1. Concept Sheet Development: Developing the Question Kara Wools-Kaloustian M.D. M.S.

2. It Starts With A Question Where do questions come from?  Clinical Practice  While developing guidelines  While reading the literature Write the question down

3. What next? Look at the literature  Has this question been asked before? If yes:  Was it asked in the same context?  Were the issues adequately addressed?  What are the remaining unknowns? If No:  Have similar questions been asked that can help guide you in structuring your inquiry?

4. Next Steps Refine your underlying (central) question  Based on literature review Develop Hypotheses  The assumed answer (s) to the question(s) that you are asking Based on literature Observation

5. Use of Existing Data Be cognizant of the minimum data set throughout concept development Once hypotheses are developed  List the specific outcome variables (dependent variables) to be assessed  List the explanatory (independent variables) to be addressed

6. Collection of New Data Are additional data elements necessary to address your specific aims?  If yes: Is it feasible to collect these elements Feasible: Questions that can be asked in a survey instrument to the sites Not Feasible: the addition of multiple patient level data elements to the existing clinical forms at all sites. Possibly Feasible: the addition of selected patient level data elements at selected sites.

7. EXAMPLE

8. Question Source of the Question  Development of pMTCT Guidelines Question: What are the outcomes of women initiated on antiretroviral treatment for clinical indications after having experienced antiretroviral treatment interruptions due to intermittent prophylaxis with cART or exposure to abbreviated antiretroviral regimens for pMTCT?

9. Literature: Structured treatment Interruptions (STI) trials Data appears to indicate that individuals receiving interruptions in their cART are more likely to die than those who receive continuous antiretroviral therapy. Whether or not this finding translates to women receiving intermittent therapy for pMTCT (and thus experiencing STI at higher CD4 counts than previously studied) is unknown.

10. Literature: Single dose or short course treatment ACTG 2508 has clearly shown that women who have previously received single dose NVP for pMTCT and who subsequently start a cART treatment regimen with an NNRTI backbone, are more likely to fail their first regimen than women starting a regimen with a PI backbone. Persistent resistance to an NNRTI more than 6 months after receiving single dose

11. Hypothesis 1 Women experiencing treatment interruptions due to intermittent prophylaxis with cART for pMTCT once initiated on antiretrovirals for treatment will have adherence rates, CD4 responses, first treatment regimen failure rates, mortality rates and LTFU rates that are equivalent to women who initiate cART with no previous history of receiving antiretrovirals for pMTCT.

12. Hypothesis 2 Women experiencing treatment interruptions due to intermittent prophylaxis with cART for pMTCT once initiated on antiretrovirals for treatment will have adherence rates, CD4 responses, first treatment regimen failure rates, mortality rates and LTFU rates that differ from women who received a non-cART regimen for pMTCT prior to initiating therapeutic HAART.

13. Outcome Variables CD4 counts after cART initiation for treatment Adherence to cART during treatment Antiretroviral stops for failure (yes, no) Time on first therapeutic regimen until failure Death after cART initiation for therapy (yes, no) Time from cART initiation for therapy until death LTFU after cART initiation for therapy (yes, no) Time from cART initiation for therapy until LTFU

14. Other Variables: Number of pregnancies at enrollment Pregnant at enrollment (yes, no) Number of pregnancies from enrollment to therapeutic cART initiation Age at all visits with the goal of determining:  Age at enrollment into program  Age at antiretroviral (any antiretroviral cART or short course or single dose) initiation for pMTCT  Age at cART initiation for treatment