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Abacavir
Indications
Abacavir is an FDA-approved drug used to treat HIV-1 infection in conjunction with other antiretrovirals. Like other nucleoside reverse-transcriptase inhibitors (NRTIs), abacavir use is typically combined 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 it is a treatment option in patients over the age of three months.[2] Commonly, abacavir is dispensed with other HIV medications such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine.[3]
Singh R. et al. conducted a clinical trial with abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg on 12 patients (four men and eight women) of Japanese ancestry to determine the safety and pharmacokinetics in a single dose tablet after fasting for eight hours. Many clinical trials are conducted with patients of European ancestry. It is helpful to enroll patients of many different ethnic backgrounds to determine any differences in the pharmacokinetics and safety of the medications being studied. The researchers collected blood samples over 72 hours after dosing to determine several pharmacokinetic parameters. The geometric mean maximum plasma concentrations for abacavir, dolutegravir, and lamivudine were 5.22, 4.13, and 3.35 micrograms/ml, respectively. The time to maximum concentration for abacavir, dolutegravir, and lamivudine were 1.01, 3.50, and 2.98 hours, respectively. The geometric mean area under the concentration-time curve for abacavir, dolutegravir, and lamivudine was 18.2, 71.6, and 16.6 micrograms times hour per ml. The research subjects did not report any adverse drug effects. The pharmacokinetic parameters for abacavir and lamivudine were similar to previously reported clinical trial data from healthy Japanese and European or African ancestry subjects. Dolultegravir was found to have a higher area under the concentration-time curve in this study compared with the two previously mentioned studies.[4]
Archary M. et al. conducted a study on the pharmacokinetics of abacavir and lamivudine in severely malnourished children (N = 75) with human immunodeficiency virus from South Africa. The children's ages ranged from 0.1 to 10.8 years and were dosed based on World Health Organization (WHO) weight-band recommendations. The children were randomized to receive treatment with abacavir and lamivudine within 14 days (early) or after nutritional recovery (delayed). Abacavir and lamivudine pharmacokinetic parameters were measured on days 1 and 14. The children received follow-up to week 48. Abacavir demonstrated a 2-compartment pharmacokinetic model. The early treatment cohort demonstrated a 31% increase in their bioavailability of abacavir. The apparent clearance (CL/F) of abacavir increased from a mean of 3.33 to 5.86 L/Hr/7 kg from day 1 to day 14. Lamivudine demonstrated an A 1-compartment pharmacokinetic model. Variability in the apparent clearance was best explained by age maturation. Archary M. et al. concluded that the WHO weight-band dosing recommendations are appropriate, and the pharmacokinetic variability of abacavir and lamivudine treatment in severely malnourished children did not affect its efficacy.[5]
Mechanism of Action
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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 to 1 hour with an absolute bioavailability of about 83%. Abacavir displays linear pharmacokinetics and possesses dose proportionality over the range of 300 to 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 distribution 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.
Abacavir is predominantly metabolized by the liver. The remaining bioavailable 2% of the compound gets excreted as an unaltered product in the urine. Two major metabolic pathways are 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, about 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, zidovudine, and lamivudine. Also, there appears to be no interaction with ethanol. [6]
The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate, which interferes with HIV viral RNA-dependent DNA polymerase (reverse transcriptase), leading to inhibition of viral replication.[7] This intracellular anabolite has been shown to have a long elimination half-life of greater than 20 hours, allowing for once-daily dosing.[6]
Administration
Abacavir is administered as 300 mg twice daily or 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) drug combinations.[8]
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.[9] The recommendation is to dose-adjust in hepatic impairment. Mild hepatic impairment denoted as Child-Pugh class A is suggested at 200 mg twice daily as an oral solution. Due to a lack of safety data, contraindications to abacavir include moderate to severe hepatic impairment, Child-Pugh class B or C.[6]
Adverse Effects
The common toxicities of the NRTI class are mitochondrial toxicity, which can present as hepatic steatosis, lipoatrophy, pancreatitis, and peripheral neuropathy.[10] Symptomatic lactic acidosis can also occur in patients, and these require monitoring due to an increased risk of mortality.[11] Additionally, patients on long-term antiretroviral therapy (ART) may experience fat redistribution: lipodystrophy.[12]
Clinicians should avoid abacavir in patients with coronary artery disease and those at increased risk of myocardial infarction due to an increased risk of hyperlipidemia and cardiovascular events.[13][14][15]
Contraindications
Contraindications to 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. This allele is highest in Caucasian populations at a frequency of 5 to 8%.[16] Also, in patients with moderate to severe hepatic impairment, Child-Pugh class B or C, abacavir administration is relatively contraindicated due to a lack of safety studies.[6]
Abacavir should also be avoided and is relatively contraindicated in individuals who test positive for HLA-DR7 and HLA-DQ3 alleles because evidence shows that switching abacavir for another NRTI leads to a reduced incidence of hypersensitivity reactions.[17]
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 before starting therapy and before continuing treatment in patients with unknown HLA-B*57101 status. Patients should have CBC with differential, serum creatinine kinase, CD4 count, HIV RNA plasma concentrations, triglycerides, and serum amylases monitored periodically.[16] Clinicians should be aware of the risk for acute and late-onset hepatotoxicity and monitor AST and ALT concentrations.[18] Signs of central fat gain or lipoatrophy should be assessed for fat gain or fat loss to fine-tune ART therapy.[19]
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 allele.[16]
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, pharmacists, 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 antiretroviral therapy (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.
The emphasis on adherence cannot be overemphasized. Clinicians, specialists, nurses, and pharmacists all must share in the effort to educate the patient and monitor pharmacotherapy adherence. For example, if the patient is chronically late in picking up their prescription, meaning there will be days without therapy, the pharmacist must call the physician's office and share this information with the nurse or prescriber. The pharmacist is also responsible for medication reconciliation and verifying dosing parameters. On follow-up visits, the nurse must verify adherence and should do so by asking open-ended questions that encourage the patient to reveal familiarity with their regimen. Failure to take the drugs in ART correctly can result in therapeutic failure for the entire drug class, as the virus can obtain adaptive drug resistance; this is why any type of ART requires open, interprofessional team communication to ensure the best chance for therapeutic success. [Level 5]
Recommendations for Increasing Successful Outcomes in Antiretroviral Therapy
- Initiation of highly active antiretroviral therapy (HAART) with a high degree 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.[20] [Level 1]
- Individual-level monitoring of entry and retention is a strong recommendation for all people diagnosed with HIV.[21][22] [Level 1]
- Systematic retention monitoring in HIV care is also strongly recommended for all HIV patients.[23] [Level 3]
- Strengths-based case management from trained social workers increases entry to HIV medical care.[24] [Level 1]
- Self-report adherence should be obtained routinely in all HIV patients.[25] [Level 3]
- Regimens of similar efficacy and tolerability, once-daily regimens are recommended in treatment naïve patients starting ART, as well as experienced patients receiving poorly tolerated/complex regimens.[25][26][27][28] [Level 1]
- Reminders and the use of communication technologies with an interactive component are recommended to increase adherence [29] [Level 1]
- Combining education and counseling using specific adherence-related tools is recommended for all patients with HIV.[30][31][32][Level 1]
- Directly administered ART (DART) is the recommended course of action in individuals with substance use disorders.[33][34][35] [Level 2]
- Cognitive-behavioral therapy is recommended in patients with depression to improve adherence.[36] [Level 2]
References
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Level 1 (high-level) evidence