Adherence and HAART: unique approaches to evaluating and improving adherence discussed

17 December 2000. Related: Conference reports, Antiretrovirals, HIV 5th Glasgow 2000.

Brian A. Boyle, MD, for HIVandHepatitis.com

Due to growing recognition that adherence is a key to successful HAART, adherence continues to gather increasing attention at most of the major conferences, and that was also true at the Fifth International Congress on Drug Therapy in HIV Infection.

A plenary session and a community forum provided an opportunity to discuss the past, present and future of adherence issues and interventions in people living with HIV. While little new data was presented, potential unique approaches to evaluating and improving adherence were discussed, many of which appear to have significant potential merit.

Dr. Jorma Koskinen of Finland on behalf of the European AIDS Treatment Group (EATG) introduced the community forum by stating that the reasons for patient nonadherence have changed over the four years that HAART has been available. According to Dr. Koskinen, the major reasons patients used to be nonadherent to HAART are (1) the complexity of HAART, (2) the size, number and taste of the pills, and (3) dietary restrictions. On the other hand, the major reasons patients are currently nonadherent with HAART include (1) gastrointestinal side effects (e.g., nausea/vomiting, diarrhoea, flatulence, and pain), (2) metabolic changes (e.g., lipid and glucose elevations), (3) fat redistribution syndrome, (4) neuropathy and (5) central nervous system side effects.

This is a very important point for clinicians to consider. In part it reflects the changing side effect profiles of the medications, but in other ways reflects a lower threshold for a side effect causing nonadherence. When HAART first became available, patients were in so much need that they would tolerate enormous medication-related discomfort and side effects. Now, with a healthier, less terminal population, patients may tend to view minor side effects as enough for them to stop or intermittently take HAART. Moreover, while Dr. Koskinen is clearly correct that new problems have arisen during the past four years that may compromise HAART adherence, data indicates that the “old” adherence problems are still major contributors to nonadherence since many clinicians have not taken full advantage of newer, less complex and more forgiving HAART regimens and even those regimens are still difficult for a significant number of patients.

Dr. Koskinen proposed that a significant, unmentioned reason for nonadherence to both HAART and safer sex might be sexual dysfunction. He believes that patients find it difficult to discuss this topic with their doctor and that as a result its adverse effect on adherence and quality of life is greatly underreported. One poster presented at this conference appears to support Dr. Koskinen’s proposal that sexual dysfunction is a significant reason for patient non adherence. In a study presented by Ammassari and colleagues [1], 5% of their patients reported sexual dysfunction and this appeared to be significantly associated with non adherence in that group.

Dr. Koskinen also proposed, again without data, that sexual dysfunction may cause non adherence with safer sex due to difficulty with using condoms and that this may result in increased sexual transmission of HIV and possibly MDR-HIV, since non adherence with antiretrovirals (ARVs) will result in increased viral load and the likelihood of resistance development. He had very few suggestions, other than sensitivity and perhaps a questionnaire, since patients may be more willing to complain of sexual dysfunction using such a questionnaire.

My own experience indicates that patients are not quite as unwilling to discuss sexual dysfunction as Dr. Koskinen suggests, especially when they are asked about problems they may be having and are aware of the many treatment options that exist, and the data from Ammassari and colleagues seems to support that experience. Further, sexual dysfunction is generally not a side effect of ARV therapy, but instead is usually related to psychological or hormonal factors. I agree, however, that addressing this issue, as well as others that may cause non adherence, is important and patient education regarding ARV side effects and possible treatments may be important.

Dr. David Bangsberg from San Francisco began his talk on adherence by pointing out that several studies have shown that physicians are no better than random at predicting adherence and that an attempt to do so may result in ARVs being inappropriately withheld. He did not, however, contend that therefore physicians should abandon any effort to assess and address adherence problems.

Many of the common problems with adherence can be identified and, to some extent, mitigated or corrected. Homelessness, drug and alcohol abuse, depression and psychiatric disease are issues that Dr. Bangsberg mentioned as areas where some intervention may significantly improve adherence and I would add to this list issues of disclosure and lack of knowledge regarding HIV and ARV therapy. Dr. Bangsberg discussed previously published data from the REACH cohort [2], a cohort of homeless and poor patients in San Francisco. His group assessed adherence in this group using three methods (unannounced pill count, MEMScap and 3-day patient report) and found that each 10% adherence difference accounted for a 0.33 log10 copy/mL viral load change.

They also found that very low levels of adherence (less than 50%) were generally not associated with the development of drug resistance, whereas levels of adherence from 70 to 95% may result in resistance development. Thus, evidence of resistance on genotyping/phenotyping may be a marker for very good adherence (in the 70 to 95% range) that is still not quite good enough. This finding reflects the relationship between drug pressure and resistance development and is one of the important differences between HIV-infected patients and patients with other chronic diseases: Very good, but not excellent, adherence (again, in the 70-95% range) in HIV-infected patients is generally bad (since it leads to resistance and virologic failure), whereas very good adherence in other chronic diseases is generally good (since increasing levels of adherence lead, generally, to better disease control). This concept emphasizes why HIV-infected patients tend to have the need for more intensive support, medical, psychiatric and social, then the general population or even populations with other chronic medical conditions.

Dr. Bangsberg reviewed some of the common reasons for non adherence, many of which have been previously discussed by this and other authors [3, 4, 5]. These include side effects, forgetting (which is generally a catch-all phrase used by patients and may include many reasons such as being away from home when a dose is due and not having it with them, falling asleep prior to taking a night-time dose, “being busy”, social obligations and work obligations), erroneous beliefs regarding HIV or ARV therapy, alcohol and drug use and depression. Dr. Bangsberg urged that patients be screened for these adherence problems prior to starting ARV therapy, especially for depression which despite its being a significant reason for non adherence may go undetected and unreported in many patients and is usually one of the non adherence issues most responsive to appropriate intervention, pharmacologic or otherwise. Further interventions are important to mitigate potential adherence problems, even if they cannot be solved and this may need to involve a team approach to adherence, which includes a psychiatrist, social worker, case manager and others.

One of the most important aspects of this issue is detecting and assessing problems that may lead to non adherence. As Dr. Bangsberg pointed out, many patients misunderstand their ARV regimen and when put on the spot feel anxious about revealing or have difficulty recalling their adherence problems. Dr. Bangsberg suggested the use of questionnaires, paper or computer-based, which inquire into issues surrounding adherence and can be used to evaluate the patients understanding of the medication regimen they are on.

My own experience in using a questionnaire to evaluate adherence supports this suggestion. Questionnaires allow the patient to list their complaints without feeling pressured for time (as they frequently do when they are sitting in their doctor’s office) and it allows for an evaluation of how the patient is actually taking their regimen (by having the patient write down exactly what they are taking and when and how they are taking it). The questionnaire is not a substitute for patient-physician interaction, but instead should be used to point out areas of concern and stimulate conversation and joint problem solving efforts. Problem solving may include simple things like carrying spare medications or filling prescriptions a few days before they run out to visual clarifications of the ARV regimen, beepers, pill boxes or other common support measures.

Continuing the discussion of how to assess and improve adherence, Dr. Fabrizio Starace of Italy listed several domains which play a role in adherence including (1) Informational (e.g., benefits of ARVs, side effects), (2) Motivational (e.g., attitudes toward medications, trust) and (3) Behavioural skills (e.g., ability to cope with side effects, ability to obtain further information or support if needed). Dr. Starace proposed that each of these domains should be assessed in order to determine where intervention is needed, e.g., does the patient have a high degree of belief in the medications and a good attitude toward treatment, but a poor ability to cope with side effects or obtain information about managing commonly encountered problems.

This may allow for deliberate tailoring of the required intervention, which may result in a more rapid, effective and cost effective adherence program. He urged clinical trials to pursue this issue, but I am not sure that we need to reinvent the wheel: Many studies in other diseases have documented that while full adherence is difficult to achieve, efforts to identify and address specific adherence problems certainly improve adherence to a significant degree.

Simplification has become such a common theme of adherence that it is even recognized in the DHHS guidelines. This theme was continued at this conference where data on the once-a-day regimens was reviewed with excitement. Professor Brian Gazzard, of London, the moderator of a conference entitled “Optimising antiretroviral therapy: Recent advances and new directions”, stated that he anticipated his clinic would begin utilizing these regimens in an effort to improve tolerance of and adherence to HAART. Several studies presented at this conference strongly indicated that patients prefer simpler regimens that have fewer pills, are dosed once-daily and do not have a meal restriction [12, 13].

Some of the simplified regimens presented recently were discussed by Dr, Mark Nelson during an outstanding presentation include didanosine (ddI) + lamivudine (3TC) + efavirenz (EFV), ddI + 3TC + nevirapine (NVP) , ddI + emtricitabine (FTC) + EFV and ddI + EFV + NVP . These regimens are based upon the long plasma half-lives of EFV and NVP and the relatively long intracellular half-lives of ddI, FTC and 3TC. One poster presented at this conference, a double cross-over pharmacokinetic study evaluating the plasma and intracellular concentrations of 3TC, concluded that 150mg BID and 300mg QD of 3TC have equivalent plasma and intracellular triphosphate Areas under the curve (AUC) but a modestly lower intracellular triphosphate concentration at trough (18-22%) and significant inter-subject variability. While there is clinical data for the use of 3TC as noted, the safest course at this point appears to be to wait for further pharmacokinetic data or for the approval of FTC.

Regardless, once-a-day regimens are certainly close, and for some patients that have significant problems with a BID regimen may even be appropriate. As time goes on and improved dosing schedules of current ARVs, e.g., ddI EC (which is already available in Europe) and d4T ER, and new medications with once-daily dosing, e.g. tenofovir and BMS-232632, become available, once-daily dosing will be the standard. As stated eloquently by Dr. Nelson patients are now asking that we give them back their lives, and once daily dosing of medications is a nice and large step in that direction.

References:

Ammassari A, Murri R, Trotta MP, et al. Determinants of non-adherence in a multi-center cohort study of patients previously na¥ve to antiretroviral therapy (AdICoNA Study). In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract 111.
Bangsberg D, et al. AIDS. 2000; 14(4): 357-66.
Boyle BA. Getting and Keeping patients on HAART. The AIDS Reader. 1999;9(6):378-380, 409. 4 Boyle BA. Adherence and HAART. The AIDS Reader. 2000;10(7):392-396.
Goujard C, Bernard N, Peyramond D, et al. Factors Determining Adherence to HAART in a Cohort of 324 HIV-1-Infected Individuals (Ciel Bleu Study). In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract 95.
DHHS Guidelines, January, 2000.
Maggiolo F, Migliorino M, Caprioli S, et al. Once-a-day therapy for HIV infection. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract TuPpB1167.
Jordan J, Carranza Rosenzweig J, Pathak D, Pilon T. Perceived influence of regimen characteristics on adherence. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract 121.
Carranza Rosenzweig J, Jordan J, Pathak D, Pilon T. Patient perspectives on potential adherence to triple combination anitretroviral regimens. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract 120.
Proena1, J., Xavier A, Brito P, Soares S, Poas J. Once daily therapy with nevirapine (Nev) /Didanosine (ddI) /Lamivudine (3TC) in a non adherent population. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract TuPeB3231.
Molina JM. In: Program and Abstracts of the 38th Infectious Disease Society of America Conference, September, 2000, New Orleans. Abstract 648.
Jordan W, Jefferson R, Yemofio F, et al. Nevirapine (NVP) + efavirenz (EFV) + didanosine (ddI): a very simple, safe, and effective once-daily regimen. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract TuPeB3207.
Yuen GJ, Lou Y, Bumgarner NT, et al. Equivalence of plasma and intracellular triphosphate lamivudine pharmacokinetics (PK) following lamivudine (3TC) 300 mg once daily compared to lamivudine 150 mg twice daily in healthy volunteers. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract 269.

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