Effectiveness of reduced-dose efavirenz in hiv therapy considering patient adherence

Abstract: Antiretroviral drugs have revolutionized HIV care and enabled better management of the infection thus allowing patients survive for many years. One proposed approach to increase access to such drugs in sub-Saharan Africa is to use of a reduced-dose alternative of the drug efavirenz, with 400 mg rather than regular 600 mg dose. This effectively would provide medication for 50 percent more persons with the same amount of active ingredient. However, antiretroviral drugs require high patient adherence to achieve intended therapeutic effect, and it is unclear if a reduced-dose therapy would have sufficient efficacy, and if it would lead to an increased risk of viral resistance. The time profile of drug plasma concentration and corresponding long-term viral load was estimated using integrated population PK/PD simulations, with model parameters based on selected research studies. The results suggest a reduced dose 400 mg, rather than 600 mg regular dose, efavirenz in HIV therapy would place strict demands on patients to maintain very high adherence levels, at least 80-90 percent, to maintain sufficient drug concentration in blood plasma, and to minimize risk of viral failure. However, it is relatively rare for HIV therapy programs in sub-Saharan Africa to consistently achieve such high adherence levels. In addition, if patients are co-administered rifampin, a drug widely used in TB care, this increases hepatic metabolism and plasma clearance rate, resulting in further reduced average drug plasma concentration. These findings suggest a reduced dose efavirenz treatment alternative may be most (only) relevant for patient categories expected to maintain high adherence; and in particular among persons who have been confirmed to have CYP2B6 genotype consistent with inherently lower drug metabolism. At usual adherence levels it is estimated a reduced dose alternative may increase the share of patients at risk of viral failure by 5 to 15 percent vs. regular dose of 600 mg.