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

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Limitations to Treatment Safety and Efficacy

Adverse Effects of Antiretroviral Agents

Last Updated: October 25, 2018; Last Reviewed: October 25, 2018

Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent
Adverse Event ARV Agent(s) or Drug Class Comments
Switch from Switch to
Bone Density Effects TDFa TAF 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 Suppression ZDV TDF, TAF, or ABCb ZDV has been associated with neutropenia and macrocytic anemia.
Cardiac QTc Interval Prolongation EFV, RPV A PI- or INSTI-based regimen High EFV and RPV exposures may cause QT prolongation.

Consider switching from EFV- or RPV-based regimens if patient is taking other medications with known risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes.
Cardiovascular Events

Myocardial infarction, ischemic stroke
ABC TDF, TAF, FTC, or 3TC ABC 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, EFV, EVG/c RAL, DTG, BIC, or RPV RAL, DTG, BIC, and RPV have less effect on lipids than RTV- or COBI-boosted PI regimens, EFV, and EVG/c.

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.
Central Nervous System, Neuropsychiatric Side Effects

Dizziness, suicidal ideation, abnormal dreams, depression
EFV, RPV ETR, PI/c, or PI/r

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. 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.

Hypertriglyceridemia (with or without elevated LDL level)
RTV- or COBI-boosted regimens, and EFV RAL, DTG, BIC, or RPV Elevated 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 switch from LPV/r to ATV or ATV/r.c
Gastrointestinal Effects

Nausea, diarrhea
LPV/r ATV/c, ATV/r, DRV/c, DRV/r, RAL, DTG, BIC, or EVG/c GI 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 substitution unless they are persistent and intolerable.
Other RTV- or COBI-boosted regimens RAL, DTG, BIC, or NNRTIs In 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 Reaction ABC TDF or TAF Never rechallenge with ABC following a suspected HSR, regardless of the patient’s HLA-B*5701 status.
NVP, EFV, ETR, RPV Non-NNRTI ART Risk of HSR with NVP is higher for women and those with high CD4 cell counts.
DTG, RAL Non-INSTI ART Reactions to NVP, ETR, RAL, DTG, and MVC may be accompanied by elevated liver transaminases.
MVC Suitable alternative ART
Insulin Resistance LPV/r, FPV/r INSTI, NNRTI Results of switch studies have been inconsistent. Studies in HIV-negative patients suggest a direct causal effect of LPV/r (and IDV) on insulin resistance. However, traditional risk factors may be stronger risk factors for insulin resistance than the use of any PI.
Jaundice and Icterus ATV, ATV/c, ATV/r DRV/c, DRV/r, INSTI, or NNRTI Increases in unconjugated bilirubin are common with ATV and generally do not require modification of therapy unless resultant symptoms are distressing to the patient.

Subcutaneous fat wasting of limbs, face, buttocks
d4T, ZDV TDF, TAF, or ABCb Peripheral lipoatrophy is associated with prior thymidine analog (d4T and ZDV) use. Switching from these ARVs prevents worsening lipoatrophy, but fat recovery is typically slow (may take years) and incomplete.
Lipohypertrophy Accumulation 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 weight or visceral fat gain.
Rash NNRTIs (especially NVP and EFV) PI- or INSTI-based regimen Mild 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/r ATV/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
TDFa ABC,b TAF (for patients with CrCl >30 mL/min), 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/r DTG, BIC, RAL, or NNRTI COBI, 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.

Nephrolithiasis and cholelithiasis
ATV, ATV/c, ATV/r DRV/c, DRV/r, INSTI, or NNRTI This switch should be made if the clinician believes ATV is the cause of the stones.
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 to Abbreviations: 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; 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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