Adherence rates lower than 95% are associated with virologic failure
By Brian Boyle, MD for HIVandHepatitis.com
In many patients, highly active antiretroviral therapy (HAART)has been remarkably effective in achieving effective control of HIV and maintenance or improvement of immunologic function.
Clinicians and HIV-infected patients have long recognized, however, the importance of strict adherence to HAART regimens.Several studies have shown that antiretroviral adherence levels less than 95%are associated with high rates of virologic failure, development of viral resistance and cross-resistance and immunologic deterioration.
The ATHENA project, an observational cohort in the Netherlands, evaluated adherence in the enrolled patients. Adherence data from that study, collected from May 1998 and June 1999, were recently published in the September 10, 2001 issue of the Archives of Internal Medicine. The study evaluated adherence in patients taking protease inhibitor- or nevirapine-based HAART using an adherence questionnaire and a measurement of plasma concentrations of the protease inhibitor or nevirapine that the patient was taking.
While 89.7% of the 224 patients who completed the questionnaire reported taking their entire HAART regimen, only 47% of the patients reported taking all of it on time and according to all dietary restrictions. Common reasons for non adherence included forgetting (35%), conflicting activities (24%), feeling ill (22%), a change in routine (19%), and not having medications available (15%).
Relative to patients who reported full adherence with their HAART regimen, patients who reported being non adherent had significantly lower antiretroviral concentrations. Further, in patients on HAART for at least 24 weeks, 28 of 72 (28%) non adherent patients failed to achieve a viral load less than 500 copies/mL versus 10 of 65 (15%) of adherent patients. A multivariate analysis revealed that the odds ratio for having a viral load greater than 500 copies/mL due to nonadherence was 4.0 (95% CI, 1.4-11.6) and for schedule or dietary deviations 2.1 (95% CI, 0.9-5.2).
The authors conclude, “Only half of our patients reported taking all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Patients reporting deviation from their antiretroviral regimen showed lower drug exposure and were less likely to have suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.”
Adherence may be improved with once daily regimens. A recent systematic review of the associations between dose regimen and medication compliance confirmed that the number of doses per day is inversely related to compliance (Claxton, Clin Ther 2001 Aug;23(8):1296-310).
Mean dose-taking compliance for once daily dosing, however, was still found to be only 79% (twice daily 69%) still way below the compliance levels required to maintain virological success in antiretroviral therapy. Moreover, the observed difference between once and twice daily regimens failed to reach significance. Clearly other interventions apart from reducing dosing frequency will be needed to ensure maximum adherence.
It is also important to realise that even taking every dose in a regimen strictly on time may not result in optimal viralogical reponse and that pharmacokinetic factos may be crucial. The first intervention for patients showing suboptimal nelfinavir levels in ATHENA was to discuss food intake and emphasise the important of taking nelfinavir with food (rather than recommending a dose adjustment). Of these patients, 50% were about target levels at the subsequent TDM test after only having dietary advice. Earlier studies have also shown that a light snack (350Kcal, 13g fat) can provide a similar PK boost to a standard meal (800Kcal, 35g fat) in HIV-negative volunteers. Taking nelfinavir with food has already been shown to produce a 200-300% increase in drug exposure .
It is significant that ATHENA is the first randomised clinical trial for TDM and showed clinical benefit in terms of increased virological efficacy for patients using nelfinavir and reduced discontinuation due to toxicity for patients treated with nelfinavir. This has been recognised in the 2001 BHIVA treatment guidelines.
TDM is available without cost in the UK due to subsidised programmes from Roche and Merck. Please contact David Back or Sarah Gibbons at Liverpool University on 0151 794 5553 for further details.
- Kurowski, M. et al, Poster LbPeB7048, XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000. 2. Viracept Summary of Product Characteristics, 8 June 2001
- Nieuwkerk P et al. Limited Patient Adherence to Highly Active Antiretroviral Therapy for HIV-1 Infection in an Observational Cohort Study. Arch Intern Med. 2001; 161: 1962-1968. http://www.ncbi.nlm.nih.gov/pubmed/11525698?dopt=Abstract
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