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Ari Bitnun, MD, MSc , FRCPC Division of Infectious Diseases ari.bitnun@sickids.ca

EARLY INITIATION OF TRIPLE COMBINATION ANTIRETROVIRAL THERAPY IN HIV-1-INFECTED NEWBORN INFANTS: IS CURE POSSIBLE?. Ari Bitnun, MD, MSc , FRCPC Division of Infectious Diseases ari.bitnun@sickids.ca. OUTLINE. Summarize the “functional HIV cure” case reported at CROI 2013

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Ari Bitnun, MD, MSc , FRCPC Division of Infectious Diseases ari.bitnun@sickids.ca

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  1. EARLY INITIATION OF TRIPLE COMBINATION ANTIRETROVIRAL THERAPY IN HIV-1-INFECTED NEWBORN INFANTS: IS CURE POSSIBLE? Ari Bitnun, MD, MSc, FRCPC Division of Infectious Diseases ari.bitnun@sickids.ca

  2. OUTLINE • Summarize the “functional HIV cure” case reported at CROI 2013 • Current guidelines & evidence for HIV post-exposure prophylaxis (HIV-PEP) for newborn infants • Review our experience with triple cART HIV-PEP in newborn infants • Where do we go from here?

  3. “FUNCTIONAL CURE CASE”CROI 2013

  4. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” • 28-month-old child born at 35 weeks gestation • Maternal history • HIV diagnosis intrapartum (rapid HIV test) • No antiretroviral therapy (precipitous delivery) • VL 2423 copies/mL, CD4 count 633 cells/ L • Wild type, subtype B virus • Infant history • Born by spontaneous vaginal delivery • HIV DNA PCR positive; VL 19,812 copies/mL • Initiated on treatment doses of ZDV, 3TC and NVP at 31 hours of life Persaud D, et. al. 20thCROI, Paper #48LB http://webcasts.retroconference.org/console/player/19411?mediaType=slideVideo

  5. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” 19,812 copies/mL 2617 c/mL 516 c/mL 265 c/mL < 50 c/mL ZDV/3TC/NVP ZDV/3TC/LPV/rtv

  6. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” • Lost to follow-up at 18 months of age • Antiretroviral therapy stopped • Re-engaged in care at 23 months of age • Clinically well • Viral load undetectable Persaud D, et. al. 20thCROI, Paper #48LB

  7. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” • HIV serology negative by ELISA & Western Blot at 2 and 2.5 years • No HIV-specific CD8 or CD4 responses to HIV-gag and HIV-nefpeptide pools • Measures of immune activation were normal • CD4 count and CD4 percent remain normal Persaud D, et. al. 20thCROI, Paper #48LB

  8. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” • Proviral DNA detection • PBMC’s, resting CD4 cells, activated CD4 cells, monocyte derived cells • Low level detection of proviral DNA in 2 of 8 assays • Residual viremia • 1 copy/mL at 24 months • < 2 copies/mL at 26 months • Unable to detect “replication competent” virus in culture of 22 x 106 resting CD4 T cells • CCR532 – wild type Persaud D, et. al. 20thCROI, Paper #48LB

  9. “FUNCTIONAL HIV CURE AFTER VERY EARLY ART IN AN INFECTED INFANT” • First well documented case of “functional cure” in an HIV-infected child • Very early antiretroviral therapy in infants may prevent establishment of latent reservoir and achieve cure in children • Potential to transform current treatment practices in HIV-infected newborns (if replicated) • Clinical trials of prompt antiretroviral therapy are in development Persaud D, et. al. 20thCROI, Paper #48LB

  10. COMBINATION ANTIRETROVIRAL THERAPY AS HIV-PEP IN NEONATESEVIDENCE & GUIDELINES

  11. VERTICAL TRANSMISSION RISK WITH ZIDOVUDINEMONOTHERAPY NEJM 1998;339:1409-14

  12. THE EVIDENCE NEWBORN POST-EXPOSURE PROPHYLAXIS • Randomized formula-fed infants of mothers with peripartum diagnosis of HIV-1 • Zidovudine for 6 weeks • Zidovudine for 6 weeks + 3 doses of nevirapine during first week of life • Ziduvudine for 6 weeks + lamivudine and nelfinavir for 2 weeks • Overall results • Overall transmission rate of 8.5% (140/1684) • In utero transmission rate of 5.7% (93/1694) • Risk of transmission higher in monotherapy group (p=0.03) NEJM 2012;366:2368-79

  13. THE EVIDENCE NEWBORN POST-EXPOSURE PROPHYLAXIS 4.8% 2.4% 2.2% NEJM 2012;366:2368-79

  14. DHHS GUIDELINE MANAGEMENT OF “HIGH RISK” INFANTS BORN TO HIV-INFECTED MOTHERS • If no antepartum maternal treatment given • Zidovudine for 6 weeks PLUS • Three doses of nevirapine in first week of life (birth, 48 hours later, and 96 hours after second dose; AI) • “…the decision to combine other drugs should be made in consultation with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on potential risks and benefits… (BIII)” http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf

  15. TRANSMISSION RISK ESTIMATES Triple cART HIV-PEP seems warranted for high risk neonates Rapid suppression of viral replication and preservation of immune function (if infected) Risk of NNRTI resistance (if infected) Committee on pediatric AIDS. Pediatrics 2003;111:1475-89

  16. TRIPLE COMBINATION ANTIRETROVIRAL THERAPY AS HIV-PEP IN NEONATESCANADIAN EXPERIENCE

  17. TRIPLE cART HIV-PEP REGIMENS • Triple cART HIV PEP in use for “high risk” scenarios for over 5 years • Regimen 1 (SickKids, CHEO) • Zidovudine for 6 weeks PLUS • Lamivudine for 6 weeks PLUS • Nevirapine for 4 weeks • Regimen 2 (CHU Sainte-Justine, CHEO) • Zidovudine for 6 weeks PLUS • Lamivudine for 6 weeks PLUS • Nelfinavir or lopinavir/r for 6 weeks

  18. TRIPLE cART HIV-PEP IN NEONATES • Review of high risk HIV-exposed children who received early triple cART HIV-PEP • Study questions • Can neonatal cART lead to sustained virologic suppression and “functional HIV cure”? • Is triple cART HIV-PEP tolerated in neonates?

  19. HIV-PEP IN NEWBORN INFANTS OF MOTHERS WITH DETECTABLE VIRAL LOAD • 129 infants received triple cART HIV-PEP • 53 - ZDV/3TC/NVP • 69 - ZDV/3TC/NFV • 7 - ZDV/3TC/LPV/rtv • HIV infection confirmed by detection of HIV using molecular detection assays from two separate samples in 12 cases (9%) • In uteroinfection (DNA PCR positive within 48 hours of birth) in 6 of 12 cases • Of the 12 infected children, 5 achieved sustained virologic suppression

  20. IS “FUNCTIONAL HIV CURE” POSSIBLE?CASE SCENARIO • Mother 28-year-old • HIV diagnosis 6 months prior to delivery • Initiated on cART 6 weeks prior to delivery • Viral load 97,701 copies/mL • CD4 count 190 cells/L • Female infant born by Cesarean section at 34+4 weeks gestation • Zidovudine, lamivudine and nevirapine initiated soon after birth • Birth HIV-1 DNA PCR positive

  21. CASE CONTINUED… • Now 6.5 years old • Remains on same antiretroviral combination •  Has maintained an undetectable • viral load CD4 count 3940 (55%) cART initiated HIV DNA PCR positive

  22. SUMMARY OF CASES WITH SUSTAINED VIROLOGIC SUPPRESSION • HIV DNA PCR positive within 48 hours of birth in 4 cases • All five initiated on cART (ZDV/3TC/NVP) on day 1 of life • HIV PCR: Cobas Ampliprep/Cobas Taqman HIV‐1 Qual Test & in house assay (limit of detection 5 copies/mL); Serology: ELISA & western blot

  23. IS TRIPLE cART TOLERATED?ADVERSE EFFECTS OF NEONATAL HIV-PEP • Non-specific symptoms (36%) • Irritability, jitteriness, vomiting, diarrhea, rash • Attributed to antiretroviral medications in minority of cases (8%) • Early treatment discontinuation (n=5) • Anemia (n=2); one child required transfusion (Hgb 60 g/L at 2 weeks of age) • Elevated CPK (n=1) • Vomiting associated with nelfinavir (n=1) • Rash & vomiting possibly related to nevirapine (n=1)

  24. SUMMARY & CONCLUSIONS #1 • The need to prescribe triple cART HIV-PEP to 129 newborn infants represents a systems failure with respect to • Timely maternal diagnosis • Timely initiation and/or adherence to antenatal cART

  25. Antenatal treatment Intrapartum treatment Neonatal treatment Uninfected Infected % infected 8.3% 4.8% 0.1%

  26. SUMMARY & CONCLUSION #2 • Triple cART HIV-PEP in neonates is generally well tolerated • Moderate transient anemia relatively common • Discontinuation of therapy due to toxicity occasionally required • There are significant practical & knowledge gaps regarding neonatal cART • Limited availability of child-friendly formulations • Pharmacokinetic studies of antiretroviral medications in neonates

  27. SUMMARY & CONCLUSION #3 • Sustained virologic suppression with early initiation of neonatal cART is associated with • Negative HIV serology • Negative HIV DNA PCR at a detection threshold of 5 copies/mL • It is plausible that neonatal cART could prevent establishment or reduce the size of HIV reservoirs

  28. THE FUTUREWHAT TO DO WITH THE 5 CHILDREN? • More detailed look for proviral DNA and replication competent virus • Peripheral blood • Lumbar puncture? • Intestinal & lymph node biopsy? • Genetic evaluation • CCR532 and protective HLA markers • To stop or not to stop? • Potential for harm – could this lead to establishment of long-lived reservoirs?

  29. REFERENCES • DHHS guidelines (available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf) • Neonatal management section on pages H7 – H23 (167 – 183) • Persaud, et. al. 20thCROI, Paper #48LB(http://webcasts.retroconference.org/console/player/19411?mediaType=slideVideo) • Luzuriaga, et. al. 20thCROI, Paper #171LB • Kakalia, et. al. 19th CAHR (P151); Can J Infect Dis Med Microbiol2010;21:53B

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