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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:3/27/2012; last reviewed:3/27/2012)

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Adverse effects have been reported with use of all antiretroviral (ARV) drugs and are among the most common reasons for switching or discontinuing therapy as well as for medication nonadherence [1]. Rates of treatment-limiting adverse events in antiretroviral therapy (ART)-naive patients enrolled in randomized trials appear to be declining with use of newer ARV regimens and are generally now occurring in less than 10% of study participants. However, most clinical trials have a relatively short follow-up duration and can underestimate longer term complications of therapy. In the Swiss Cohort study, the presence of laboratory adverse events was associated with higher rates of mortality during 6 years of follow-up, highlighting 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 (ART-naive women with CD4 counts >250 cells/mm3) seem to have a higher propensity of developing Stevens-Johnson syndrome, rashes, and hepatotoxicity from nevirapine (NVP) [3-5] and have higher rates of lactic acidosis from 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., alcoholism [9] or coinfection with viral hepatitis, which may increase risk of hepatotoxicity [10-12]); 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 predisposing patients to abacavir (ABC) hypersensitivity reaction (HSR) [13-14].

Although the therapeutic goals of ART include achieving and maintaining viral suppression and improving immune function, an overarching goal should be to select a regimen that is not only effective but also is safe. This requires consideration of not only the toxicity potential of an ARV regimen but also an 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 HIV therapy outweigh its risks and that some conditions such as anemia, cardiovascular disease (CVD), and renal impairment may be more likely in the absence of ART [15-16].

Information on adverse events is outlined in multiple tables in the guidelines. Table 13 provides clinicians with a list of the most common and/or severe known ARV-associated adverse events listed by drug class. Appendix B, Tables 1–6 summarize the most common adverse effects of individual ARV agents. Some approaches to the management of complications of ART have been published and will not be discussed in these tables [17-20].

Table 13. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects (See Appendix B for additional information listed by drug.)

 Adverse Effects

NRTIs

NNRTIs

PIs

INSTI

EI
Bleeding events    

All PIs: ↑ 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 MI in some but not all cohort studies. Absolute risk greatest among 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 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. 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.      
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 of HIV-uninfected individuals in short-term studies.
    
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 (diarrhea, nausea, vomiting)

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

    
 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: HIV/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-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 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 prior to initiation of ABC and 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, and respiratory symptoms.
• Symptoms worsen with continuation of ABC
• Median onset of reactions is 9 days; ~ 90% of reactions within first 6 weeks
• Onset of rechallenge reactions is within hours of rechallenge dose
• Patients, regardless of HLA-B*5701 status, should not be rechallenged with ABC if HSR 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 combined with EFV than with a ritonavir-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 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 BMD than 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: 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, CNS = central nervous system, 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, 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, TEN = toxic epidermal necrosis, TG = triglyceride, TPV = tipranavir, TPV/r = tipranavir + ritonavir, ZDV = zidovudine

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