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

Table 20. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy
Adverse Effect  Drug Class
Bone Density Effects TDF: Associated with greater loss of BMD than other NRTIs, especially when given with a PK booster. 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 ATV/r and LPV/r: PR prolongation. Risk factors include pre-existing heart disease and concomitant use of medications that may cause PR prolongation. N/A FTR: QTc prolongation was seen at 4 times the recommended dose. Use with caution in patients with pre-existing heart disease or QTc prolongation, or concomitant use of medications that may prolong QTc interval.
Cardiovascular Disease ABC: Associated with an increased risk of MI in some cohort studies. Absolute risk greatest in patients with traditional CVD risk factors. N/A Boosted DRV 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 after ARV initiation. N/A N/A
Diabetes Mellitus and Insulin Resistance ZDV N/A LPV/r, but not with boosted ATV or DRV N/A N/A
Dyslipidemia ZDV > ABC: ↑ TG and ↑ LDL

TAF: ↑ TG, ↑ LDL, and ↑ 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 > DRV/r and ATV/r: ↑ TG
EVG/c: ↑ TG, ↑ LDL, ↑ HDL N/A
Gastrointestinal Effects ZDV > Other NRTIs: Nausea and vomiting N/A GI intolerance (e.g., diarrhea, nausea, vomiting)

LPV/r > DRV/r and ATV/r: Diarrhea
EVG/c: Nausea and diarrhea IBA: In a study of 40 people, 8% of patients reported diarrhea.
Hepatic Effects When TAF, TDF, 3TC, and FTC are withdrawn in Patients with HBV/HIV Coinfection or when HBV Resistance Develops: Patients with HBV/HIV coinfection may develop severe hepatic flares.

ZDV: Steatosis
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.

ATV: Jaundice due to indirect hyperbilirubinemia
DTG: Persons with HBV or HCV coinfection may be at higher risk of DTG-associated hepatotoxicity.

MVC: Hepatotoxicity with or without rash or HSRs reported.

FTR: Transaminase elevation was seen more commonly in patients with HBV/HCV. Transient elevation of bilirubin observed in clinical trials.

Hypersensitivity Reaction

Excluding rash alone or Stevens-Johnson syndrome
ABC: Contraindicated if patient is HLA-B*5701 positive.

Median onset for HSR is 9 days after treatment initiation; 90% of reactions occur within 6 weeks.

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-B*5701 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.
Injection Site Reaction       RPV IM Injection:
Reported in >80% of patients; reactions may include localized pain/discomfort (most common), nodules, induration, swelling, erythema, hematoma.    
  CAB IM Injection:
Reported in >80% of patients; reactions may include localized pain/discomfort (most common), nodules, induration, swelling, erythema, hematoma. 
T-20 SQ Injection:
Reported in almost all patients; pain, tenderness, nodules, induration, ecchymosis, erythema.
Lactic Acidosis Reported with Older NRTIs, d4T, ZDV, and ddI, but not with ABC, 3TC, FTC, TAF, or TDF. N/A N/A N/A N/A
Lipodystrophy Lipoatrophy: Associated with history of exposure to d4T or ZDV (d4T > ZDV). Not reported with ABC, 3TC or FTC, TAF or TDF. 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 History of Exposure to ddI, ddC, or d4T: Peripheral neuropathy (can be irreversible) Neuropsychiatric Events: EFV > RPV, DOR, ETR

EFV: Somnolence, insomnia, abnormal dreams, dizziness, impaired concentration, depression, psychosis, suicidal ideation, ataxia, encephalopathy. Some symptoms may subside or diminish after 2–4 weeks. Bedtime dosing and taking without food may reduce symptoms. Risk factors include psychiatric illness, concomitant use of agents with neuropsychiatric effects, and genetic factors.

RPV: Depression, suicidality, sleep disturbances

DOR: Sleep disorders and disturbances, dizziness, altered sensorium; depression and suicidality and 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, and LPV/r All INSTIs MVC, IBA, FTR
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.

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.

FTR: SCr > 1.8 x ULN seen in 19% in a clinical trial, but primarily with underlying renal disease or other drugs known to affect creatinine.

Stevens-Johnson Syndrome/Toxic Epidermal Necrosis N/A NVP > EFV, ETR, RPV Some reported cases for DRV, LPV/r, and ATV RAL N/A
Weight Gain Weight gain has been associated with initiation of ART and subsequent viral suppression. The increase appears to be greater with INSTIs than with other drug classes. Greater weight increase has also been reported with TAF than with TDF, and greater with DOR than EFV. INSTI > other ARV drug classes N/A
Key: 3TC = lamivudine; ABC = abacavir; ART= antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BMD = bone mineral density; CAB = cabotegravir; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; CPK = creatine phosphokinase; Cr = creatinine; CVD = cardiovascular disease; d4T = stavudine; ddC = zalcitabine; 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; FTR = fostemsavir; GI = gastrointestinal; HBV = hepatitis B virus; HCV = hepatitis C virus; HDL = high-density lipoprotein; HSR = hypersensitivity reaction; IBA = ibalizumab; IDV = indinavir; IM = intramuscular; 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; SQ = subcutaneous; SQV = saquinavir; SQV/r = saquinavir/ritonavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ULN = upper limit of normal; ZDV = zidovudine