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Drugs

, Volume 60, Issue 2, pp 447–479 | Cite as

Abacavir

A Review of its Clinical Potential in Patients with HIV Infection
  • Pauline S. Hervey
  • Caroline M. PerryEmail author
Adis Drug Evaluation

Summary

Abstract

Abacavir is a carbocyclic 2′-deoxyguanosine nucleoside analogue. It is metabolised intracellularly to a 2′-deoxyguanosine nucleoside analogue which competitively inhibits HIV reverse transcriptase and terminates proviral DNA chain extension.

In double-blind trials in antiretroviral therapy-experienced or -naive patients, reductions in HIV RNA levels were greater and more prolonged in patients receiving abacavir in combination with other antiretroviral drugs than in those receiving placebo in combination with the same agents. Furthermore, abacavir in combination with lamivudine and zidovudine reduced viral load to below detectable levels in a proportion of patients, and to a similar extent to the protease inhibitor indinavir in combination with lamivudine and zidovudine. Greatest viral load reductions were seen in antiretroviral therapy-naive patients.

Preliminary results suggest that the viral suppression achieved with a protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) can be maintained as effectively with abacavir in combination with 2 NRTIs as it can be by continuing the protease inhibitor-containing treatment regimen. Initial virological data from studies of combination regimens including abacavir and protease inhibitors appear promising but larger controlled trials are required to confirm these observations.

Nausea is the most frequently reported adverse event in patients receiving abacavir-containing combination therapy. Adverse events tend to be reported most frequently soon after starting treatment; the majority of events are mild or moderate in intensity and transient. Other adverse events reported in >5% of patients include vomiting, malaise and fatigue, headache, diarrhoea, sleep disorders, cough, anorexia and rash. A major cause of abacavir treatment discontinuation is the development of a hypersensitivity reaction which has been reported in 3 to 5% of patients. The reaction usually occurs within 6 weeks of commencing treatment, shows evidence of multiorgan system involvement and typically includes fever and/or rash. Symptoms resolve rapidly after discontinuation of treatment. Continuing treatment or rechallenge can result in more severe symptoms, life-threatening hypotension and even death.

Conclusion: Abacavir used in combination with other antiretroviral drugs effectively reduces viral load in both adults and children with HIV infection. Although these responses are greatest in individuals with little or no previous antiretroviral treatment, useful responses are still sometimes achieved in heavily pretreated individuals. Abacavir in combination with lamivudine and zidovudine provides a simple and convenient dosage regimen which is generally well tolerated, able to produce sustained suppression of viral replication and has the advantage of sparing other classes of antiretroviral drugs for subsequent use. This triple combination represents an alternative antiretroviral regimen for patients intolerant to protease inhibitors or those wishing to retain the option of protease inhibitors for later use. Further clinical studies are needed to define the activity of abacavir in combination with protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

Pharmacodynamic Properties

Abacavir (also known as 1592U89), a carbocyclic 2’-deoxyguanosine nucleoside analogue, is metabolised by a unique set of intracellular enzymes to a 2′-deoxyguanosine nucleoside analogue, which competitively inhibits HIV reverse transcriptase and terminates proviral DNA chain extension. Carbovir triphosphate prevents HIV replication by competitively inhibiting reverse transcriptase and terminating proviral DNA extension. It is highly selective for HIV reverse transcriptase with an inhibition constant (Ki) of 21 nmol/L compared with Ki values for DNA polymerases α, β, γ and ε which are 90 to 2900 times greater.

The drug demonstrates good inhibitory activity against laboratory strains of HIV-1 and -2 and patient-derived HIV strains in peripheral blood mononuclear cells. In addition, when combined with most other antiretroviral drugs, abacavir has synergistic or additive activity against HIV-1.

Abacavir resistance identified during a dose-finding monotherapy study was associated with mutations at positions M184V, L74V, K65R and Y115F in the HIV-1 reverse transcriptase coding region. Single mutations were not associated with reduced sensitivity to abacavir but multiple mutations were. Administration of abacavir with lamivudine and zidovudine altered the pattern of development and rate of acquisition of mutations. Cross-resistance to other nucleoside reverse transcriptase inhibitors (NRTIs) is associated with phenotypic resistance to ≥2 NRTIs or ≥3 NRTI mutations. The M184V mutation alone, which confers high level resistance to lamivudine, does not result in reduced sensitivity to abacavir.

Minimal cytotoxicity was observed in a variety of human leukaemic and liver tumour cell lines exposed to abacavir. In addition, abacavir showed no evidence of reduced mitochondrial DNA synthesis and showed only low toxicity to human bone marrow progenitor cells in vitro.

Pharmacokinetic Properties

Abacavir is rapidly absorbed after oral administration. Maximum plasma concentrations (Cmax) ranging from 0.64 to 4.38 mg/L were reached approximately 0.8 to 1 hour after multiple doses of abacavir 100, 300 or 600mg twice daily. Absolute bioavailability of the 300mg tablet has been reported to be 83%. After a single oral 300mg dose in fasted individuals, the area under the concentration-time curve (AUC) was 5.48 mg/L· h. Administration of abacavir with food does not significantly affect absorption. Although abacavir is about 50% protein bound, penetration into the CSF does occur with CSF AUC0–6 to plasma AUC0–6ratios ranging from 27 to 33%.

The mean elimination half-life of abacavir is <2 hours. Abacavir is extensively metabolised by hepatic enzymes, including alcohol dehydrogenase. Less than 2% of the drug appears unchanged in the urine, which is the major route of excretion. The clearance (CL/F) of abacavir in infants and children aged >3 months is slightly higher than in adults (least-squares mean CL/F 1.07 L/h/kg for an 8 mg/kg dose in children vs 0.75 L/h/kg for a 300mg dose in adults). However, preliminary data indicate that clearance in neonates (aged <30 days) is substantially lower than in children and adults.

Abacavir does not inhibit human liver cytochrome P450 enzymes, so few drug interactions are expected with drugs metabolised via this route. Alcohol increases abacavir AUC (0.7 g/kg of alcohol administered with a single 600mg dose of abacavir resulted in a 41% increase in abacavir AUC) but abacavir does not alter alcohol pharmacokinetics. Methadone has no effect on the extent of abacavir absorption but abacavir slightly increases methadone clearance. The pharmacokinetics of adefovir, amprenavir, indinavir, zidovudine and/or lamivudine were unaffected by concomitantly administered abacavir.

Therapeutic Efficacy

Abacavir in combination with 2 NRTIs has produced rapid and prolonged reductions in plasma HIV RNA levels and increases in CD4+ cell counts. In patients not previously treated with antiretroviral agents, abacavir in combination with lamivudine and zidovudine suppressed plasma HIV RNAlevels to a greater extent than placebo, lamivudine and zidovudine. After 16 weeks of treatment, plasma HIV RNA levels were below the limit of detection (LOD <400 copies/ml) for 75% of patients receiving abacavir in combination with lamivudine and zidovudine but for only 35% of those receiving lamivudine and zidovudine dual therapy.

Reductions in viral load attained with abacavir in combination with lamivudine and zidovudine were similar to those obtained with indinavir in combination with lamivudine and zidovudine. For 51% of patients in each treatment group, plasma HIV RNA was below the LOD (<400 copies/ml) after 48 weeks. However, results of patients with high viral loads at baseline (>100 000 copies/ml) showed that a greater proportion of patients in the indinavir group than in the abacavir group had HIV levels ≤50 copies/ml at 48 weeks (45 vs 31%, nonsignificant).

In adult patients who had received prior antiretroviral therapy, abacavir in combination with lamivudine and zidovudine or in addition to stable background therapy (SBG) also produced reductions in viral load. At 16 weeks, a significantly greater proportion of patients treated with abacavir plus SBG had reductions in HIV RNA levels to <400 copies/ml than recipients of placebo plus SBG (39 vs 8%; p < 0.001). The addition of abacavir to a stable regimen of lamivudine plus zidovudine resulted in significant decrease from baseline in HIV RNA levels (median decrease 2.65 log10 copies/ml; p < 0.01 vs baseline); the percentage of patients with undetectable viral load (LOD <400 copies/ml) was 67% at 48 weeks. However, reductions were less marked in heavily treated patients in another trial: after 48 weeks of treatment with abacavir, lamivudine and zidovudine, HIV RNA was reduced to below the LOD (<400 copies/ml) in 10% of heavily pretreated paediatric patients. In the placebo, lamivudine and zidovudine arm, the corresponding figure was 1%.

Abacavir in combination with 2 NRTIs has maintained viral suppression to a similar extent to a protease inhibitor plus 2 NRTIs in antiretroviral therapy-experienced patients. After 24 weeks, the proportion of patients experiencing a viral load rebound to >400 copies/ml or discontinuing treatment was 8.5% in those receiving abacavir plus NRTIs and 13.2% for those remaining on a protease inhibitor plus 2 NRTIs.

When used in dual combination with selected protease inhibitors, abacavir produced similar reductions in viral load to those seen with abacavir and NRTIs in antiretroviral therapy-naive individuals. No benefit from using abacavir in combination with protease inhibitors and non-nucleoside reverse transcriptase inhibitors in ‘ salvage’ regimens for patients failing to respond to other antiretroviral combinations has yet been demonstrated.

Tolerability

Nausea was the most frequently reported event in patients receiving abacavir in clinical trials. Vomiting, nausea and malaise/fatigue occurred more commonly with abacavir in combination with lamivudine and zidovudine than with dual lamivudine and zidovudine therapy. These adverse events tended to occur soon after treatment initiation and were often transient and usually only mild or moderate in intensity. Other adverse events reported in >5% of patients include headache, diarrhoea, sleep disorders, cough, anorexia and rash. Treatment discontinuations due to adverse events in clinical trials of 48 weeks’ duration have been reported for 7 to 17% of patients.

One of the most frequent causes of treatment withdrawal is a hypersensitivity reaction to abacavir which has been reported in 3 to 5% of patients. The reaction usually occurs within 6 weeks of commencing treatment, may show evidence of multiorgan system involvement and involves fever and/or rash in the majority of cases. Continuing treatment can result in worsening of symptoms and even death. Once abacavir is stopped, symptoms usually resolve within 24 hours. Rechallenge leads to a rapid return of symptoms, which are frequently more severe and have included life-threatening hypotension and death. The presentation of hypersensitivity reactions in children aged >3 months appears to be similar to that in adults and occurs at a similar frequency.

Dosage and Administration

The recommended dosage of abacavir in adult patients with HIV infection is 300mg twice daily in combination with other antiretroviral agents. Infants, children and adolescents aged 3 months to 16 years should receive oral abacavir 8 mg/kg twice daily up to a maximum daily dosage of 600 mg/day. Studies are still underway to determine the appropriate dosage for neonates. Abacavir may be taken with or without food and it has a low potential for drug interactions.

Keywords

Viral Load Adis International Limited Lamivudine Zidovudine Indinavir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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