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January 8, 2009 Antiretroviral Treatment of HIV-1 Infected Children Lisa Frenkel, MD

January 8, 2009 Antiretroviral Treatment of HIV-1 Infected Children Lisa Frenkel, MD. Antiretroviral Treatment of HIV-1 Infected Children Lisa M. Frenkel, MD Professor of Pediatrics and Laboratory Medicine University of Washington and Seattle Children's Hospital

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January 8, 2009 Antiretroviral Treatment of HIV-1 Infected Children Lisa Frenkel, MD

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  1. January 8, 2009 Antiretroviral Treatment of HIV-1 Infected Children Lisa Frenkel, MD

  2. Antiretroviral Treatment of HIV-1 Infected Children Lisa M. Frenkel, MD Professor of Pediatrics and Laboratory Medicine University of Washington and Seattle Children's Hospital email: lfrenkel@u.washington.edu

  3. Case 1: A woman brings her 7 month old infant “baby girl” to clinic because the baby is breathing rapidly. During pregnancy the mother was followed in your clinic and her HIV EIA was (-) at 28 weeks gestation. She has been breastfeeding her child. “Baby girl” has had routine immunizations. She does not have rhinorrhea, vomiting or diarrhea. She does not have a fever, rales, rhochi or wheezes, but her respiratory rate is 78 breathes/minute. • What is the differential diagnosis? • What tests do you recommend? • What empiric treatment do you provide?

  4. Case 1: 7 month old “baby girl” with no fever, rales, rhochi or wheezes.Respiratory rate is 68 breaths/minute. • What is the differential diagnosis? • Pneumocyctis pneumonia • Acute bronchospasm • Acidosis • What tests do you recommend? • HIV-1 rapid serology of mother • HIV-1 DNA, RNA or p24Ag of baby • Chest x-ray • Sputum for Pneumocystis jirovecii • direct immunofluorescence assay (DFA) • PCR • What empiric treatment do you provide? • Co-trimoxazole • Dapsone • Atovaquone

  5. Maternal blood cells and HIV do not cross a healthy placenta, but the mother’s antibodies cross • Maternal HIV antibodies persist in infant for 18 months • HIV EIA (+) even when uninfected • Definitive diagnosis • Polymerase chain reaction (PCR) amplification of HIV DNA or RNA • Core HIV protein (p24Ag) • Presumptive diagnosis • Maternal antibodies & an ill infant

  6. Teaching Point -- Case 1: “baby girl” with pneumocystis pneumonia (AIDS) infected by mother with acute, asymtomic HIV infection • HIV-1 infection of women in late gestation or during breastfeeding frequently is transmitted to their infants either in utero or via breast milk • Communities with a high incidence HIV-1 should repeat HIV testing in late gestation • Women not tested during gestation should receive rapid HIV testing in labor • Interventions can decrease mother-to-child-transmission: • Antiretroviral prophylaxis of fetus in utero and infant after birth • Elective Cesarean • Exclusive breastfeeding • Artificial feeding • HIV PCR or p24Ag are needed for accurate early diagnosis, however, when unavailable empiric treatment should be based on clinical diagnosis

  7. Access to HIV-1 Testing during Gestation and to Antiretrovirals to Reduce Mother-to-Child-Transmission Varies but is Improving

  8. Acess to Antiretrovirals to Reduce Mother-to-Child-Transmission Varies but is Improving

  9. MAJOR ISSUE:Multiple impediments to HIV-1 testing during gestation and to antiretrovirals to reduce mother-to-child-transmission in resource-poor communities • Women do not access prenatal care • HIV testing not offered as part of routine obstetrical care • Insufficient time for testing, CD4 counts and initiation of antiretrovirals • Stigma associated with HIV testing and interventions, ART and artificial infant feeding

  10. Teaching Point -- Case 1: “Baby girl” with pneumocystis pneumonia (AIDS), infected by mother with acute, asymtomic HIV infection • Pneumocystis pneumonia is common in HIV infected infants not • receiving prophylaxis • Pneumocystis jirovecii • an ubiquitous fungus • infects most infants - immunocompromised become ill • slow growing - prophylaxis is effective when begun at 4 - 6 weeks of age • HIV infected infants should receive prophylaxis until 5 years old, or CD4 counts above threshold for safely stopping prophylaxis • DFA and PCR on induced sputa are very sensitive, however, when unavailable empiric treatment should be based on clinical diagnosis • Co-trimoxazole is the most effective prophylaxis and treatment • Corticosteroids may improve outcome of severe cases

  11. Case 2: • A HIV infected woman brings her 7 day old infant “baby boy” to clinic. He appears healthy, and is breastfeeding well. • You check the baby’s HIV DNA/RNA test from the day of birth. • His “birth” HIV DNA/RNA is (-). The mother asks you for advice to keep “baby boy” free of HIV infection. • What do you recommend?

  12. HIV infection in infants between 0-24 months after randomized to nevirapine vs. nevirapine/zidovudine vs. placebo • for 14 weeks after birth • NI Kumwenda et al. NEJM 2008; 359 : 119-29.

  13. Case 1 and 2 -- continued: The mother chose daily nevirapine prophylaxis for her “baby boy”. He is clinically well, however a HIV DNA PCR is (+) when he is 2.5 months old. The “baby girl” you treated for pneumocystis improves with a 3 week course of co-trimoxazole.Both the “baby boy” and the “baby girl” are in your clinic today. The boy is now 3 and girl 10 months old. • What do you recommend?

  14. Children, mean 4.7 years Incidence AIDS 0 5 10 15 Years since HIV-1 infection Clinical course of HIV infection in children can be “rapid” or “slow” D Dunn et al. J Infect Dis 2008:197:398–404

  15. When to start ART in Infants/Children - WHO focus • Presumptive diagnosis - when PCR unavailable - Seropositive + severe symptoms - oral thrush - severe pneumonia - severe sepsis - Severe maternal disease (%CD4<20), AIDS or death 2. At time of infant diagnosis by HIV PCR or p24Ag (+) • ~40% HIV-1 infants die in first 1 years of life (Dabis, AIDS 2001;15:771; Fassinou, AIDS 2004;18:1905; Newell, Lancet 2004;364:1236; Brahmbhatt JAIDS 2006;41:504) • ART successful and non-toxic (Luzuriaga, NEJM 2004;350:2471) • If start ART early, should ART be stopped later when CD4 normal? 3. Clinical symptoms - Stages 3 and 4, and 1 and 2 if low CD4 4. Immunologic status - Low CD4 for age 5. Family/Caregiver “ready” • Understand life-long therapy • Able to adhere to prescribed regimen - gastrostomy tubes • Can store and administer liquids • Teach child to swallow pills

  16. When to start ART - WHO Clinical Stages 1-4 • Asymptomatic or persistent generalized lymphadenopathy • Mild clinical symptoms • Persistent hepato-splenomegally • Papular pruritic eruptions • Fungal infections • Cheilitis • Linear gingival erythema • Extensive papilomas or molluscum • Herpes zoster • Recurrent upper respiratory tract infections • Moderate clinical symptoms • Malnutrition • Persistent diarrhea or recurrent fever • Thrush or leukoplakia • Lymph node or pulmonary TB, • Recurrent bacterial pneumonias • Lymphocytic interstitial pneumonitis • Necrotizing gingivitis

  17. When to start ART - WHO Clinical Stages 1-4 4. Severe clinical symptoms • Severe wasting - stunted growth • Pneumocystis pneumonia • Recurrent severe bacterial infections • Chronic HSV >1 month • Extrapulmonary TB • Esophageal candidiasis • Kaposi sarcoma • CMV retinitis, colitis • CNS Toxoplasmosis • Extrapulmonary cryptococcosis • HIV encephalopathy • Disseminated mycosis • Disseminated non-TB mycobacteria • Chronic cryptosporidiosis • Chronic Isospora • Cerebral or B cell non-Hodgkin lymphoma • Progressive multifocal leukoencephalopathy • Symptomatic nephropathy • Symptomatic cardiomyopathy

  18. When to start ART - WHO Immune Parameters • Asymptomatic children - CD4 tests on 2 occasions if sole basis for ART • Immunologic status qualifying for ART without symptoms vary by age • CD4% or absolute CD4 cells • <12mo: <25% or <1500/uL • 12-36mo: <20% or <750/uL • 3-5yo: <15% or <350/uL • >5: <15% or <200/uL • Total lymphocyte count (TLC) • <12mo: <4000/uL • 12-36mo: <3000/uL • 3-5yo: <2500/uL • 5-8yo: <2000/uL

  19. Infants Incidence AIDS 0 5 10 15 Years since in utero/peripartum HIV-1 infection A trial of early ART:Children with HIV Early Anti-retroviral Therapy: CHER • A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244

  20. Randomized Trial - When to Start ART in Infants - CHER • HIV-1 infected South African infants 6-12 weeks old - HIV-1 DNA PCR used diagnosed infection - 6-12 week old CD4% >25% randomized to immediate or delayed ART: - antiretroviral therapy (ART) when the CD4% dropped below 20% - immediate ART with a planned interruption at 1 year of age - immediate ART with a planned interruption at 2 years of age - ART – Lopinavir/r + zidovudine+ lamivudine 2. Participants characteristics • Perinatal chemoprophylaxis: • 62% nevirapine • 20% nevirapine + zidovudine • 2% three antiretrovirals • 11% no antiretrovirals • Started ART at median 7.4 weeks old, CD4 35% • Deaths: 20 infants (16%) vs. 10 (4%) after 32 weeks in study • 76% lower death risk (hazard ratio 0.24, 95% CI 0.11 to 0.52, P = 0.002) • A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244

  21. CHER Results: Death or CDC stage C or severe B event in infants randomized to early or deferred ART • A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244

  22. What antiretroviral therapy (ART) should be used for “baby boy” and “baby girl” in your clinic? • “ART” composed of 2 nucleosides + either a NNRTI (nevirapine or efavirenz) or a protease inhibitor? • Nevirapine is utilized for ART worldwide – due to low cost • Protease inhibitors less available • If use ART that “fails” select for resistant nucleoside • Accumulation of nucleoside mutations diminishes efficacy of ALL ART regimens • What ART do you prescribe?

  23. Efficacy ART (ZDV+3TC+NVP) in Infants Previously Given single-dose Nevirapine (Mashi Trial) Lockman et al. N Engl J Med 2007;356:135 • Infected infants starting ART: • N= 15 sdNVP • N= 15 placebo • CD4<25% or • symptoms, • 2-33 months old (median 8.4) • Difference in Failure Rate: P< 0.001

  24. Efficacy ART (ZDV+3TC+NVP) in Women Previously Given single-dose Nevirapine (Mashi Trial) Lockman et al. N Engl J Med 2007;356:135 • Infected infants starting ART • CD4<25% or • symptoms, • 2-33 (median 8.4 mo) • N= 15 sdNVP • N= 15 placebo • P< 0.001

  25. A. In Utero “Established” Infection Dynamics of NVP resistant HIV-1 Frequency and decay of NVP resistant by timing of HIV-1 infection: B. In Utero “Acute” Infection C. Peripartum Infection Infants’ Age (months) # NVP-resistant / total # infants N= 20/23 (87%) N= 3/9 (33%) N= 8/21 (38%) (7 missing specimens >6 weeks of age)

  26. What antiretroviral therapy (ART) should be used for “baby boy” and “baby girl” in your clinic? • Remembering -- • If use ART that “fails” select for resistant nucleoside • Accumulation of nucleoside mutations diminishes efficacy of ALL ART regimens • CHOOSE ART based on drug-resistance test or history of nevirapine • Nevirapine-ART for “baby girl” • Protease Inhibitor-ART for “boy”

  27. Teaching Point -- Case 1: 8 month old “baby girl” with AIDS Case 2: 3 month old “baby boy” with asymptomatic HIV and history of prolonged exposure to nevirapine

  28. Two Approaches to Management of ART 1. World Health Organization (WHO): - Initiate and modify ART based on clinical disease or CD4 failure - If ART failure in question, plasma HIV-1 RNA >10,000 copies/mL 2. USA Department of Health and Human Services (DHHS) HIV Treatment Guidelines: - Maintain plasma HIV RNA <50 c/mL - Comparison of two cohorts: - NNRTI-ART: 3-month delay until treatment modification - Death HR= 1.23 (95% CI 1.08, 1.40); P = 0.002 - Immune failure HR= 1.21 (95% CI 1.07, 1.36) P = 0.002 - PI-ART: 3-month delay until treatment modification - Death HR= 0.93 (95% CI 0.87, 0.99) P = 0.03 - Immune failure HR= 1.21 = 0.98 (95% CI 0.94, 1.03) P = 0.45 Peterson et al. AIDS 2008;22:2097-2106 

  29. When should ART be started in children 1-5 years old? And, in adults? Not a clear answer………observational studies suggest….

  30. Decreased rate of AIDS when starting ART with higher CD4 cells in cohort study • Phillips AN et al. When should ART for HIV be started? Brit Med J 2007;334:76. • Egger M et al. Prognosis of HIV-1 infected patients starting HAART: a collaborative analysis of prospective studies. Lancet 2002;360:119.

  31. But, is it better to initiate ART earlier? Concerns with starting ART early: - Costly (# person/years ART) - Adherence suboptimal due to: • Toxicities –mild (e.g. head aches); severe (e.g. cardiac) • Psychologic obstacles: • Recognizes diseased state • Lack of disclosure – inconvenient to take medicine - Exhaustion of treatment options – due to drug-resistance Problems with starting ART late: - May be ineffective – higher death rates in the first months of treatment (IRIS?) - Toxicities may be greater ART started when HIV-1 disease is more advanced Now many ARV options. Also, more effective and better tolerated ART. Primary Question: Are the benefits of ART in children and adults greater if started at CD4 >350, 200-350 or >200 c/uL?

  32. Pilot study ongoing by INSIGHT Network • Goal to assess whether patients will enroll into a randomized study assessing when to start therapy • Concerned that biases of patients and health care about when to start ART may compromise a study • Communities currently starting ART at <200 cells/uL are best suited to evaluate “when to start ART” • The multiple new ARV and multiple ongoing trials comparing these, will allow more ART regimens to sequence over a lifetime…………..

  33. Case 3: A 6 year old HIV infected boy has developed spastic paraparesis, thrush, and lost 10 kg over the past few months . His father and mother have AIDS and active tuberculosis (growing in culture, susceptibility testing incomplete). On a chest x-ray your patient has bilateral pulmonary disease, and his sputum has acid-fast bacilli. • You initiate: • Isoniazid • Rifampicin • Pyrazinamide • Ethambutol • Pyridoxine • Do you start ART? • Would you start ART with pneumocystis or cryptococcal infections?

  34. ART is often not initiated during acute opportunistic infections (OI) due to concern for: • immune reconstitution inflammatory syndrome (IRIS) • drug interactions IRIS - immune reconstitution inflammatory syndrome: - Recovery of immune reactivity can result in symptoms - worsening or unmasking of M. tuberculosis - increased mortality from Cryptococcus - zoster - worsening vision with CMV retinitis - worsening of multifocal leukoencephalopathy - Corticosteroids may diminish symptoms Adjusting for co-administration with rifampicin: - Nevirapine (and efavirenz) concentrations decreased - Virologic suppression of EFV-ART unaffected, NVP-ART inferior Boulle et al. JAMA 2008;300: 530-9 - Kaletra (LPV/rt (4:1)), when modified to LPV/rt (1:1) - AUC ~50% less with rifampicin - Cmin similar with and without rifampicin Ren et al. JAIDS 2008;47:566-9- - Rifabutin does not induce cytochrome P-450, thus, preferred, but costly

  35. Randomized trial of ART initiated during or after acute opportunistic infections (OI) – (MTB-excluded) • Study design to assess time to start ART when treating OI: • ART given within 14 days of treating OI vs ART deferred to after OI • Stratified by opportunistic infections and CD4 (< or ≥50 cells/mm3) • Tuberculosis excluded (evaluated in a separate ongoing study) • ART = lopinavir/ritonavir (LPV/r), stavudine (d4T), tenofovir/emtricitabine (TDF/FTC) • Outcomes:  death or AIDS progression; no progression and HIV viral load ≥50; or no progression and viral load <50 copies/mL • Results (Feb 2008) • 141 patients were randomized to each arm (immediate vs. deferred ART). • OI: Pneumocystic carinii pneumonia (PCP) 63%, cryptococcal meningitis 13%, pneumonia 10%, and 30% had more than one OI identified at entry • Immediate ART - median of 12 (range 9-13 days); deferred ART - 45 (range 41-55) days • No statistically significant difference in the primary endpoint:  • 14% vs 24% for death or AIDS progression • 38% vs 31% for no progression and HIV viral load ≥50 copies/mL • 48% vs 45% for no progression and viral load <50 copies/mL • However, immediate ART had:  • Fewer deaths/AIDS progressions (20 vs. 34, p = 0.035) • Longer time to death/AIDS progression (stratified HR = 0.53, p = 0.02) • Faster increase in CD4 counts to >50 and >100 cells/uL • A  Randomized Strategy Trial, ACTG 5164, CROI 2008, (abstr. 142)

  36. Percentage of people on treatment who are children, by country, 2005 Latin America and Caribbean[Median: 8%] Africa[Median: 7%] Panama Honduras UR Tanzania Argentina Uganda Haiti Ctr African Republic Guyana Zambia Brazil South Africa El Salvador Kenya Venezuela Zimbabwe Peru Namibia Rwanda 0% 2% 4% 6% 8% 10% 12% 14% 16% Mozambique Malawi Asia[Median: 4%] Côte d'Ivoire Nigeria Cambodia Ghana Viet Nam India 0% 2% 4% 6% 8% 10% 12% 14% 16% China 0% 2% 4% 6% 8% 10% 12% 14% 16% Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on “3 by 5.” 7.3 Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on "3 by 5."

  37. Individuals Receiving Needed Antiretroviral Therapy (ART) in Low- and Middle-Income Countries with More Than 25% “Coverage“ in June 2006. Coverage generally lower in children due to: - delayed diagnosis - fewer children, less public health concern - complex dosing / scarcity of liquid medicines Steinbrook R. NEJM 2006;355:1081

  38. $$$ $$$ $$$ $$$ $$$ $$$ Goal of Antiretroviral Treatment: Balance Benefits vs. Risks 1. Suppress plasma virus to <50c/uL - persistent CD4+ cell gain 2. Minimize inconvenient, poorly-tolerated or toxic ART 3. Sustainable program within public health system • Programs with long-term efficacy are costly: • Test for drug-resistance in newly diagnosed, +/- ART-failure • Quantification of plasma HIV-1 RNA and CD4 • Provide “new” antiretrovirals, without cross-resistance

  39. Thank you for your attention. Questions?

  40. M184V + thymidine analog mutations M184V only or wild-type Mutations Accumulate During Virologic Failure of AZT/3TC/ABC Increasing NRTI cross-resistance Subjects (%) 9-16 (n = 39) (n = 24) (n = 20) (n = 34) (n = 28) (n = 16) Weeks On Therapy After First Genotype Test CNA3005. Melby T et al. 8th CROI, Chicago, 2001. Abstract 448

  41. Next session: January 22, 2009 Listserv: itechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

  42. Next session: November January 22, 2009 Roy Colven, MD HIV Dermatology: Virtual Office Hours: Cases from India

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