BALANCING CARDIAC RISK AND IMMUNOLOGIC BENEFITS IN DECISIONS ON HIV ANTIRETROVIRAL TREATMENT INITIATION

Purpose:    Some antiretroviral drugs may be associated with increased risk of cardiovascular morbidity.  However, late initiation of antiretroviral therapy (ART) may diminish immunological benefits. The appropriate timing for initiating ART that accounts for these tradeoffs is currently unknown. 

Method:    We developed a stochastic dynamic programming model for optimizing quality-adjusted life expectancy (QALE) while balancing benefits of ART and cardiac risk.  The population was stratified by age, gender, and CD4 count.  Mortality was decomposed into HIV-specific, cardiac, and background age/gender-specific death rates.  The optimal decision about ART initiation and remaining QALE was calculated for each age and CD4 state up to ≥650 cell/mm³.  We compared the expected remaining QALE between the optimal decision and if treatment is initiated regardless of CD4 count.

Result:    For a 35 year-old male, it is optimal to start treatment at any CD4 count as long as ART is associated with a fixed percentage increase in cardiac mortality rate of less than 440% above baseline or a time-variable linear increase of less than 4% of baseline for each year on ART.  If ART increases cardiac mortality rate by 5-22% for each year on treatment, it is optimal to wait until CD4 counts drop below 650 cells/mm³.    For a 55 year-old male, it is optimal to start treatment at any CD4 count if increased risk from ART is a fixed multiplier less than 65% above baseline or a variable increase less than 3% for each year on ART.  Optimal ART initiation state drops below 650 cells/mm³ if additional cardiac mortality rate increases by 4-9% with each year on treatment, and below 500 cells/mm³ if the increase is 10-45% with each year on treatment.   For all patients, regardless of age or CD4 count, the gain in QALE from following the optimal policy compared with always starting treatment (even at CD4≥650 cell/mm³) is less than one month under a wide range of assumptions about ART-associated cardiac toxicity.

Conclusion:    The optimal time to initiate ART depends on the magnitude and time-dependence of the additional cardiac mortality from ART.  However, unless cardiac mortality risk increases significantly, the gain in life expectancy from following the optimal policy versus early treatment initiation is small and may be outweighed by the simplicity of a “treat always” recommendation.