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Adverse Effects of Antiretroviral Agents

(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.

#1840 - Australian adverse drug reactions
June 2018 - Feedback

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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#1841 - EFV and suicide ideation
June 2018 - Feedback

The retrospective study is published: Mollan KR, et al. Ann Intern Med. 2014;161:1-10.

Switching Antiretroviral Therapy Because of Adverse Effects

#1842 Switching Antiretroviral Therapy Because of Adverse Effects
June 2018 - Feedback

Antiretroviral drugs available in Australia under the Pharmaceutical Benefits Scheme (section 100)

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);
• Comorbidities;
• 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.

 Table 15 (page 1)
Table 15 (page 2)

Table 15 (page 3)

#1843 - Australian hyperlipidaemia management guidelines
June 2018 - 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. Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers. J Cardiovasc Electrophysiol. Oct 2016;27(10):1206-1213. Available at https://www.ncbi.nlm.nih.gov/pubmed/27333947

  10. 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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