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Adverse Effects of Antiretroviral Agents

(Last updated:14/7/2016; last reviewed:14/7/2016)

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 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.

#1540 - Australian adverse drug reactions
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These can be reported here: http://www.tga.gov.au/safety/problem-medicine.htm

(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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Table 14. Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects
Adverse Effects 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, anticoagulant or antiplatelet agents, vitamin E

 N/A N/A
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
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.

 N/A N/A
Cholelithiasis  N/A N/A

ATV: Cholelithiasis and kidney stones may present
concurrently.


Median onset is 42 months.

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

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

 N/A N/A
Dyslipidemia d4T > ZDV > ABC:

TG and LDL

TAF > TDF: ↑TG, ↑LDL, ↑HDL (no change in TC:HDL
ratio)

 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
Gastrointestinal Effects

ddI and ZDV > other

NRTIs: Nausea and
vomiting
ddI: Pancreatitis

 N/A

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

 

 

 N/A
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.
 

NVP > other NNRTIs


NVP: Severe
hepatotoxicity
associated with skin
rash or hypersensitivity.
Two-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 postexposure
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 HLAB*5701 status, should not be
rechallenged 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.

Two-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 
 
#1541 - HSR in patients taking RAL
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The incidence of HSR (drug-related or not) in patients taking RAL in the BENCHMRK study was 0.6%, although no cases have been reported in post-marketing experience.

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.

 N/A N/A N/A N/A
Lipodystrophy

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: ↑ CPK, weakness and rhabdomyolysis
 N/A
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

#1542 - EFV and suicide ideation
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The retrospective study is published: Mollan KR, et al. Ann Intern Med. 2014;161:1-10.

N/A

All INSTIs: 
Insomnia, depression, and suicidality have been infrequently reported with INSTI use, primarily in patients with preexisting psychiatric conditions.



N/A
Rash FTC: Hyperpigmentation 
All NNRTIs
ATV, DRV, FPV, LPV/r, TPV
RAL, EVG
MVC
Renal Effects/Urolithiasis
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.

N/A

ATV and LPV/r: Increased risk of chronic kidney disease in a large cohort study.

IDV: ↑ SCr, pyuria; renal atrophy or hydronephrosis

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

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

#1543 Switching Antiretroviral Therapy Because of Adverse Effects
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Antiretroviral drugs available in Australia under the Pharmaceutical Benefits Scheme (section 100)

Some patients experience treatment-limiting ART-associated toxicities, and 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);
• Comorbidities;
• Adherence history;
• Prior intolerances to any ARVs; and
• Concomitant medications and supplements for potential drug interactions with ARVs.

A patient's 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. 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.

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#1544 - Australian hyperlipidaemia management guidelines
August 2015 - Feedback

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.

References

  1. O'Brien ME, Clark RA, Besch CL, et al. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr. 2003;34(4):407-414. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=pubmed&dopt=Abstract&list_uids=14615659.
  2. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. Dec 22 2000;14(18):2895-2902. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=PubMed&dopt=Citation&list_uids=11153671.
  3. Saves M, Raffi F, Clevenbergh P, et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in human immunodeficiency virusinfected patients. The APROCO Study Group. Antimicrob Agents Chemother. Dec 2000;44(12):3451-3455. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=PubMed&dopt=Citation&list_uids=11083658.
  4. Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. Sep 12 2008;22(14):1890-1892. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=PubMed&dopt=Citation&list_uids=18753871.
  5. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS. Aug 24 2015;29(13):1723-1725. Available at http://www.ncbi.nlm.nih.gov/pubmed/26372287.
  6. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=18256392.
  7. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111-1118. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=pubmed&dopt=Abstract&list_uids=18444831.
  8. Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther. 2010;7:32. Available at http://www.ncbi.nlm.nih.gov/pubmed/20723261.
  9. Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS. Jan 2 2007;21(1):41-46. Available at http://www.ncbi.nlm.nih.gov/pubmed/17148966.

 

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