Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Limitations to Treatment Safety and Efficacy

Adverse Effects of Antiretroviral Medications

Adverse effects have been reported with all antiretroviral (ARV) medications. Commonly reported reasons for switching or discontinuing oral or injectable therapy were due to adverse effects, especially with the initiation of antiretroviral therapy (ART) regimens in the late 1990s and early 2000s.¹ Fortunately, newer ART regimens are associated with fewer serious and intolerable adverse effects. Generally, <10% of participants who are ART-naive and who enrolled in randomized trials of newer agents experience treatment-limiting adverse events.^2,3 However, the short-term and long-term complications of ART may be underestimated because most clinical trials use specific inclusion criteria that exclude individuals with certain underlying medical conditions, and the duration of participant follow-up is relatively short (generally 2–4 years).

ART is recommended for all people with HIV regardless of CD4 T lymphocyte cell count, and with current treatments and approaches/strategies, therapy must be continued indefinitely. To achieve and sustain viral suppression over a lifetime, both long-term and short-term ART adverse effects must be anticipated and managed. From a safety and tolerability standpoint, the focus of management has evolved from identifying and managing toxicities related to early ARVs to individualizing therapy to avoid or mitigate long-term adverse effects, such as atherosclerotic cardiovascular disease, diabetes and other metabolic complications, kidney dysfunction, neuropsychiatric events, and accelerated declines in bone mineral density.

Antiretroviral Regimen Selection

When selecting an ARV regimen, clinicians must consider potential adverse effects and any prior history of drug intolerance. Additionally, several factors may predispose people with HIV to adverse effects of ARV medications. These factors include:

• Concomitant use of medications with overlapping and additive toxicities.
• Comorbid conditions that increase the risk of adverse effects. For example, underlying liver disease from alcohol use, coinfection with viral hepatitis, and/or liver steatosis^4,5 may increase the risk of hepatotoxicity when some protease inhibitors are used; and borderline or mild renal dysfunction increases the risk of nephrotoxicity from tenofovir disoproxil fumarate (TDF).⁶
• Certain ARVs that may exacerbate pre-existing conditions. For example, psychiatric disorders may be exacerbated by efavirenz (EFV), rilpivirine, and, infrequently, by integrase strand transfer inhibitors.^7,8
• Drug–drug interactions that may increase the toxicities of ARV medications or concomitant medications. For example, when pharmacokinetic boosters such as ritonavir or cobicistat are used.⁹
• Genetic factors that predispose people with HIV to some adverse effects of medications that are no longer commonly used in clinical practice, such as abacavir (ABC) hypersensitivity reaction,^10,11 EFV neuropsychiatric toxicity^9,12 or QTc (QT corrected for heart rate) prolongation,^13,14 and atazanavir (ATV)-associated hyperbilirubinemia.¹⁵
• Dosing errors, which can predispose people with HIV to adverse effects when medications are administered at incorrect doses—whether at doses that are too high or at inappropriate intervals—and can increase the likelihood of adverse effects.

Management of Adverse Effects

ART-associated adverse effects can range from acute and potentially life-threatening to chronic and insidious. When people with HIV experience treatment-limiting toxicities associated with ART, selecting new ART regimens that pose either no or a lower risk of exacerbating the condition or contributing to further complications is warranted. Serious life-threatening effects (e.g., hypersensitivity reaction due to ABC, symptomatic hepatotoxicity, severe cutaneous reactions) require the immediate discontinuation of all ARV medications and re-initiation of an alternative regimen without overlapping toxicity. Toxicities that are not life-threatening (e.g., urolithiasis with ATV, renal tubulopathy with TDF) can usually be managed by substituting another ARV medication for the presumed causative medication without interrupting ART. Chronic, non–life-threatening adverse effects (e.g., dyslipidemia) can be addressed either by switching the potentially causative medication for another medication or by managing the adverse effect with nonpharmacological interventions or pharmacologic interventions such as statins. Management strategies must be individualized for each person with HIV. When adverse effects occur during the use of long-acting injectable ARV drugs, management may be challenging due to the persistence of drug in the body over the course of many months to years. Oral lead-in regimens for cabotegravir plus rilpivirine are available to assess short-term tolerability.

Switching from an effective ARV agent or regimen to a new agent or regimen must be done carefully and only when the potential benefits of the change outweigh the potential risks of altering treatment. The fundamental principle of regimen switching is to maintain viral suppression. When selecting a new agent or regimen, providers should be aware that drug-resistant viruses previously acquired or selected, even those not detected by past genotypic resistance testing, are archived in HIV reservoirs. The resistant virus, even if absent from subsequent resistance test results, may reappear under selective drug pressure. See Optimizing Antiretroviral Therapy in the Setting of Viral Suppression for further discussion. It is critical that providers review the following information before implementing any treatment switch:

• Medical and complete ARV history, including prior virologic responses to ART
• All previous drug resistance test results
• Viral tropism (if maraviroc is being considered)
• HLA-B*5701 status (if ABC is being considered)
• Comorbidities
• Pregnancy status and the desire and/or ability to become pregnant or use contraceptives
• Hepatitis B virus (HBV) status. People with evidence of chronic HBV infection should not discontinue ARVs active against HBV (e.g., TDF, tenofovir alafenamide, lamivudine, emtricitabine). If discontinuation is necessary due to adverse effects, consult the HBV/HIV Coinfection section for guidance.
• Adherence history
• Prior intolerances to any ARVs
• Concomitant medications and supplements, considering any potential drug interactions with ARVs
• Cost to people with HIV and options for patient assistance programs if needed (see Cost Considerations and Antiretroviral Therapy)

For the first few months after an ART switch, the person should be closely monitored for any new adverse effects, and HIV viral load should be monitored to ensure continued viral suppression.

Information on the adverse effects of ARVs is outlined in several tables in these Guidelines. Table 21 provides clinicians with a list of the most common and/or severe ARV-associated adverse events for each drug class. The most common adverse effects of individual ARV agents are summarized in Appendix A, Tables 3, 4, 5, 6, 7, 8, 9, and 10.

Table 21. Common and/or Severe Adverse Effects Associated With Antiretroviral Medications

References

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2. Orkin C, Molina JM, Cahn P, et al. Safety and efficacy of doravirine as first-line therapy in adults with HIV-1: week 192 results from the open-label extensions of the DRIVE-FORWARD and DRIVE-AHEAD phase 3 trials. Lancet HIV. 2024;11(2):e75-e85. Available at: https://pubmed.ncbi.nlm.nih.gov/38141637.
3. Orkin C, DeJesus E, Sax PE, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials. Lancet HIV. 2020;7(6):e389-e400. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32504574.
4. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14(18):2895-2902. Available at: https://pubmed.ncbi.nlm.nih.gov/11153671.
5. Saves M, Raffi F, Clevenbergh P, et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in human immunodeficiency virus-infected patients. The APROCO Study Group. Antimicrob Agents Chemother. 2000;44(12):3451-3455. Available at: https://pubmed.ncbi.nlm.nih.gov/11083658.
6. Brennan A, Evans D, Maskew M, et al. Relationship between renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir. AIDS. 2011;25(13):1603-1609. Available at: https://pubmed.ncbi.nlm.nih.gov/21646902.
7. Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. 2008;22(14):1890-1892. Available at: https://pubmed.ncbi.nlm.nih.gov/18753871.
8. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS. 2015;29(13):1723-1725. Available at: https://pubmed.ncbi.nlm.nih.gov/26372287.
9. Cross HM, Chetty S, Asukile MT, Hussey HS, Lee Pan EB, Tucker LM. A proposed management algorithm for late-onset efavirenz neurotoxicity. S Afr Med J. 2018;108(4):271-274. Available at: https://pubmed.ncbi.nlm.nih.gov/29629676.
10. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579. Available at: https://pubmed.ncbi.nlm.nih.gov/18256392.
11. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111-1118. Available at: https://pubmed.ncbi.nlm.nih.gov/18444831.
12. Variava E, Sigauke FR, Norman J, et al. Brief report: late efavirenz-induced ataxia and encephalopathy: a case series. J Acquir Immune Defic Syndr. 2017;75(5):577-579. Available at: https://pubmed.ncbi.nlm.nih.gov/28520619.
13. Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G> T polymorphism, increased plasma efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther. 2010;7:32. Available at: https://pubmed.ncbi.nlm.nih.gov/20723261.
14. Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers. J Cardiovasc Electrophysiol. 2016;27(10):1206-1213. Available at: https://pubmed.ncbi.nlm.nih.gov/27333947.
15. Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS. 2007;21(1):41-46. Available at: https://pubmed.ncbi.nlm.nih.gov/17148966.