8 Disease: DiagnosisSlide98
98
May 2015
www.aidsetc.org
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 recommendedPreventing DiseaseToxicity of anti-HHV-8 therapy outweighs potential benefitsEarly initiation of ART likely to be mosteffective prevention measure
HHV-8 Disease: PreventionSlide99
99
May 2015
www.aidsetc.org
ART for all: initiate or optimize
Limited studies of HHV-8-specific agents
KS:Ganciclovir, foscarnet may regress lesions; cidofovir ineffective in 1 studyChemotherapy if visceral KS; consider if widely disseminated cutaneous KSCastleman 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 specialistHHV-8 Disease: TreatmentSlide100
100
May 2015
www.aidsetc.org
Early ART initiation is likely to prevent KS and PEL
ART should be given to all with KS,
muticentric Castleman disease, or PELInsufficient evidence to support specific ARV regimensHHV-8 Disease: Starting ARTSlide101
101
May 2015
www.aidsetc.org
IRIS reported in HHV-8-infected patients who initiate ART
KS: new onset KS or exacerbations of previously stable disease
Castleman disease: clinical decompensationPEL: no dataART is key component of therapy and should not be delayedHHV-8 Disease: Monitoring and Adverse EventsSlide102
102
May 2015
www.aidsetc.org
ART recommended for all with HHV-8 disease
May prevent KS progression or recurrence
HHV-8 Disease: Preventing RecurrenceSlide103
103
May 2015
www.aidsetc.org
HHV-8
seropositivity
does not appear to affect pregnancy outcome; screening for HHV-8 not indicatedAntiviral therapy for HHV-8 infection during pregnancy is not recommendedDiagnosis as in nonpregnant womenFor treatment, consult with specialistPerinatal transmission occurs infrequently, higher risk with higher maternal antibody titer; may be associated with increased infant mortality
HHV-8 Disease: Considerations in PregnancySlide104
104
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in
Pregnancy
Progressive Multifocal LeukoencephalopathySlide105
105
May 2015
www.aidsetc.org
Opportunistic infection, caused by the
polyoma
virus JC virusCharacterized by focal demyelination in the CNSWorldwide distribution, seroprevalence of 39-69% in adultsPrimary infection usually in childhoodNo recognized acute JC virus infectionLikely asymptomatic chronic carrier state
PML: EpidemiologySlide106
106
May 2015
www.aidsetc.org
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 rateUsually occurs with low CD4 count, but may occur with CD4 count >200 cells/μL and in those on ARTRarely occurs in HIV-uninfected immuno-compromised personsReported in persons treated with immunomodulatory humanized antibodies (eg
,
natalizumab
,
efalizumab
, infliximab, rituximab) PML: Epidemiology (2)Slide107
107
May 2015
www.aidsetc.org
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
PML: Clinical ManifestationsSlide108
108
May 2015
www.aidsetc.org
Compatible clinical syndrome and radiographic findings allow presumptive diagnosis in most cases
Clinical: steady progression of focal neurological deficits
Imaging: MRI is preferredPML: DiagnosisSlide109
109
May 2015
www.aidsetc.org
MRI distinct white matter lesions in brain areas corresponding to clinical deficits
Usually
hyperintense on T2 and FLAIR, hypointense on T1Usually no mass effectContrast enhancement in 10-15% but usually sparseIRIS PMN may have different appearanceDiffusion-weighted imaging and MR spectroscopy may give additional
diagnositic
information
CT scan: single or multiple hypodense,
nonenhancing
white matter lesionsPML: Diagnosis (2)Slide110
110
May 2015
www.aidsetc.org
PML, CT scan PML, MRI scan
PML: Diagnosis (3)
Credit: Images courtesy AIDS Images Library (www.aids-images.ch)Slide111
111
May 2015
www.aidsetc.org
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 macrophagesSerologic testing generally not useful, butnewer approaches under investigation
PML: Diagnosis (4)Slide112
112
May 2015
www.aidsetc.org
Preventing exposure
No known way to prevent exposure
Preventing diseaseART is the only effective way to prevent PMLPrevention of progressive immunosuppression caused by HIV PML: PreventionSlide113
113
May 2015
www.aidsetc.org
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 viremiaEffectiveness 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
PML: TreatmentSlide114
114
May 2015
www.aidsetc.org
Targeted treatments: no proven effective therapies
Cytarabine
, cidofovir: studies show no clinical benefit; not recommended5HT2a receptor inhibitors: clinical trial data lacking; cannot be recommendedInterferon-alfa: no clinical benefit; cannot be recommended Topotecan: limited data; not recommended
PML: Treatment (2)Slide115
115
May 2015
www.aidsetc.org
ART should be started immediately upon diagnosis of PML
For persons on ART with HIV viremia, optimize ART to achieve HIV suppression
PML: Starting ARTSlide116
116
May 2015
www.aidsetc.org
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 initiationIf clinical worsening, repeat MRI promptlyPML: Monitoring and Adverse EventsSlide117
117
May 2015
www.aidsetc.org
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 occurFeatures may be atypical, may include mass effect, edema, contrast enhancement on MRI, more rapid clinical course; perivascular mononuclear inflammatory infiltration on histopathologyPML: Monitoring and Adverse Events (2)Slide118
118
May 2015
www.aidsetc.org
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 responseContrast-enhanced MRI at 2-6 weeks – document status of inflammation and edemaART should be continued
PML: Monitoring and Adverse Events (3)Slide119
119
May 2015
www.aidsetc.org
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”)PML: Treatment FailureSlide120
120
May 2015
www.aidsetc.org
Effective ART regimen
PML: Preventing RecurrenceSlide121
121
May 2015
www.aidsetc.org
Diagnosis as in
nonpregnant
adultsTreatment: optimal ARTPML: Considerations in PregnancySlide122
122
May 2015
www.aidsetc.org
Epidemiology
Clinical
Manifestations & DiagnosisPreventing Infection
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
Human PapillomavirusSlide123
123
May 2015
www.aidsetc.org
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 oropharynxMost HPV infections resolve or become latent and undetectableTumorigenesis requires persistent infection with oncogenic HPV type
Transmitted by sexual contact
HPV Disease: EpidemiologySlide124
124
May 2015
www.aidsetc.org
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 cancersTypes 6 and 11 associated with 90% of genital wartsHPV Disease: Epidemiology (2)Slide125
125
May 2015
www.aidsetc.org
Cervical dysplasia and cancer:
In women with HIV infection
Higher rates of cervical cancerHigher rates of:HPV infection Oncogenic HPV types Cervical intraepithelial neoplasia (CIN)(low grade and high grade)Increased risk with lower CD4 cell countsVulvar and vaginal intraepithelial neoplasia also more common
HPV Disease: Epidemiology (3)Slide126
126
May 2015
www.aidsetc.org
Anal dysplasia and cancer:
In women and men with HIV infection
Higher incidence of anal cancerHigher rates of anal intraepithelial neoplasia (AIN) Higher risk of anal cancer with lower CD4 countsHPV Disease: Epidemiology (4)Slide127
127
May 2015
www.aidsetc.org
Genital and anal warts:
Incidence and prevalence are higher in HIV-infected patients
HPV Disease: Epidemiology (5)Slide128
128
May 2015
www.aidsetc.org
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 increasingIncidence of low-grade VIN lesions and anogenital warts lower with ART, though rate of high-grade VIN unchangedConflicting data re impact of ART on oral warts – some, but not all, studies report increased rates after ART initiation
HPV Disease: Epidemiology (6)Slide129
129
May 2015
www.aidsetc.org
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
HPV Disease: Epidemiology (7)Slide130
130
May 2015
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 clustersOften asymptomatic; may cause itching or discomfortDiagnosis: visual inspection; biopsy if uncertain diagnosis HPV DNA: no data support use for routine diagnosis or management
HPV Disease: Clinical Manifestations and Diagnosis
Condyloma
acuminata
, perianal
Credit: P. Volberding, MD; UCSF Center
for HIV Information Image LibrarySlide131
131
May 2015
www.aidsetc.org
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 testCytology (Pap) and colposcopy techniques as in HIV-uninfected womenDigital examination of vaginal, vulvar, perianal regions, and anal canal to feel for masses
High-resolution colposcopy and biopsy as needed
HPV Disease: Clinical Manifestations and Diagnosis (2)Slide132
132
May 2015
www.aidsetc.org
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:Visual inspectionAnal cytologyDigital examination to feel for massesHigh resolution anoscopy as needed
Biopsy of suspicious lesions
HPV Disease: Clinical Manifestations and Diagnosis (3)Slide133
133
May 2015
www.aidsetc.org
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 womenAnal and other noncervical specimens: no recommendationPrior to HPV vaccination: no recommendation
HPV Disease: Clinical Manifestations and Diagnosis (4)Slide134
134
May 2015
www.aidsetc.org
Vaccination
HPV vaccines (
quadrivalent and bivalent), prevent HPV 16 and 18 cervical, vaginal, and vulvar infections, precancers, and cancers in femalesQuadrivalent vaccine also prevents HPV 16 and 18 anal infections and precancersHPV 6 and 11 infectionsNo efficacy data in HIV-infected individuals (studies ongoing), though
quadrivalent
vaccine shown to be safe and immunogenic
HPV Disease: Preventing InfectionSlide135
135
May 2015
www.aidsetc.org
HPV vaccine (bivalent or
quadrivalent
) is strongly recommended for HIV-infected girls aged 9-12 yearsAlso 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 HPV Disease: Preventing Infection (2)Slide136
136
May 2015
www.aidsetc.org
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 screeningHPV Disease: Preventing Infection (3)Slide137
137
May 2015
www.aidsetc.org
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 HPV Disease: Preventing Infection (4)Slide138
138
May 2015
www.aidsetc.org
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 degreeEffect on genital, anal, or oral HPV-related cancer or precancer in HIV-infected men or their sex partners not knownIn the U.S., insufficient evidence to recommend adult male circumcision for the purpose of reducing risk ofoncogenic HPV infection
HPV Disease: Preventing Infection (5)Slide139
139
May 2015
www.aidsetc.org
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 HIV-infected adolescents and young women who were infected via sex; high rate of cervical abnormalities in perinatally infected adolescentsAnnual screening should continue for life: HIV-infected women remain at risk of development of cervical cancerHPV Disease: Preventing Disease – Cervical Cancer Slide140
140
May 2015
www.aidsetc.org
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
HPV Disease: Preventing Disease – Cervical Cancer (2)Slide141
141
May 2015
www.aidsetc.org
Management of abnormal results
ASC-US
Immediate referral for colposcopy or repeat cytology in 6-12 monthsGreater than ASC-US (ASC-H, LSIL, or HSIL)Refer for colposcopyHPV Disease: Preventing Disease – Cervical Cancer (3)Slide142
142
May 2015
www.aidsetc.org
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 solutionConcomitant cervical and vulvar lesions: vaginal colposcopy No available screening procedure for vulvar cancer; biopsy or refer if suspected lesions
HPV Disease: Preventing Disease – Vaginal and Vulvar Cancer Slide143
143
May 2015
www.aidsetc.org
No national recommendations for routine screening; some specialists recommend anal
cytologic
screening of all HIV-infected men and women:Annual digital rectal exam for massesManagement of abnormal anal Pap resultsASC-US, ASC-H, LSIL, or HSIL: high-resolution anoscopyBiopsy of visible lesions
HPV Disease: Preventing Disease – Anal Cancer Slide144
144
May 2015
www.aidsetc.org
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 specialistHPV Disease: Treatment – Genital and Oral WartsSlide145
145
May 2015
www.aidsetc.org
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 weeksImiquimod 5% cream applied to lesions at bedtime and washed off in morning, 3 nonconsecutive nights per week for up to 16 weeksSinecatechins 15% ointment applied to area TID for up to 16 weeks
HPV Disease: Treatment – Genital and Oral Warts (2)Slide146
146
May 2015
www.aidsetc.org
Provider-applied treatment
For complex or
multicentric lesions, or lesions inaccessible to patientCryotherapy (liquid nitrogen or cryoprobe), repeat every 1-2 weeks for up to 4 weeksTrichloroacetic or bichloroacetic acid 80-90% aqueous solution to lesions, repeat weekly for up to 6 weeks
HPV Disease: Treatment – Genital and Oral Warts (3)Slide147
147
May 2015
www.aidsetc.org
Provider-applied treatment (cont’d)
Surgical excision or laser surgery
Podophyllin resin 10-25% in tincture of benzoin; weekly for up to 6 weeksOther treatments: consider if above are not effective:Topical cidofovir (not available commercially)Intralesional interferon not recommendedOral warts: surgical treatment is most common; many
topicals
cannot be used on oral mucosa
HPV Disease: Treatment – Genital and Oral Warts (4)Slide148
148
May 2015
www.aidsetc.org
Manage with a specialist
Follow ASCCP guidelines, in general
HPV Disease: Treatment – CIN and Cervical CancerSlide149
149
May 2015
www.aidsetc.org
High-grade CIN:
Satisfactory colposcopy: ablation or excision
Unsatisfactory colposcopy: excisionRecurrent high-grade CIN: diagnostic excisional methods; hysterectomy is acceptable Invasive cervical, vaginal, vulvar cancerFollow National Comprehensive Cancer Network guidelinesStandard treatment appears safe and effectiveComplication and failure rates may be higher in HIV-infected women
HPV Disease: Treatment – CIN and Cervical Cancer (2)Slide150
150
May 2015
www.aidsetc.org
HIV-infected adolescents
Follow ASCCP guidelines for adolescents and young women
Progression and recurrence of lesions is more commonFor 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 HPV Disease: Treatment – CIN and Cervical Cancer (3)Slide151
151
May 2015
www.aidsetc.org
Consult with specialists; individualize care
Low-grade VIN/VAIN: can observe or manage as for vulvovaginal warts
VIN: local excision, laser vaporization, ablation, imiquimodVAIN: topical 5-fluorouracil (5-FU), laser vaporization, excisionVulvar and vaginal cancer: individualize care, follow National Comprehensive Cancer Network guidelines
HPV Disease: Treatment – VIN, VAIN, Vulvar and Vaginal CancersSlide152
152
May 2015
www.aidsetc.org
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 patientsOthers: topical 5-FU, cryotherapy, laser therapy, surgical excisionLocal TCA has been used for AIN; intra-anal imiquimod shows moderate efficacy for intra-anal AINAnal cancer: consult with specialist; combination radiation and chemotherapy used most commonly
HPV Disease: Treatment – AIN and Anal CancerSlide153
153
May 2015
www.aidsetc.org
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
HPV Disease: Treatment – Other HPV-Associated Cancers Slide154
154
May 2015
www.aidsetc.org
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 AINHPV Disease: Starting ARTSlide155
155
May 2015
www.aidsetc.org
Increased risk of recurrence of CIN and cervical cancer in HIV-infected patients
Frequent
cytologic screening and colposcopy according to guidelinesNo IRIS has been described in association with HPV infectionsHPV Disease: Monitoring and Adverse EventsSlide156
156
May 2015
www.aidsetc.org
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 fistulasAnal cancer treatment (radiation + chemotherapy) associated with high rate of morbidity, including proctitisHPV Disease: Monitoring and Adverse Events (2)Slide157
157
May 2015
www.aidsetc.org
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 VINFor persistent or recurrent CIN, manage according to ASCCP guidelinesVIN: no consensus; consider surgical excisionHPV Disease: Treatment FailureSlide158
158
May 2015
www.aidsetc.org
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 useVIN: no guidelines; twice-yearly vulvar inspection appears reasonableHigh-grade VIN: manage as with CIN 2 (cytology at 6 and 12 months after treatment, annually thereafter)No indication for secondary prophylaxisHPV Disease: Preventing RecurrenceSlide159
159
May 2015
www.aidsetc.org
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 pregnancyPodophyllin 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
HPV Disease: Considerations in PregnancySlide160
160
May 2015
www.aidsetc.org
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)
HPV Disease: Considerations in Pregnancy (2)Slide161
161
May 2015
www.aidsetc.org
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 doneASC-US: manage as in nonpregnant women, except may defer colposcopy until ≥6 weeks postpartumCIN: treatment not recommended during pregnancy, unless invasive disease; reevaluate with cytology and colposcopy after 6 weeks postpartum
Vaginal delivery appropriate, if no contraindications
HPV Disease: Considerations in Pregnancy (3)Slide162
162
May 2015
www.aidsetc.org
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 cancerHPV Disease: Considerations in Pregnancy (4)Slide163
163
May 2015
www.aidsetc.org
HPV vaccines: not recommended during pregnancy, though available data do not show negative effect on pregnancy outcomes
HPV Disease: Considerations in Pregnancy (5)Slide164
164
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Exposure
Preventing Disease
Treatment
Preventing
Recurrence
Considerations in Pregnancy
Hepatitis C VirusSlide165
165
May 2015
www.aidsetc.org
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 virus7 genotypesGenotype 1: ~75% of HCV infections in United States; ~90% of HCV infections in U.S. blacksHCV Disease: EpidemiologySlide166
166
May 2015
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 syringesOther risks: intranasal cocaine use, tattoo placementHCV Disease: Epidemiology (2)
www.aidsetc.org
www.aidsetc.orgSlide167
167
May 2015
www.aidsetc.org
Sexual transmission
HIV appears to increase risk of sexual transmission of HCV
In HIV-infected MSM, multiple outbreaks of acute HCVRisk factors: unprotected receptive anal sex, sex toys, recreational drug use, concurrent STDIn HIV-uninfected MSM, HCV transmission inefficientHeterosexual transmission uncommon; increased risk if partner is HIV/HCV coinfected
HCV Disease: Epidemiology (3)Slide168
168
May 2015
www.aidsetc.org
Perinatal transmission
HIV appears to increase transmission risk
HCV incidence: 1-3% if HCV-infected mothers had detectable plasma HCV4-7% if mothers had detectable plasma HCV RNA10-20% if mothers had HIV/HCV coinfection HCV Disease: Epidemiology (4)Slide169
169
May 2015
www.aidsetc.org
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)
HCV Disease: Epidemiology (5)Slide170
170
May 2015
www.aidsetc.org
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 elevatedRecognizing possible acute HCV is important, given greater efficacy of treatment in early HCV
HCV Disease: Clinical ManifestationsSlide171
171
May 2015
www.aidsetc.org
Chronic hepatitis C:
Often asymptomatic
Fatigue is commonWith 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 diseaseHCV Disease: Clinical Manifestations (2)Slide172
172
May 2015
www.aidsetc.org
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 treatmentHCV RNA correlated with likelihood of response to HCV treatmentHCV Disease: DiagnosisSlide173
173
May 2015
www.aidsetc.org
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 weeksTest for HCV RNA if risk of HCV, high ALT, but negative or indeterminate serologic test HCV Disease: Diagnosis (2)Slide174
174
May 2015
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, tattooingEncourage safer sex, especially condom use, to reduce sexual transmission of HCVHCV Disease: Preventing Exposure
www.aidsetc.org
www.aidsetc.orgSlide175
175
May 2015
www.aidsetc.org
No vaccine or recommended
postexposure
prophylaxisAfter acute HCV, treatment within 6-12 months may prevent chronic infection; high rates of HCV clearanceAcutely infected patients should be offered treatment, unless contraindicationsPeginterferon (PegIFN) +/– ribavirin (RBV)Some experts recommend observation for ~3-6 months to see if HCV will clear spontaneously
HCV Disease: Preventing DiseaseSlide176
176
May 2015
www.aidsetc.org
Prevent liver damage:
Avoid alcohol consumption
Avoid hepatotoxins; limit acetaminophen intake (<2 g/day)Avoid iron supplementation unless iron deficiencyVaccinate against HAV, HBV if nonimmuneIf cirrhosis, consult with specialistSerial 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
HCV Disease: Preventing Disease (2)Slide177
177
May 2015
www.aidsetc.org
Liver transplant is not absolutely contraindicated in HIV/HCV coinfection
May refer
coinfected patients with well-controlled HIV and liver decompensation or early HCCART associated with reduced risk of liver disease progressionTreat with ART in accordance with usual ART guidelinesDosage adjustment of some ARVs may be needed for patients with decompensated cirrhosis
HCV Disease: Preventing Disease (3)Slide178
178
May 2015
www.aidsetc.org
Goals of treatment, therapy regimens, and monitoring parameters generally are the same for HIV/HCV-
coinfected
patients as for HCV monoinfectedHCV treatment is evolving rapidly and a number of new drugs are now available, with more expected within the next few yearsSee most recent HCV treatment guidelines (http://www.hcvguidelines.org) for current recommendations
HCV Disease: TreatmentSlide179
179
May 2015
www.aidsetc.org
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 reinfectionMethods that prevent sexual transmission of HIV should prevent sexual transmission of HCVHCV Disease: Preventing RecurrenceSlide180
180
May 2015
www.aidsetc.org
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 HCV Disease: Considerations in PregnancySlide181
181
May 2015
www.aidsetc.org
HCV treatment with
PegIFN
and ribavirin is contraindicated during pregnancy IFN: has antigrowth and antiproliferative effects; is abortifacient in monkeysRibavirin: FDA category X; teratogenic at low dosages in many animal speciesBoth 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
HCV Disease: Considerations in Pregnancy (2)Slide182
182
May 2015
www.aidsetc.org
Perinatal HCV transmission: higher risk for HIV-
coinfected
women Limited data on efficacy of medical or surgical preventive measuresCesarean delivery does not decrease risk of perinatal HCV transmission, and may increase risk of maternal morbidity in HIV-infected womenCesarean 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
HCV Disease: Considerations in Pregnancy (3)Slide183
183
May 2015
www.aidsetc.org
Epidemiology
Clinical Manifestations
DiagnosisPreventing Exposure
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
Hepatitis B VirusSlide184
184
May 2015
www.aidsetc.org
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 useMore efficient transmission than HIV-1In higher-prevalence countries, perinatal transmission is most commonHBV Disease: EpidemiologySlide185
185
May 2015
www.aidsetc.org
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 mortalityHBV Disease: Epidemiology (2)Slide186
186
May 2015
www.aidsetc.org
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 EuropeHBV Disease: Epidemiology (3)Slide187
187
May 2015
www.aidsetc.org
Acute hepatitis B:
May be asymptomatic
Symptoms may include RUQ abdominal pain, nausea, vomiting, fever, arthralgias, jaundiceHBV Disease: Clinical ManifestationsSlide188
188
May 2015
www.aidsetc.org
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 stagesOther manifestations: polyarteritis
nodosa
, glomerulonephritis, vasculitis
HBV Disease: Clinical Manifestations (2)Slide189
189
May 2015
www.aidsetc.org
All HIV-infected persons should be tested for HBV
Test for
HBsAg, HBcAb, and HBsAbHBsAb 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 DNAHBV DNA and ALT elevation distinguish active from inactive HBVHBV Disease: Diagnosis Slide190
190
May 2015
www.aidsetc.org
Isolated positive anti-
HBc
:May reflect a false-positive result, distant exposure with loss of anti-HBs, or “occult” chronic HBV infectionMore common in HIV-infected patients, especially if underlying HCV infectionTest for HBV DNA: if positive, treat as chronically infected, if negative, consider susceptible to HBV and vaccinate accordinglyHBV Disease: Diagnosis (2) Slide191
191
May 2015
www.aidsetc.org
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])
HBV Disease: Diagnosis (3)Slide192
192
May 2015
www.aidsetc.org
Additional evaluation
Screening for HCC:
Chronic HBV increases risk of HCCRisk and natural history of HBV-related HCC in HIV-coinfected patents has not been determinedLiver imaging recommended every 6 months if cirrhotic, Asian male > age 40, Asian female >age 50, sub-Saharan African male >age 20 HBV Disease: Diagnosis (4)Slide193
193
May 2015
www.aidsetc.org
Additional evaluation
Assessment of liver fibrosis:
Important for guiding when to start screening for esophageal varices and HCC in cirrhotic patientsLiver biopsy or noninvasive methodsIndividualize 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 regimenNoninvasive methods (eg
, transient
elastography
, serum biochemical indices): increasing evidence and experience in HBV
HBV Disease: Diagnosis (5)Slide194
194
May 2015
www.aidsetc.org
C
ounsel
all HIV-infected patients about reducing risk of exposure to HBV Emphasize transmission
risks
of sharing
needles
and syringes,
tattooing, body piercing, unprotected sexHBV Disease: Preventing ExposureSlide195
195
May 2015
www.aidsetc.org
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 countsDecreased response to vaccination in coinfected patients: check anti-HBs titers 1 month after 3-shot seriesIf no response, consider revaccinationSome experts might wait to revaccinate until sustained CD4 increase with effective ART
HBV Disease: Preventing DiseaseSlide196
196
May 2015
www.aidsetc.org
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
HBV Disease: Preventing Disease (2)Slide197
197
May 2015
www.aidsetc.org
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
HBV Disease: Preventing Disease (3)Slide198
198
May 2015
www.aidsetc.org
HAV-susceptible HIV-
infected
patients should receive HAV vaccineCheck HAV IgG 1 month after vaccination; if negative, revaccinate when CD4 >200 cells/µL All HBV patients should avoid alcohol consumption
HBV Disease: Preventing Disease (4)Slide199
199
May 2015
www.aidsetc.org
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
HBV Disease: TreatmentSlide200
200
May 2015
www.aidsetc.org
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 resistanceHBV Disease: Treatment (2)Slide201
201
May 2015
www.aidsetc.org
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 indefinitelyAlternative 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
HBV Disease: Treatment (3)Slide202
202
May 2015
www.aidsetc.org
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
HBV Disease: Treatment (4) Slide203
203
May 2015
www.aidsetc.org
HBV/HCV/HIV triple infection:
Faster progression of liver fibrosis, higher risk of HCC, increased mortality
Try to treat both hepatitis viruses, if feasibleInclude anti-HBV therapy with ART; introduce HCV therapy as neededIf ART is not desired, consider treatment with interferon-alfa-based therapy for both HBV and HCVHBV Disease: Treatment (5)Slide204
204
May 2015
www.aidsetc.org
ART strongly recommended for all with HIV/HBV coinfection, regardless of ART
ART that includes agents with activity against both viruses is recommended
HBV Disease: Starting ARTSlide205
205
May 2015
www.aidsetc.org
Monitoring treatment response:
HBV DNA every 12 weeks
Complete virologic response: undetectable HBV DNA at 24-48 weeksNonresponse: <1 log10 copies/mL decrease in HBV DNA at 12 weeksSustained virologic response: undetectable HBV DNA 6 months after stopping therapyHBeAg
every 6 months (if
HBeAg
positive)
HBeAg
loss, development of HBeAb (uncommon)Liver histology, transaminasesHBV Disease: MonitoringSlide206
206
May 2015
www.aidsetc.org
Tenofovir
Renal toxicity; more frequent if underlying renal disease or prolonged treatmentCheck electrolytes and serum creatinine at baseline and every 3-6 months; urinalysis every 6 monthsChange to alternative therapy if renal toxicity occursDosage adjustment required if used in patients with baseline renal insufficiencyEntecavirLactic acidosis reported in patients with cirrhosis
HBV Disease: Adverse EventsSlide207
207
May 2015
www.aidsetc.org
Telbivudine
CPK elevations and myopathy reported; check CPK at baseline and every 3-6 months, and if symptoms occur
Discontinue if CPK elevationAdefovir Renal tubular disease at higher dosages; uncommon at HBV treatment dosageInterferon-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)
HBV Disease: Adverse Events (2)Slide208
208
May 2015
www.aidsetc.org
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
HBV Disease: Adverse Events (3)Slide209
209
May 2015
www.aidsetc.org
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 ARTMonitor transaminases monthly for first 3-6 months, then every 3 monthsFlares can be deadly; treat HBV when treating HIVContinue anti-HBV drugs to prevent flares when switching to ART regimens not containing lamivudine, emtricitabine, or tenofovir
HBV Disease: IRISSlide210
210
May 2015
www.aidsetc.org
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 difficultTest 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
HBV Disease: IRIS (2)Slide211
211
May 2015
www.aidsetc.org
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) HBV Disease: IRIS (3)Slide212
212
May 2015
www.aidsetc.org
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 neededMany experts suggest HBV resistance testingMay help distinguish noncompliance and resistance, evaluate patients with unclear treatment history, assess different adefovir resistance pathways, and predict level of resistance to entecavir
HBV Disease: Treatment FailureSlide213
213
May 2015
www.aidsetc.org
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 aloneCross-resistance to emtricitabine, telbivudine, perhaps entecavirIf lamivudine-resistant HBV is suspected or documented, add
tenofovir
to lamivudine
HBV Disease: Treatment Failure (2)Slide214
214
May 2015
www.aidsetc.org
Treatment failure with
tenofovir
:Consider entecavir (especially if experienced with lamivudine or emtricitabine)In vivo resistance to tenofovir not yet reportedTreatment 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
HBV Disease: Treatment Failure (3)Slide215
215
May 2015
www.aidsetc.org
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
HBV Disease: Treatment Failure (4)Slide216
216
May 2015
www.aidsetc.org
ESLD management as in HIV-uninfected patients
Refer to
hepatologistIFN contraindicatedNucleos(t)ide analogues safe and effectiveHCC 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
HBV Disease: Treatment Failure (5)Slide217
217
May 2015
www.aidsetc.org
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 stoppedHBV Disease: Preventing RecurrenceSlide218
218
May 2015
www.aidsetc.org
All pregnant women should be screened for
HBsAg
, HBcAb, and HBsAb and vaccinated against HBV if sAg negative and sAb negativeHepatitis A vaccination can be givenAcute HBV: treatment is supportive (including maintaining normal blood glucose levels and clotting status); higher risk of preterm labor and delivery
HBV Disease: Considerations in PregnancySlide219
219
May 2015
www.aidsetc.org
Perinatal HBV transmission (including failure of prophylaxis) correlated with high maternal HBV DNA levels
ART including HBV-active drugs recommended for all
coinfected pregnant womenDrugs with anti-HBV activity will lower HBV levels and may decrease risk that HBV immune globulin and vaccine will fail to prevent perinatal HBV transmissionHBV treatment may lower risk of IRIS-related HBV flare on ARTIndefinite treatment is recommended; if ARVs are discontinued postpartum, monitor LFTs frequently
HBV Disease: Considerations in Pregnancy (2)Slide220
220
May 2015
www.aidsetc.org
Tenofovir
/
emtricitabine or tenofovir/lamivudine is recommended as NRTI backbone for ART in pregnant HIV/HBV-coinfected womenMore experience in pregnancy with lamivudineEntecavir, 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 effectsHBV Disease: Considerations in Pregnancy (3)Slide221
221
May 2015
www.aidsetc.org
Infants born to
HBsAg
+ women: hepatitis B immune globulin and hepatitis B vaccine within 12 hours of birth2nd and 3rd doses of vaccine at 1 and 6 monthsHBV Disease: Considerations in Pregnancy (4)Slide222
222
May 2015
www.aidsetc.org
http://www.aidsetc.org
http://aidsinfo.nih.gov
Websites to Access the GuidelinesSlide223
223
May 2015
www.aidsetc.org
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.orgAbout This Slide Set