(Last updated:17/10/2017; last reviewed:17/10/2017)
The overall benefits of viral suppression and improved immune function as a result of effective antiretroviral therapy (ART) far outweigh the risks associated with the adverse effects of some antiretroviral (ARV) drugs. However, adverse effects have been reported with the use of all antiretroviral (ARV) drugs and, in the earlier era of combination ART, were among the most common reasons for switching or discontinuing therapy and for medication nonadherence.1 Fortunately, newer ARV regimens are associated with fewer serious and intolerable adverse effects than regimens used in the past. Generally, less than 10% of ART-naive patients enrolled in randomized trials have treatment limiting adverse events. However, the longer-term complications of ART can be underestimated because most clinical trials enroll a select group of patients based on highly specific inclusion criteria and the duration of participant follow-up is relatively short. As ART is now recommended for all patients regardless of CD4 T lymphocyte (CD4) cell count, and therapy has to be continued indefinitely, the focus of patient management has evolved from identifying and managing early ARV-related toxicities to individualizing therapy to avoid long-term adverse effects such as bone or renal toxicity, dyslipidemia, insulin resistance, or accelerated cardiovascular disease. To achieve sustained viral suppression over a lifetime, both long-term and short-term ART toxicities must be anticipated and overcome. The clinician must consider potential adverse effects when selecting an ARV regimen, as well as the individual patient's comorbidities, concomitant medications, and prior history of drug intolerances.
Several factors may predispose individuals to adverse effects of ARV medications, such as:
- Concomitant use of medications with overlapping and additive toxicities;
- Comorbid conditions that increase the risk of or exacerbate adverse effects (eg, alcoholism or coinfection with viral hepatitis2,3 may increase the risk of hepatotoxicity; psychiatric disorders may be exacerbated by efavirenz [EFV]- and, infrequently, by integrase strand transfer inhibitor [INSTI]-related CNS toxicities;4,5 and borderline or mild renal dysfunction increases the risk of nephrotoxicity from tenofovir disoproxil fumarate [TDF])
- Drug-drug interactions that may increase toxicities of ARV drugs or concomitant medications
- Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction,6,7 EFV neuropsychiatric toxicity,8 and QTc prolongation,8,9 and atazanavir (ATV)-associated hyperbilirubinemia.9
Information on the adverse effects 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.
(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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Spontaneous bleeding, hematuria in hemophilia.
TPV: Intracranial hemorrhage associated with CNS lesions, trauma, alcohol abuse, hypertension, coagulopathy, anticoagulant or antiplatelet agents, vitamin E
|Bone Density Effects||
TDF: Associated with greater loss of BMD than other NRTIs; osteomalacia may be associated with renal tubulopathy and urine phosphate wasting
TAF: Smaller declines in BMD than with TDF.
|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|
|Cardiac Conduction Effects||
|RPV, EFV, QTc prolongation||
SQV/r, ATV/r, and LPV/r: PR prolongation. Risk factors include pre-existing heart disease and other medications. SQV/r: QT prolongation. Obtain ECG before administering SQV
ABC and ddI: Associated with an increased risk of MI in some cohort studies.
DRV, FPV, IDV, and LPV/r:
Associated with MI and stroke in some cohorts.
ATV: Cholelithiasis and kidney stones may present
|Diabetes Mellitus (DM)/Insulin Resistance||ZDV, d4T, and ddI||N/A||
Reported for some (IDV, LPV/r), but not all PIs
|Dyslipidemia||d4T > ZDV > ABC:
↑TG and LDL
TAF > TDF: ↑TG, ↑LDL, ↑HDL (no change in TC:HDL
TDF has been associated with lower lipid levels than ABC or TAF
|EFV:↑ TG, ↑ LDL, ↑ HDL||
All RTV- or COBI-boosted PIs: ↑TG, ↑LDL, ↑HDL
LPV/r = FPV/r and LPV/r > DRV/r and ATV/r: ↑TG
|EVG/c: ↑TG, ↑ LDL, ↑ HDL||N/A|
ddI and ZDV > other
NRTIs: Nausea and
GI intolerance (e.g., diarrhea, nausea, vomiting)
Common with LPV/r and more frequent than with DRV/r and ATV/r: Diarrhea
EVG/c: Nausea and D
|Hepatic effects||Reported with most NRTIs.
ddI: Prolonged exposure linked to noncirrhotic portal hypertension, esophageal varices.
When TAF, TDF, 3TC, and FTC are withdrawn or when HBV resistance develops: HIV/HBVcoinfected patients may develop severe hepatic flares.
EFV: Fulminant hepatitis progressing to hepatic failure requiring transplantation or death have been reported.
EFV and NVP are not recommended in patients with hepatic insufficiency (Child-Pugh class 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|
Excluding rash alone or Stevens-Johnson syndrome
ABC: Contraindicated if
Risk is greater for ARV-naive
Two-week dose escalation of
|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|
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.
Lipoatrophy: 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 Creatine Phosphokinase||ZDV: Myopathy||N/A||N/A||RAL, DTG: ↑ CPK, rhabdomyolysis, and myopathy or myositis have been reported
|Nervous System/Psychiatric Effects||d4T > ddI and ddC:
Peripheral neuropathy: (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 to 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.
RPV: Depression, suicidality, sleep disturbances
The retrospective study is published: Mollan KR, et al. Ann Intern Med. 2014;161:1-10.
The retrospective study is published: Mollan KR, et al. Ann Intern Med. 2014;161:1-10.
||ATV, DRV, FPV, LPV/r, TPV
||TDF: ↑ SCr, hypophosphatemia, urinary phosphate wasting, glycosuria, hypokalemia, non-anion gap metabolic acidosis. Concurrent use of TDF with COBI or RTVcontaining regimens appears to increase risk.
TAF: Less impact on renal biomarkers and lower rates of proteinuria than TDF.
RPV: Inhibits Cr secretion without reducing renal glomerular function
ATV and LPV/r: Increased risk of chronic kidney disease in a large cohort study.
IDV, ATV: Stone, crystal formation; adequate hydration may reduce risk.
(COBI as a boosting agent for DRV or ATV): Inhibits Cr secretion without reducing renal glomerular function.
|Cobi 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|
a In 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: 3TC = lamivudine; ABC = abacavir; ART= antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BMD = bone mineral density; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; CPK = creatine phosphokinase; Cr = creatinine; CrCl = creatinine clearance; 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 = highdensity 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; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; SQV = saquinavir; SQV/r = saquinavir/ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TG = triglyceride; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine
Switching Antiretroviral Therapy Because of Adverse Effects
Some patients experience treatment-limiting ART-associated toxicities. In these cases, ART must be modified. ART-associated adverse events can range from acute and potentially life threatening to chronic and insidious. Serious life-threatening events (eg, hypersensitivity reaction due to ABC, symptomatic hepatotoxicity, or severe cutaneous reactions) require the immediate discontinuation of all ARV drugs and reinitiation of an alternative regimen without overlapping toxicity. Toxicities that are not life-threatening (eg, urolithiasis with atazanavir [ATV], renal tubulopathy with tenofovir disoproxil fumarate [TDF]) can usually be managed by substituting another ARV agent for the presumed causative agent without interrupting ART. Other, chronic, non–life-threatening adverse events (eg, dyslipidemia) can be addressed either by switching the potentially causative agent for another agent or by managing the adverse event with additional pharmacological or nonpharmacological interventions. Management strategies must be individualized for each patient.
Switching from an effective ARV regimen (or agent) to a new regimen (or agent) 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. Even if resistance mutations are absent from subsequent resistance test results, they 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;
• All previous resistance test results;
• Viral tropism (if maraviroc [MVC] is being considered);
• HLA-B*5701 status (if ABC is being considered);
• Adherence history;
• Prior intolerances to any ARVs; and
• Concomitant medications and supplements for potential drug interactions with ARVs.
A patient's willingness to accept 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. Therefore, clinicians should investigate all potential causes for an adverse event. 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.
Please refer to the lipid management section of the: Australian Absolute Cardiovascular risk guidelines published jointly by the Heart Foundation, Stroke Foundation, Diabetes Australia and Kidney Health Australia. The Heart Foundation produces a comprehensive range of independent, evidence-based cardiovascular health information. Please refer to the lipid management section of the: Australian Absolute Cardiovascular risk guidelines published jointly by the Heart Foundation, Stroke Foundation, Diabetes Australia and Kidney Health Australia. Australian cardiovascular risk calculator provides a Framingham 5 year CVD risk calculation D:A:D cardiovascular risk calculator: provides an HIV specific risk calculator based on the DAD cohort, but has not been validated in another population.
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Please refer to the lipid management section of the: Australian Absolute Cardiovascular risk guidelines published jointly by the Heart Foundation, Stroke Foundation, Diabetes Australia and Kidney Health Australia.
The Heart Foundation produces a comprehensive range of independent, evidence-based cardiovascular health information.
Australian cardiovascular risk calculator provides a Framingham 5 year CVD risk calculation
D:A:D cardiovascular risk calculator: provides an HIV specific risk calculator based on the DAD cohort, but has not been validated in another population.
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