1. CHER Trial: Early Antiretroviral Therapy and Mortality Among HIV- Infected Infants New England J Med 2008;359 (21): 2233-2244

2. Background- Standard HIV screening & therapy ► WHO recommends screening of infants with: ► Known maternal HIV ► Clinical signs & symptoms of possible HIV ► HIV antibody test (ELISA) ► Sensitive in age >18 months ► Confirm all positive tests w/ PCR ► If PCR not available, repeat ELISA at 18 months ► HIV DNA PCR, RNA assay ► Most sensitive and specific, test of choice under 18 months

3. Background- current WHO guidelines for starting ART Clinical Stage Criteria 4Treat 3 Treat, except ► >18mon & CD4 >15% ► >5yrs & CD4>10% or >200 1 & 2 Treat ► <18mon & CD4<25% ► 18-59mon & CD4<15% ► >5 & CD4 5 & CD4 <10% or <200

4. CHER Trial: Early antiretroviral therapy and mortality among HIV-infected infants ► Phase 3, randomized, open-label trial ► Clinical question: Does the early diagnosis of HIV and initiation of antiretroviral therapy in infants reduce mortality or the progression of HIV? ► Primary end-points: 1) Time to death 2) Failure of first-line antiretroviral therapy

5. Methods ► Setting: ► 377 infants enrolled from two HIV research centers in South Africa (Soweta & Cape Town) between Aug 2005 – Feb 2007 ► Inclusion criteria: ► Infants 6 – 12 weeks of age ► Positive DNA PCR ► RNA viral load >1000 ► CD4 >25% ► Exclusion criteria:

6. Methods con’t ► Study design  Phase 3, open, randomized, controlled trial  Randomly assigned to 3 treatment groups: 1.Early therapy group: 96 weeks 2.Early therapy group: 40 weeks 3.Deferred therapy group  Outcome measures: ► Primary:  Time to death  Failure of first-line antiretroviral therapy ► Failure to reach CD4 20% by 24 wks ► Decrease in CD4 <20% after 24wks ► Severe stage B or C events (clinical failure) ► Toxicity requiring drug changes or discontinuation

7. Validity ► 1. Randomized?- yes ► 2. Randomization process blinded from investigators?- yes ► 3. Groups similar?- yes

8. Validity con’t Table 1. Baseline characteristics

9. Validity con’t ► 4. Patients maintained in randomized groups? - yes, intention to treat principle ► Although proportion of deferred therapy group evaluated partway through trial and started on antiretroviral therapy due to finding of difference in mortality between groups (total number not specified) ► Additional 155 HIV infected infants referred from centers other than the two primary centers ► 5. Blinded?- no ► Patients ► Clinicians ► Outcome assessors

10. Validity con’t ► 6. Follow-up complete?  Non-completion ► Early therapy groups: 6% ► Deferred therapy group: 3%  Adherence rates  Zidovudine 87.8%  Lamivudine 90.2%  Lopinavir-ritonavir 92.1% ► 7. Follow-up appropriate length? ► Pts followed every 4 weeks until wk 24, every 8 wks until wk 48, every 12 weeks thereafter ► Median follow up 40 weeks

11. Results con’t ► Overall mortality  Deferred therapy 16% vs. Early therapy groups 4% (relative reduction of 76%, p<0.001) ► Progression of HIV  Deferred therapy 25.6% vs. Early therapy groups 6.3% (relative reduction 75%, p<0.001) ► CD4 percentage  12 wks: -7.5% Deferred group, +4.8% Early therapy (absolute difference 12.3%, p<0.001)  24 wks: -5.6% Deferred group, +5.9% Early therapy (absolute difference 11.5%, p<0.001)  32 wks: -4.8% Deferred group, +4.5% Early therapy (absolute difference 9.3%, p<0.001)

12. Discussion ► 1. Study limitations, questions? ► 2. Clinically significant?

13. Discussion ► 3. Applicable to our patient population? ► Yes ► 4. Future directions?

14. Key Points ► Early HIV diagnosis and initiation of therapy at a median of 7wks reduced infant mortality by 76% and reduced HIV progression by 75% ► This study advocates starting early antiretroviral therapy upon diagnosis regardless of CD4 percentage, CD4 count or clinical stage