Interactions between antineoplastic agents and ARV drugs.

Drug-drug interactions can be a serious complication of taking multiple medications and account for 3% to 5% of all in-hospital medication errors.1 The consequences of drug interactions vary, ranging from excessive blood levels causing drug toxicities to therapeutic failures following sub-optimal blood levels. While the advent of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has revolutionized HIV care, the immunosuppression caused by this disease still increases the risk of cancer illnesses among this population. HIV-infected patients are burdened by a higher prevalence of neoplastic diseases, and along with the presence of HIV-associated co-morbidities and opportunistic infections, remain targets for polypharmacy, which in turn leads to drug-drug interactions. The elucidation and understanding of the cytochrome P450 enzyme system has allowed us to study and at the same time speculate, based on the CYP characteristics of each agent, upon the nature of the drug-drug interactions that may arise upon coadministration. Since both antineoplastic agents and antiretrovirals are substrates, inducers, or inhibitors of the cytochrome P450 enzyme system, interactions occur when these groups of medications are administered concurrently. This article will review current literature regarding these interactions, mostly between the HIV-1 protease, nucleoside, and non-nucleoside reverse transcriptase inhibitors and commonly-used antineoplastic agents. Currently there are six major classes of HIV antiretroviral agents available for use in highly active antiretroviral therapy (HAART), namely: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), integrase inhibitors (IIs), chemokine receptor (CCR5) antagonists. Since NRTIs, fusion and integrase inhibitors do not undergo hepatic metabolism through the cytochrome P450 (CYP450) enzyme system, their drug interaction profile is minimal. NNRTIs, PIs and maraviroc (a CCR5-antagonist) are extensively metabolized by the CYP system and so are highly susceptible to drug-drug interactions.2 HIV-infected patients with additional cancer diagnoses receive numerous medications including antiretroviral agents, antineoplastics, drugs for supportive care, and medications for other co-morbidities or HIV/AIDS-associated opportunistic infections. Such patients are at risk for polypharmacy and drug-drug interactions.3 Serious adverse drug events often accompany drug-drug interactions that account for significant morbidity, damage to vital organs and sometimes death.4,5,6 Despite the impact of combined antiretroviral therapy on HIV-related mortality, malignancies remain the second most common cause of death following HIV infection in developed countries.7,8 Whereas patients who receive antineoplastic agents along with their antiretroviral agents may achieve better responses and higher rates of survival than those who receive only antineoplastic therapy,9 the likelihood of clinically significant drugdrug interactions increases. This is mostly because, similar to many of the commonly used antineoplastic agents, both protease inhibitors and the non-nucleoside reverse transcriptase inhibitors are either substrates, potent inhibitors, or inducers of the cytochrome P450 (CYP) enzyme system. As a consequence, coadministration of these drugs could result in pharmacokinetic interactions that either increase or decrease serum concentrations, potentially affecting toxicity or pharmacodynamic interactions that may increase or decrease efficacy, potentially leading to unexpected and unpredictable results. This review will discuss major drug interactions that occur between antiretroviral agents and antineoplastic agents in HIV-infected patients. Where studies have not been carried out, knowledge of the metabolic pathways will enable providers to predict potential drug-drug interactions.