Australian Commentary to the US DHHS Guidelines for the use of Antiretroviral Agents in Adults and Adolescents with HIV

US DHHS Guidelines with Australian Commentary

Table of Contents

Adverse Effects of Antiretroviral Agents

DHHS Last Updated: May 2023Australian Commentary Last Updated: July 2023

Several reports have identified associations between the use of integrase strand transfer inhibitors (INSTIs) and increased weight and/or body mass index (BMI). It is unclear if this is a causal relationship or is associated with increased morbidity from conditions typically associated with increased weight such as type 2 diabetes mellitus or hyperlipidaemia.1-6 One report has reported increased systolic blood pressure and incidence of diabetes in women how added or switched to an INSTI compared to those who remained on non-INSTI regimen.6 Continued observation for data reporting on possible associations between weight gain and INSTIs is warranted. There is also a single retrospective cohort reporting an association between weight gain and switching from a TDF- to a TAF-containing antiretroviral regimen7

  1. Norwood et al. J Acquir Immune Defic Syndr 2017;76:527–531
  2. Menard et al. AIDS 2017, 31:1499–1502
  3. Hill et al. Journal of Virus Eradication 2019; 5: 41–43
  4. Lake et al. CROI 2019. Abstract #669
  5. Bourgi et al. CROI 2019. Abstract #670
  6. Kerchberger et al. CROI 2019 Abstract #672
  7. Gomez et al. Infection. 2019 Feb;47(1):95-102

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 steatosis2,3 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 3456789, 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.

This table focuses on ARV-associated adverse effects that a patient may experience as a result of taking an ARV regimen. For information regarding potential adverse effects of ARVs on fetuses and newborns when certain ARVs are taken around the time of conception or during pregnancy, refer to the Perinatal Guidelines.

In this table, N/A indicates either that there are no reported cases for that particular side effect or that data for that specific ARV drug class are not available. See Appendix B, Tables 3456789, and 10 for additional information listed by drug.

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

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 or for lenacapavir 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.

Adverse Event
ARV Agent(s) or Drug Class
Switch from
Switch to
Bone Density EffectsTDFaTAF or ABCb

NRTI-sparing regimens or regimens using only 3TC or FTC as the NRTI may be considered, if appropriate.
Declines in BMD have been observed upon initiation of most ART regimens. Switching from TDF to alternative ARV agents has been shown to increase bone density, but the clinical significance of this increase remains uncertain.

TAF is associated with smaller declines in BMD than TDF, and patients show improvement in BMD upon switching to TAF. The long-term impact of TAF on patients with osteopenia or osteoporosis is unknown; close clinical monitoring is recommended in this setting.
Bone Marrow SuppressionZDVRegimen not including ZDVZDV has been associated with neutropenia and macrocytic anemia.

Nephrolithiasis and cholelithiasis
ATV, ATV/c, ATV/rDRV/c, DRV/r, INSTI, or NNRTIThis switch should be made if ATV is the presumed cause of the calculi.
Cardiac QTc Interval ProlongationEFV, RPV, FTRBoosted ATV or DRV, DOR, or INSTI-based regimen (that does not combine with RPV)High EFV, RPV, and FTR exposures may cause QT prolongation.
Consider switching from EFV- or RPV- based regimens if the patient is taking other medications with known risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes.
For FTR, if there is no alternative ARV drug option, consider switching the concomitant medication.
Cardiovascular Events

Myocardial infarction, ischemic stroke
ABCTDF or TAFABC use has been associated with CV disease and cardiac events in some, but not all, observational studies.

TDF has been associated with lower lipid levels than TAF.
RTV- or COBI-boosted PI regimens, EFVINSTI, RPV, or DORIf lipids are a concern, see Dyslipidemia below.

Large observation cohorts have found an association between some PIs (DRV, FPV, IDV, LPV/r) and an increased risk of CV events. However, this association has not been seen with ATV. Further study is needed.

Hypertriglyceridemia (with or without elevated LDL level)
RTV- or COBI-boosted EFV-based regimensINSTI, DOR, or RPVElevated TG and LDL levels are more common with LPV/r and FPV/r than with other RTV-boosted PIs. Improvements in TG and LDL levels have been observed with the switch from LPV/r to ATV or ATV/r. c
Gastrointestinal Effects

Nausea, diarrhea
LPV/rBoosted ATV or DRV, INSTI, NNRTIGI intolerance is common with boosted PIs and is linked to the total dose of RTV. More GI toxicity is seen with LPV/r than with ATV/r or DRV/r. GI effects are often transient and do not warrant ARV substitution unless they are persistent and intolerable.
Other RTV- or COBI-boosted regimensBIC, DTG, RAL, or NNRTIIn a trial of treatment-naive patients, rates of diarrhea and nausea were similar for EVG/c/TDF/FTC and ATV/r plus TDF/FTC.
Hypersensitivity ReactionABCAny appropriate ABC-sparing regimenNever rechallenge with ABC following a suspected HSR, regardless of the patient’s HLA-B*5701 status.
EFV, ETR, NVP, RPVNon-NNRTI ARTRisk of HSR with NVP is higher for women and those with high CD4 counts.
DTG, RALNon-INSTI ARTReactions to NVP, ETR, RAL, DTG, and MVC may be accompanied by elevated liver transaminases.
MVCSuitable alternative ART
Insulin ResistanceLPV/rINSTI, NNRTIResults of switch studies have been inconsistent. Studies in HIV-negative patients suggest a direct causal effect of LPV/r on insulin resistance. However, traditional risk factors for insulin resistance may be stronger risk factors than the use of any PI.
Jaundice and IcterusATV, ATV/c, ATV/rDRV/c, DRV/r, INSTI, or NNRTIIncreases in unconjugated bilirubin are common with ATV and generally do not require modification of therapy unless resultant symptoms are distressing to the patient.
LipoatrophyPeripheral lipoatrophy (loss of subcutaneous fat of the limbs, face, and buttocks) is associated with prior thymidine analog (d4T and ZDV) use. Despite switching from these ARVs, fat recovery remains slow (may take years) and incomplete.
LipohypertrophyAccumulation of visceral, truncal, dorsocervical, and breast fat has been observed during ART, particularly during use of older PI-based regimens (e.g., IDV), but whether ART directly causes fat accumulation remains unclear. There is no clinical evidence that switching to another first line regimen will reverse lipohypertrophy.
Neuropsychiatric Side Effects

Dizziness, suicidal ideation, abnormal dreams, depression, ataxia, encephalopathy

INSTIs may be used, but monitoring is recommended (see Comments column).
In most patients, EFV-related CNS effects subside within 4 weeks after initiation of the drug, but in some patients, ataxia or encephalopathy may appear months to years after EFV-initiation. Persistent or intolerable effects should prompt substitution of EFV.

INSTIs are associated with insomnia. Depression and suicidality have been infrequently reported with INSTI use, primarily in patients with pre-existing psychiatric conditions.
RashNNRTIs (especially NVP and EFV)PI- or INSTI-based regimenMild rashes that develop after initiation of NNRTIs other than NVP rarely require treatment switch. When serious rash develops due to any NNRTI, switch to another drug class.
DRV/c, DRV/rATV/c, ATV/r, or another drug class (e.g., INSTI)Mild rashes following DRV/r use may resolve without modification of therapy. For more severe reactions, change to an alternative boosted PI or an agent from another drug class.
Renal Effects

Including proximal renal tubulopathy and elevated creatinine
TDFaABC,b TAF (for patients with CrCl >30 mL/min, unless on chronic hemodialysis), NRTI-sparing regimens, or regimens using only 3TC or FTC as the NRTI may be considered if appropriate.TDF may cause tubulopathy.

Switching from TDF to TAF is associated with improvement in proteinuria and renal biomarkers. The long-term impact of TAF on patients with pre-existing renal disease, including overt proximal tubulopathy, is unknown, and close clinical monitoring is recommended in this setting
ATV/c, ATV/r, LPV/rBIC, DTG, EVG/c/TAF/FTC, RAL, boosted DRV, or NNRTICOBI, DTG, BIC, and, to a lesser extent, RPV, can increase SCr through inhibition of creatinine secretion. This effect does not affect glomerular filtration. However, assess patient for renal dysfunction if SCr increases by >0.4 mg/dL.
a In patients with chronic active HBV infection, another agent that is active against HBV should be substituted for TDF.
b ABC should be used only in patients known to be HLA-B*5701 negative.
c TDF reduces ATV levels; therefore, unboosted ATV should not be coadministered with TDF.

Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BMD = bone mineral density; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; CrCl = creatine clearance; CV = cardiovascular; d4T = stavudine; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; FTR = fostemsavir; GI = gastrointestinal; HBV = hepatitis B virus; HSR = hypersensitivity reaction; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides; ZDV = zidovudine


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