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Revised Guidelines for the Use of AntiretroviralAgents in
HIV-1-Infected Adults and Adolescents - abacavir
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From: U.S. Food & Drug Administration (FDA)
[mailto:fda@service.govdelivery.com]
On November 3, 2008, the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents released a revised version of theGuidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.
The following changes have been made to the January 29, 2008 version of the guidelines. Key new updates are highlighted throughout the posted document (see below).
Format Changes This revision is developed under a new format, whereby the relevant tables and references for each section are incorporated into the body of the document. Some larger tables are placed in an appendix at the end of the document. A separate PDF file with all the tables can be found at the AIDSinfo Web site.
Rating Changes A new rating scheme is used in this guideline to be more consistent with other guidelines in infectious diseases. The changes are outlined below:
Strength of Recommendations The D (should usually not be offered) and E (should never be offered) ratings have been removed. The A, B, and C ratings rate the strength of the statement. For example, an A rating for not to initiate nevirapine in women with pre-treatment CD4 cell count >250 cells/mm3 indicates a strong recommendation to not initiate nevirapine in these patients.
Quality of Evidence Previously, only randomized trials with clinical endpoints were given a I ranking. In this new rating scheme, a I ranking includes randomized trials with either clinical or validated laboratory outcomes (e.g., viral load). A II rating includes non-randomized trials or well-designed observational cohort studies with long term clinical outcomes. A III rating remains a recommendation based on expert opinion.
Content Changes he key changes to the different sections of the guidelines are outlined below:
Laboratory Monitoring
· A new table (Table 3) provides recommendations for laboratory tests to obtain at baseline and while receiving antiretroviral therapy to monitor for safety and treatment responses.
· The Panel recommends that resistance testing be considered in patients with viral loads of 500-1,000 copies/mL but recognizes that it may not always be reliable at those levels (BII).
What to Start in Antiretroviral-Naïve Patients
Protease Inhibitor-Based Regimens:
· Ritonavir-boosted darunavir has been added as a preferred PI component (AI).
· Once-daily ritonavir-boosted lopinavir has been moved from alternative to preferred PI component (except for pregnant women) (AI).
Dual-NRTI Options:
· Abacavir + lamivudine has been moved from a preferred to an alternative dual-NRTI component because of concerns regarding an increased risk of myocardial infarction in patients with high cardiac risk factors, as suggested by large observational cohort studies, and concerns regarding virologic potency in patients with baseline viral loads >100,000 copies/mL (BI).
from Jules: the Guidelines say "Tenofovir/emtricitabine was compared to abacavir/lamivudine in the ACTG 5202 study and the HEAT trial. The final results of these studies have not been published. Preliminary data from the ACTG trial suggest potential of inferior virologic responses in participants randomized to abacavir/lamivudine and had a pre-treatment HIV-RNA >100,000 copies/mL. See the section below for more detailed discussions regarding the results of these trials." see below
Combinations Not to Use or to Use with Caution:
· A combination of unboosted atazanavir + didanosine + emtricitabine (or lamivudine) is not recommended because of efficacy concerns (BI).
· A combination of nevirapine + tenofovir + emtricitabine (or lamivudine) should be used with caution and with close monitoring of virologic responses because of reports of early virologic failure in several small studies (CII).
Management of Treatment-Experienced Patients
Regimen Simplification:
· A new section on Regimen Simplification for virologically suppressed patients has been added to the discussion of Management of the Treatment-Experienced Patient.
Additional Updates
The following sections and their relevant tables have been updated:
· Introduction
· CD4+ T-cell count
· Viral Load Testing
· Coreceptor Tropism Assay
· What Not to Use
· Exposure Response and Therapeutic Drug Monitoring (and table for recommended antiretroviral drug concentrations)
· HIV-Infected Adolescents
· HIV-Infected Illicit Drug Users
· HIV-Infected Women
· Adherence to Antiretroviral Therapy (with a new table)
· Antiretroviral-Associated Adverse Effects (and table for detection and management of adverse effects)
· Antretroviral Drug Interactions (with a new format for interactions between antiretroviral and other drugs)
· Tables describing the characteristics of antiretroviral drugs
The complete November 3, 2008 version of the adult treatment guidelines is available on the AIDSinfo web site
athttp://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1
Richard Klein _Office of Special Health Issues _Food and Drug Administration
Kimberly Struble _Division of Antiviral Drug Products _Food and Drug Administration
Guidelines say:
"The ACTG 5202 study, a randomized controlled trial in more than 1,800 participants, evaluated the efficacy and safety of abacavir/lamivudine versus tenofovir/emtricitabine when used in combination with either efavirenz or ritonavir-boosted atazanavir. Treatment randomization was stratified based on a screening HIV RNA of <100,000 copies/mL or >100,000 copies/mL. An independent Data Safety Monitoring Board recommended early termination of the >100,000 copies/mL stratification group because of a significantly shorter time to study-defined virologic failure in the abacavir/lamivudine arm compared with the tenofovir/emtricitabine arm [65]. Participants who had HIV RNA levels <100,000 copies/mL at study screening remain randomized and on study.
In a contrasting smaller study (HEAT), 688 participants received abacavir/lamivudine or tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir. A subgroup analysis according to baseline HIV RNA of <100,000 copies/mL or >100,000 copies/mL yielded similar percentages of participants with HIV RNA <50 copies/mL at 96 weeks for the two regimens (63% vs. 59% for those who had <100,000 copies/mL and 56% vs. 58% for those who had >100,000 copies/mL, respectively) [66].
Concern has also been raised regarding the potential cardiovascular risks of abacavir-containing regimens. The D:A:D study group reported an analysis of myocardial infarction (MI) risk in a large, multinational, observational cohort that involved 33,345 participants and had 157,912 person-years of follow-up [67]. Recent (within 6 months) or current, but not cumulative or past use (last use >6 months) of abacavir predicted an increased risk of MI (relative risk [RR], 1.9; 95% CI, 1.5-2.6). The heightened risk of MI with recent abacavir exposure was accentuated in participants who had pre-existing cardiac risk factors.
A second study also suggested an increased risk of MI associated with abacavir use [68]. An analysis of 2,752 participants in the continuous treatment arm of the SMART study indicated that abacavir use was associated with an increased risk of MI when compared with other NRTI use (RR, 4.3; 95% CI, 1.4-13.0). Risk was concentrated in individuals with five or more known cardiovascular risk factors.
In contrast to these two studies that suggested an increased MI risk among abacavir users, Cutrell et al found no increased MI risk in a pooled analysis of 54 clinical trials, which involved 9,639 abacavir recipients, compared with 5,044 participants who received regimens without abacavir (RR,·9; 95% CI,·4-1.9) [69].
Although conflicting data exist regarding abacavir-based regimens, the combination of abacavir/lamivudine is now considered to be an alternative, rather than a preferred, dual-NRTI option. Pending additional data, abacavir/lamivudine should be used with caution in individuals who have plasma HIV RNA levels >100,000 copies/mL, as well as in persons at higher risk for cardiovascular disease."
GSK issued this statement:
"HIV patients continue to require multiple treatment options over the course of their lives. The totality of the clinical data and experience generated for EPZICOM thus far support its continued use and its importance as a treatment option for HIV patients. __HIV treatment requires a personalized approach - the right medicine, for the right patient at the right time. Prior treatment history, co-morbidities, viral resistance patterns, and the need to preserve future treatment options must all be taken into account when choosing any HIV treatment regimen, including EPZICOM."__Judith Ng-Cashin, MD_VP HIV Clinical Therapeutic Area
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