Abacavir

Article Author:
Jared Vincent Fernandez
Article Editor:
Ahmed Munir
Updated:
2/11/2019 8:43:15 PM
PubMed Link:
Abacavir

Indications

Abacavir is an FDA-approved drug used to treat HIV-1 infection in combination with other antiretrovirals.  Like other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir use is typically in combination with other HIV medications.  Abacavir is not recommended for use by itself.[1]  It can be taken by mouth as a tablet or solution and may is a treatment option in patients over the age of three months.[2]  Commonly, abacavir is dispensed together with other HIV medications such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine.[3]

Mechanism of Action

Abacavir is a nucleoside reverse transcriptase inhibitor.  Within this class, it is specifically a carbocyclic 2’-deoxyguanosine, also known as a guanosine analog.  After oral ingestion, abacavir sulfate is rapidly absorbed and reaches peak concentrations at about 0.63-1 hour with an absolute bioavailability of about 83%.  Abacavir displays linear pharmacokinetics and possesses dose proportionality over the range of 300-1200 mg/day.  Taking abacavir with food has not had any clinically relevant effect on exposure to the drug and can be safely ingested in the presence or absence of food.  The volume of administration by parental route is about 0.86 +/- 0.15 L/kg.  Plasma protein binding is about 50% and has an independent relationship with the plasma concentration of the drug.

The liver accomplishes the majority of abacavir's metabolism.  The remaining bioavailable 2% of the compound gets excreted as an unaltered product in the urine. Two major metabolic pathways are known as the uridine diphosphate glucuronyltransferase, and the alcohol dehydrogenase pathway processes abacavir within the liver.  Enzymatic metabolism produces an inactive glucuronide metabolite (361W94, approximately 36% of the dose recovered in the urine) and an additional inactive carboxylate metabolite (2269W93, approximately 30% of the dose recovered in the urine) — the other 15% of the compound ends up in the urine as minor metabolites, which comprise less than 2% of the orally ingested amount.  Elimination through stool makes up about 16% of the original dose.  CYP450 metabolism of abacavir does not play a substantial role in abacavir, and no observable drug interactions that alter clinical decision making exist within recommended doses of methadone, or alcohol, zidovudine, abacavir, and lamivudine.[4]

The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate, which interferes with HIV viral RNA-dependent DNA polymerase, leading to inhibition of viral replication.[5] This intracellular anabolite has been shown to have a long elimination half-life of greater than 20 hours, allowing for once-daily dosing.[4]

Administration

Abacavir is administered as 300 mg twice daily or as 600 mg once daily.  It is also available as part of several co-formulated tablets.  These different co-formulations are part of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).[6]

There are no dosage adjustments recommended in patients with renal impairment and Abacavir is well tolerated in patients that would benefit from NRTI use with renal pathology from other antiretrovirals.[7]  Dosing adjustment in hepatic impairment is recommended.  Mild hepatic impairment denoted as Child-Pugh class A is suggested at 200 mg twice daily as an oral solution.  Contraindications to abacavir include moderate to severe hepatic impairment, Child-Pugh class B or C, due to lack of evidence.[4]

Adverse Effects

The common toxicities of the NRTI class are mitochondrial toxicity, which can present as hepatic steatosis, lipoatrophy, pancreatitis, and peripheral neuropathy.[8]  Symptomatic lactic acidosis can also occur in patients and these require monitoring due to an increased risk of mortality.[9]  Additionally, patients on long-term antiretroviral therapy (ART) may experience fat redistribution: lipodystrophy.[10]

Abacavir should be avoided in people with coronary artery disease and in those at increased risk of myocardial infarction due to an increased risk of hyperlipidemia and cardiovascular events.[11][12][13]

Contraindications

Contraindications to the use of abacavir in ART therapy include hypersensitivity to abacavir or any formulation component, moderate to severe hepatic impairment, and patients who are positive for the HLA-B*5701 allele.[14]  Also, in patients with moderate to severe hepatic impairment, Child-Pugh class B or C, abacavir administration is relatively contraindicated due to lack of study.[4]

Abacavir should also be avoided in patients and is relatively contraindicated in individuals who test positive for HLA-DR7 and HLA-DQ3 because evidence shows that withholding abacavir leads to a reduced incidence of hypersensitivity reactions.[15]

Monitoring

There is some potential for drug-induced injury to the body that requires monitoring when administering abacavir to patients with HIV.  Patients should receive screening for HLA-B*57101 genotype status prior to the start of therapy and before a continuation of therapy in patients with unknown HLA-B57101 status.  Patients should have CBC with differential, serum creatinine kinase, CD4 count, HIV RNA plasma level, triglycerides, and serum amylases monitored periodically.[14]  Clinicians should be aware of the risk for acute and late-onset hepatotoxicity and monitor AST and ALT levels.[16]  Signs of central fat gain or lipoatrophy should be assessed for fat gain or fat loss to fine-tune ART therapy.[17]

Toxicity

Serious and sometimes fatal hypersensitivity reactions can potentially occur with abacavir.  Patients who possess the HLA-B*5701 allele also carry a higher risk for a hypersensitivity reaction to abacavir; however, hypersensitivity reactions have occurred in those who do not carry the HLA-B*5701 allele.  All patients should receive screening for the HLA-B*5701.[14]

Enhancing Healthcare Team Outcomes

Managing the administration of abacavir to HIV patients requires an interprofessional team of healthcare professionals that includes a nurse, laboratory technologists, pharmacist, social workers and several physicians in different specialties. After HIV diagnosis, prompt admission into HIV medical and adherence/retention in that care is fundamental to the administration of effective antiretroviral therapy.  Adherence to ART is one of the top factors of favorable HIV treatment outcomes and is necessary to decrease the occurrence of drug resistance within the patient.  Common obstacles to successful ART stem from an absence of social support and alcohol or substance abuse, which prevent patients from having sustained therapy.

Recommendations for increasing successful outcomes in antiretroviral therapy 

  • Initiation of highly active antiretroviral therapy (HAART) with high levels of adherence, defined as greater than 95% refills and plasma drug concentrations above the therapeutic steady-state concentration, is associated with low levels of antiretroviral resistance.[18] (Level I)
  • Individual-level monitoring of entry and retention is a strong recommendation for all people diagnosed with HIV.[19][20] (Level I)
  • Systematic retention monitoring in HIV care is also strongly recommended for all HIV patients.[21] (Level III) 
  • Strengths-based case management from trained social workers increases entry to HIV medical care.[22] (Level I)
  • Self-report adherence should be obtained routinely in all HIV patients.[23] (Level III)
  • Regimens of similar efficacy and tolerability, once daily regimens are recommended, in treatment naïve patients starting ART,[23][24](Level I) as well as experienced patients receiving poorly tolerated/complex regimens.[25][26](Level I)
  • Reminders and use of communication technologies with an interactive component are recommended to increase adherence [27] (Level I)
  • Combining education and counseling using specific adherence related tools is recommended for all patients with HIV.[28][29][30](Level I)
  • Directly administered ART (DART) is the recommended course of action in individuals with substance use disorders.[31][32][33] (Level II)
  • Cognitive behavioral therapy is recommended in patients with depression to improve adherence.[34] (Level II)