(Last updated:May 01, 2014; last reviewed:May 01, 2014)
Adverse effects have been reported with the use of all antiretroviral (ARV) drugs and are among the most common reasons cited for switching or discontinuing therapy and for medication non-adherence.1 However, with the use of newer ARV regimens, rates of treatment-limiting adverse events in antiretroviral therapy (ART)-naive patients enrolled in randomized trials appear to be declining and are generally now occurring in less than 10% of study participants. However, because most clinical trials have a relatively short follow-up duration, the longer term complications of ART can be underestimated. In the Swiss Cohort study during 6 years of follow-up, the presence of laboratory adverse events was associated with higher rates of mortality, which highlights the importance of adverse events in overall patient management.2
Several factors may predispose individuals to adverse effects of ARV medications. For example, compared with men, women (especially ART-naive women with CD4 counts >250 cells/mm3) seem to have a higher propensity to develop Stevens-Johnson syndrome, rashes, and hepatotoxicity from nevirapine (NVP)3-5 and have higher rates of lactic acidosis due to nucleoside reverse transcriptase inhibitors.6-8 Other factors may also contribute to the development of adverse events:
(See Appendix B for additional information listed by drug. Empty spaces in the table may mean no reported cases for the particular side effect or no data are available for the specific ARV drug class)
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|Bleeding events||N/A||N/A||PIs: Increased spontaneous bleeding, hematuria in patients with hemophilia reported with some PIs
TPV: Reports of intracranial hemorrhage. Risks include CNS lesions, trauma, surgery, hypertension, alcohol abuse, coagulopathy, and concomitant use of anti-coagulant or anti-platelet agents, including vitamin E
|Bone Density Effects||TDF: Associated with greater loss of BMD than ZDV, d4T, and ABC.
Osteomalacia reported in association with proximal renal tubulopathy.
|Decreases in BMD observed in studies of regimens containing different NRTIs combined with NNRTIs, PIs, or INSTIs.||N/A|
|Bone marrow suppression||ZDV: Anemia, neutropenia||N/A||N/A||N/A||N/A|
|Cardiovascular disease (CVD)||ABC and ddI: Associated with an increased risk of MI in some, but not all, cohort studies. Absolute risk is greatest in patients with traditional CVD risk factors.||N/A||PIs: Associated with MI and stroke in some cohort studies. Data on newer PIs (ATV, DRV, and TPV) are limited.
SQV/r, ATV/r, and LPV/r: PR interval prolongation. Risks include structural heart disease, conduction system abnormalities, cardiomyopathy, ischemic heart disease, and co-administration with drugs that prolong PR interval.
SQV/r: QT interval prolongation in patients in a healthy volunteer study. Risks include underlying heart conditions, pre-existing prolonged QT or arrhythmia, or use with other QT-prolonging drugs. ECG is recommended before SQV initiation and should be considered during therapy.
|Diabetes mellitus (DM)/insulin resistance||ZDV, d4T, and ddI||N/A||
Reported for some PIs (IDV, LPV/r), but not all PIs
|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
|EVG/cobi/TDF/FTC: ↑ TG, ↑ LDL, ↑ HDL||N/A|
|Gastrointestinal (GI) effects||Nausea and vomiting:
ddI and ZDV > other NRTIs Pancreatitis: ddI
|GI intolerance (e.g., diarrhea, nausea, vomiting)
Common with NFV;
LPV/r > DRV/r and ATV/r
|Nausea and diarrhea:
|Hepatic effects||Reported with most NRTIs
ddI: Prolonged exposure has been linked to non-cirrhotic portal hypertension, including some cases with esophageal varices.
Steatosis: Most commonly seen with ZDV, d4T, or ddI
Flares: HIV/HBV-co-infected patients may develop severe hepatic flares when TDF, 3TC, and FTC are withdrawn or when HBV resistance develops
|NVP > other NNRTIs
|All PIs: Drug-induced hepatitis and hepatic decompensation (and rare cases of fatalities) have been reported with all PIs. The frequency of hepatic events is higher with TPV/r than with other PIs.
IDV, ATV: Jaundice due to indirect hyperbilirubinemia
TPV/r: Contraindicated in patients with moderate to severe hepatic insufficiency (Child Pugh classification B or C)
|N/A||MVC: Hepatotoxicity with or without rash or HSRs reported|
Excluding rash alone or SJS
||N/A||RAL: HSR reported when RAL given in combination with other drugs known to cause HSR. All ARVs should be stopped if HSR occurs.
DTG: Reported in <1% of patients in clinical development program
|MVC: Reported as part of a syndrome related to hepatotoxicity|
|Lactic acidosis||NRTIs, especially d4T, ZDV, and ddI:
|Lipodystrophy||Lipoatrophy: Thymidine analogs (d4T > ZDV). May be more likely when NRTIs combined with EFV than with a RTV-boosted PI.||Lipohypertophy: Trunk fat increase observed with EFV-, PI-, and RAL-containing regimens; however, causal relationship has not been established.||N/A|
|Myopathy/elevated CPK||ZDV: Myopathy||N/A||N/A||RAL: ↑ CPK
Muscle weakness and rhabdomyolysis
|Nervous System/Psychiatric Effects||Peripheral neuropathy (pain and/or paresthesia, lower extremities > upper extremities): d4T > ddI and ddC (can be irreversible)
d4T: Associated with rapidly progressive, ascending neuromuscular weakness resembling Guillain-Barré syndrome (rare)
|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. Risks include history of psychiatric illness, concomitant use of agents with neuropsychiatric effects, and increased plasma EFV concentrations because of genetic factors or increased absorption with food. An association between EFV and suicidal ideation, suicide, and attempted suicide (especially among younger patients and those with history of mental illness or substance abuse) was found in one retrospective analysis of several comparative trials.
||N/A||All INSTIs: insomnia
RAL: Depression and suicidal ideation (uncommon)
||ATV, DRV, FPV, LPV/r, TPV
||RAL, EVG/cobi/TDF/FTC: Uncommon
|TDF: ↑ SCr, proteinuria, hypophosphatemia, urinary phosphate wasting, glycosuria, hypokalemia, non-anion gap metabolic acidosis
Concurrent use with PI appears to increase risk.
|N/A||ATV and LPV/r: Associated with increased risk of chronic kidney disease in a large cohort study.
IDV: ↑ SCr, pyuria; hydronephrosis or renal atrophy
IDV, ATV: Stone, crystal formation; adequate hydration may reduce risk.
|cobi (a component of EVG/cobi/TDF/FTC) and DTG: Can increase SCr by reducing tubular secretion of Cr without reducing renal glomerular function; however, assess for renal dysfunction, especially if SCr increase by >0.4 mg/dL.||N/A|
|SJS/TEN||ddI, ZDV: Reported cases||NVP > DLV, EFV, ETR, RPV||FPV, DRV, IDV, LPV/r, ATV: Reported cases||RAL||N/A|
Switching Antiretroviral Therapy Because of Adverse EffectsMost patients do not experience treatment-limiting ART-associated toxicities; however, some patients do, and in these cases, ART must be modified. ART-associated adverse events can range from acute and potentially life threatening to chronic and insidious. Acute life-threatening events (e.g., acute hypersensitivity reaction due to ABC, lactic acidosis due to stavudine [d4T] and didanosine [ddI], liver and/or severe cutaneous toxicities due to NVP) usually require the immediate discontinuation of all ARV drugs and re-initiation of an alternative regimen without overlapping toxicity. Non-life threatening toxicities (e.g., urolithiasis with atazanavir [ATV], renal tubulopathy with tenofovir [TDF]) can usually be handled by substituting another ARV agent for the presumed causative agent without interruption of ART. Other, more 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 additional pharmacological or non-pharmacological interventions. Management strategies must be individualized for each patient.
Table 15. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent
Switching a successful ARV regimen should be done carefully and only when the potential benefits of the change outweigh the potential complications of altering treatment. The fundamental principle of regimen switching is to maintain viral suppression. Before any treatment switch is implemented, it is critical to review the patient’s medical and full ARV history including the patient’s prior virologic responses, resistance test results, viral tropism (when MVC is being considered), HLA B*5701 status (when ABC is being considered), co-morbidities, adherence history, concomitant medications and supplements and their potential for drug interactions, and prior intolerances to any ARV drugs.
|Adverse Event||ARV Agent(s)/Drug Class||Comments|
|Switch from||Switch to|
|Bone Density Effects
||TDFa||ABCb||Declines in BMD have been observed with the start of most ART. Modification of ART because of reduced BMD should be predicated on the clinical significance of the decline. Switching from TDF to alternative ARV agents has been shown to increase bone density, but the clinical significance of this increase remains uncertain.
|Bone Marrow Suppression
|ZDV||TDF or ABCb||N/A|
|CNS/Neuropsychiatric Side Effects
Dizziness, suicidal ideation, sleep disturbance, abnormal dreams, depression
|EFV||Alternative NNRTI (RPV, ETR, NVP), a PI, or an INSTI
||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 with an alternate ARV agent.
Hypertriglyceridemia (with or without high low-density LDL level)
|RTV- or cobi-boosted regimens or EFV
||RAL, DTG, RPV, NVP, or unboosted ATVc
||Elevated TG and LDL levels are more common with LPV/r and FPV/r than with other RTV-boosted PIs. Improved TG and LDL levels have been seen following a switch from LPV/r to RTV-boosted and -unboosted ATV.c
|LPV/r||ATV/r, DRV/r, RAL, DTG, EVG/cobi/TDF/FTC
||GI intolerance is relatively 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 in nature, and do not warrant switching therapy. If GI adverse effects are persistent or intolerable, consider drug substitution.
|Other RTV-boosted regimens or EVG/cobi/TDF/FTC
||RAL, DTG, unboosted ATV,c NNRTIs
||In a trial of treatment-naive patients, rates of diarrhea and nausea were similar for boosted EVG/cobi/TDF/FTC and ATV/r plus TDF/FTC.
|HSR||ABC||TDF||Never re-challenge with ABC following a suspected HSR, regardless of the patient’s HLA B*5701 status.
|NVP, EFV, ETR, RPV
||Risk of HSR with NVP is higher for women and those with high CD4 cell counts.
Suitable alternative ART
|Reactions to NVP, ETR, RAL, DTG and MVC may be accompanied by elevated liver transaminases.
||NNRTI (NVP or RPV), INSTI, unboosted ATVc
||Results of switch studies have been inconsistent. Studies in HIV-negative patients given short courses of a PI suggest a direct causal effect of LPV/r (and IDV) on insulin resistance. However, traditional risk factors, such as obesity and family history of diabetes, may be stronger risk factors for insulin resistance than use of any PIs.
|Jaundice and Icterus
||DRV/r, INSTI, or NNRTI
||Increases in unconjugated bilirubin are commonly seen with ATV and generally do not require modification of therapy unless jaundice/icterus is distressing to the patient.
Subcutaneous fat wasting of limbs, face, buttocks
||TDF or ABCb
||Peripheral lipoatrophy is a legacy of prior thymidine analog (d4T and ZDV) use. Switching from these ARVs prevents worsening lipoatrophy, but fat recovery is typically slow, incomplete, and may take years.
Accumulation of visceral abdominal, truncal, dorsocervical, and breast fat
|Lipohypertrophy has been observed during ART, particularly during use of older PI-based regimens (e.g., IDV), but whether ART directly causes increases in fat depots remains unclear. There is no clinical evidence that switching to any currently recommended first line regimen will reverse weight or visceral fat gain.
|Rash||NNRTIs (especially NVP and EFV)
||PI- or INSTI- based regimen
||Rash can be seen with any NNRTI but occurs more frequently and is more severe with use of NVP, followed by EFV. Mild rashes developing after initiation of NNRTIs other than NVP rarely require treatment switch. When serious rash develops with use of any NNRTI, a switch to an agent from another ARV drug class is recommended.
||ATV/r or another class, such as INSTI
||Mild rashes following DRV/r initiation do not necessarily require treatment switch. Close follow-up until the rash subsides is recommended. For more severe reactions, therapy can be changed to an alternative RTV-boosted PI or an agent from another drug class.
Including proximal renal tubulopathy, elevated creatinine
||ABCb||Phosphate wasting as a consequence of TDF nephrotoxicity may lead to osteomalacia.
||DTG, RAL, or NNRTI
||cobi and DTG, and to a lesser extent RTV, RPV, and RAL, can increase SCr soon after treatment initiation because of inhibition of tubular secretion of creatinine. This effect does not affect glomerular filtration. However, assess for renal dysfunction, especially if SCr increases by >0.4 mg/dL.
Nephrolithiasis and cholelithiasis
||DRV/r, INSTI, or NNRTI
||Nephrolithiasis (a frequent complication of IDV) has been observed with ATV. Cholelithiasis is also reported with ATV.
|a For patients with chronic active HBV infection, another agent active against HBV should be added to substitute 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 co-administered with TDF. Long term data for unboosted ATV are unavailable.
Key to Abbreviations: ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; BMD = bone mineral density; CNS = central nervous system; cobi = cobicistat; d4T = stavudine; ddI = didanosine; DRV/r = ritonavir-boosted darunavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HSR = hypersensitivity reaction; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV/r = ritonavir-boosted lopinavir; MVC = maraviroc; 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; TDF = tenofovir disoproxil fumarate; TG = triglycerides; ZDV = zidovudine