Despite the undoubted benefits of antiretrovirals,1-3
control of the human immunodeficiency virus is only maintained effectively if treatment is taken without interruptions, respecting not only the number of doses and pills, but also the dosage conditions. Proper adherence is a key element in optimizing the efficacy of the drugs prescribed.4
The consequences of inadequate adherence are widely known: emergence of mutations in the viral genome that confer resistance to specific antiretrovirals, possibility of cross resistance among drugs of the same family that may limit the future therapeutic alternatives, transmission of resistant HIV strains, and increased economic burden on society.5
A treatment regimen's complexity has been shown to be strongly related to adherence.6-8 Experts on the topic of adherence have warned of the need to design simpler antiretroviral regimens without losing the therapeutic potency.9 Drugs may also be extremely toxic,10, 11 causing adverse events that may diminish considerably patients' quality of life. A relationship between adherence and quality of life has been suggested, although a causality is not clear.12
New Therapeutic Strategies: Simplification of Treatment
In recent years one of the main efforts of the scientific community has been focused on developing therapeutic strategies based on simplified antiretroviral regimens. Simplification strategies are defined as the switch from a known, efficacious, yet complex therapy to a simpler but equally potent one. Thus, patients' quality of life and adherence to treatment may benefit from this switch.13
The most common simplification strategies used to date have been based on switching older protease inhibitors (PIs) to newer formulations that require fewer pills or doses, or to PI-sparing regimens (using efavirenz, nevirapine, and abacavir).14
Recently, several studies have been designed to assess the efficacy of treatments administered once a day.15
Impact of Simplified Treatments on Patients' Adherence and Quality of Life
To date, studies assessing the impact of switching PI-containing regimens to those containing other drugs such as abacavir or nonnucleoside reverse transcriptase inhibitors (NNRTIs) on adherence and quality of life are still scarce. Clumeck et al., in a study based on replacing a PI with abacavir, revealed that, while adherence in the abacavir group improved at week 48 of follow-up, it diminished with respect to baseline in the PI group at week 48.16
Barreiro et al. evaluated adherence and quality of life in patients that replaced the PI with nevirapine and found that therapeutic failure attributable to lack of adherence was 90 percent in the PI group while only 22 percent of patients failed due to inadequate adherence in the nevirapine group.17
Also, quality of life increased significantly in the patients taking NNRTIs. However, we have observed the contrary assessing adherence and quality of life in a group of HIV-infected patients for whom initial treatment with PI-containing regimens failed. Patients were randomized to switch their therapeutic regimen to either two nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz or two NRTIs plus one or more new PI. No significant differences in adherence levels existed when both groups were compared. However, an important improvement in quality of life was noted in the efavirenz group.18
When patients were asked about this improvement, 44 percent of them attributed it to the simplification of therapy. The lack of statistical differences in adherence may be attributed to the fact that all patients received educational counseling about adherence in each visit during the follow-up.
Individuals chronically nonadherent may benefit from simpler regimens. Accordingly, Knobel et al. developed a prospective study in which patients with virologic failure (HIV RNA >5,000 copies/mL), a two NRTI + PI-containing therapy and severe nonadherence (less than 50 percent of consumption of prescribed doses or withdrawal) were switched to Combivir + abacavir and later on to Trizivir (when approved). At week 24 of follow-up, 50 percent of patients reported a level of adherence higher than 90 percent and 44 percent of patients had HIV RNA levels <500 copies/mL.19
Still lacking are data on patients receiving treatment once a day (QD). This therapeutic strategy is novel and its long-term clinical and virological efficacy has yet to be fully determined. Smith presented a study at the XIV International AIDS Conference showing results from a survey of 536 HIV-positive patients.20 Eighty percent of subjects affirmed that it was easier to remember to take medication in a QD regimen while 65 percent of patients thought that a twice-daily (BID) regimen provided greater facility in remembering to take medication.
In a study developed by our team, switching to a QD regimen was related to the improvement of several health-related dimensions in the MOS-HIV questionnaire: mental health, energy, and general quality of life.21 Patients also indicated a greater degree of facility in taking medication, preference of the new treatment when compared with the previous, and a higher level of satisfaction with the number of pills required per day. Nevertheless, no statistically significant differences were found regarding adherence, either in QD group evolution, or in the comparison between the QD and BID groups. Patients included in the study had both undetectable viral loads and demonstrated adequate adherence before switching to a QD regimen.
Undoubtedly, quality of life may benefit from a simplified treatment that results in fewer disruptions in the patient's life and it is more convenient for daily routines. Moreover, a simpler treatment increases the patient's satisfaction with therapy.
QD regimens have heretofore been offered to patients with a good virologic and immunologic status. Although patients who have been able to incorporate medication into their daily life as a habit will not necessarily show differences in adherence after switching from a BID to a QD regimen, it is imperative to develop studies to determine if these differences appear in historically adherent patients. For those patients who have marked difficulties in adapting a treatment to their daily lives because of, for example, complex job timetables or a hidden HIV condition, a QD regimen may represent a considerable improvement.
The impact of QD regimens in non-adherent patients also needs to be assessed. Nevertheless, it must be stressed that lack of adherence may sometimes be related to emotional conditions, such as the denial of illness or existence of symptoms of depression. Clinicians should attempt to ascertain the applicable cause of poor adherence in individual cases, offering alternative therapies and referring patients to appropriate specialists, as necessary.
Simplification strategies may facilitate the adaptation of a treatment to a patient's life but should always be offered in an individualized manner, considering the previous pharmacologic history, as well as the patient's preferences and lifestyle. Some patients will favor a simplified treatment but for others, a change in treatment may pose a source of stress (eg, new timetable, new drug names, fear of possible and unknown adverse events, or treatment failure). Thus, one of the basic pillars for successful treatment is to assure that the therapy chosen is the result of clinician and patient input and agreement.
Carmina R. Fumaz and Bonaventura Clotet is Psychologist in the HIV Unit and Head of the HIV Unit, respectively, at the Lluita contra la SIDA Foundation, HIV Unit, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain.
- Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced Human Immunodeficiency Virus infection. N Engl J Med 1998;338:853-860.
- Mellors JW, Muñoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-954.
- O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996;334:426-431.
- Vanhove GF, Schapiro JM, Winters MA, et al. Patient compliance and drug failure in protease inhibitor monotherapy. JAMA 1996;24:1955-1956.
- Mehta S, Moore RD, Graham NMH. Potential factors affecting adherence with HIV therapy. AIDS 1997;11:1665-1670.
- Tuldrà A, Fumaz CR, Ferrer MJ, et al. Factors related to adherence to HAART in patients in usual clinical follow-up. XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Abstract WePeB5831.
- Trotta MP, Ammassari A, Melzi S, et al. Treatment-related factors and highly active antiretroviral therapy adherence. J Acquir Immune Defic Syndr 2002;15;31(suppl 3):S128-131.
- Stone VE, Hogan JW, Schuman P, et al. Antiretroviral regimen complexity, self-reported adherence, and HIV patients' understanding of their regimens: Survey of women in the HER study. J Acquir Immune Defic Syndr, 2001;28:124-131.
- Friedland GH, Williams A. Attaining higher goals in HIV treatment: the central importance of adherence. AIDS 1999;13(suppl 1):S61-72.
- Max B, Sherer R. Management of the adverse effects of antiretroviral therapy and medication adherence. Clin Infect Dis 2000;30 (2): 96-116.
- D'Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.C.O.N.A. Study Group. AIDS 2000;14 (5):499-507.
- Mannheimer S, Friedland G, Matts J, et al. Antiretroviral adherence correlates with quality of life. 8th CROI, Chicago, USA, February 4-8, 2001. Abstract 485.
- Ribera E, Aguirrebengoa K, Miralles C, et al. Simplificación del tratamiento antirretroviral. Enferm Infecc Microbiol Clin 2002;20(suppl 2):48-57.
- Martínez E, Podzamczer D, Ribera E, et al. Switching protease inhibitors to nevirapine, efavirenz or abacavir: a randomized, multicenter, open-label, simplification trial. XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Abstract WeOrB1262.
- Negredo E, Ribera E, Viciana P, et al. QD multicenter study: simplification therapy with once-daily NVP+ddI+TDF (tenofovir). XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Late breaker LbPeB9017.
- Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1 infected patients with undetectable plasma HIV-1 RNA. AIDS 2001;15:1517-1526.
- Barreiro P, Soriano V, Blanco F, et al. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy. AIDS 2000;14(7): 807-812.
- Fumaz CR, Tuldrà A, Ferrer MJ, et al. Quality of life, emotional status and adherence in patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Inmune Defic Syndr 2002;29(3):244-253.
- Knobel H, Guelar A, Vallecillo G, et al. Simplified antiretroviral therapy with zidovudine, lamivudine, and abacavir as salvage therapy for heavily non-adherent patients. XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Abstract WePeB5829.
- Smith MF. HIV patients prefer once-daily regimens. XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Abstract MoPeB3290.
- Fumaz CR, Tuldrà A, Ferrer MJ, et al. Impact of a once-daily three-drug regimen on the quality of life and adherence of HIV-1+ patients with viral load suppression. XIV International AIDS Conference, Barcelona, Spain, July 7-12, 2002. Abstract WePeB5834.