Abacavir

Fidelia Bernice, Pharm.D., Paul A. Pham, Pharm.D.
Pediatric Dosing Author: Lisa Hutchins, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other ARVs.

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Ziagen

Abacavir (ABC)

GlaxoSmithKline

oral

tablet

300 mg

$11.17 per tab

oral

solution

20 mg/mL

$0.73 (per mL)

Abacavir (generic)

ABC

Mylan Pharmaceuticals

oral

tablet

300 mg

$9.64 - 10.06 per tab

oral

solution

20 mg/mL

$0.65 (per mL)

Trizivir

ABC + AZT + 3TC

GlaxoSmithKline

oral

tablet

ABC 300 mg + AZT 300 mg + 3TC 150 mg

$32.19 per tab

Abacavir, Zidovudine, and Lamivudine (generic)

ABC + AZT + 3TC

Lupin

oral

tablet

ABC 300 mg + AZT 300 mg + 3TC 150 mg

$28.97 per tab

Epzicom

ABC + 3TC

GlaxoSmithKline

oral

tablet

ABC 600 mg + 3TC 300 mg

$51.67 per tab

Abavavir and Lamivudine (generic)

ABC + 3TC

Teva

oral

tablet

ABC 600 mg + 3TC 300 mg

$46.45 per tab

Kivexa (brand name available in Europe)

ABC + 3TC

GlaxoSmithKline

oral

tablet

ABC 600 mg + 3TC 300 mg

variable

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Pill burden: 2 pills/d (Ziagen, Trizivir) or 1 pill/d (Epzicom, Kivexa)

  • ABC 300 mg PO twice daily with or without food (as Ziagen or Trizivir).
  • ABC 600 mg PO once daily with or without food (as Ziagen, Epzicom, or Kivexa).

ADULT RENAL DOSING

DOSING IN HEMODIALYSIS

Usual dose

DOSING IN PERITONEAL DIALYSIS

No data-Usual dose likely

DOSING IN RENAL REPLACEMENT THERAPY

No data-Usual dose likely

PEDIATRIC DOSING

PEDIATRIC RENAL DOSING

No renal dosage adjustment is necessary.

OTHER PEDIATRIC INFORMATION

  • Switching from twice-daily to once-daily ABC has been studied in 3 small clinical trials (PENTA 15, PENTA 13, and Arrow) of HIV-infected children who had undetectable viral loads and were clinically stable. The studies showed similar AUC(0-24) between twice-daily and once-daily dosing, however, once-daily dosing resulted in lower trough concentrations in younger children. After switching to once-daily ABC, most children had good clinical outcomes.

ADVERSE DRUG REACTIONS

GENERAL

Rates of adverse reactions are defined during combination therapy with other antiretrovirals.

COMMON

  • Headache
  • Fatigue
  • Malaise
  • Nausea
  • Skin rash

OCCASIONAL

  • HYPERSENSITIVITY REACTION (HSR): noted in ~4% of pts: fever, rash, fatigue, malaise, GI Sx, myalgias, and arthralgias.
    • Over 93% occur within the first 6 wks of therapy, with a median time of onset of 11 days.
    • Requires discontinuation, but can continue ABC with close monitoring until dx certain or likely (sx generally worsen with each dose).
    • DO NOT RE-CHALLENGE, since anaphylactic-like reaction and death reported.
    • HSR more common in Caucasians and associated with HLA-DR7, HLA-DQ3, and HLA-B*5701 haplotypes.
    • Genetic testing for HLA-B*5701 (cost $70-80) virtually eliminates the risk of HSR, though patients should still be counseled about HSR before initiation.
      • ABC should NOT be given to patients with a positive test.

RARE

  • MITOCHONDRIAL TOXICITY: lipoatrophy and lactic acidosis with hepatic steatosis described with NRTI class, although most common with ddI, d4T, ddC, and AZT.
    • Unclear whether it occurs at all with ABC, since ABC is one of the least likely NRTIs to cause mitochondrial toxicity in vitro.
  • Possible increased risk of myocardial infarction (see D:A:D and SMART references)

DRUG INTERACTIONS

Not a substrate, inducer, or inhibitor of CYP3A4. No interaction is likely with PIs, NNRTIs, MVC, and RAL. ABC metabolized by alcohol dehydrogenase and glucoronyl transferase.

Drug-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

3TC

3TC AUC decreased by 15%.

Not clinically significant. Use a standard dose.

Alcohol

ABC AUC increased by 41%.

Clinical significance is unknown. No dose adjustment recommended.

AZT

No significant interaction.

Use a standard dose.

Food

ABC AUC was decreased by 5%(NS).

Administer ABC with or without food.

Methadone

Methadone clearance increased by 23%;
ABC: 34% decrease in Cmax.

Monitor for methadone withdrawal, but dose adjustment unlikely to be necessary.

Ribavirin

Decreased EVR to HCV treatment.

Avoid co-administration

TDF

Suboptimal virologic suppression when ABC/TDF/3TC once daily was used as a triple nucleoside regimen without PIs or NNRTIs. However, preliminary analysis of ABC/AZT/3TC with TDF as a nucleoside regimen did not show similar suboptimal results and no evidence of drug interaction.

Do not co-administer ABC/TDF/3TC once-daily as a triple nucleoside regimen. Minimal data on the use of this combination with a 4th agent.

Tipranavir

Decreased ABC AUC by 40%.

Clinical significance is unknown. Active intracellular carbovir triphosphate not measured. Use a standard dose.

RESISTANCE

  • 74V: Intermediate resistance to ABC and ddI. The most common mutation to be selected by ABC/3TC-containing regimens without thymidine analog. M184V further decreases susceptibility.
  • 65R: Low-level resistance, and intermediate resistance to ddI, TDF, 3TC, FTC. It can be selected by ABC/3TC-containing regimens without thymidine analog, though 74V is more common. Intermediate ABC and ddI resistance with 65R + 184V. M184V partially restores TDF susceptibility.
  • 184V + ≥3 TAMs: Intermediate-to high-level resistance. Greater ABC resistance with 41L/210W/215Y TAM pathway than with 67N/70R/219 pathway. High-level resistance with≥4 TAMs.
  • 115F: Can be selected by ABC, and causes low-level resistance. Intermediate resistance with 115F + 184V.
  • 184V: Can cause low-level loss of susceptibility to ABC, but by itself is not associated with clinically relevant resistance.

PHARMACOLOGY

MECHANISM

Intracellular phosphorylation to active carbovir triphosphate, which competitively inhibits HIV DNA polymerase.

PHARMACOKINETIC PARAMETERS

Absorption

Well absorbed with 83% oral bioavailability.

Metabolism and Excretion

81% metabolized by alcohol dehydrogenase and glucuronyl transferase with renal excretion of metabolites; 16% recovered in stool and 1% unchanged in urine.

Protein Binding

50%

Cmax, Cmin, and AUC

Mean steady-state Cmax=3mcg/mL; AUC=6 mcg hr/mL. Intracellular levels of carbovir triphosphate 100 FM/million cells.

T1/2

Serum: 1.5 hrs; intercellular (carbovir triphosphate):-12-20hrs.

DOSING FOR DECREASED HEPATIC FUNCTION

Usual dose or 200 mg twice daily (limited clinical data).

PREGNANCY RISK

Category C: rodent studies demonstrated placental passage. Teratogenic in rodent studies resulting in anasarca, skeletal malformation at 1000 mg/kg dose (35x human therapeutic levels) during organogenesis. However, rabbit studies using 8.5x human therapeutic levels did not result in fetal malformation. No adequate human data, placental passage was 32-66%.

BREAST FEEDING COMPATIBILITY

No human data. Breastfeeding is not recommended in the U.S in order to avoid post-natal transmission of HIV to the child, who may not yet be infected.

COMMENTS

  • Triple-NRTI regimens such as Trizivir are no longer recommended by the DHHS Guidelines due to suboptimal virologic activity.
  • HLA-B*5701 should be ordered in all pts before starting ABC, and ABC should not be given to those who test positive.
  • Recent data suggest a decreased virologic response compared to TDF/FTC in pts with baseline VL >100,000, and possible increased risk of MI.
  • Pros: One of most potent NRTIs, with VL reduction of 1.5-2.0 logs in monotherapy; good data on ABC/3TC as a well-tolerated and effective once-daily dual-NRTI backbone; development of 74V mutation with failure may allow sequencing to TDF, though clinical data lacking; co-formulated with 3TC (Epzicom, Kivexa) and with AZT/3TC (Trizivir); HLA B*5701 pre-screening essentially eliminates HSR risks discussed below.
  • Cons: Hypersensitivity reaction; requires pre-treatment screening and counseling/education; it can be fatal with rechallenge. Shorter intracellular half-life than TDF, and no susceptibility benefit with M184V. May be inferior compared to TDF in pts with baseline VL >100,000 c/mL (ACTG 5202). May increase the risk of cardiovascular disease in pts with risk factors (D:A:D and SMART studies).

Basis for recommendation

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Accessed [9/14/2019] [G1-G4]



    Comment:
    Current DHHS HIV Guidelines. "What Not to Use Section" describes the recommendation against triple NRTI therapy for the management of HIV infection.


  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Accessed [9/14/2019] [G1-G4]



    Comment:
    Current DHHS HIV Guidelines. "What Not to Use Section" describes the recommendation against triple NRTI therapy for the management of HIV infection.


References

  1. Paediatric European Network for Treatment of AIDS (PENTA). Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir Ther. 2010;15(3):297-305.  [PMID:20516550]

    Comment: The study helped establish the drug as a potential incorporation into a once-daily regimen due to its long half-life.

  2. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-40.  [PMID:19952143]

    Comment: The randomized controlled trial compared TDF/FTC and ABC/3TC in combination with EFV or boosted ATV. At a median follow-up of 60 weeks, among pts with VL >100K c/mL, the time to virologic failure was significantly shorter in the ABC/3TC group than in the TDF/FTC group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P< 0.001), 57 virologic failures (14%) were observed in the ABC/3TC group versus 26 (7%) in the TDF/FTC group. In pts with VL < 100K c/mL, there was no significant difference in time to virological failure between groups.

  3. D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417-26.  [PMID:18387667]

    Comment: A retrospective review of D:A:D observational cohort for cardiovascular disease risks associated with NRTI use included 33,347 pts (157,912 pt-yrs of follow-up). There were 517 MIs, including 192 in pts receiving ABC-containing regimens. After adjusting for confounding risk factors, the relative risk for ABC use within the last 6 months was 1.9 (95% CI 1.5-2.5). There was also increased risk associated with ddI treatment, but not d4T or AZT. Greatest risk (and greatest increased risk) in pts with risk factors for cardiovascular disease. The pathophysiologic mechanism of this effect, if real, has not been identified. Other studies have not shown this risk, but they may have been underpowered to show a risk of infrequent toxicity. However, the usual caveats with observational studies apply.

  4. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006;296(7):769-81.  [PMID:16905783]

    Comment: Continuation of ACTG 5095 compared AZT/3TC/EFV to AZT/ABC/3TC/EFV in ART-naive pts. No significant differences between 3vs 4-drug regimens; approximately 80% of pts had VL < 50 through 3 yrs. 10% treated with AZT/3TC/ABC/EFV had ABC HSR, vs. 7% on AZT/3TC/EFV.

  5. Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005;192(11):1921-30.  [PMID:16267763]

    Comment: A high rate of virologic failure in the TDF+ABC+3TC arm, with 49% experiencing virologic failure compared to 5.4% of pts taking EFV. Among TDF-treated pts for whom virologic data are available, 64% had both the K65R and M184V mutations and 36% had M184V alone. TDF/ABC/3TC is not recommended as a triple-NRTI regimen, and data minimal for use with a 4th agent.

  6. Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr. 2005;38(4):417-25.  [PMID:15764958]

    Comment: EFV + once- or twice-daily ABC as part of an ABC/3TC backbone were equivalent, with 66% and 68% of pts achieving VL <50, respectively.

  7. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005;10(2):239-46.  [PMID:15865218]

    Comment: The PENTA 13 cross-over PK study evaluated ABC 8mg/kg BID vs. 16mg/kg QD in 24 HIV infected children ages 2-13 years old who had undetectable/low viral loads and stable CD4 counts. Although AUC (0-24) was comparable between QD and BID dosing, Cmin of QD ABC was lower in younger children (2-6 y/o).

  8. DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39(7):1038-46.  [PMID:15472858]

    Comment: ABC/3TC + EFV was non-inferior to AZT/3TC + EFV in a randomized, double-blind study involving 649 naive pts. Response rate (< 50) through wk 48 was 70% and 69% in ABC and AZT group, respectively. Pts on ABC/3TC had less nausea, vomiting, fatigue, and anemia than pts taking AZT, but more HSR. ABC/3TC associated with a greater increase in CD4 (209 vs 155) and CD4%.

  9. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004;350(18):1850-61.  [PMID:15115831]

    Comment: Compared triple-NRTI regimen of AZT/3TC/ABC with 2 EFV-containing regimens, AZT/3TC + EFV and AZT/3TC/ABC + EFV. The triple-NRTI arm was stopped early because of a higher rate of virologic failure vs. EFV-based regimens (21% vs 10%, p < 0.001). Triple NRTI regimens should only be used as an alternative in pts who cannot take PI or NNRTI-based regimens.

  10. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727-32.  [PMID:11888582]

    Comment: This study found an extraordinary association between the presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 alleles and HSR to ABC (OR 822 [43-15675], p< 0.0001). The authors concluded that if ABC was withheld in the presence of these alleles, the prevalence of HSR would decrease from 9-5% to 2.5%. Positive predictive value for HSR 100%, negative predictive value 97%.

  11. Staszewski S, Keiser P, Montaner J, et al. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial. JAMA. 2001;285(9):1155-63.  [PMID:11231744]

    Comment: AZT/3TC + ABC was equivalent to AZT/3TC + unboosted IDV, with 51% in both groups achieving VL < 400 at 48 wks. Trend favoring IDV-based regimen in pts with baseline VL >100,000, with 45% vs 31% achieving < 50 (a treatment difference -14% (95% CI, -27% to 0%). Although this trial demonstrated equivalency at < 400 endpoints, the decreased potency at high VL suggests lower potency overall.

  12. Paula Munderi and the DART Trial Team; Safety of Nevirapine Compared to Abacavir on a Background of Zidovudine/Lamivudine as First-line Antiretroviral Therapy: A Randomized Double-blind Trial; CROI; Vol. 109LB;

    Comment: A 24-week randomized double-blind trial compared the safety of NVP or ABC when combined with zidovudine/lamivudine in 599 ARV-naive patients in Uganda. 6 (2%) on ABC and 14 (4.7%) on NVP developed a serious adverse reaction (HR = 0.41; 95% CI 0.16-1.08; log-rank p = 0.06). 19/20 of these SAR were consistent with a hypersensitivity reaction. Grade 4 toxicities were more common in the NVP treated group (64 ABC vs 91 NVP, p=0.008), but the majority of these were due to bone marrow suppression. 8 patients (all NVP) developed grade 4 LFTs elevation.

  13. Mallal S, Phillips E, Carosi G, et al.; PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030); 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 2007, Sydney Australia;

    Comment: Study randomized 1956 ABC-naive patients to the standard of care or screening with the HLA-B*5701 test before starting ABC. Incidence of both clinically diagnosed and immunologically confirmed HSR significantly lower in screening arm vs. control arm. No cases of immunologically confirmed HSR observed in the prospective screening arm. HLA-B*5701 had a 100% sensitivity.

  14. SMART/INSIGHT and D:A:D Study Groups; Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients; AIDS; Vol. 22; pp. F17-24;

    Comment: A retrospective review of 2752 pts enrolled in continuous treatment arm of SMART evaluated cardiovascular (CV) disease risks associated with NRTI components of ARV regimens. CV risk factors comparable between groups: the median age of 40, 73% males, 39% smokers, 7% had diabetes, and 4% with prior CV disease. Use of ABC associated with increased risk of MI (AHR = 4.3), CV-related death (AHR = 1.8), with significantly increased risk seen in those with 5 or more CV risk factors.

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Last updated: February 7, 2020