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

Limitations to Treatment Safety and Efficacy

Adverse Effects of Antiretroviral Agents

(Last updated: April 8, 2015; last reviewed: April 8, 2015)

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 Fortunately, newer ARV regimens are less toxic than regimens used in the past. Generally less than 10% of antiretroviral therapy (ART)-naive patients enrolled in randomized trials have treatment-limiting adverse events. 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 a median of 6 years of follow-up, the presence of laboratory adverse events probably or certainly related to ART was associated with higher rates of mortality, which highlights the importance of monitoring for 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 T lymphocyte cell 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:

  • Concomitant use of medications with overlapping and additive toxicities;
  • Comorbid conditions that increase the risk of or exacerbate adverse effects (e.g., alcoholism9 or coinfection with viral hepatitis10-12 increases the risk of hepatotoxicity);
  • Drug-drug interactions that may lead to an increase in drug toxicities (e.g., interactions that result from concomitant use of statins with protease inhibitors); or
  • Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction.13,14

The therapeutic goals of ART are to safely achieve and maintain viral suppression and improve immune function. To accomplish these goals, the clinician must consider the toxicity potential of an ARV regimen, as well as the individual patient’s underlying conditions, concomitant medications, and prior history of drug intolerances. In addition, it should be appreciated that, in general, the overall benefits of ART outweigh its risks and that some non-AIDS related conditions (e.g., anemia, cardiovascular disease, renal impairment) may be more likely in the absence of ART.15,16

Information on the adverse events of ARVs is outlined in several tables in the guidelines. Table 14 provides clinicians with a list of the most common and/or severe known ARV-associated adverse events for each drug class. The most common adverse effects of individual ARV agents are summarized in Appendix B, Tables 1-6.

Table 14. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects

N/A indicates either that there are no reported cases for the particular side effect or that data for the specific ARV drug class are not available. See Appendix B for additional information listed by drug.

Table 14. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects
Adverse Effect NRTIs NNRTIs PIs INSTI EI
Bleeding Events  N/A N/A Spontaneous bleeding, hematuria in hemophilia.

TPV: Intracranial hemorrhage associated with CNS lesions, trauma, alcohol abuse, hypertension, coagulopathy, anti-coagulant or anti-platelet agents, vitamin E

Bone Density Effects TDF: Associated with greater loss of BMD than other NRTIs.

Osteomalacia has been reported in association with proximal renal tubulopathy.
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
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 Associated with MI and stroke in some cohorts.

SQV/r, ATV/r, and LPV/r: PR prolongation. Risks include pre-existing heart disease, other medications.

SQV/r: QT prolongation. Obtain ECG before administering SQV.

Cholelithiasis  N/A N/A ATV: Cholelithiasis and kidney stones may present concurrently.

Median onset is 42 months.

Diabetes Mellitus /Insulin Resistance  ZDV, d4T, and ddI N/A

Reported for some (IDV, LPV/r), but not all PIs

Dyslipidemia d4T > ZDV > ABC:

↑LDL and TG

EFV ↑TG, ↑LDL, ↑HDL All RTV-boosted PIs: LDL, ↑TG, ↑HDL

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

Gastrointestinal Effects Nausea and vomiting:
ddI and ZDV > other NRTIs

Pancreatitis: ddI

GI intolerance (e.g., diarrhea, nausea, vomiting)

Common with LPV/r, more frequent than DRV/r and

Nausea and diarrhea:
Hepatic Effects Reported with most NRTIs.
Steatosis most common with ZDV, d4T, or ddI.

ddI: Prolonged exposure linked to non-cirrhotic portal hypertension, esophageal varices.

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

NVP: Severe hepatotoxicity associated with skin rash or hypersensitivity. 2-week NVP dose escalation may reduce risk. Risk is greater for women with pre-NVP CD4 count >250 cells/mm3 and men with pre-NVP CD4 count >400 cells/mm3. NVP should never be used for post-exposure prophylaxis, or in patients with hepatic insufficiency (Child-Pugh B or C).
All PIs: Drug-induced hepatitis and hepatic decompensation have been reported; greatest frequency with TPV/r.

IDV, ATV: Jaundice due to indirect hyperbilirubinemia

TPV/r: Contraindicated in patients with hepatic insufficiency (Child-Pugh B or C)
 N/A MVC: Hepatotoxicity with or without rash or HSRs reported
Hypersensitivity Reaction

Excluding rash alone or Stevens-Johnson syndrome
ABC: Contraindicated if HLA-B*5701 positive. Median onset 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, regardless of HLA-B*5701 status, should not be re-challenged with ABC if HSR is suspected.

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 count >250 cells/mm3 and men with pre-NVP CD4 count >400 cells/mm3. Overall, risk is higher for women than men.

2-week dose escalation of NVP reduces risk.

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 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.

Lipodystrophy Lipoatrophy: d4T > ZDV. May be more likely when NRTIs combined with EFV than with an 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 Creatine Phosphokinase ZDV: Myopathy N/A N/A RAL: ↑CPK, 
weakness and rhabdomyolysis

Nervous System/Psychiatric Effects Peripheral neuropathy: 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 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 (especially among younger patients and those with history of mental illness or substance abuse) was found in a retrospective analysis of comparative trials. N/A All INSTIs: Insomnia

RAL: Depression and suicidal ideation (uncommon)
Rash FTC: Hyperpigmentation 
Renal Effects/

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: Increased chronic kidney disease risk in a large cohort study.

IDV: ↑SCr, pyuria, renal atrophy or hydronephrosis

IDV, ATV: Stone, crystal formation; adequate hydration may reduce risk.

COBI (in EVG/c/TDF/FTC) and DTG: Inhibits Cr secretion without reducing renal glomerular function. N/A
Stevens-Johnson Syndrome/Toxic Epidermal Necrosis ddI, ZDV: Reported cases NVP > DLV, EFV, ETR, RPV FPV, DRV, IDV, LPV/r, ATV: Reported cases RAL N/A

Key to Abbreviations: 3TC = lamivudine; ABC = abacavir; ALT= alanine amionotransferase; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BMD = bone mineral density; Cr = creatinine; CrCl = creatinine clearance; CNS = central nervous system; COBI or c = cobicistat; CPK = creatine phosphokinase; CVD = cardiovascular disease; d4T = stavudine; ddC = zalcitabine; ddI = didanosine; DLV = delavirdine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EI = entry inhibitor; ETR = etravirine; EVG = elvitegravir; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HDL = high-density lipoprotein; HSR = hypersensitivity reaction; 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; PT= prothrombin time; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; SQV = saquinavir; SQV/r = saquinavir/ritonavir; TDF = tenofovir disoproxil fumarate; TG = triglyceride; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

Switching Antiretroviral Therapy Because of Adverse Effects

Most 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 managed by substituting another ARV agent for the presumed causative agent without interruption of ART. Other, 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.

Switching from an effective ARV regimen to a new regimen must 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. When selecting a new agent or regimen, providers should be aware that resistance mutations selected for, regardless of whether previously or currently identified by genotypic resistance testing, are archived in HIV reservoirs, and even if absent from subsequent resistance test results, may reappear under selective pressure. It is critical that providers review the following before implementing any treatment switch:

  • the patient’s medical and complete ARV history including prior virologic responses to ART;
  • resistance test results;
  • viral tropism (when maraviroc [MVC] is being considered);
  • HLA B*5701 status (when ABC is being considered);
  • co-morbidities;
  • adherence history;/li>
  • prior intolerances to any medications; and
  • concomitant medications and supplements and their potential for drug interactions with ARVs.

Patient acceptance of new food or dosing requirements must also be assessed. In some cases, medication costs may also be a factor to consider before switching treatment. Signs and symptoms of ART-associated adverse events may mimic those of comorbidities, adverse effects of concomitant medications, or HIV infection itself. Therefore, concurrent with ascribing a particular clinical event to ART, alternative causes for the event should be investigated. In the case of a severe adverse event, it may be necessary to discontinue or switch ARVs pending the outcome of such an investigation. For the first few months after an ART switch, the patient should be closely monitored for any new adverse events. The patient’s viral load should also be monitored to assure continued viral suppression.

Table 15 lists several major ART-associated adverse events and potential options to appropriately switch agents in an ARV regimen. The table focuses on the ARVs most commonly used in the United States and lists substitutions that are supported by ARV switch studies, findings of comparative ARV trials and observational cohort studies, or expert opinion. 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.

Table 15. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent
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 regimens. 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 ZDV has been associated with neutropenia and macrocytic anemia.
Central Nervous System/ Neuropsychiatric Side Effects 

Dizziness, suicidal ideation, abnormal dreams, depression
EFV Alternative NNRTI (RPV, ETR, NVP), a PI/c or PI/r, 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.

Hypertriglyceridemia (with or without elevated 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. Improvements in TG and LDL levels observed with switch from LPV/r to ATV or ATV/r.c 
Gastrointestinal Effects

Nausea, diarrhea
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 persistent and intolerable.
Other RTV- or COBI-boosted regimens 
RAL, DTG, unboosted ATV,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 Never re-challenge with ABC following a suspected HSR, regardless of the patient’s HLA B*5701 status.
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.
Insulin Resistance
LPV/r, FPV/r 
NNRTI (NVP or RPV), INSTI, unboosted ATVc
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 use of any PI.
Jaundice and Icterus
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
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 (may take years) and incomplete.
Accumulation of visceral, truncal, dorso-cervical, and breast fat has been observed during ART, particularly during use of older PI-based regimens (e.g., IDV), but whether ART directly causes increased fat deposits 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 developing 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 may resolve with close follow-up only. For more severe reactions, change to an alternative boosted PI or an agent from another drug class.
Renal Effects

Including proximal renal tubulopathy, elevated creatinine

ABCb TDF may cause tubulopathy.
ATV/c, ATV/r, LPV/r
COBI and DTG, and to a lesser extent RPV can increase SCr through inhibition of creatinine secretion. This effect does not affect glomerular filtration. However, assess for renal dysfunction if SCr increases by >0.4 mg/dL.

Nephrolithiasis and cholelithiasis

Assuming that ATV/r is believed to cause the stones.
a In patients with chronic active HBV infection, another agent 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. Long term data for unboosted ATV are unavailable.

Key to Abbreviations: ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BMD = bone mineral density; CD4= CD4 T lymphocyte; CNS = central nervous system; COBI or c = cobicistat; d4T = stavudine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; 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; NVP = nevirapine; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; TDF = tenofovir disoproxil fumarate; TG = triglycerides; ZDV = zidovudine 


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