CHER Trial: Early Antiretroviral Therapy and Mortality Among HIV-Infected Infants

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

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: • Early therapy group: 96 weeks • Early therapy group: 40 weeks • 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