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Updated Adult and Adolescent ARV Guidelines

The Adult and Adolescent ARV Guidelines were updated on February 12, 2013. 

Please send your comments with the subject line "Comments on Adult and Adolescent ARV Guidelines" to ContactUs@aidsinfo.nih.gov by February 26, 2013.

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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:2/12/2013; last reviewed:2/12/2013)

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Adverse effects have been reported with use of all antiretroviral (ARV) drugs; they are among the most common reasons for switching or discontinuing therapy and for medication nonadherence.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 (NRTIs).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 may increase the risk of or exacerbate adverse effects (e.g., alcoholism9 or coinfection with viral hepatitis10-12 may increase 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 [PIs]); or
  • Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction (HSR).13,14

The therapeutic goals of ART include achieving and maintaining viral suppression and improving immune function, but an overarching goal should be to select a regimen that is not only effective but also safe. This requires consideration of 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 conditions (e.g., anemia, cardiovascular disease [CVD], renal impairment), may be more likely in the absence of ART.15,16

Information on adverse events of ARVs is outlined in several tables in the guidelines. Table 13 provides clinicians with a list of the most common and/or severe known ARV-associated adverse events by drug class. The most common adverse effects of individual ARV agents are summarized in Appendix B, Tables 1–6.

Table 13. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects
(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)
Click here to view this table as an image

 Adverse Effects

 NRTIs

 NNRTIs

 PIs

 INSTI

 EI
Bleeding events     All PIs: Increased spontaneous bleeding, hematuria in patients with hemophilia

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 marrow suppression ZDV: Anemia, neutropenia        
Cardiovascular disease (CVD) ABC and ddI: Associated with an increased risk of MI in some, but not all, cohort studies. Absolute risk greatest in patients with traditional CVD risk factors.   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 coadministration 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.

    
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, 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 due to genetic factors or increased absorption with food.   RAL: Depression (uncommon)  
Cholelithiasis     ATV:
  • History of kidney stones increases risk and patients may present with cholelithiasis and kidney stones concurrently
  • Typically presents as abdominal pain
  • Reported complications include cholecystitis, pancreatitis, choledocholithiasis, and cholangitis
  • Median time to onset is 42 months (range 1–90 months)
   
Diabetes mellitus (DM)/insulin resistance  ZDV, d4T, and ddI  
  • 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

    
Gastrointestinal (GI) effects Nausea and vomiting:
ddI and ZDV > other NRTIs

Pancreatitis: ddI

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

Diarrhea:
Common with NFV;
LPV/r > DRV/r and ATV/r

 Nausea and diarrhea:
EVG/COBI/TDF/FTC
  
Hepatic effects Reported for most NRTIs

ddI: Prolonged exposure linked to non-cirrhotic portal hypertension, some cases with esophageal varicees

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

NVP:
  • Severe hepatic toxicity with NVP is often associated with skin rash or symptoms of hypersensitivity.
  • In ARV-naive patients, risk is greater for 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.
  • Risk is greatest in the first few months of treatment.
  • 2-week dose escalation of NVP reduces risk of rash and possibly hepatotoxicity if related to hypersensitivity.
  • NVP is contraindicated in patients with moderate to severe hepatic insufficiency (Child-Pugh classification B or C).
  • Liver failure observed in HIV-uninfected individuals receiving NVP for post-exposure prophylaxis. NVP should never be used for this indication.
All PIs: Drug-induced hepatitis and hepatic decompensation (and rare cases of fatalities) have been reported with all PIs to varying degrees. 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)

   MVC: Hepatotoxicity with or without rash or HSRs reported
Hypersensitivity reaction (HSR)
(excluding rash alone or Stevens-Johnson syndrome [SJS])		 ABC:
  • HLA-B*5701 screening should be performed before initiation of ABC. ABC should not be started if the HLA-B*5701 test result is positive.
  • Symptoms of HSR include (in descending frequency): fever, skin rash, malaise, nausea, headache, myalgia, chills, diarrhea, vomiting, abdominal pain, dyspnea, arthralgia, and respiratory symptoms.
  • Symptoms worsen with continuation of ABC.
  • Median onset of reactions is 9 days; approximately 90% of reactions occur within the first 6 weeks of treatment.
  • The onset of re-challenge reactions is within hours of re-challenge dose
  • Patients, regardless of HLA-B*5701 status, should not be re-challenged with ABC if HSR is suspected.
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.
  • In ARV-naive patients, risk is greater for 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.
   RAL MVC: Reported as part of a syndrome related to hepatotoxicity
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
  • Females and obese patients at increased risk

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
       
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.  
Myopathy/elevated creatine phosphokinase (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 with PI appears to increase risk.

   IDV: ↑ serum creatinine, pyuria; hydronephrosis or renal atrophy

IDV, ATV: Stone, crystal formation; adequate hydration may reduce risk.
 EVG/COBI/TDF/FTC:
  • COBI can cause non-pathologic decrease in CrCl.
  • May increase risk of TDF-related nephrotoxicity
 
Osteopenia/
osteoporosis
TDF: Associated with greater loss of BMD than 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)        
 Rash    All NNRTIs  ATV, DRV, FPV RAL, EVG/COBI/TDF/FTC: Uncommon  MVC
Stevens-Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) ddI, ZDV: Reported cases NVP > DLV, EFV, ETR, RPV FPV, DRV, IDV, LPV/r, ATV: Reported cases  RAL  

Key to Abbreviations: 3TC = lamivudine, ABC = abacavir, ALT = alanine aminotransferase, ARV = antiretroviral, AST = aspartate aminotransferase, ATV = atazanavir, ATV/r = atazanavir + ritonavir, BMD = bone mineral density, CrCl = creatinine clearance, CNS = central nervous system, COBI = cobicistat, CPK = creatine phosphokinase, CVD = cardiovascular disease, d4T = stavudine, ddC = zalcitabine, ddI = didanosine, DLV = delaviridine, DM = diabetes mellitus, DRV = darunavir, DRV/r = darunavir + ritonavir, 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, SJS = Stevens-Johnson syndrome, SQV = saquinavir, SQV/r = saquinavir + ritonavir, TDF = tenofovir disoproxil fumarate, TEN = toxic epidermal necrosis, TG = triglyceride, TPV = tipranavir, TPV/r = tipranavir + ritonavir, ZDV = zidovudine

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