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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Drugs>Antiretrovirals>
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Abacavir

Paul Pham, Pharm.D. and John G. Bartlett, M.D.
09-20-2010

Zambia Specific Information

  • HLA-B*5071 more common in whites and rare in African pts.
  • In substudy of DART trial in Uganda, suspected hypersensitivity reaction (HSR) reported in only 2% of pts.
  • When compared to NVP + AZT + 3TC, ABC+ AZT + 3TC regimen was better tolerated with less treatment discontinuation.
  • ABC +3TC (+ NVP or EFV) can be considered as an alternative NRTI in patients with CRF who can not tolerate TDF + FTC.
  • If PI-based regimens not available, ABC+AZT+3TC can be considered in women with CD4 >250, HIV-2 infection, or severe reactions to NVP or EFV.

REFERENCES

Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other ARVs.

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Ziagen Abacavir (ABC)GlaxoSmithKline oral
tablet
300 mg
$10.26 per tab
      oral
suspension
10 mg/mL (240ml bottle)
$161.78 (per 240ml)
Trizivir ABC + AZT + 3TCGlaxoSmithKline oral
tablet
ABC 300 mg + AZT 300 mg + 3TC 150 mg
$26.81 per tab
Epzicom ABC + 3TCGlaxoSmithKlineoral
tablet
ABC 600 mg + 3TC 300 mg
$35.78 per tab
Kivexa (brand name available in Europe)ABC + 3TCGlaxoSmithKlineoral
tablet
ABC 600 mg + 3TC 300 mg
variable

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^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).

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Usual dose

DOSING IN HEMODIALYSIS

Usual dose

DOSING IN PERITONEAL DIALYSIS

No data-Usual dose likely

DOSING IN HEMOFILTRATION

No data-Usual dose likely

ADVERSE DRUG REACTIONS

COMMON

Nausea, abdominal pain, malaise, and headache reported in approximately 7% of pts in clinical trials (8-11% when given with AZT).

OCCASIONAL

HYPERSENSITIVITY REACTION (HSR) noted in ~4% of pts: fever, rash, fatigue, malaise, GI Sx, myalgias, and arthralgias. Over 93% occur within first 6 wks of therapy, with 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 RECHALLENGE, 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 risk of HSR, though pts should still be counseled about HSR before initiation. ABC should NOT be given to pts with 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 infaction (see D:A:D and SMART references)

DRUG INTERACTIONS

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

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
3TC 3TC AUC decreased by 15%.Not clinically significant. Use standard dose.
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 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 use of this combination with a 4th agent.
AZT No significant interaction.Use standard dose.
Tipranavir Decreased ABC AUC by 40%. Clinical significance unknown. Active intracellular carbovir triphosphate not measured. Use standard dose.
AlcoholABC AUC increased by 41%.Clinical significance unknown. No dose adjustment recommended.
FoodABC 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

RESISTANCE

  • 74V: Intermediate resistance to ABC and ddI. 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. Can be selected by ABC/3TC-containing regimens without thymidine analog, though 74V 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

Pharmacology

COMMENTS

Trizivir (AZT/3TC/ABC) equivalent to unboosted IDV-based HAART regimen in pts with baseline VL <100,000, but inferior to EFV-based HAART regimens. Since Trizivir (without a PI or NNRTI) is inferior to gold standard EFV-based regimen, it is recommended by the DHHS Guidelines only as alternative regimen when PI- or NNRTI-based regimens cannot be used. Addition of ABC to AZT/3TC/EFV did not improve virologic response in ART-naive patients. 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 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; coformulated 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; can be fatal with rechallenge; shorter intracellular half-life than TDF, and no susceptibility benefit with M184V. Less long-term data than with TDF. May be inferior compared to TDF in pts with baseline VL >100,000 c/mL (ACTG 5202). May increase risk of cardiovascular disease in pts with risk factors (D:A:D and SMART studies).

REFERENCES

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