Modeling the HIV-1 Antiretroviral Therapeutic Drug Interaction

Editor: To model the antiretroviral therapeutic (ART) drug interaction with the HIV-1 virus, a two-domain model is proposed that separates HIV-1 into a stable nonproliferating domain where the virus is integrated into the host resting memory CD4⁺ T cells ¹ and a second domain where the virus is in the blood in a rapidly reproductive state. ¹ ART inhibits blood HIV-1 reproduction to a level sufficient to prevent progression to the AIDS end stage, which is the goal of ART. Twenty-five FDA approved antiretroviral drugs grouped into six classes are aimed toward this goal: NRTIs (nucleoside/nucleotide inhibitors), NNRTIs (non-NRTIs), PIs (protease inhibitors), FIs (fusion inhibitors), CCR5s (chemokine cell receptor 5 antagonists), and INSTIs (integrase inhibitors). ²

HIV-1 integrated into host memory CD4⁺ T cells is in a stable state ¹ and unaffected by ART. Consequently, proliferation in the blood will continue, if unchecked by drugs. ¹ Against this dual function capability of HIV-1, no cure is possible, and control levels of HIV-1 must be maintained throughout the host's life span. Adherence to treatment regimen, thus, becomes critical. ³ The interaction of the HIV-1× ART is unique in that it is unaffected by differences in human host characterizations. In consequence, truly random assignment of patients to experimental/control groups in preclinical research is not necessary. ⁴

In place of current indirect measures of inhibitory control (e.g., number of weeks to achieve control levels of HIV-1, or number of months of controlled HIV-1 versus uncontrolled HIV-1), a proposed direct measure of inhibition is rate: r = HIV_J − HIV_k/HIV_J − HIV_N, where j and k refer to HIV-1 cps/mL in the initial and subsequent observations; whereas N refers to the total overall cps/mL. Rate is a superior measure based on scientific simplicity. It integrates into one measure the HIV values of initial cps/mL × ART duration. Importantly, the rate measure can also provide a check on self-reports of adherence/nonadherence. It can decrease only if patient is nonadherent. In a retrospective case history research study with 10 Syracuse VA HIV-1 outpatients, rate was found to provide a quantitative basis for the highly active antiretroviral therapy (HAART) characterization, showing a stable high rate of inhibition, r_s = 0.9–1.0 of the total virus cps/mL with almost no variability among patients.

To contextualize the descriptive narrative aforementioned, Table 1 presents treatment regimen duration and initial and current HIV viremia levels (cps/mL),. Outcome measure was the indirect measure of controlled (<75 cps/mL) versus uncontrolled (>75 cps/mL). Controlled values ranged from 6 to 139 versus <5 months of uncontrolled viremia in the n = 10 sample. Owing to raw score differences in treatment duration (M), raw score values were expressed in unit normal values × 100 before statistical analysis. (correlated t = 4.10, α = <0.01, df = 10). Rates of suppression for each patient were all within a narrow range: 0.98–1.0 of cps/mL.