What are the common adverse effects of Highly Active Antiretroviral Therapy (HAART)?

Common Adverse Effects of HAART

HAART is associated with multiple organ system toxicities, with the most clinically significant being metabolic complications (lipodystrophy, hyperlipidemia, hyperglycemia), mitochondrial toxicity (lactic acidosis, hepatic steatosis), hepatotoxicity, and neuropsychiatric effects—the specific adverse effect profile depends heavily on the drug class used. 1

Drug Class-Specific Adverse Effects

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Mitochondrial Toxicity (Most Serious)

• Lactic acidosis with hepatic steatosis is the most severe NRTI complication, with an estimated incidence of 1.3 cases per 1,000 person-years of NRTI exposure and carries a high mortality rate. 1, 2
• Risk factors include female sex, obesity, prolonged NRTI use, and pregnancy—particularly dangerous with stavudine plus didanosine combination, which is now contraindicated. 1, 3
• Early warning signs include nonspecific gastrointestinal symptoms (nausea, abdominal distention, abdominal pain, vomiting, diarrhea), dyspnea, generalized weakness, ascending neuromuscular weakness, myalgias, paresthesias, and unexplained weight loss. 1, 4
• Stavudine and didanosine carry the highest mitochondrial toxicity risk; newer agents like tenofovir and abacavir have significantly lower risk. 2, 3

Peripheral Neuropathy

• Zalcitabine, stavudine, and didanosine cause neuropathic effects that can combine with HIV's direct neurologic effects. 1
• Monitor for symptoms and consider treatment discontinuation if severe. 3

Bone Marrow Suppression

• Zidovudine causes hematologic toxicity including neutropenia and severe anemia. 5
• Requires monitoring of complete blood counts and may necessitate dose interruption. 5

Pancreatitis

• Mitochondrial toxicity from NRTIs (particularly stavudine and didanosine) can manifest as pancreatitis. 4
• Fatal and nonfatal pancreatitis has occurred with stavudine-didanosine combinations (now contraindicated). 3

Lipoatrophy

• Long-term NRTI exposure, particularly stavudine, is associated with peripheral fat atrophy affecting face and extremities. 1, 3
• Prevalence increases with duration of therapy; alternative antiretrovirals should be considered. 3

Protease Inhibitors (PIs)

Metabolic Complications

• Hyperlipidemia: Elevation of total cholesterol, LDL, and triglycerides occurs primarily with PIs, with ritonavir showing the strongest association. 1
• Dyslipidemias may be severe enough to require therapeutic intervention and are associated with potential accelerated atherosclerosis. 1
• Management includes low-fat diet, exercise, and statins (preferably pravastatin or low-dose atorvastatin due to CYP450 interactions). 1

Hyperglycemia and Diabetes

• New-onset diabetes mellitus, diabetic ketoacidosis, and exacerbation of preexisting diabetes occur in 3-17% of patients. 1
• Symptoms typically appear at a median of 60 days (range 2-390 days) after PI initiation. 1
• Monitor fasting blood glucose closely, especially in patients with preexisting diabetes; counsel patients on warning signs (polydipsia, polyphagia, polyuria). 1

Lipodystrophy (Fat Accumulation)

• Fat accumulation in abdomen, dorsocervical fat pad ("buffalo hump"), and breasts increases with duration of antiretroviral therapy. 1
• No clearly effective therapy exists; discontinuation or class switching has limited benefit. 1

Hepatotoxicity

• PI-associated liver enzyme abnormalities can occur anytime during treatment, with ritonavir- or ritonavir/saquinavir-containing regimens showing higher rates. 1
• Hepatitis C coinfection is a major risk factor for PI-induced hepatotoxicity. 1
• Other risk factors include hepatitis B infection, alcohol abuse, baseline elevated liver enzymes, stavudine use, and concomitant hepatotoxic agents. 1

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Hepatotoxicity

• Nevirapine causes severe hepatotoxicity in approximately 9.4% of patients, with twice the incidence in females (12% vs 6% in males), and fulminant hepatic necrosis can be fatal. 1
• Two-thirds of nevirapine-associated clinical hepatitis occurs within the first 12 weeks. 1
• May present as hypersensitivity syndrome with rash, fever, and eosinophilia. 1
• Monitor liver enzymes every 2 weeks for the first month, then monthly for 12 weeks, then every 1-3 months. 1
• Patients with severe nevirapine hepatotoxicity should never receive nevirapine again. 1

Rash

• Rash typically begins within 1-2 weeks after initiating therapy and resolves within 4 weeks. 1
• Discontinue if severe rash develops. 6
• Higher incidence in pediatric patients compared to adults. 6

Neuropsychiatric Effects (Efavirenz)

• Nervous system symptoms are frequent, usually beginning 1-2 days after initiation and resolving in 2-4 weeks. 6
• Dosing at bedtime improves tolerability. 6
• Serious psychiatric symptoms including severe depression and suicidal ideation require immediate medical evaluation. 6
• Common symptoms include impaired concentration, abnormal dreams, dizziness, insomnia. 6

QTc Prolongation (Efavirenz)

• Consider alternatives in patients taking medications with known Torsade de Pointes risk or in patients at higher risk. 6

Common Gastrointestinal Effects (All Classes)

• Nausea, vomiting, diarrhea, anorexia, and abdominal pain are among the most frequently reported adverse effects across all drug classes. 1, 7, 8
• These symptoms are a commonly cited cause of poor adherence. 8

Immune Reconstitution Inflammatory Syndrome

• Patients with advanced HIV disease and subclinical opportunistic infections may experience new immunologic responses to pathogens after HAART initiation. 1
• New symptoms should not be interpreted as antiretroviral therapy failure; treat opportunistic infections appropriately while maintaining the antiretroviral regimen. 1

Critical Monitoring Recommendations

Before and During HAART:

• Liver function tests (especially with underlying hepatic disease, hepatitis B/C coinfection, or concomitant hepatotoxic medications). 6
• Fasting lipid panel (total cholesterol and triglycerides). 6
• Fasting blood glucose (particularly with PI use). 1
• Complete blood count (with zidovudine). 5
• Signs of lipodystrophy and lipoatrophy. 1, 3

Warning Signs Requiring Immediate Evaluation:

• Nonspecific gastrointestinal symptoms with dyspnea, weakness, or weight loss (possible lactic acidosis). 1, 4
• Severe psychiatric symptoms or suicidal ideation (with efavirenz). 6
• Severe rash or hypersensitivity symptoms. 6
• Symptoms of hyperglycemia (polydipsia, polyphagia, polyuria). 1

Drug Interactions and Contraindications

• Stavudine plus didanosine is absolutely contraindicated due to fatal lactic acidosis risk, particularly in pregnancy. 3
• PIs inhibit CYP450 pathway; NNRTIs have variable effects (nevirapine induces, delavirdine inhibits, efavirenz is mixed). 1
• These interactions can result in life-threatening drug toxicity; discuss all new medications including over-the-counter and alternative medications. 1
• Avoid zidovudine with stavudine and with ribavirin (exacerbates anemia). 5, 3