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

Limitations to Treatment Safety and Efficacy

Adverse Effects of Antiretroviral Agents

Adverse effects have been reported with all antiretroviral (ARV) drugs and were among the most common reasons for switching or discontinuing therapy, and for medication nonadherence in the earlier era of combination antiretroviral therapy (ART).¹ Fortunately, newer ARV regimens are associated with fewer serious and intolerable adverse effects than regimens used in the past. Generally, <10% of ART-naive patients enrolled in randomized trials experience treatment-limiting adverse events. However, the long-term complications of ART can be underestimated because most clinical trials use highly specific inclusion criteria which exclude individuals with certain underlying medical conditions, and the duration of participant follow-up is relatively short. As ART is recommended for all patients regardless of CD4 T lymphocyte (CD4) cell count, and because therapy must be continued indefinitely, the focus of patient management has evolved from identifying and managing early ARV-related toxicities to individualizing therapy to avoid long-term adverse effects, including diabetes and other metabolic complications, atherosclerotic cardiovascular disease, kidney dysfunction, bone loss, and weight gain. To achieve and sustain viral suppression over a lifetime, both long-term and short-term ART toxicities must be anticipated and managed. When selecting an ARV regimen, clinicians must consider potential adverse effects, as well as the individual’s comorbidities, concomitant medications, and prior history of drug intolerances.

Several factors may predispose individuals to adverse effects of ARV medications and include the following:

• 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^2,3 may increase the risk of hepatotoxicity when efavirenz (EFV) or protease inhibitors are used; and borderline or mild renal dysfunction increases the risk of nephrotoxicity from tenofovir disoproxil fumarate (TDF).
• Certain ARVs that may exacerbate pre-existing conditions. For example, psychiatric disorders may be exacerbated by EFV, rilpivirine, and, infrequently, by integrase strand transfer inhibitors.^4,5
• Drug-drug interactions that may increase toxicities of ARV drugs or concomitant medications. For example, when pharmacokinetic boosters such as ritonavir or cobicistat are used, or when isoniazid is used with EFV.⁶
• Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction,^7,8 EFV neuropsychiatric toxicity,^6,9 QTc prolongation,^10,11 and atazanavir (ATV)-associated hyperbilirubinemia.¹²

Information on the adverse effects of ARVs is outlined in several tables in these Guidelines. Table 20 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 B, Tables 3, 4, 5, 6, 7, 8, 9, and 10.

Table 20. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy

Adverse effects for ARV drugs that are no longer commonly used in clinical practice (ddI, d4T, FPV/r, IDV, NFV, SQV/r, and TPV/r) have been removed from this table, with the exception of lipodystrophy and peripheral neuropathy associated with ddI and d4T. Because these effects may persist long after discontinuation of ddI or d4T, and patients may still present with these long-lasting toxicities, the drugs remain listed among the ARVs associated with these two effects. Refer to the product labels or to the archived July 10, 2019, version of the Guidelines for information regarding the adverse effects associated with these older ARVs.

Switching Antiretroviral Drugs Due to Adverse Effects

Some patients experience treatment-limiting toxicities associated with ART. In these cases, ART must be modified. ART-associated adverse events can range from acute and potentially life-threatening to chronic and insidious. Serious life-threatening events (e.g., hypersensitivity reaction due to ABC, symptomatic hepatotoxicity, severe cutaneous reactions) require the immediate discontinuation of all ARV drugs 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 agent for the presumed causative agent without interrupting ART. Other chronic, non life-threatening adverse events (e.g., dyslipidemia) can be addressed either by switching the potentially causative agent for another agent or by managing the adverse event with pharmacological or nonpharmacological interventions. Management strategies must be individualized for each patient. When adverse effects occur during the use of a long-acting ARV, management might be challenging due to the persistence of drug in the body over the course of many months. Oral lead-in regimens for cabotegravir plus rilpivirine are available to assess short-term tolerability.

Switching a patient 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:

• The patient’s medical and complete ARV history, including prior virologic responses to ART;
• All previous drug resistance test results;
• Viral tropism (if maraviroc [MVC] is being considered);
• HLA-B*5701 status (if ABC is being considered);
• Comorbidities;
• The patient’s pregnancy status, ability to use effective contraceptives, and desire for pregnancy;
• Hepatitis B virus (HBV) status. Patients 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; and
• Concomitant medications and supplements, considering any potential drug interactions with ARVs.

A patient’s willingness to accept new food requirements or dosing schedule must also be assessed. In some cases, medication costs may also be a factor to consider before switching treatment. Signs and symptoms of comorbidities, adverse effects of concomitant medications, or HIV itself may mimic adverse effects caused by ART. Therefore, clinicians should investigate all potential causes for an adverse event. In the case of a severe adverse event, it may be necessary to discontinue or switch ARVs pending the outcome of such an investigation. For the first few months after an ART switch, the patient should be closely monitored for any new adverse events. The patient’s HIV viral load should also be monitored to assure continued viral suppression.

Table 21 lists several major ART-associated adverse events and the options for appropriate switches between agents in an ARV regimen. The table focuses on the ARVs most commonly used in the United States and lists substitutions that are supported by ARV switch studies, the findings of comparative ARV trials and observational cohort studies, or expert opinion. Switching agents in an effective ARV regimen should be done carefully and only when the potential benefits of the change outweigh the potential risks of altering treatment.

Table 21. Antiretroviral Therapy-Associated Adverse Effects That Can Be Managed with Substitution of Alternative Antiretroviral Agents

This table focuses on ARV-associated adverse effects that patients may experience as a result of a current ARV regimen. For information regarding ARV choices to use in individuals of childbearing potential and during pregnancy to avoid potential ARV adverse effects on fetuses and newborns refer to the Perinatal Guidelines.