Toxicity & side effects: switching therapy

Lisa A. Spacek, M.D., Ph.D.

DEFINITION

  • Modification of ART regimen in virologically suppressed patients[2]
    • To reduce or prevent toxicity[16]
    • To improve long-term adherence, reduce pill burden and dosing frequency, decrease dietary requirements
    • To avoid drug interactions

INDICATIONS

DHHS guidelines

  • Rates of treatment-limiting adverse effects (AEs) are < 10% in ART-naive patients enrolled in trials; however, this may underestimate long-term toxicity.[2]
    • AEs: cardiovascular disease, CNS effect, cholelithiasis, insulin resistance, dyslipidemia, GI effects, hepatotoxicity, hypersensitivity reaction, lipodystrophy, nephrotoxicity, drug-related rash, and Stevens-Johnson syndrome/toxic epidermal necrosis. DHHS guidelines lists ART-associated common and/or severe AEs, Table 13.[2]
  • Reasons to switch
    • Switch from drugs that are no longer recommended as preferred or alternative choices for initial therapy
    • Switch to newer drugs or drug coformulations that improve adherence
      • Higher adherence rates seen with once-daily versus twice-daily regimens[10]
  • Candidates for switching ART: patients without suspected drug-resistance and without history of treatment failure; patients with documented or suspected drug resistance (e.g., history of dual-NRTI therapy or transmitted resistance) who may benefit from switching to recently approved agents with activity against drug-resistant virus[8]
    • Within class substitution
      • NRTI: switch from ZDV or d4T to TDF or ABC to simplify regimen and to treat or prevent toxicity
      • NNRTI: switch from EFV/TDF/FTC to RPV/TDF/FTC due to ongoing CNS side effects (only if viral load suppressed)[13][15]
      • PI: switch from twice-daily to once-daily boosted PI
      • INSTI: switch from twice-daily RAL+TDF/FTC to single-tablet EVG/cobi/TDF/FTC or to once-daily DTG + TDF/FTC
    • Out-of-class substitutions
      • Consider genetic barrier to resistance of both current and potential regimen; those without known resistance on first or second regimen may switch from boosted PI to NNRTI- or INSTI-based reigmens;[8] however, switch from boosted PI to RAL was associated with increased risk of virologic failure in those with documented or suspected pre-existing NRTI resistance.[17] The same concern applies to NNRTIs and other INSTIs
      • Prior to MVC use, documentation of R5-only virus is required, but no clinical data on whether proviral DNA tropism assay can be used to predict successful switch to MVC[3]

IAS-USA guidelines

  • Single-agent switches to reduce toxicity, improve adherence and tolerability, and avoid drug interaction are endorsed. Goal to maintain regimen potency and virologic suppression.[1]
  • Avoid treatment interruptions. If planned surgery or severe toxicity, prior to interruption, consider drug half-lives (NNRTIs) and avoid inadvertant monotherapy.

CLINICAL RECOMMENDATION

General 

  • Evaluate clinical and lab data to identify causative drug, rule out other causes, consider single drug switch or treat the adverse effect. If severe toxicity, may need to stop all drugs.

Cardiovascular disease (CVD)

  • HIV infection itself increases risk of CVD, absolute risk greatest in those with traditional risk factors.
  • PIs associated with MI and stroke. RTV-boosted PIs increase risk of hyperlipidemia, LPV/r > DRV/r and ATV/r.
  • ATV/r and LPV/r associated with PR interval prolongation. SQV/r can prolong PR and QT intervals.
  • ABC and ddI associated with increased risk of MI in some but not all studies; greatest risk in pts with traditional CVD risk factors.
  • NNRTIs increase TG, HDL, LDL (EFV>NVP).
  • All RTV-boosted PIs increase LDL, TG, HDL (LPV/r>DRV/r and ATV/r).

Gastrointestinal effects

  • Diarrhea: associated with PIs: NFV, LPV/r > DRV/v and ATV/r. Control with fiber supplementation or anti-motility agents, consider change to different PI or switch drug class. Nausea and diarrhea seen with EVG/cobi/TDF/FTC.
  • Hepatotoxicity: severe hepatic toxicity seen with NVP, contraindicated in women with CD4 >250, men with CD4 >400, and Child-Pugh Class B and C, never use for post-exposure prophylaxis; steatosis seen with NRTIs; non-cirrhotic portal hypertension with ddI; drug-induced hepatitis seen with all PIs, TPV/r has more hepatic events than other PIs. MVC hepatotoxicity with or without rash or hypersensitivity reaction reported.
    • Meta-analysis did not find NVP-associated hepatotoxicity or rash in virologically suppressed patients switching to NVP, regardless of CD4 count.[12]
  • Pancreatitis: Associated with PI-induced hypertriglyceridemia and ddI.
  • Hyperbilirubinemia: ATV and IDV cause indirect hyperbilirubinemia.
  • HBV co-infected pts may experience flare if TDF, FTC or 3TC are withdrawn or HBV resistance develops.
  • IRIS-associated hepatitis: TB, MAC, HBV, HCV co-infection.

Hypersensitivity reaction (HSR)

  • ABC: Systemic HSR in 5-8%, progressive with each dose: fever, rash, malaise, dyspnea, N/V, HA; median onset, 9d; 90% in first 6 wks of exposure to ABC. Switch to TDF or NRTI-sparing regimen. DO NOT rechallenge with ABC.
    • Perform HLA-B*5701 testing prior to initiating ABC; those positive for haplotype should not receive ABC; those negative are extremely unlikely to develop HSR
  • NVP: hepatotoxicity and rash with fever, malaise, fatigue, oral lesions, conjunctivitis, facial edema and granulocytopenia. Two week dose escalation, NVP 200 mg PO once daily x 14d, then NVP 400 mg (XR tablet) PO once daily, reduces risk.
  • RAL, MVC, DTG: HSR reported, MVC-related HSR may include hepatotoxicity.
  • Stop or switch for severe rash, systemic symptoms or rash with hepatotoxicity.

Metabolic abnormalities

  • DM/insulin resistance: DM reported in up to 6% with HIV infection; impaired glucose tolerance, 15-20%. IDV, LPV/r, DRV/r associated with impaired insulin sensitivity. ATV/r not found to alter insulin sensitivity. Insulin-sensitizing agents preferred.[11]Lactic acidosis: NRTIs (ddI, d4T, ZDV). Fatigue, N/V, diarrhea, abdominal pain, pancreatitis. Elevated liver enzymes in hepatic steatosis. Check serum lactate, bicarbonate, arterial pH. Severe lactic acidosis, stop NRTIs. Preferred and alternative agents: TDF or ABC.
  • Lipoatrophy: associated with thymidine analogs, d4T > ZDV. Switch to TDF or ABC. Polylactic acid (e.g., Sculptra) and calcium hydroxylapatite (e.g., Radiesse) approved for facial lipoatrophy. Lipohypertrophy seen in EFV-, PI- and RAL-containing regimens. Liposuction for visceral abdominal fat accumulation. Buffalo humps have been shown to recur after liposuction, surgical removal more effective.
  • Rash: NNRTIs, ATV, DRV, FPV, RAL, EVG/cobi/TDF/FTC and MVC. Mild-moderate rash common and does not require discontinuation.
    • Stop or switch for severe rash (mucosal involvement or desquamation), systemic symptoms (ABC), or rash with hepatotoxicity (NVP).
  • DRV and FPV: sulfa-allergic pts may be at increased risk (but not contraindicated for mild-moderate sulfa allergy).
  • Use caution when starting NNRTIs, ABC, and/or TMP/SMX simultaneously.

Rash

  • NNRTIs, ATV, DRV, FPV, RAL, EVG/cobi/TDF/FTC and MVC. Mild-moderate rash common and does not require discontinuation.
  • Stop or switch for severe rash (mucosal involvement or desquamation), systemic symptoms (ABC), or rash with hepatotoxicity (NVP).
  • DRV and FPV: sulfa-allergic pts may be at increased risk (but not contraindicated for mild-moderate sulfa allergy).
  • Use caution when starting NNRTIs, ABC, and/or TMP/SMX simultaneously.

Nervous system effects

  • CNS: Somnolence, insomnia, abnormal dreams, dizziness, impaired concentration, depression, psychosis and suicidal ideation associated with EFV during first 2-4 wks; usually improves over time. Recommend EFV qhs on empty stomach during early therapy. Switch to another active agent for depression, psychosis, hallucinations, prolonged or intolerable side effects (>3-4 wks).

Renal effects

  • Renal insufficiency: Underlying renal insufficiency may increase risk of renal toxicity. Adjust drug dose based on calculated creatinine clearance. Monitor renal function at routine intervals.
  • EVG/cobi/TDF/FTC: Cobicistat inhibits tubular secretion of creatinine, causing a early nonpathologic decrease in creatinine clearance, with average creatinine elevation of 0.15 mg/dL. If progressive, or if increase in serum creatinine >0.4 mg/dL, look for other causes. Effect also seen with RTV, DTG, RAL, but to lesser degree.
  • TDF: Associated with proteinuria, rapid kidney failure and chronic kidney disease.[6] Switch from TDF to ABC or NRTI-sparing regimen or increase dosing interval. Most specific form of TDF nephrotoxicity is proximal renal tubular dyfunction with phosphate wasting and risk for osteomalacia.
  • Nephrolithiasis: Stone and crystal formation, IDV or ATV. Adequate hydration may reduce risk.
  • ATV, IDV, and possibly LPV/r associated with development of chronic kidney disease, independent of stone formation.[7][5]

Bone marrow effects

  • Anemia/Leukopenia: ZDV is the only ARV likely to cause bone marrow toxicity, especially macrocytic anemia. Switch to TDF, ABC or use NRTI-sparing regimen. It not on ZDV, rule out other causes.

Bone

  • Osteopenia/Osteoporosis: Early, non-progressive decline in bone mineral density seen with initiation of most ARV regimens; greater decline seen with TDF-based regimens. Also consider osteomalacia in TDF-treated patients with evidence of proximal tubulopathy. Bone densitometry recommended in HIV-infected post-menopausal women and in men >50 yo. Rule out hypogonadism and vitamin D deficiency. Treatment includes bisphosphonates, adequate calcium and vitamin D. Avoid bisophosphonates in osteomalacia.

MONITORING AFTER TREATMENT SWITCHING

Check VL 2-6 wks after change to confirm potency of new regimen, may also include CD4 count and markers of renal and liver function.

Basis for recommendation

  1. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308(4):387-402.  [PMID:22820792]

    Comment: IAS-USA guidelines endorse switching for toxicity or improved adherence in patients, short- and long-tem toxic effects, and simplification based on past ART and past (in those virologically suppressed) or current drug resistance testing. Avoid treatment interruptions.

  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Last updated February 12, 2013. Available at: http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.... Accessed 10/28/13. Adverse Effects of Antiretroviral Agents Section, Table 13.

    Comment: Table 13 lists side effect profiles and comments on each drug class.

References

  1. Pou C, Codoñer FM, Thielen A, et al. HIV-1 tropism testing in subjects achieving undetectable HIV-1 RNA: diagnostic accuracy, viral evolution and compartmentalization. PLoS One. 2013;8(8):e67085.  [PMID:23936293]

    Comment: Proof-of-concept study of 30 participants with VL < 50 c/ml after 2 years on first-line ART revealed absence of de novo CXCR4-using HIV-1 production; however, tropism results in plasma vs peripheral blood mononuclear cells are not necessarily equivalent. Clinical evaluation of proviral tropism testing will determine application in setting of undetectable viral load.

  2. Bernardini C, Maggiolo F. Triple-combination rilpivirine, emtricitabine, and tenofovir (Complera™/Eviplera™) in the treatment of HIV infection. Patient Prefer Adherence. 2013;7:531-42.  [PMID:23814462]

    Comment: Review of coformulated RPV/FTC/TDF emphasizes strategic use of this combination to treat those with baseline VL < 100,000 c/ml, women with pregancy potential, those with high CNS toxicity risk or high cardiovascular risk, and those requiring methadone maintenance. In the pooled analysis of ECHO and THRIVE trials, in pts with baseline VL > 100,000 c/mL, those with >95% adherence had about 20% higher response rates than those with ≤ 95% adherence, in both the RPV/FTC/TDF and EFV/FTC/TDF groups.
    Rating: Important

  3. Ryom L, Mocroft A, Lundgren J. HIV therapies and the kidney: some good, some not so good? Curr HIV/AIDS Rep. 2012;9(2):111-20.  [PMID:22370968]

    Comment: Review of clinical data addressing nephrotoxicity of ARVs. Table 1 lists ARVs, mechanisms, and presentations. Routine screening recommended. Kidney biopsy to establish accurate diagnosis.
    Rating: Important

  4. Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26(7):867-75.  [PMID:22313955]

    Comment: Retrospective Veterans Health Administration-based study (N=10,841) reported that after multivariable adjustment, each year of exposure to TDF was associated with 34% increased risk of proteinuria (95%CI, 25-45%; p< 0.0001), 11% increased risk of rapid decline (95%CI, 3-18%; p=0.0033), and 33% increased risk of CKD (95%CI, 18-51%; p< 0.0001). Two mechanisms of injury are discussed: drug accumulation in the proximal tubule resulting in mitochondrial injury and acute tubular necrosis resulting in tubulointerstitial scarring.
    Rating: Important

  5. Mocroft A, Kirk O, Reiss P, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS. 2010;24(11):1667-78.  [PMID:20523203]

    Comment: EuroSIDA cohort data identified 225 (3%) HIV+ people who developed chronic kidney disease (CKD) during 21,482 PY of follow-up (4 yrs median f/u) for an incidence of 1.05 per 100 PY of follow-up (95% CI, 0.9–1.2). Multivariate analysis showed increased rate of CKD associated with increasing cumulative exposure to TDF (IRR, 1.2; 95%CI, 1.1–1.3; P< 0.0001), IDV (IRR 1.1; 95%CI, 1.1–1.2; P< 0.0001), ATV (IRR, 1.2; 95%CI; 1.1–1.3, P< 0.0003) and LPV/r (IRR 1.1; 95%CI, 1.0–1.2; P< 0.030).
    Rating: Important

  6. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396-407.  [PMID:20074791]

    Comment: Phase 3, non-inferiority RCT of 702 virologically suppressed patients (>3mos with VL< 50 c/ml) selected to continue twice-daily LPV/r or switch to twice-daily RAL combined with OBT. Lower than expected virologic efficacy was seen with RAL (84%) versus those continuing LPV/r (91%). Total cholesterol, non-HDL cholesterol and triglycerides decreased in those who switched to RAL.
    Rating: Important

  7. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(5):651-81.  [PMID:19640227]

    Comment: Evidence-based guidelines for the management of HIV+ pts includes discussion of ART adverse effects.

  8. Parienti JJ, Bangsberg DR, Verdon R, et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009;48(4):484-8.  [PMID:19140758]

    Comment: Meta-analysis of 11 studies included 3029 participants found modest increase (2.9%, 95%CI 1-4.8%) in adherence seen with once-daily regimens versus twice-daily regimens. Effect seen in ART initiation rather than switching.

  9. Samaras K. Prevalence and pathogenesis of diabetes mellitus in HIV-1 infection treated with combined antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;50(5):499-505.  [PMID:19223782]

    Comment: Review of HIV- and ART-associated diabetes mellitus, insulin resistance, and metabolic sydrome.

  10. De Lazzari E, León A, Arnaiz JA, et al. Hepatotoxicity of nevirapine in virologically suppressed patients according to gender and CD4 cell counts. HIV Med. 2008;9(4):221-6.  [PMID:18366445]

    Comment: Meta-analysis of 4 published randomized studies (N=410) did not support the risk of NVP-associated hepatotoxicity, rash and death when stable and virologically suppressed patients were switched to nevirapine-containing ART. Risk of hepatotoxicity within the first 3 months was 2% and 4% in the "low CD4" and "high CD4" groups (breakpoint at 400 cells/μL for men and 250 cells/μL for women), respectively. Combined OR for hepatotoxicity in all participants was 1.5 (95%CI, 0.4-5.0). The risk of hepatotoxicity at any point during the study was similar in both groups, with a combined hazard ratio of 0.8 (95% CI 0.3-2.5).
    Rating: Important

  11. Cohen C, Wohl D, Arribas JR, et al. STaR study: single tablet regimen RPV/FTC/TDF maintains non-inferiority to EFV/FTC/TDF and has minimal impact on fasting lipids in ART-naive adults through week 96. 15th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Abstract O06. Antiviral Therapy 2013; 18 Suppl 3:A7.

    Comment: 96 wk data, randomized, open-label comparison of single-tablet regimen (STR) EFV/FTC/TDF vs RPV/FTC/TDF in 786 ART-naive and genotypic sensitivity to EFV, FTC, TDF and RPV. Snapshot analysis results found RPV-based STR non-inferior to EFV-based STR, 86% vs 82%, respectively. Minimal impact on fasting lipid profile with RPV/FTC/TDF.
    Rating: Important

  12. European AIDS Clinical Society Guidelines, v.7.0, October 2013. Accessed October 28, 2013.http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf

    Comment: Clinically-oriented document, Part 3, "Prevention and Management of Co-morbidities in HIV-positive Persons."
    Rating: Important

  13. Mills AM, Cohen C, Dejesus E, et al. Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. HIV Clin Trials. 2013;14(5):216-33.  [PMID:24144898]

    Comment: Industry-sponsored, phase 2b, open-label single-arm study of 49 pts virologically suppressed ≥ 3 mos on single tablet regimen EFV/FTC/TDF without known resistance mutations switched to RPV/FTC/TDF. At 48 wks, 46/49 pts (94%) remained suppressed and virologic failure occurred in 2/49 pts (4%) without emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch.
    Rating: Important

  14. Boyle A, Sonecha S, Mandalia S, Nelson M. An investigation into the frequency and reasons why patients switch antiretroviral theraoy and which antiretrovirals are commonly implicated in toxicity. Journal of the International AIDS Society 2012, 15(Suppl 4):18121. Accessed 10/29/13 at: http://www.jiasociety.org/index.php/jias/article/view/18121

    Comment: Retrospective report of 923 regimen switches occurring in 722 patients in 18 mos (Dec 2009 to May 2011). Calculated switch rate was 8% per year. Toxicity most often cited (49%) as reason for switch, followed by simplification (15%), clinical trials (8%), virologic failure (8%) and drug interactions (4%).

  15. Fisher M, Palella F, Tebas P, et al. SPIRIT study: switching boosted PI to Rilpivirine In combination with Truvada as an STR adults. 11th International Congress on Drug Therapy in HIV infection. November 11–15, 2012; Glasgow, UK. Abstract no P285. Study results presented at 8th International Conference on HIV Treatment and Prevention Adherence, Abstract #151. Slide set accessed 10/29/13 at:http://www.iapac.org/AdherenceConference/presentations/ADH8_OA151.pdf

    Comment: SPIRIT study, phase 3b, 48 wk study of switch from PI/r-based ART to RVP/FTC/TDF coformulation in 476 pts with VL < 50 c/ml for > 6 mos, without known drug resistance to study agents on first or second ART regimen. Participants randomized 2:1 to immediate switch (n=317) or delayed switch (n=159). Results showed RPV/FTC/TDF non-inferior to PI/r-based ART.
    Rating: Important

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Last updated: October 3, 2015