Revisión sistemática

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Abacavir: una revisión actualizada sobre sus propiedades y aplicaciones

Traducción oficial
Año 2015
Revista Rev. cuba. farm
Enlaces Virtual Health Library
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El Plan Estratégico Nacional para la Prevención y Control de las ITS/VIH/sida, 2014-2018 en Cuba establece un grupo de acciones entre las que se encuentra la estandarización y optimización de esquemas de terapia antirretroviral, adecuación del inicio del tratamiento a las recientes recomendaciones de la Organización Mundial de la Salud, mejorar la calidad de la atención, la adherencia y la reducción del costo de los medicamentos. Para cumplir estas tareas se prevé introducir en el Cuadro Básico de Medicamentos algunos antirretrovirales genéricos cubanos para incrementar las posibles combinaciones de Terapia Antirretroviral de Alta Eficacia a disposición de los pacientes que viven con el virus de la inmunodeficiencia humana y sustituir importaciones. Se realizó una revisión bibliográfica exhaustiva para la actualización de la comunidad médica y científica; se examinaron las principales características del abacavir: propiedades químico-físicas del principio activo, sus presentaciones comerciales, mecanismo de acción, farmacocinética y resistencia, reacciones adversas e interacciones, aplicaciones terapéuticas, dosificaciones, ajustes de dosis y seguridad en el embarazo. Para ello se consultaron un total de 58 artículos que incluyeron revisiones bibliográficas, trabajos originales, fichas técnicas, libros, conferencias y reportes. El abacavir es un antirretroviral relativamente nuevo y ampliamente recomendado por las guías de tratamiento por su efectividad demostrada(AU)

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Revisión sistemática

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Virological efficacy of abacavir: systematic review and meta-analysis.

Año 2014
Revista The Journal of antimicrobial chemotherapy
Enlaces DOI , Pubmed
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OBJECTIVES:

The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine. Several randomized clinical trials (RCTs) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment (cART) and we have reviewed the available evidence.

DESIGN:

Systematic review and meta-analysis of RCTs using standard Cochrane Collaboration methodologies.

METHODS:

We calculated risk ratios (RRs) with 95% CIs. The primary outcome was the rate of patients with viral load (VL) below the pre-defined cut-off at 48 weeks and/or at 96 weeks. Where available, results were analysed according to VL screening levels (<100,000 or >100,000 copies/mL) with conventional meta-analytical pooling by subgroups and meta-regression.

RESULTS:

Meta-analytical pooling of RCTs with a direct comparison of abacavir/lamivudine and tenofovir/emtricitabine according to baseline VL at 48 weeks (six trials, 4118 patients) showed that the proportions of subjects with VL <50 copies/mL were similar in the overall comparison (RR 0.98; 95% CI 0.94-1.03), in the low baseline VL strata (RR 1.01; 95% CI 0.99-1.03) and in the high baseline VL strata (RR 0.96; 95% CI 0.90-1.03). Meta-regression analysis at 48 weeks confirms the results of subgroup analysis. Similar virological results were found at 96 weeks (four trials, 2003 patients). Differences in the occurrence of adverse events requiring discontinuation of treatment favoured tenofovir recipients (RR 1.26; 95% CI 0.99-1.61), but this difference, mostly related to suspected abacavir hypersensitivity reaction, was not statistically significant.

CONCLUSIONS:

Our cumulative, cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL.

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Revisión sistemática

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Once-daily abacavir in place of twice-daily administration.

Año 2005
Autores Goedken AM , Herman RA
Revista The Annals of pharmacotherapy
Enlaces DOI , Pubmed
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OBJECTIVE:

To review the safety and efficacy of a once-daily dosage regimen for abacavir, a nucleoside reverse transcriptase inhibitor.

DATA SOURCES:

English-language MEDLINE and Iowa Drug Information Service database reports were accessed from 1966 to March 2005. International Pharmaceutical Abstracts was searched from 1970 to March 2005. The key words used in all searches were abacavir and Ziagen. Article bibliographies were used to identify additional relevant articles. The Internet was searched to identify abstracts of poster and oral presentations that have not yet been published. The manufacturer was also contacted to obtain unpublished information.

STUDY SELECTION AND DATA EXTRACTION:

Publications were included that provided information related to the safety and efficacy of abacavir when used once daily. Preference was given to randomized, double-blind, controlled trials comparing once-daily abacavir regimens with other antiretroviral regimens. Abstracts from professional meetings were included for unpublished studies, and conference coverage reviews were included if the abstracts were not available.

DATA SYNTHESIS:

In trials directly comparing once- and twice-daily abacavir, little difference was shown in the efficacy of the 2 regimens. Despite similar adverse effect profiles, significantly more severe hypersensitivity reactions and severe diarrhea were seen with once-daily abacavir in one trial.

CONCLUSIONS:

Once-daily administration of abacavir has not been shown to be inferior to twice-daily dosing, but it may put patients at increased risk for severe hypersensitivity reactions and diarrhea. More data are needed to confirm this risk.

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Revisión sistemática

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Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data.

Año 2011
Revista AIDS (London, England)
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BACKGROUND:

The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC.

OBJECTIVE:

To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs).

METHODS:

Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel-Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model.

RESULTS:

Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39-1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62-1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63-2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67-1.00; P = 0.05).

CONCLUSION:

This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

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Revisión sistemática

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Abacavir‐based triple nucleoside regimens for maintenance therapy in patients with HIV

Año 2013
Revista Cochrane Database of Systematic Reviews
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BACKGROUND:

Regimen simplification can be defined as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy may be considered candidates for a simplification strategy and, among them, those who have achieved virologic suppression. Several clinical trials have evaluated the efficacy of triple nucleoside combination as a simplification therapy in patients who achieved virologic suppression

OBJECTIVES:

The aim of this review is to combine randomised, controlled trials to examine whether in patients with undetectable viraemia on a Protease inhibitor (PI) based regimen simplification treatment with abacavir (ABC)-based triple-nucleoside combinations has similar rates of efficacy and tolerability compared with a PI regimen or simplification with a NNRTIs (efavirenz-EFV- or nevirapine-NVP) containing regimen. Studies were included if they had at least two of the three interventions, including one 3NRTI arm.

SEARCH METHODS:

Electronic databases and conference proceedings were searched (1996-2012) with relevant search terms without limits to language.

SELECTION CRITERIA:

Randomised controlled trials (RCTs) only are included in this review. Patients population is represented by HIV-infected adult patients treated with a PI-containing regimen (PI or boosted PI),  with undetectable viral load. Patients on a PI-containing regimen had three possibilities: continue the PI regimen or switch to a simplification maintenance regimen, including switch to a NNRTI (EFV or NVP) containing regimen, or switch to a triple-NRTI regimen (ABC-zidovudine-lamivudine)

DATA COLLECTION AND ANALYSIS:

The primary outcomes were: proportion of patients discontinuing or switching antiretroviral therapy due to virologic failure or to adverse events; death (all cause) and AIDS defining illness; occurrence of myocardial infarction and cardiovascular disease. Secondary outcomes  were: proportion of patients maintaining an undetectable viral load (e.g. HIV-RNA <50 or <400 copies/mm3); change in mean CD4+ cell count; occurrence of lipodystrophy. We applied Cochrane Collaboration tools to assess each individual study for risk for bias.

MAIN RESULTS:

We included eight RCT, for a total of 1,610 patients. All the studies included HIV-1 infected patients virologically suppressed after a successful treatment with PI containing ART. Articles included in the analysis were published between 2001 and 2010, and could be classified as low risk of bias trials in most of the domains considered. Overall, there was no significant difference between the participants on triple nucleoside combination and controls, either PI-based or NNRTI based in terms of overall failures, death and AIDS related events, and rates of patients with viral load below the detectability cut-off. For the outcomes discontinuation for adverse events and virologic failures, the RRs were not significant , albeit  being not far from the alpha level of 0.05, thus suggesting a weak evidence of lower incidence of side effects  and an higher incidence of virologic failure in the 3NRTI group compared to controls . Change in lipids and in CD4 cells from baselines were reported in 7 studies, but inconsistency in reporting these data did not allow quantitative analysis. However, all agreed that simplification with ABC had a favourable and significant impact on lipid metabolism compared to control group. An increase in CD4 cells count from baseline was evident in all analysed studies, without significant differences between ABC and controls in individual studies.

AUTHORS' CONCLUSIONS:

The strategy of switching to triple nucleoside regimens shows weak evidence of lower incidence of side effects and a higher incidence of virologic failure in the 3NRTI group compared to controls. Simplification with 3NRTI holds the advantages of preserving other classes of antiretroviral drugs, to lower blood lipids, and to be cost effective and simple to administer.Thus, simplification with triple nucleoside regimens AZT + 3TC + ABC should be still considered for individuals who are unable to tolerate or have contraindications to NNRTI or PI based regimens. Additional data are needed on longer-term efficacy of triple NRTI regimens, particularly on the development of antiretroviral resistance. Though studies in the current review were conducted between 2001 and 2010, the large majority of patients from studies analysed received old PI regimens (e.g., indinavir, ritonavir, nelfinavir, saquinavir) not longer recommended by International Guidelines. Since current guidelines recommend new "lipid -friendly" PI, future studies should compare regimens containing these news PIs to triple NRTI regimens. More realistically, however, there are opportunities to examine these issues in existing cohorts.

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Revisión sistemática

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Co‐formulated abacavir‐lamivudine‐zidovudine for initial treatment of HIV infection and AIDS

Año 2013
Revista Cochrane Database of Systematic Reviews
Enlaces DOI , PMC , Pubmed
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BACKGROUND:

UNAIDS estimates that 34 million people are currently living with the human immunodeficiency virus (HIV) worldwide. Currently recommended regimens for initiating HIV treatment consist of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir-boosted protease inhibitor (PI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs). However, there may be some patients for whom NNRTIs and PIs may not be appropriate. This is an update of the review published in the Cochrane Library Issue 3, 2009.

OBJECTIVES:

To evaluate the effects of any fixed-dose combination of three NRTIs (co-formulated abacavir-lamivudine-zidovudine) for initial treatment of HIV infection.

SEARCH METHODS:

Between December 2010 and July 2011, we used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language or publication status.

SELECTION CRITERIA:

We selected randomised controlled trials (RCTs) with a minimum follow-up time of six months which compared co-formulated abacavir-lamivudine-zidovudine with either PI-based or NNRTI-based therapy among antiretroviral-naive HIV-infected patients aged at least 13 years.

DATA COLLECTION AND ANALYSIS:

Three authors independently selected eligible studies, assessed risk of bias, and extracted data; resolving discrepancies by consensus. We calculated the risk ratio (RR) or mean difference (MD), as appropriate, with its 95% confidence interval (CI) and conducted meta-analysis using the random-effects method because of significant statistical heterogeneity (P<0.1).

MAIN RESULTS:

We identified 15 potentially eligible RCTs, four of which met our inclusion criteria. The four included RCTs were conducted in the United States of America (USA); USA, Puerto Rico, Guatemala, Dominican Republic, and Panama; USA and Mexico; and Botswana, respectively. The RCTs compared co-formulated abacavir-lamivudine-zidovudine to treatment based on efavirenz (NNRTI), nelfinavir (PI), atazanavir (PI), and co-formulated lopinavir-ritonavir (PI), respectively. Overall, there was no significant difference in virological suppression between co-formulated abacavir-lamivudine-zidovudine and NNRTI- or PI-based therapy (4 trials; 2247 participants: RR 0.73, 95% CI 0.39 to 1.36). However, the results showed significant heterogeneity (I2=79%); with co-formulated abacavir-lamivudine-zidovudine inferior to NNRTI (1 trial, 1147 participants: RR 0.35, 95%CI 0.26 to 0.49) but with a trend towards co-formulated abacavir-lamivudine-zidovudine being superior to PI (3 trials, 1110 participants: RR 1.07, 95%CI 1.00 to 1.16; I2=0%). We found no significant differences between co-formulated abacavir-lamivudine-zidovudine and either PI or NNRTI on CD4+ cell counts (3 trials, 1687 participants: MD -0.01, 95%CI -0.11 to 0.09; I2=0%), severe adverse events (4 trials: RR 1.22, 95%CI 0.78 to 1.92; I2=62%) and hypersensitivity reactions (4 trials: RR 4.04, 95% CI 0.41 to 40.02; I2=72%). Only two studies involving PIs reported data on the lipid profile. One study found that the mean increase in total cholesterol from baseline to 96 weeks was significantly lower with co-formulated abacavir-lamivudine-zidovudine than with nelfinavir, but there were no differences with triglyceride levels. The second study found the fasting lipid profile to be comparable in both co-formulated abacavir-lamivudine-zidovudine and atazanavir arms at 48 weeks.
The significant heterogeneity of effects for most outcomes evaluated was largely due to differences in the control therapy used in the included trials (i.e. NNRTIs or PIs). Using the GRADE approach, we rated the overall quality of the evidence on the relative effects of co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection as moderate. The main reason for downgrading the quality of the evidence was imprecision of the findings. The estimate of the treatment effect for each outcome has wide confidence intervals, which extend from the fixed-dose NRTI combination regimen being appreciably better to the regimen being appreciably worse than PI- or NNRTI-based regimens.

AUTHORS' CONCLUSIONS:

This review provides evidence that co-formulated abacavir-lamivudine-zidovudine remains a viable option for initiating antiretroviral therapy, especially in HIV-infected patients with pre-existing hyperlipidaemia. The varied geographical locations of the included trials augment the external validity of these findings. We are moderately confident in our estimate of the treatment effects of the triple NRTI regimen as initial therapy for HIV infection. In the context of the GRADE approach, such moderate quality of evidence implies that the true effects of the regimen are likely to be close to the estimate of effects found in this review; but there is a possibility that they could be substantially different.  Further research should be geared towards defining the subgroup of HIV patients for whom this regimen will be most beneficial.

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Revisión sistemática

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No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis.

Año 2012
Revista Journal of acquired immune deficiency syndromes (1999)
Enlaces DOI , Pubmed
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BACKGROUND:

Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen.

METHODS:

From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel-Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA-requested adverse event reports of MI provided by each investigator.

RESULTS:

The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%).

CONCLUSIONS:

To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk.

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Estudio primario

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Impact of tenofovir versus abacavir on HIV-related endothelial dysfunction.

Año 2011
Revista AIDS patient care and STDs
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Resumen estructurado de revisiones sistemáticas

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HLA-B*5701 screening for abacavir (ziagen) hypersensitivity in HIV patients

Año 2010
Autores HAYES , Inc
Revista HTA Database
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RECORD STATUS:

None

CITATION:

HLA-B*5701 screening for abacavir (ziagen) hypersensitivity in HIV patients Lansdale: HAYES, Inc.. Genetic Testing Publication. 2008

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Revisión sistemática

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Adverse events associated with abacavir use in HIV-infected children and adolescents: a systematic review and meta-analysis.

Año 2016
Revista The lancet. HIV
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BACKGROUND:

Concerns exist about the toxicity of drugs used in the implementation of large-scale antiretroviral programmes, and documentation of antiretroviral toxicity is essential. We did a systematic review and meta-analysis of adverse events among children and adolescents receiving regimens that contain abacavir, a widely used antiretroviral drug.

METHODS:

We searched bibliographic databases and abstracts from relevant conferences from Jan 1, 2000, to March 1, 2015. All experimental and observational studies of HIV-infected patients aged 0-18 years who used abacavir, were eligible. Incidence of adverse outcomes in patients taking abacavir (number of new events in a period divided by population at risk at the beginning of the study) and relative risks (RR) compared with non-abacavir regimens were pooled with random effects models.

FINDINGS:

Of 337 records and 21 conference abstracts identified, nine studies (eight full-text articles and one abstract) collected information about 2546 children, of whom 1769 (69%) were on abacavir regimens. Among children and adolescents taking abacavir, hypersensitivity reactions (eight studies) had a pooled incidence of 2·2% (95% CI 0·4-5·2); treatment switching or discontinuation (seven studies) pooled incidence was 10·9% (2·1-24·3); of grade 3-4 adverse events (six studies) pooled incidence was 9·9% (2·4-20·9); and adverse events other than hypersensitivity reaction (six studies) pooled incidence was 21·5% (2·8-48·4). Between-study inconsistency was significant for all outcomes (p<0·0001 for all inconsistencies). Incidence of death (four studies) was 3·3% (95% CI 1·5-5·6). In the three randomised clinical trials with comparative data, no increased risk of hypersensitivity reaction (pooled RR 1·08; 95% CI 0·19-6·15), grade 3 or 4 events (0·79 [0·44-1·42]), or death (1·72 [0·77-3·82]) was noted for abacavir relative to non-abacavir regimens. None of the reported deaths were related to abacavir.

INTERPRETATION:

Abacavir-related toxicity occurs early after ART initiation and is manageable. Abacavir can be safely used for first-line or second-line antiretroviral regimens in children and adolescents, especially in sub-Saharan Africa were HLA B5701 genotype is rare.

FUNDING:

WHO.

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