Adverse Effects of Antiretroviral Agents

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

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 for additional information listed by drug.

Adverse Effect	Drug Class
Adverse Effect	NRTIs	NNRTIs	PIs	INSTI	EIs
Bleeding Events	N/A	N/A	Spontaneous bleeding, hematuria in hemophilia TPV: Intracranial hemorrhage is associated with CNS lesions, trauma, alcohol abuse, hypertension, coagulopathy, anticoagulant or antiplatelet agents, and the use of vitamin E supplements.	N/A	N/A
Bone Density Effects	TDF: Associated with greater loss of BMD than other NRTIs. Osteomalacia may be associated with renal tubulopathy and urine phosphate wasting. TAF: Associated with smaller declines in BMD than those seen with TDF.	Decreases in BMD observed after the initiation of any ART regimen.			N/A
Bone Marrow Suppression	ZDV: Anemia, neutropenia	N/A	N/A	N/A	N/A
Cardiac Conduction Effects	N/A	RPV, EFV: QTc prolongation	SQV/r, ATV/r, and LPV/r: PR prolongation. Risk factors include pre-existing heart disease and the use of other medications. SQV/r: QT prolongation. Obtain ECG before administering SQV.	N/A	N/A
Cardiovascular Disease	ABC and ddI: Associated with an increased risk of MI in some cohort studies. Absolute risk greatest in patients with traditional CVD risk factors.	N/A	DRV, FPV, IDV, and LPV/r: Associated with cardiovascular events in some cohorts	N/A	N/A
Cholelithiasis	N/A	N/A	ATV: Cholelithiasis and kidney stones may present concurrently. Median onset is 42 months.	N/A	N/A
Diabetes Mellitus and Insulin Resistance	ZDV, d4T, and ddI	N/A	Reported for some (IDV, LPV/r), but not all, PIs.	N/A	N/A
Dyslipidemia AU comment: Australian hyperlipidaemia management guidelines	d4T > ZDV > ABC: ↑ TG and LDL TAF: ↑ TG, ↑ LDL, ↑ HDL (no change in TC:HDL ratio) TDF has been associated with lower lipid levels than ABC or TAF.	EFV: ↑ TG, ↑ LDL, ↑ HDL	All RTV- or COBI-Boosted PIs: ↑ TG, ↑ LDL, ↑ HDL LPV/r and FPV/r > DRV/r and ATV/r: ↑ TG	EVG/c: ↑ TG, ↑ LDL, ↑ HDL	N/A
Gastrointestinal Effects	ddI and ZDV > Other NRTIs: Nausea and vomiting ddI: Pancreatitis	N/A	GI intolerance (e.g., diarrhea, nausea, vomiting) NFV and LPV/r > DRV/r and ATV/r: Diarrhea	EVG/c: Nausea and diarrhea	IBA: 8% of patients reported diarrhea in a study of 40 people.
Hepatic Effects	Reported with most NRTIs. ZDV, d4T, and ddI: Steatosis ddI: Prolonged exposure linked to noncirrhotic portal hypertension and esophageal varices. When TAF, TDF, 3TC, and FTC are Withdrawn in Patients with HBV/HIV Coinfection or When HBV Resistance Develops: Patients with HBV/HIV coinfection may develop severe hepatic flares.	EFV: Most cases relate to an increase in transaminases. Fulminant hepatitis leading to death or hepatic failure requiring transplantation have been reported. NVP: Severe hepatotoxicity associated with skin rash or hypersensitivity. A 2-week NVP dose escalation may reduce risk. Risk is greater for women with pre-NVP CD4 counts >250 cells/mm³ and men with pre-NVP CD4 counts >400 cells/mm³. NVP should never be used for post-exposure prophylaxis. EFV and NVP are not recommended in patients with hepatic insufficiency (Child-Pugh class B or C).	All PIs: Drug-induced hepatitis and hepatic decompensation have been reported; greatest frequency occurs with TPV/r. TPV/r: Contraindicated in patients with hepatic insufficiency (Child Pugh class B or C). IDV and ATV: Jaundice due to indirect hyperbilirubinemia	N/A	MVC: Hepatotoxicity with or without rash or HSRs reported.
Hypersensitivity Reaction Excluding rash alone or Stevens-Johnson syndrome	ABC: Contraindicated if patient is HLA-B5701 positive. Median onset for HSR is 9 days; 90% of reactions occur within first 6 weeks of treatment. HSR Symptoms (in Order of Descending Frequency): Fever, rash, malaise, nausea, headache, myalgia, chills, diarrhea, vomiting, abdominal pain, dyspnea, arthralgia, and respiratory symptoms Symptoms worsen with continuation of ABC. Patients should not be rechallenged with ABC if HSR is suspected, regardless of their HLA-B5701 status.	NVP: Hypersensitivity syndrome of hepatotoxicity and rash that may be accompanied by fever, general malaise, fatigue, myalgias, arthralgias, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, renal dysfunction, granulocytopenia, or lymphadenopathy. Risk is greater for ARV-naive women with pre-NVP CD4 counts >250 cells/mm³ and men with pre-NVP CD4 counts >400 cells/mm³. Overall, risk is higher for women than men. A 2-week dose escalation of NVP reduces risk.	N/A	RAL: HSR reported when RAL is given with other drugs also known to cause HSRs. All ARVs should be stopped if HSR occurs. DTG: Reported in <1% of patients in clinical development program	MVC: HSR reported as part of a syndrome related to hepatotoxicity.
Lactic Acidosis	Reported with NRTIs, Especially d4T, ZDV, and ddI: Insidious onset with GI prodrome, weight loss, and fatigue. May rapidly progress with tachycardia, tachypnea, jaundice, weakness, mental status changes, pancreatitis, and organ failure. Mortality high if serum lactate >10 mmol/L. Women and obese patients at increased risk.	N/A	N/A	N/A	N/A
Lipodystrophy	Lipoatrophy: d4T > ZDV. More likely when NRTIs are coadministered with EFV than with an RTV-boosted PI.	Lipohypertrophy: Trunk fat increase observed with EFV-, PI-, and RAL-containing regimens; however, causal relationship has not been established.			N/A
Myopathy/Elevated Creatine Phosphokinase	ZDV: Myopathy	N/A	N/A	RAL and DTG: ↑ CPK, rhabdomyolysis, and myopathy or myositis have been reported.	N/A
Nervous System/Psychiatric Effects	d4T > ddI: Peripheral neuropathy (can be irreversible) d4T: Associated with rapidly progressive, ascending neuromuscular weakness resembling Guillain-Barré syndrome (rare)	Neuropsychiatric Events: EFV > RPV, DOR > ETR EFV: Somnolence, insomnia, abnormal dreams, dizziness, impaired concentration, depression, psychosis, and suicidal ideation. Symptoms usually subside or diminish after 2–4 weeks. Bedtime dosing may reduce symptoms. Risk factors include presence of psychiatric illness, concomitant use of agents with neuropsychiatric effects, and increased EFV concentrations because of genetic factors or increased absorption with food. An association between EFV and suicidal ideation, suicide, and attempted suicide was found in a retrospective analysis of comparative trials. RPV: Depression, suicidality, sleep disturbances DOR: Sleep disorders and disturbances, dizziness, altered sensorium; depression and suicidality/self-harm	N/A	All INSTIs: Insomnia, depression, and suicidality have been reported with INSTI use, primarily in patients with pre-existing psychiatric conditions.	N/A
Rash	FTC: Hyperpigmentation	All NNRTIs	ATV, DRV, FPV, LPV/r, and TPV	All INSTIs	MVC, IBA
Renal Effects/Urolithiasis	TDF: ↑ SCr, proteinuria, hypophosphatemia, urinary phosphate wasting, glycosuria, hypokalemia, and non-anion gap metabolic acidosis. Concurrent use of TDF with COBI- or RTV-containing regimens appears to increase risk. TAF: Less impact on renal biomarkers and lower rates of proteinuria than TDF.	RPV: Inhibits Cr secretion without reducing renal glomerular function.	ATV and LPV/r: Associated with increased risk of chronic kidney disease in a large cohort study. IDV: ↑ SCr, pyuria, renal atrophy, or hydronephrosis IDV, ATV: Stone or crystal formation. Adequate hydration may reduce risk. COBI (as a Boosting Agent for DRV or ATV): Inhibits Cr secretion without reducing renal glomerular function.	DTG, COBI (as a Boosting Agent for EVG), and BIC: Inhibits Cr secretion without reducing renal glomerular function	IBA: SCr abnormalities ≥Grade 3 reported in 10% of trial participants.
Stevens-Johnson Syndrome/Toxic Epidermal Necrosis	Some reported cases for ddI and ZDV.	NVP > DLV, EFV, ETR, RPV	Some reported cases for FPV, DRV, IDV, LPV/r, and ATV.	RAL	N/A
Key to Abbreviations:3TC = lamivudine; ABC = abacavir; ART= antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BMD = bone mineral density; CD4 = CD4 T lymphocyte; Cr = creatinine; CNS = central nervous system; COBI = cobicistat; CPK = creatine phosphokinase; CVD = cardiovascular disease; d4T = stavudine; ddI = didanosine; DLV = delavirdine; DOR = doravirine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EI = entry inhibitor; ETR = etravirine; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HDL = high-density lipoprotein; HSR = hypersensitivity reaction; IBA = ibalizumab; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV/r = lopinavir/ritonavir; MI = myocardial infarction; MVC = maraviroc; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; SQV = saquinavir; SQV/r = saquinavir/ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

Adverse Event	ARV Agent(s) or Drug Class		Comments
Adverse Event	Switch from	Switch to	Comments
Bone Density Effects	TDF^a	TAF or ABC^b 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 ABC^b	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.
Dyslipidemia 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.
Gastrointestinal Effects Nausea, diarrhea	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.
Lipoatrophy Subcutaneous fat wasting of limbs, face, buttocks	d4T, ZDV	TDF, TAF, or ABC^b	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.
Rash	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	TDF^a	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.
Stones 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-B5701 negative. ^cTDF 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