Systemic therapy for malignancy in patients on antiretroviral medications

INTRODUCTION — The morbidity and mortality associated with HIV have been substantially decreased with the use of potent antiretroviral therapy (ART). For most individuals with HIV who are treated with potent ART, AIDS has been transformed into a chronic disease. (See "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings" and "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)

With increased longevity, both AIDS-related and non-AIDS-related malignancies have become an important cause of illness among individuals infected with HIV. The specific malignancies associated with an increased incidence in people infected with HIV are reviewed elsewhere. (See "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV infection and malignancy: Management considerations".)

PRIORITIZATION BETWEEN CANCER AND HIV TREATMENT — Systemic therapy of malignancy in patients infected with HIV may present challenges because of the overlapping toxicities and potential drug-drug interactions between anticancer and antiretroviral agents. Avoiding unexpected toxicity or lack of therapeutic effectiveness requires close collaboration between the infectious disease expert managing the antiretroviral therapy (ART) for HIV infection and the medical oncologist treating the cancer.

Optimal management of HIV infection involves treatment with combinations of antiretroviral medications. However, advanced malignancy can pose an immediate threat to health and survival, and this may require that antineoplastic treatment take priority over ART [1,2]. As the agents utilized to treat both cancer and HIV infection evolve, we are able to optimally treat both HIV and the malignancy.

There are significant risks associated with stopping ART, as was demonstrated when intermittent ART was found to be inferior to constant dosing. Dose modifications or the use of alternative medications for either the ART or the anticancer treatment may be required to balance the competing treatment needs. Newer-generation antiretroviral drug classes (eg, integrase inhibitors) have a decreased risk of drug-drug interactions with anticancer agents. (See 'Management' below.)

OVERLAPPING TOXICITIES — Chemotherapy can be associated with a wide range of toxicities. If a patient being treated with antiretroviral agents for HIV infection develops malignancy and the proposed anticancer treatment regimen has the potential for serious overlapping toxicity, the following options exist (in decreasing order of preference):

●Substitute an alternative antiretroviral drug with a different toxicity profile.

●Select an alternative chemotherapy regimen without overlapping toxicity.

Key areas of potential additive toxicity are discussed in this section.

Neurotoxicity — Neurotoxicity is an important complication of both select antiretroviral and anticancer chemotherapy agents.

The older nucleoside reverse transcriptase inhibitors (NRTIs) that are no longer used clinically, such as didanosine and stavudine, were associated with peripheral neuropathy that may be irreversible and therefore persistent from past use [3]. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)", section on 'Risk factors'.)

Platinum compounds, taxanes, vinca alkaloids, and brentuximab vedotin are the chemotherapeutics most frequently associated with peripheral neuropathy. Chemotherapy-induced neuropathy with these agents is generally cumulative or dose related, with management consisting of dose reduction or lower dose intensity. A wide range of other anticancer agents have also been associated with various neurotoxicities. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy".)

Myelotoxicity — Bone marrow suppression, especially neutropenia, is a frequent and important complication in patients with untreated or advanced HIV infection. In particular, zidovudine, which is used for pediatric patients as well as treatment-experienced patients in resource-limited settings who have failed initial therapy, is associated with severe neutropenia in approximately 8 percent of patients with advanced AIDS, and it should be avoided, if possible, in patients about to receive marrow-toxic chemotherapy [4]. Boosted protease inhibitors or integrase inhibitors may also potentiate neutropenia in the setting of cancer [5].

Furthermore, drug-drug interactions, either at the level of enzymatic metabolism or drug efflux transporters, could increase the exposure of hematopoietic stem cells to cytotoxic chemotherapy [6]. Even targeted agents not commonly associated with myelotoxicity may have bone marrow suppression as a more common side effect when combined with ART [7].

Since most cytotoxic chemotherapy regimens are associated with neutropenia, and since these agents have a narrow therapeutic index, combinations of chemotherapy with zidovudine should be avoided, and an alternative NRTI or integrase inhibitors should be prescribed. If zidovudine use cannot be avoided, less myelosuppressive chemotherapy should be administered, if feasible, and the patient should be monitored closely for neutropenia.

Hepatotoxicity — A wide range of chemotherapy agents can cause hepatoxicity or require dose modification in patients with hepatic dysfunction. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents".)

Selected antiretroviral agents may also cause hepatotoxicity that can potentially affect chemotherapy dosing:

●Didanosine (an older NRTI), stavudine, and zidovudine can produce hepatotoxicity associated with lactic acidosis and steatosis [8]. Maraviroc has been noted to rarely produce hepatotoxicity associated with allergic features [9]. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors", section on 'Hepatic steatosis' and "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors", section on 'Hyperlactatemia and lactic acidosis'.)

These agents should be stopped or replaced before initiating cytotoxic chemotherapy with agents that are metabolized by the liver. Of note, both didanosine and zidovudine are most commonly used in resource-limited regions.

Other NRTIs (abacavir, emtricitabine, lamivudine, and tenofovir), a non-NRTI (efavirenz), and unboosted integrase inhibitors are less likely to be hepatotoxic and often can be substituted.

●Serum bilirubin is often used as a surrogate for liver function and, thus, as a guide for dose adjustment of cancer chemotherapy agents. However, several antiretroviral agents (particularly atazanavir, which is used in treatment-experienced patients in resource-limited regions) inhibit uridine diphospho-glucuronosyltransferase 1A1 (UGT1A1), which causes unconjugated hyperbilirubinemia similar to that seen in Gilbert syndrome [10-12] (see "Gilbert syndrome"). Consequently and in this context, chemotherapeutic agents need not be modified for hyperbilirubinemia when paired with these specific agents.

Measurements of serum transaminases and alkaline phosphatase are useful when assessing liver function in HIV patients on these antiretroviral agents, and they should be done more frequently in such patients. Unconjugated hyperbilirubinemia in the absence of other evidence of hepatic dysfunction is unlikely to be clinically significant but may mask signs of hepatotoxicity due to chemotherapeutic agents.

Cardiotoxicity — The long QT syndrome is a disorder of myocardial repolarization that is associated with an increased risk of life-threatening arrhythmia. A wide range of anticancer agents can also cause QT prolongation, including some cytotoxic agents and many of the newer molecularly targeted anticancer agents. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Drugs that prolong the QT interval'.)

Antiretroviral agents that are associated with QT prolongation include rilpivirine [13], atazanavir [14], ritonavir-boosted lopinavir (which is used mostly in resource-limited settings) [15], and saquinavir [16]. Combinations of agents that can prolong the QT interval should be avoided because of the potential for arrhythmias and sudden death. (See "Cardiac and vascular disease in patients with HIV", section on 'Long QT syndrome'.)

DRUG-DRUG INTERACTIONS — Newer-generation antiretroviral drugs (eg, integrase inhibitors and entry inhibitors) have a decreased propensity for drug-drug interactions with anticancer agents. Additionally, drug interactions between monoclonal antibodies and antiretroviral drugs are unlikely due to pharmacokinetics [17].

Some less commonly used antiretroviral agents that are a component of potent antiretroviral therapy (ART) can act as substrates, inhibitors, or inducers of the cytochrome P450 (CYP450) isoenzyme system, which consists of a number of hepatic enzymes responsible for clearing a wide range of toxins from the body. Both antiretroviral and anticancer drugs may affect different isoenzymes and result in agent-specific drug interactions. For more detailed information on potential drug-drug interactions, refer to the University of Liverpool HIV Drug Interactions website or the drug interactions program within UpToDate. Such drug interaction programs are meant to be a general guide, and consultation with a clinical pharmacist may provide more specific insight.

Since there are often limited data available from clinical trials, potential interactions are often based on information about the pharmacokinetic pathways for specific drugs. For various standard combination chemotherapy regimens, each drug in the regimen should be assessed for drug interaction potential. In complex regimens, it may be difficult to modify the dose since the dose of each drug in the original combination took into account not only the pharmacokinetics, but also the pharmacodynamics of all agents.

The metabolic pathways involved for individual drugs vary significantly and make it difficult to generalize interactions based on drug class. Interactions may fall into one of two general categories:

●Drugs that inhibit elimination – Drugs that inhibit a route of elimination may cause the substrate drug to increase to a potentially supratherapeutic or toxic level, resulting in the need to decrease the dose of the substrate. As an example, an antiretroviral agent may increase the concentration or bioavailability of the anticancer agent by inhibiting or acting as a substrate for a specific isoenzyme that is responsible for the metabolism and clearance of that anticancer agent. This may result in increased toxicity because of the narrow therapeutic index normally associated with these drugs.

●Drugs that induce elimination – Drugs that induce a route of elimination may cause the substrate drug to decrease to a potentially subtherapeutic level. As an example, the metabolism and clearance of the anticancer agent may be increased by induction of the relevant CYP450 isoenzyme by an antiretroviral agent, thus resulting in decreased efficacy and the potential need to increase the dose of the anticancer agent [18]. The exception is prodrugs, which require metabolism to their active species. Two common anticancer prodrugs are irinotecan and cyclophosphamide. In this case, the drug-drug interaction concern is in the opposite direction as drugs that undergo metabolism result in a less active or even toxic metabolite.

MANAGEMENT — Decisions about switching or stopping antiretroviral regimens should only be made after close consultation between the care provider managing the HIV medications and those managing the cancer chemotherapy.

Although patients with HIV are evaluated in clinical trials for some cancer therapies [19,20], there are no formal guidelines to direct treatment and avoid overlapping toxicities and drug-drug interactions when antiretroviral agents and anticancer agents are administered concurrently. ART such as integrase inhibitors and entry inhibitors have a decreased risk of drug-drug interactions with anticancer agents. (See "HIV infection and malignancy: Management considerations", section on 'Treatment'.)

Dose modifications — At the current time, there is no guidance on dose adjustment of either potent antiretroviral therapy (ART) or chemotherapy in order to minimize drug interactions. The AIDS Malignancy Consortium (AMC), a National Cancer Institute (NCI)-supported clinical trials group, is conducting prospective clinical trials with molecularly targeted agents in patients on potent ART, and it has completed such a trial with sunitinib [7]. Clinicians and clinical investigators should be aware of the potential for interactions that can be inferred from knowledge of drug metabolism and use this information for decision making.

The importance of a partnership between oncologists and specialists in infectious diseases to manage these patients and to discuss strategies using combinations of drugs cannot be overemphasized. As life expectancy for patients with HIV increases, and as more patients develop malignancies (whether HIV related or not), understanding the potential interactions between cancer chemotherapy agents and antiretroviral drugs will grow in importance.

Modifying antiretroviral therapy — In general, for patients receiving systemic cancer therapy, an antiretroviral regimen is modified rather than discontinued completely if it is necessary to minimize toxicity and/or drug-drug interactions. This is especially valid given the changing landscape of anticancer therapy which includes checkpoint inhibitor immunotherapy and molecularly targeted agents in additional to cytotoxic chemotherapy. Molecularly targeted agents tend to be administered orally on a chronic basis and, thus, are not conducive to a temporary interruption of ART, which should be avoided under most circumstances.

For example, ART that includes an unboosted integrase inhibitor plus two nucleoside reverse transcriptase inhibitors (NRTIs), is generally well tolerated and has a low potential for drug-drug interactions. Most patients can also be switched to a newer regimen. However, if a patient requires ART containing a boosted protease inhibitor and has no other treatment options, such treatment may be discontinued in patients who are to receive high-dose chemotherapy as preparation for autologous bone marrow transplantation. As an example, an etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy regimen was used to successfully treat patients with AIDS-related lymphomas; ART was interrupted to ensure that the maximum intensity of the regimen could be given without toxicity or drug-drug interactions [21].

Initiating antiretroviral therapy — Most patients starting a modern ART regimen (eg, an unboosted integrase inhibitor plus two NRTIs) are able to concurrently initiate chemotherapy with a low risk of drug-drug interactions. This approach has been associated with improved reconstitution of the immune system, with fewer opportunistic infections, better chemotherapy tolerance, and improved oncologic outcomes. Guidelines for the initiation and interruption of ART are discussed elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Comorbid conditions' and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Safety and efficacy of immunotherapy — In HIV-positive patients with cancer, checkpoint inhibitor immunotherapy can be administered safely and effectively in conjunction with ART. These data are discussed separately. (See "HIV infection and malignancy: Management considerations", section on 'Safety and efficacy of immunotherapy'.)

SUMMARY

●Cancer in patients infected with HIV – The development of highly active antiretroviral therapy (ART) for the treatment of HIV infection has transformed AIDS into a chronic disease for most individuals infected with the disease. With increased longevity, both AIDS-related and non-AIDS-related malignancies have become an increasingly important cause of illness among individuals infected with HIV. (See "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings" and "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV infection and malignancy: Management considerations" and "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)

●Toxicities – Concurrent therapy with antiretroviral and anticancer agents may result in a range of overlapping toxicities. These include neurotoxicity, myelotoxicity, hepatotoxicity, and cardiotoxicity. (See 'Overlapping toxicities' above.)

●Drug-drug interactions – There is significant potential for drug-drug interactions between certain antiretroviral agents (ie, boosted protease inhibitors) and anticancer drugs (ie, cytochrome P450 34A [CYP3A4] substrates) because of shared pharmacokinetic pathways and the narrow therapeutic index of these agents. (See 'Drug-drug interactions' above.)

•The combination of an integrase inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIs), and other newer ART regimens, have very few drug-drug interactions with commonly used chemotherapy regimens.

•For more specific information on potential drug-drug interactions, refer to the University of Liverpool HIV Drug Interactions website or the drug interactions program within UpToDate.

●Management – In general, for patients receiving systemic cancer therapy, an antiretroviral regimen is modified rather than discontinued completely if it is necessary to minimize toxicity and/or drug-drug interactions. However, there are no formal guidelines to direct management when patients require concurrent management of both HIV infection and malignancy, except for a limited number of chemotherapy agents. (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michelle A Rudek, PharmD, PhD (deceased), who contributed to earlier versions of this topic review.