Drug–Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection

Abstract

The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug–drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug–drug interaction, a useful list of pharmacogenomic markers is provided.

HIV‐1, HAART and cancer: A complex relationship

“…Drug–drug interactions rely on many factors, such as the route of elimination, the effect on enzymes and transporters involved in drug metabolism. Both HAART and antioneoplastic drugs can be metabolized by CYP450 enzyme family and serve as CYP450 inhibitors, which can lead to drug accumulation and potential toxicity, or as CYP450 inducers, which leads to drug elimination and decreased efficacy, except for active metabolites of several drugs . As an example, ritonavir*, a PI and a potent CYP3A4 inhibitor, was reported to be associated with more severe toxicity in combination with chemotherapy compared to nonritonavir‐based HAART .…”

“…As an example, ritonavir*, a PI and a potent CYP3A4 inhibitor, was reported to be associated with more severe toxicity in combination with chemotherapy compared to nonritonavir‐based HAART . On the contrary, NNRTIs are mainly CYP3A inducers . HAART regimen should be modified when facing undesirable drug–drug interactions or elevated toxicity .…”

“…88 On the contrary, NNRTIs are mainly CYP3A inducers. 89 HAART regimen should be modified when facing undesirable drug-drug interactions or elevated toxicity. 38 In this case, preference can be given to the INSTI-based regimen, which is supposed to be relatively safe.…”

“…90 Regarding the complexity of multidrug interaction, if a patient is HAART-naive, it is recommended to start HAART more than a week before or after the cancer treatment in order to differentiate between adverse effects. 38 It is also recommended that clinicians consult major reviews dedicated to the topic of potential drug-drug interactions between HAART and chemotherapeutic drugs, 89,91,92 treatment guidelines 38 and refer to available resources such as http://www.hiv-druginteractions.org to optimize clinical management of HIV-infected patients with cancer and increase therapeutic benefit.…”

Evaluating Antiretroviral Therapy Initiation in HIV-Associated Malignancy: Is There Enough Evidence to Inform Clinical Guidelines?

“…19–23 Several experts therefore cite the need for prospective studies to further direct chemotherapy dosing, such that toxicities, especially bone marrow suppression, can be minimized without delivering subtherapeutic chemotherapy or risking development of HIV resistance. 24 …”