1. Statistical Comments on Retrospective Analysis Girish Aras, Ph.D. Jonathan Ma, Ph.D. Center for Drug Evaluation and Research, FDA

2. Data Analysis Plan Logistic Regression model Dependent variable (Virological Failure) is ‘explained’ with independent variables ( baseline covariates ).

3. Baseline Covariates Baseline Log (HIV-1 RNA) New Drug Covariate Genotypic Measures –Genotypic Sensitivity Score –No. of PI, NRTI and NNRTI mutations Phenotypic Measures –Overall Sensitivity Score –No. of PI, NRTI and NNRTI drugs with Phenotypic sensitivity

4. Relative Risk (Risk Ratio, RR) P 0 = Probability of virological failure when a covariate is at a given level P 1 = Probability of virological failure when a covariate is at one unit higher than the previous level RR = P 1 / P 0

5. Odds ratio RR is the quantity of interest but typically not estimable from a retrospective study OR (Odds Ratio) = P 1 /(1-P 1 ) ÷ P 0 /(1-P 0 ) OR can be estimated from a retrospective study, but may not of interest in itself When P 1 and P 0 are small, RR  OR

6. Odds Ratios for Various Relative Risks — Relative Risk — Odds Ratio P1P1 P 0 =0.05 P 0 =0.1 P 0 =0.15 P 0 =0.2 P 0 =0.25 Odds Ratio or Relative Risk

7. Odds Ratios for Various Relative Risks P0P0 Odds Ratio RR=3 RR=2.5 RR=2 RR=1.5

8. Mutation-Drug Resistance Table Table 1 in DAP titled ‘mutations associated with resistance to specific antiretroviral drugs’ is largely based on in vitro data and/or exploratory subgroup analyses A general consensus is yet to emerge on this table.

9. Mutation-Drug Resistance Table Most of the studies were available to the resistance collaborative group before the DAP was developed

10. 95% Confidence Interval for Odds Ratio for Overall Genotypic Sensitivity Score: Model C (Univariate) and E (Multivariate)

11. 95% confidence interval for Odds ratio for Number of PI Mutations: Model D and F

12. 95% Confidence Interval for Overall Phenotypic Score: Model C (Univariate) and Model G (Multivariate)

13. Conclusions These exploratory analyses suggest predictive link between virological failure and genotypic and phenotypic measures at the baseline They will provide insight in generating specific hypotheses to be tested in future confirmatory studies