Clinical Pharmacology in HIV Therapy

Abstract

The success of combination antiretroviral therapy in the treatment of HIV-1-positive individuals has shifted clinical attention toward combination antiretroviral drug regimens that optimize tolerability, long-term safety, and durable efficacy. Wherever patients have access to treatment, morbidity and mortality are increasingly driven by non-HIV-associated comorbidities, which may be observed earlier than in age-matched controls and despite the best available combination antiretroviral therapy. Similarly, HIV-1-positive individuals are now diagnosed and treated earlier with anticipated lifelong therapy. The contribution of specific antiretroviral agents to long-term morbidity and mortality is dependent on the pharmacologic characteristics of these agents, and it is increasingly important in this context.

Keywords: Anti-Retroviral Agents; Attention; Clinical; Comorbidity; HIV; HIV Infections; HIV-1; Health Services Accessibility; Morbidity; Pharmacology; antiretroviral therapy; drug interactions; drug nephrotoxicity; pharmacokinetics.

Figure 1.

Diary of key sentinel timeline events from discovery to evolution of therapy of HIV-1. AZT, Zidovudine.

Figure 2.

Targeting HIV-1. HIV-1 life cycle and classes of antiretroviral agents that interfere with these specific steps. The seven steps in the HIV lifecycle are identified by numbered circles. Classes of antiretroviral drugs are shown as red lines near the life cycle step that they inhibit. NNRTI, non-nucleoside reverse transcription inhibitor; NRTI, nucleoside reverse transcription inhibitor; RT, reverse transcription; RTI, reverse transcription inhibitor.

Figure 3.

The proximal kidney tubule is the target for tenofovir-associated nephrotoxicities. Handling of tenofovir (TFV), the active metabolite of tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF), by the proximal tubular cells of the kidney. TFV exits the tubular circulation primarily via the organic anion transporter 1 (OAT1) on the basolateral membrane, and after it is within the cell, it exits into the urine via the apical multidrug resistance protein type 4 (MRP 4) and possibly, MRP 2. TAF is more stable in plasma than TDF, with minimal hydrolyses to TFV. The bulk of TAF is rather transported to target cells. MATE1, multidrug and toxin extrusion transporter 1; OCT2, organic cation transporter 2.

Figure 4.

Agents that interfere with creatinine secretion in proximal tubule raising its actual serum value. Creatine is secreted at the basolateral membrane via the organic cation transporter 2 (OCT2), and both dolutegravir and rilpivirine and commonly used drugs compete with this process. Creatinine exits the proximal tubular cells via multidrug and toxin extrusion transporter 1 (MATE1). Pharmacoenhancers cobicistat and ritonavir compete with this step as well as other drugs. MRP 2, multidrug resistance protein type 2; MRP 4, multidrug resistance protein type 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; TFV, tenofovir.