A quantitative basis for antiretroviral therapy for HIV-1 infection

Abstract

Highly active antiretroviral therapy (HAART) has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.

Figure 1

Determining inhibitory potential from complex dose-response curves of antiretroviral drugs. (a) Median-effect plots for hypothetical drugs with m = 1 or 3 and the same IC₅₀. Clinical concentrations 100–1,000 × IC₅₀ are assumed (shaded). (b) Dose-response curves RAL in primary CD4⁺ T cells from 35 donors (thin lines) and mean curve (thick line). m = 0.98 ± 0.12. The clinical concentration range is shaded. (c) Dose-response curves for ATV. The clinical concentration range with standard dosing (qd with RTV) is shaded. (d) Mean dose-response curves for commonly used antiretroviral drugs. (e) Median-effect plots for classes of antiretroviral drugs. Plots from (d) are grouped by drug class or subclass, and, within each group, normalized by IC₅₀. The deoxyadenosine analogs ddI and TDF have very different slopes in the clinical range and are plotted separately. (f) Median-effect plots normalized by C_max. The shaded area represents the approximate clinical concentration range, the lower end of which is not precisely defined here because the relationship between C_min and C_max varies for different drugs. However, except for NRTIs, clinical concentrations generally remain within a log of C_max. Where appropriate here and in Fig. 1g, values reflect concentrations achieved with pharmacokinetic boosting. For RTV, the 100 mg dose is assumed. (g) Mean IIP_ave ± SD for commonly used antiretrovirals. Conventional dose-response curves (f_u vs. log D) obscure the dramatic difference in the antiviral activity between a drug with a steep dose-response curve (DRV) and a hypothetical drug with the same IC₅₀ and m = 1 (inset).

Figure 2

Combined effects. (a) Bliss independence and Loewe additivity models for hypothetical drugs D₁ and D₂. Loewe additivity is based on isobolograms depicting the concentrations of D₁ and D₂ needed to produce 50% inhibition (black line). Deviations to the left or right reflect synergy or antagonism, respectively, if Loewe additivity is the model for combined effects. (b) Median-effect plots for D₁ and D₂ alone (solid lines) and predictions of the combined effects of D₁ + D₂ by the Bliss and Loewe models (dotted lines). D₁ and D₂ have slopes of 1 and 1.5, respectively, and are diluted in constant ratio from 10 × C_max which is assumed to be 10 × IC₅₀. (c) Degree of independence (DI) index for quantifying experimental (Exp) combined effects in relations to the models. (d) Representative combination experiments. Drugs were diluted at constant ratio from initial concentrations chosen to maximize the differences between the Bliss and Loewe predictions (see Methods). The figures show experimental measurements for single drugs and combinations (solid lines) and the predictions of the models (dotted lines). These examples illustrate characteristic patterns of Bliss independence (RAL-FTC), Loewe additivity (ETR-NVP), intermediate effect (ABC-NVP), and synergy (AZT-NVP). (e) Expected combination effects based on the binding site criterion. (f) Observed combination effects categorized by DI values: synergy, DI > 1.2; Bliss, 0.8 < DI < 1.2; intermediate, 0.2 < DI < 0.8; Loewe, −0.2 < DI < 0.2, antagonism, DI < −0.2. Because of lower infection with R5-tropic pseudoviruses, PI-MVC combinations could not be analyzed. Individual variation in the combined effect was substantial for some combinations (Supplementary Figure S4).

Figure 3

Estimating the inhibitory potential of triple combinations. (a) Expansion of the Bliss and Loewe models to three drugs. The three drug Bliss formula is based on a simple extension of the idea that the fraction of viruses unaffected by the blocks imposed by three drugs acting at different steps in the life cycle (f_u1+2+3) is the product of the fraction unaffected by each drug. The Loewe formula is based on the idea the inhibitors act in a mutually exclusive way or compete for the same binding site as discussed by Chou. It is derived from the general expression for an n drug combination with no synergy of antagonism as described in Supplementary Information, Methods. (b) Median-effect plots for hypothetical drugs D₁, D₂, and D₃ alone (solid lines) and predictions of the combined effects of D₁+D₂+ D₃ by the Bliss and Loewe models (dotted lines). D₁, D₂, and D₃ are diluted in constant ratio from 10 × C_max and assumed to have IC₅₀ values of 0.1, 0.1, and 0.01 × C_max and slopes 1, 1.5, and 0.8, respectively.

Figure 4

Inhibitory potential of three drug combinations. (a) Estimated IIP_ave1+2+3 for triple combinations of 19 commonly used antiretroviralss. Combinations are color coded by drug class, excluding combinations with more than one drug from the NNRTI, PI, or InSTI classes, or NRTI subclasses. The black bars represent the range of estimated IIP_ave1+2+3 values with the Loewe prediction at the left and the Bliss prediction at the right. Regimens are sorted based on the midpoint of the range. An estimate based on the weighted average of the three pairwise DI index values is shown as a green dot. IIP_ave1+2+3 values above the Loewe-Bliss range represent synergy, typically for regimens including thymidine analogues. The red line represents the minimum IIP_ave1+2+3 for a regimen achieving suppression of viremia in > 80% of patients. (b) Inhibitory potential of selected three drug combinations along with component single drugs and drug pairs. For combinations, inhibitory potential is shown as a range of IIP_ave1+2+3 values between the Loewe and Bliss predictions. For each component two drug combination, an estimate of IIP_ave based on experimentally determined DI index values is shown as a green bar. For three drug combinations, green bars represent estimates based on a weighted average of pairwise DI index values. Values are shown for currently recommended initial HAART regimens^, and, for purposes of comparison, a suboptimal TDF+3TC+ABC regimen.