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1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and AdolescentsCytomegalovirus Slide Set Prepared by the AETC National Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America

2. About This Presentation These slides were developed using recommendations published in July 2013. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC National Resource Center http://www.aidsetc.org www.aidsetc.org

3. 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

4. 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

5. CMV Disease: Clinical Manifestations • Retinitis • Colitis, cholangiopathy • Esophagitis • Pneumonitis • Neurologic disease www.aidsetc.org

6. 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

7. 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

8. 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 PediatricAIDS Initiative www.aidsetc.org

9. 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 Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library www.aidsetc.org

10. 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; UCSFCenter for HIV Information ImageLibrary www.aidsetc.org

11. 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

12. CMV Disease: Clinical Manifestations (8) Neurologic disease • Dementia: lethargy, confusion, fever, but may mimic HIV-1 dementia • CSF: lymphocytic pleocytosis, low-to-normal glucose, normal-to-elevated protein • Ventriculoencephalitis: more acute course; cranial nerve palsies, nystagmus, other focal neurologic signs, rapid progression to death • CT or MRI: periventricular enhancement www.aidsetc.org

13. 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

14. 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

15. 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

16. Pneumonitis: interstitial infiltrates + compatible clinical presentation + multiple CMV inclusion bodies in lung tissue, and absence of other likely pathogens Neurologic disease: clinical syndrome + CMV in CSF or brain tissue; detection enhanced by PCR CMV Disease:Diagnosis(3) Brain biopsy with CMV inclusions Credit: Images courtesy of AIDS ImagesLibrary (www.aids-images.ch) www.aidsetc.org

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. CMV Disease: Treatment (5) Retinitis (cont’d) • Small peripheral lesions: • Preferred • Systemic antiviral therapy as above www.aidsetc.org

24. CMV Disease: Treatment (6) Colitis, esophagitis • Preferred • Ganciclovir 5 mg/kg IV Q12H, may switch to valganciclovir 900 mg PO Q12H when patient can absorb and tolerate PO therapy • Alternative • Foscarnet 60 mg/kg IV Q8H or 90 mg/kg IV Q12H – if treatment-limiting toxicities or resistance to ganciclovir • Oral valganciclovir if PO therapy can be absorbed • For mild cases, if ART can be initiated or optimized quickly, can consider withholding CMV therapy • Duration: 21-42 days, or until signs and symptoms have resolved www.aidsetc.org

25. 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

26. 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

27. CMV Disease: Starting ART • IRIS may cause retinal damage in patients with active CMV retinitis, or recent or past CMV retinitis • Incidence or severity of IRIS may be reduced by delaying ART until retinitis is controlled • CMV replication usually controlled 1-2 weeks after start of CMV therapy • Weigh brief delay in ART initiation against risk of other OIs • Most experts would not delay ART for more than 2 weeks after starting CMV therapy for retinitis or other CMV end-organ disease • Use clinical judgment in case of neurologic disease www.aidsetc.org

28. 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

29. 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

30. 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

31. 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

32. 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

33. CMV Disease: Treatment Failure (2) Treatment options for first relapse: • Ganciclovir implant • Reinduction with the same drug, followed by maintenance therapy • Changing to alternative drug at first relapse: usually not more effective, unless drug resistance or significant side effects • Ganciclovir + foscarnet: superior to monotherapy but greater toxicity www.aidsetc.org

34. CMV Disease: Treatment Failure (3) Later relapse: often owing to drug resistance • Resistance occurs in long-term therapy(25-30% by 9 months of therapy) • Similar rates for ganciclovir, foscarnet, cidofovir • Consider resistance testingin blood • >90% correlation with virus in eye • Can be done in <48 hours • Most virus with high-level resistance to ganciclovir (UL97 + UL54 mutations) respond to foscarnet www.aidsetc.org

35. CMV Disease: Treatment Failure (4) Low-level ganciclovir resistance: • Consider ganciclovir implant(higher local levels of ganciclovir) High-level ganciclovir resistance: • Switch to alternative therapy • Usually also resistant to cidofovir, sometimesto foscarnet • Consider repeated intravitreous fomivirsen(combine with systemic therapy) www.aidsetc.org

36. 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

37. 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 post-infusion hydration and probenecid) (avoid in patients with sulfa allergy) www.aidsetc.org

38. 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

39. 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

40. 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

41. 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

42. 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

43. Websites to Access the Guidelines • http://www.aidsetc.org • http://aidsinfo.nih.gov www.aidsetc.org

44. About This Slide Set • This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in July 2013. • See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org www.aidsetc.org