Drug interactions involving combination antiretroviral therapy and other anti-infective agents: repercussions for resource-limited countries.

The scale-up of antiretroviral treatment (ART) in resource-poor countries has been impressive, both in its scope and in its impact. In 2003, 400,000 people in resource-limited settings were receiving antiretroviral drugs (ARVs); by 2006, this number had increased to 2 million people [1]. Treatment of common infections occurring with HIV is also increasing, as most HIV-infected persons live in areas where infectious diseases such as tuberculosis (TB) and malaria are prevalent. The use of over-the-counter and natural health products is also pervasive [2]. Therefore, the management of HIV infection in these settings will require multiple concurrent medications, with a potential for drug interactions and overlapping toxicities. Although in recent years there has been a significant expansion in access to ARVs in resource-poor countries, options are limited in most areas. In 2006, 95% of individuals receiving first-line ARVs in resource-poor settings were being treated with 1 of 4 fixed-dose regimens: stavudine (d4T) lamivudine (3TC) nevirapine (NVP); zidovudine (AZT) 3TC NVP; d4T 3TC efavirenz (EFV); or AZT 3TC EFV [1]. Currently, the World Health Organization (WHO) recommends a first-line regimen that includes a thiacytadine analogue (either 3TC or emtricitabine), a companion nucleoside reverse-transcriptase inhibitor (NRTI) (either AZT, tenofovir [TDF], abacavir [ABC], or d4T), and a nonNRTI (NNRTI) (either EFV or NVP) [3]. Second-line regimens include 2 previously unused NRTIs (didanosine, TDF, ABC, 3TC, and/or AZT) coupled with either a ritonavir (RTV)– boosted protease inhibitor (PI) (either lopinavir, saquinavir, indinavir, atazanavir, or fosamprenavir) or unboosted nelfinavir. Available antimicrobial drugs such as itraconazole, ketoconazole, clarithromycin, and rifampin have serious interactions or overlapping toxicities with ARVs. Cost, as well as political and infrastructural constraints, limits access to drugs—such as fluconazole, azithromycin, and rifabutin—that have fewer interactions [4]. Thus, even when drug interactions are well characterized, clinicians caring for HIV-infected patients have few options. Now that HIV treatment is available in many resource-limited countries, clinicians must understand the basic principles of drug metabolism. In this review, we describe new insights into mechanisms of CYP450 induction and inhibition. In addition, we provide a comprehensive review of the major interactions between ARVs recommended by WHO as firstor second-line therapy for HIV in resource-limited settings and drugs used to treat TB, malaria, and fungal, bacterial, and parasitic diseases.