Drug-Drug Interactions Between HIV Medications and Chemotherapy Agents

Chung-Shien Lee, PharmD BCOP BCPS
Assistant Professor
St. John’s University College of Pharmacy
Queens, NY

Human immunodeficiency virus (HIV) continues to affect millions of Americans and others around the globe. At the end of 2015, an estimated 1.1 million persons 13 years of age or older were living with HIV infection in the United States.¹ In 2016, the number of new HIV diagnoses in the United States was 39,782, and the number of deaths was 6,160.² Both of these numbers have decreased substantially and continue to decline following the introduction of antiretroviral therapy (ART). HIV has become a chronic disease state for those dependent on lifelong use of ART.

Patients living with HIV have a significantly increased risk of developing some cancers compared to similar patients without HIV.^3,4 Patients who are diagnosed with both HIV and cancer present a challenging treatment scenario. Cancer treatment can supersede the treatment of other diseases because of its urgency and the poor prognosis that often accompanies the disease. Patients taking ART and being treated with chemotherapy are at risk for drug-drug interactions (DDIs). Management strategies to consider when the risk of DDIs is present include selecting an alternative chemotherapy or ART or temporarily discontinuing the ART. Temporarily withholding ART is the less desirable clinical plan, but risks and benefits must be considered in each scenario. For example, if a patient with HIV is taking ARTs that have potential DDIs and is diagnosed with a curable cancer, then all attempts should be made to achieve appropriate treatment of the cancer. If concomitant treatment with an interacting ART and chemotherapy is necessary, dose adjustments to either therapy may be warranted in order to increase the chance of cure and minimize toxicity.

Several classes of medications can be used in combination as ART. They are listed and their potential for DDIs is summarized in (Table 1-see PDF). Protease inhibitors (PIs), integrase inhibitors (except raltegravir), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), and cobicistat in particular have a higher likelihood of DDIs because of their cytochrome P450 3A4 (CYP3A4) metabolism. Dolutegravir, raltegravir, and maraviroc have fewer DDIs and could be alternatives.^27,28,30 Oral chemotherapy agents are more prone to DDIs with ART. More than half of the oral chemotherapy agents (mostly tyrosine kinase inhibitors) are substrates of CYP3A. In addition, patients being treated with chemotherapy are sometimes concomitantly taking acid-suppressive therapy. Patients taking rilpivirine and atazanavir should avoid concomitant use of proton pump inhibitors.^16,17

Risks for additive toxicities are also present with any concomitant medication use. Neurotoxicity (specifically neuropathy, with didanosine and stavudine) can occur, and the use of didanosine and stavudine with platinum agents, taxanes, vinca alkaloids, and proteasome inhibitors should be avoided, if possible.^6,9,32 Zidovudine use should be avoided with concomitant myelosuppressive chemotherapy because of its attendant risk of severe neutropenia.¹⁰ The use of didanosine, stavudine, zidovudine, and maraviroc can lead to hepatotoxicity; therefore chemotherapy that can also cause hepatotoxicity or be metabolized by the liver should be used with caution.^6,9,10,30,33 QT prolongation with protease inhibitors (ritonavir, atazanavir, saquinavir) and rilpivirine is of concern.^16,17,23,24 Concomitant QT-prolonging chemotherapy and supportive care should be avoided in order to circumvent the potential for arrhythmias and death.

In conclusion, because of the paucity of data studying DDIs between ART and chemotherapy, pharmacists should be vigilant about the possibility of DDIs when concomitant therapy is given. Consideration should also be given to the supportive care medications that may be needed in patients being treated with chemotherapy and ART. Pharmacotherapy in these patients should be individualized, and communication and collaboration with various specialties should be constant throughout treatments.

References

1. Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2010–2015. HIV Surveillance Supplemental Report 2018;23(No. 1). Available at www.cdc.gov/ hiv/library/reports/hiv-surveillance.html. Published March 2018. Accessed February 12, 2019.
2. Xu J, Murphy SL, Kochanek KD, et al. Deaths: Final Data for 2016. Natl Vital Stat Rep. 2018 July;67(5):1-76.
3. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007 July 7;370(9581):59-67.
4. Hernández-Ramírez RU, Shiels MS, Dubrow R, et al. Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study. Lancet HIV. 2017 Nov;4(11):e495-e504. doi: 10.1016/S2352-3018(17)30125-X. Epub 2017 August 10.
5. Ziagen (abacavir) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; September 2015.
6. Videx (didanosine) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co.; December 2018.
7. Emtriva (emtricitabine) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; December 2018.
8. Epivir (lamivudine) [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc.; November 2018.
9. Zerit (stavudine) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co.; December 2018.
10. Retrovir (zidovudine) [prescribing information]. Saddle Brook, NJ: Acetris Health, LLC; December 2018.
11. Viread (tenofovir disoproxil fumarate) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; December 2018.
12. Pifeltro (doravirine) [prescribing information]. Whitehouse Station, NJ: Merck and Co., Inc.; August 2018.
13. Sustiva (efavirenz) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co.; October 2017.
14. Intelence (etravirine) [prescribing information]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; November 2018.
15. Viramune (nevirapine) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; September 2018.
16. Edurant (rilpivirine) [prescribing information]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; February 2018.
17. Reyataz (atazanavir) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co.; March 2018.
18. Prezista (darunavir) [prescribing information]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; January 2019.
19. Lexiva (fosamprenavir) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; September 2009.
20. Crixivan (indinavir) [prescribing information]. Whitehouse Station, NJ: Merck and Co., Inc.; May 2018.
21. Kaletra (lopinavir and ritonavir) [prescribing information]. Barceloneta, Puerto Rico: AbbVie, Ltd. November 2018.
22. Viracept (nelfinavir) [prescribing information]. Research Triangle Park, NC: ViiV Healthcare Co.; September 2016.
23. Norvir (ritonavir) [prescribing information]. North Chicago, IL: AbbVie Inc.; November 2018.
24. Invirase (saquinavir) [prescribing information]. South San Francisco, CA: Genentech, Inc.; March 2018.
25. Aptivus (tipranavir) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; June 2018.
26. Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; February 2018.
27. Tivicay (dolutegravir) [prescribing information]. Research Triangle Park, NC: ViiV Healthcare Co.; September 2018.
28. Isentress (raltegravir) [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; January 2019.
29. Fuzeon (enfuvirtide) [prescribing information]. South San Francisco, CA: Genentech, Inc.; December 2018.
30. Selzentry (maraviroc) [prescribing information]. Research Triangle Park, NC: ViiV Healthcare Co.; July 2018.
31. Rudek MA, Flexner C, Ambinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol. 2011 September;12(9):905-912. doi: 10.1016/S1470-2045(11)70056-0. Epub 2011 May 12.
32. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf. 1998 December;19(6):481-494.
33. Walker UA, Bäuerle J, Laguno M, et al. Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology. 2004 February;39(2):311-317.