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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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 2 Viral Infections Cytomegalovirus Herpes Simplex Virus Varicella-Zoster Virus Human Herpesvirus-8 Progressive Multifocal Leukoencephalopathy Human Papillomavirus Hepatitis C Hepatitis B www.aidsetc.org May 2015 3 Cytomegalovirus (CMV) Disease Epidemiology Clinical Manifestations Diagnosis Preventing Disease Treatment Monitoring Preventing Recurrence Considerations in Pregnancy www.aidsetc.org May 2015 4 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 May 2015 5 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 May 2015 6 CMV Disease: Clinical Manifestations Retinitis Colitis, cholangiopathy Esophagitis Pneumonitis Neurologic disease www.aidsetc.org May 2015 7 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 May 2015 8 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 9 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 May 2015 10 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 11 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 May 2015 12 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 May 2015 13 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 www.aidsetc.org May 2015 14 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 www.aidsetc.org May 2015 15 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 May 2015 16 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 17 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 May 2015 18 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 May 2015 19 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 May 2015 20 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 21 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 May 2015 22 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 May 2015 23 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 24 CMV Disease: Treatment (5) Retinitis (cont’d) Small peripheral lesions: Preferred Systemic antiviral therapy as above www.aidsetc.org May 2015 25 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 26 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 27 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 May 2015 28 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 29 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 30 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 31 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 May 2015 32 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 33 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 May 2015 34 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 35 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 36 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 37 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 38 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 39 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 40 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 41 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 42 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 43 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 44 Herpes Simplex Virus Disease Epidemiology Clinical Manifestations Diagnosis Preventing Disease Treatment Preventing Recurrence Considerations in Pregnancy www.aidsetc.org May 2015 45 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 46 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 47 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 48 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 49 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 50 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 51 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 May 2015 52 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 53 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 54 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 55 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 56 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 57 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 58 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 59 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 May 2015 60 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 61 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 May 2015 62 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 63 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 64 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 65 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 66 Varicella-Zoster Virus Epidemiology Clinical Manifestations Diagnosis Preventing Exposure & Disease Treatment Monitoring Preventing Recurrence Considerations in Pregnancy www.aidsetc.org May 2015 67 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 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 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 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: 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 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 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 www.aidsetc.org May 2015 197 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 www.aidsetc.org May 2015 198 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 www.aidsetc.org May 2015 199 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 www.aidsetc.org May 2015 200 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 www.aidsetc.org May 2015 201 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 www.aidsetc.org May 2015 202 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 www.aidsetc.org May 2015 203 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 www.aidsetc.org May 2015 204 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 www.aidsetc.org May 2015 205 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 www.aidsetc.org May 2015 206 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) www.aidsetc.org May 2015 207 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 www.aidsetc.org May 2015 208 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 www.aidsetc.org May 2015 209 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 www.aidsetc.org May 2015 210 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) www.aidsetc.org May 2015 211 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 www.aidsetc.org May 2015 212 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 www.aidsetc.org May 2015 213 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 www.aidsetc.org May 2015 214 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 www.aidsetc.org May 2015 215 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 www.aidsetc.org May 2015 216 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 www.aidsetc.org May 2015 217 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 www.aidsetc.org May 2015 218 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 www.aidsetc.org May 2015 219 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 www.aidsetc.org May 2015 220 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 www.aidsetc.org May 2015 221 Websites to Access the Guidelines http://www.aidsetc.org http://aidsinfo.nih.gov www.aidsetc.org May 2015 222 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 www.aidsetc.org May 2015 223