Benjamin Young

Background: Cases of renal dysfunction have been reported in HIV-infected patients taking tenofovir (TDF), but few large studies have examined population-level changes in renal function associated with TDF use in patients in routine care. Methods: The authors analyzed data from participants in the HIV Outpatient Study (HOPS) who had normal baseline renal function and received >1 month of TDF-containing (n = 593) or TDF-sparing (n = 521) HAART after November 1, 2001. Results: Median baseline CrCl estimated by Cockcroft-Gault equation was 106 mL/min for TDF-exposed and 110 mL/min for TDF-unexposed patients (P = 0.06). In multivariable analyses, 1-year changes in CrCl (mL/min) from baseline were —5.7 among TDF-exposed and 2.6 among TDF-unexposed (P < 0.001). Incident renal disease was diagnosed in 7 TDF-exposed and 3 TDF-unexposed patients. Conclusions: In this large cohort of HIV-infected outpatients, use of TDF-containing HAART was associated with modest decreases in CrCl during the first year, but not with frequent, clinically significant renal toxicity.

Current highly active antiretroviral therapy (HAART) for the treatment of HIV infection requires the concomitant administration of three or four different agents, often with a high potential for drug–drug interactions. Additionally, some HIV-positive patients still require concomitant treatment with drugs for opportunistic infections, some require medication to treat unrelated medical conditions and/or the metabolic complications of antiretroviral therapy, others may self-medicate with herbal formulations and/or over-the-counter drugs, and still others many take drugs for recreational reasons or to manage addiction. Therefore, the virtually limitless number of drug combinations that may be taken by patients undergoing treatment of HIV infection makes drug–drug interactions almost inevitable. Managing these interactions is one of the major challenges associated with the multidrug regimens used for HIV therapy. This paper provides an overview of the most common interactions between antiretrovirals in the same and different classes—nucleoside analogue reverse transcriptase inhibitors (NRTI), protease inhibitors (PI), and non-nucleoside reverse transcriptase inhibitors (NNRTI)—by focusing on principles rather than specific interactions. The paper also addresses interactions between these antiretrovirals and other commonly used medications that may be prescribed concomitantly.

Several dual nucleoside reverse transcriptase inhibitor (NRTI) combinations provide efficacy when combined with a 3rd agent. However, there are a number of issues with current NRTI and nucleotide reverse transcriptase inhibitor (NtRTI) combinations that often lead to treatment failure and limited treatment options. These issues include suboptimal potency, drug interactions, toxicities, tolerability issues, and selection of resistance mutations that confer cross-resistance. Options for simplified NRTI backbones include fixed-dose combinations and agents that allow once-daily dosing; however, once-daily treatment choices are currently limited because of a lack of data on potential combinations. This article provides an historical perspective on the use of NRTI backbones in the treatment of HIV infection and outlines the advantages and disadvantages of currently available backbone combinations. In addition, it provides a brief introduction to backbone combinations under investigation as potential options for initial therapy. In an environment where several NRTI/NtRTI backbones offer comparable efficacy, treatment decisions will increasingly be made based on toxicity, resistance, and convenience considerations.

Increasing knowledge of the principles of viral dynamics in HIV infection has dramatically changed our understanding of the disease. Basic concepts of viral kinetics and implications for the treatment of HIV-infected persons are reviewed.