January 10, 2011

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 19 

Table 13. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects (January 10, 2011)

Page 1 of 3 (See Appendix B for additional information listed by drug.)

Adverse Effects NRTIs NNRTIs PIs INSTI EI

Bleeding events All PIs: ↑ spontaneous bleeding, hematuria in 

hemophilia

TPV: Reports of intracranial hemorrhage. Risks 

include CNS lesions; trauma; surgery; 

hypertension; alcohol abuse; coagulopathy, anticoagulant, or anti-platelet agents including 

vitamin E

Bone marrow 

suppression

ZDV: Anemia, neutropenia

Cardiovascular 

disease (CVD)

ABC and ddI: Associated with 

myocardial infarction (MI) in some 

but not all cohort studies. Risk 

greatest among those with traditional 

CVD risk factors. 

PIs: Associated with MI and stroke in some 

cohort studies. Risk greatest among those with 

traditional CVD risk factors. Limited data on 

newer PIs (ATV, DRV, TPV).

SQV/r, ATV/r, and LPV/r: PR interval 

prolongation. Risks include structural heart 

disease, conduction system abnormalities, 

cardiomyopathy, ischemic heart disease, and 

coadministration with drugs that prolong PR 

interval.

SQV/r: QT interval prolongation in a healthy 

volunteer study. Risks include underlying heart 

conditions, pre-existing prolonged QT or 

arrhythmia, or use with other QT-prolonging 

drugs. ECG prior to SQV initiation is 

recommended and should be considered during 

therapy.

Central nervous 

system (CNS) effects

d4T: Associated with rapidly 

progressive ascending neuromuscular 

weakness resembling Guillain-Barré 

syndrome (rare)

EFV: Somnolence, insomnia, abnormal dreams, 

dizziness, impaired concentration, depression, 

psychosis, suicidal ideation. Most symptoms 

subside or diminish after 2–4 weeks. Bedtime 

dosing may reduce symptoms. Risks include 

history of psychiatric illness, concomitant use of 

agents with neuropsychiatric effects, and ↑

plasma EFV concentrations due to genetic 

factors or absorption (i.e., with food).

Diabetes mellitus 

(DM)/Insulin 

resistance/

ZDV, d4T, and ddI •Reported for some PIs (IDV, LPV/r), but not 

all PIs studied

• ATV +/- RTV not found to alter insulin 

sensitivity

Dyslipidemia d4T > ZDV > ABC: 

•↑ LDL and TG

EFV

•↑TG

•↑LDL 

•↑HDL 

↑LDL, ↑TG, ↑HDL: all RTV-boosted PIs

↑TG: LPV/r = FPV/r and LPV/r > DRV/r and 

ATV/r

Gastrointestinal (GI) Nausea and vomiting: ddI and ZDV

> other NRTIs

Pancreatitis: ddI

GI intolerance (diarrhea, nausea, vomiting)

Diarrhea: common with NFV. LPV/r > DRV/r

and ATV/r
January 10, 2011

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 20 

Adverse Effects NRTIs NNRTIs PIs INSTI EI

Hepatic effects Reported for most NRTIs

ddI: prolonged exposure linked to 

noncirrhotic portal hypertension, 

some cases with esophageal varicees

Steatosis: most commonly seen with 

ZDV, d4T, or ddI

Flares: hepatitis B virus (HBV)-

coinfected patients may develop 

severe hepatic flare when TDF, 3TC, 

and FTC are withdrawn or when 

HBV resistance develops.

NVP > other NNRTIs

NVP:

•Severe hepatic toxicity with NVP is often 

associated with skin rash or symptoms of 

hypersensitivity.

•For ARV-naïve patients, risk is greater for 

women with pre-NVP CD4 count >250 

cells/mm3 and men with pre-NVP CD4 count 

>400 cells/mm3. Risk is higher for women.

•2-week dose escalation of NVP reduces risk of 

rash and possibly hepatotoxicity if related to 

hypersensitivity.

•Given high risk in those with competent 

immune systems, NVP should never be used 

for post-exposure prophylaxis in HIVuninfected individuals.

• NVP is contraindicated in patients with ChildPugh classification B or C.

All PIs: Drug-induced hepatitis and hepatic 

decompensation (and rare cases of fatalities) have 

been reported with all PIs to varying degrees. 

TPV/r has a higher frequency of hepatic events 

than other PIs.

IDV, ATV: jaundice due to indirect 

hyperbilirubinemia

TPV/r: Contraindicated in patients with 

moderate to severe hepatic insufficiency (ChildPugh classification B or C)

Hypersensitivity 

reaction (HSR)

(excluding rash alone 

or Stevens Johnson 

syndrome[SJS])

ABC:

•HLA-B*5701 screening prior to 

initiation of ABC. Should not be 

started if HLA-B*5701 is positive.

•Symptoms of HSR include (in 

descending frequency): fever, skin 

rash, malaise, nausea, headache, 

myalgia, chills, diarrhea, vomiting, 

abdominal pain, dyspnea, arthralgia, 

respiratory symptoms

•Worsen with continuation of ABC

•Median onset 9 days; ~ 90% of 

reactions within first 6 weeks

•Onset of rechallenge reactions is 

within hours of rechallenge dose

NVP:

•Hypersensitivity syndrome of hepatic toxicity 

and rash that may be accompanied by fever, 

general malaise, fatigue, myalgias, arthralgias, 

blisters, oral lesions, conjunctivitis, facial 

edema, eosinophilia, granulocytopenia, 

lymphadenopathy, or renal dysfunction.

•For ARV-naïve patients, risk is greater for 

women with pre-NVP CD4 count >250 

cells/mm3 and men with pre-NVP CD4 count 

>400 cells/mm3. Risk is higher for women.

•2-week dose escalation of NVP reduces risk.

Lactic acidosis NRTIs, especially d4T, ZDV, and

ddI

•Insidious onset with GI prodrome, 

weight loss, and fatigue. May be 

rapidly progressive, with 

tachycardia, tachypnea, jaundice, 

muscular weakness, mental status 

changes, respiratory distress, 

pancreatitis, and organ failure.

•Mortality up to 50% in some case 

series, especially in patients with 

serum lactate >10 mmol/L

• Increased risk: female sex, obesity

Laboratory findings:

•↑ lactate (often >5 mmol/L), anion 

gap, AST, ALT, PT, bilirubin

•↑ amylase and lipase in patients 

with pancreatitis

• arterial pH, serum bicarbonate, 

serum albumin

Table 13. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects

Page 2 of 3
January 10, 2011

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 21 

Adverse Effects NRTIs NNRTIs PIs INSTI EI

Lipodystrophy Lipoatrophy: Thymidine analogs 

(d4T > ZDV). May be more likely 

when combined with EFV vs. 

boosted PI.

Lipohypertophy: Trunk fat increase observed with EFV-, PI-, and RAL-containing regimens; however, causal relationship has 

not been established.

Myopathy/elevated 

CPK

ZDV: myopathy RAL: ↑ CPK. 

muscle weakness and 

rhabdomyolysis

Nephrotoxicity/

urolithiasis

TDF: ↑ serum creatinine, proteinuria, 

hypophosphatemia, urinary phosphate 

wasting, glycosuria, hypokalemia, 

non-anion gap metabolic acidosis

Concurrent use of PI may increase 

risk.

IDV: ↑ serum creatinine, pyuria; hydronephrosis 

or renal atrophy

IDV, ATV: Stone, crystal formation; adequate 

hydration may reduce risk.

Osteopenia/

osteoporosis 

TDF: Associated with greater loss 

of bone mineral density (BMD) 

compared with ZDV, d4T, and ABC.

Decreases in BMD observed in studies of regimens containing different NRTIs combined with either 

NNRTIs or PIs.

Peripheral 

neuropathy

Peripheral neuropathy (pain and/or 

paresthesias, lower extremities > 

upper extremities): d4T > ddI and

ddC (can be irreversible)

d4T: Associated with rapidly 

progressive ascending neuromuscular 

weakness resembling Guillain-Barré 

syndrome (rare)

Rash All NNRTIs ATV, DRV, FPV MVC

Stevens-Johnson 

syndrome (SJS)/

toxic epidermal 

necrosis (TEN)

ddI, ZDV: Reported cases NVP > DLV, EFV, ETR

For NVP risks include:

•Female sex

•Black, Asian, Hispanic race/ethnicity

FPV, DRV, IDV, LPV/r, ATV: Reported cases

Acronyms:

Drug Classes: EI = entry inhibitor; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PIs = protease inhibitor

Antiretroviral Drugs: 3TC = lamivudine; ABC = abacavir; ATV = atazanavir; ATV/r = atazanavir + ritonavir; d4T = stavudine; ddC = zalcitabine; ddI = didanosine; DLV = delaviridine; DRV = darunavir; DRV/r = 

darunavir + ritonavir; EFV = efavirenz; ETR = etravirine; FPV = fosamprenavir; FPV/r = fosamprenavir + ritonavir; FTC = emtricitabine; IDV = indinavir; LPV/r = lopinavir + ritonavir; MVC = maraviroc; NFV = 

nelfinavir; NVP = nevirapine; RAL = raltegravir; RTV = ritonavir; SQV/r = saquinavir + ritonavir; TDF = tenofovir; TPV = tipranavir; ZDV = zidovudine

Other: ALT = alanine aminotransferase; ARV = antiretroviral; AST = aspartate aminotransferase; BMD = bone mineral density; CNS = central nervous system; CPK = creatine phosphokinase; CVD = cardiovascular 

disease; DM = diabetes mellitus; ECG = electrocardiogram; GI = gastrointestinal; HBV = hepatitis B virus; HDL = high-density lipoprotein; HSR = hypersensitivity reaction; LDL = low-density lipoprotein; MI = 

myocardial infarction; PT = prothrombin time; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrosis; TG = triglyceride

Table 13. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects

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