CMV infection in HIV infected patient. Nia Kurniati Cipto Mangunkusumo Hospital Jakarta, Indonesia

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1 CMV infection in HIV infected patient Nia Kurniati Cipto Mangunkusumo Hospital Jakarta, Indonesia

2 Background CMV infection are commonly found as HIV co-infection Vertical transmission is the important source of infection in infant In pre HAART era this co-infection has low survival Gabriel et al. Med Sci Monit 2007;13:177-81

3 Epidemiology Seropositivity among pregnant women in this region is high (India 35 90%, ) Chakravarti A, et al. Indian J Med Microbiol 2009;27:3-11 Symptomatic CMV infections was 23.1% among HIV-1 infected newborns and 6.7% among HIV-1 uninfected neonates. (French cohort) Guibert G, et al. Clin Infect Dis 2009; 48: % of HIV-infected children were co-infected with CMV. Khamduang W, et al. J Acquir Immune Defic Syndr 2011; 58(2):

4 Clinical Manifestation CMV Retinitis Esophagitis Colitis Hepatitis Pneumonitis

5 Diagnosis of Infection ( disease) Birth 2 wks month Congenital CMV infection: virus isolation in human fibroblast, CMV specific T-cell Acquired CMV infection: virus isolation/pcr Infection: antibody assay Shoby CT, et al. Indian Pediatr 2002;39:561-4 Ritter M, et al. Eur J Immunol 2012, Dec 26 (epub)

6 Problems Problem in diagnosis: When to decide whether it is infection or disease Problem in treatment: When to start When to stop When to restart

7 DIAGNOSIS OF CMV INFECTION

8 Case#1 A 7 month old girl was hospitalized for severe pneumonia. She had history of chronic diarrhea Her mother recently diagnosed with pulmonary TB Body weight 3.95 kg (< P 3 WHO chart) Microcephaly, hepatosplenomegaly

9 Within a week we have confirmation of HIV: PCR HIV was positive, CD4 5% Respons to therapy was slow, liver enlargement was prominent AST/ALT 120/135 IU/L We planned to check for certain OI (hepatitis B, C, TORCH)

10 Q1 HBsAg and anti HCV were negative IgM CMV 50 AU/L and IgG 130 IU/L Do you think we can diagnose CMV infection with antibody assay? Yes OR No

11 Diagnosis of CMV Sensitivity Specificity Positive Predictive Value Negative Predictive Value Antigen detection: 89.18% Antigen detection: 100% Antigen detection: 100% Antigen detection: 93.54% PCR: 100% PCR:72,41% PCR: 69.81% PCR: 100% IgM CMV: 72,97% IgM CMV: 62,06 IgM CMV: 55.1% IgM CMV: 78.26% Bhatia J, Chah BV, Mehta AP, Deshmukh M, Sirsat RA, Rodrigues C. Comparing serology, antigenemia assay and polymerase chain reaction for the diagnosis of cytomegalovirus infection in renal transplant patients.

12 Q2 A. Diagnosis of CMV disease can be established B. We need positive PCR CMV to deliver IV Ganciclovir C. Therapy of IV Ganciclovir can be started without confirmation of CMV isolation in this case

13 Answer A. Positive antibody assay in infant < 12 years old reflects maternal CMV infection B. True. We should detect CMV antigen accompanied by end-organ manifestation before starting treatment C. There is no guideline to give therapy based on clinical and antibody assay only

14 Follow up More evaluation showed no sign of retinitis. We decided to give IV ganciclovir. The patient gradually got better on the 3rd week of treatment, and ARV was started. She is now almost 2 years old, clinically well without ganciclovir maintenance and the last CD4 is > 15%

15 Case #2 A 7 month baby girl diagnosed with HIV infection During the process of diagnostic, her abdomen were getting bigger and she had constant low grade fever. On examination she looked like a healthy baby at her age, normocephaly, except for liver enlargement. Laboratory study revealed normal CBC, increase ALT/AST (560/947), positive IgG and IgM to CMV

16 CD4 was 30% (1483 cells/ml) Urine CMV PCR was positive BERA and eye examination revealed normal Birth weight 3900 g birth length 46 cm

17 Question Do you think that this is a CMV disease? Yes or No In term of prognostic, should we define congenital or acquired infection?

18 Congenital CMV Infection Small for gestational age (50%) Petechiae (76%) Jaundice (67%) Hepatosplenomegaly (60%) Chorioretinitis (20%) Microcephaly (53%) Intracranial calcifications (55%) Hearing impairment ( 65%)

19 Management We diagnosed CMV disease in this patient and started IV ganciclovir for 3 weeks, without valganciclovir maintenance. ARV was started by the end of week 3 On follow up her ALT/AST were decreased to normal level and her liver enlargement was also decreased. Urine PCR was also negative.

20 SECONDARY PREVENTION

21 Case #3, N, 14 months old girl Lymphadenitis BCG Excision biopsy PCR BCG CMV Retinitis IgM 50 AU/ml, IgG g/dl Funduscopy HIV Positive antibody assay PCR RNA 5.2 log 10 copies/ml CD4: 14.6% (328 cell/ml)

22 Other findings Hepatosplenomegaly (ALT 205 IU/L, AST 192 IU/L) HBs-Ag negative, anti HCV negative Anti Toxoplasma negative

23 Management Anti TB drugs ( Rifampicin, Isoniazide, Pyrazinamide) for 9 months Co-trimoxazole IV Ganciclovir (which we changed to Oral valganciclovir for 6 month) ARV (AZT + 3TC + NVP)

24 Question #3 At 18 month post starting therapy (age 4 y.o), patient had hematemesis and melena. Ultrasound showed cirrhotic liver and spleen enlargement. IgM CMV persists at 50 AU/mL. Other liver infection panel was negative Do we need to restart Valganciclovir treatment? Yes or No

25 Follow up Liver biopsy was declined by her father Diagnosis of active CMV hepatitis was made, and decided to restart Valganciclovir. Treatment lasted for 12 month which resulted in clinical improvement Annual funduscopy ensure no relaps of retinitis CD4 maintain on 20 25%

26 Treatment Infant: Start therapy in confirmation of CMV disease Evaluate at 6 weeks, decide to stop or continue (HIV) CMV retinitis: IV Ganciclovir (duration not stated for infant and children) Valganciclovir for 3 6 months reduction of morbidity and mortality ARV needs 3 to 6 months to control HIV replication and to stimulate the immune system to control CMV infection. Kaplan JE, et al. Guidelines for prevention and treatment of opportunistic infections in HIVinfected adults and adolescents Mofenson LM, et al. Guidelines for prevention and treatment of opportunistic infections among HIV exposed and HIV Infected Children. 2009

27 Stop and start secondary prophylaxis Secondary prophylaxis should be reinstituted in children aged 1--5 years when the CD4 count decreases to <500 cells/mm3 or CD4 percentage to <15%, and for children aged 6 years when the CD4 count decreases to <100 cells/mm3 or CD4 percentage to <15% (BIII). Mofenson LM, et al. Guidelines for prevention and treatment of opportunistic infections among HIV exposed and HIV Infected Children. 2009

28 Prophylaxis Secondary prophylaxis (Chronic Maintenance Therapy) is recommended for CMV retinitis in older children and adult (AII), combine with other modalities. There is no clear guideline in younger children Discontinuing prophylaxis may be considered for children aged 1--5 years who are receiving HAART and have a sustained (e.g., >6 months) increase in CD4 count to >500 cells/mm3 or CD4 percentage to >15% For children aged 6 years, an increase in CD4 count to >100 cells/mm3 as for adults (CIII)

29 Issues to be resolved Diagnosis in infant Treatment indication in relatively stable children with disease manifestation Duration of treatment Prophylaxis

30 THANK YOU