The current antiretroviral treatment standard for HIV-infected patients is to use combination therapies to reduce and maintain HIV-RNA plasma concentrations below detectable levels (1-3). In 1997, the Swiss treatment guidelines (3) recommended treating HIV-infected patients with highly active antiretroviral therapy (HAART), including at least one protease inhibitor (PI). Few exceptions to this rule were considered acceptable for patients with high CD4 cell counts, low viremia, or poor compliance. Although HAART significantly reduces morbidity and mortality (4), it presents several practical difficulties because of the complexity of the drug regimens, the self-discipline from patients they require, and their potential side effects. For these reasons, many patients who might benefit from HAART are not treated with this therapy. The magnitude of this problem, however, has not been studied thoroughly and factors contributing to nonprescription, interruption, or refusal of recommended treatment are still not well established. They may include factors related to the physician as well as the patient's beliefs, lifestyle, and clinical condition.

In this study, we measured the prevalence of HAART prescription in a large population-based cohort of HIV-infected patients and investigated reasons why HAART was either never prescribed or discontinued. We also assessed those patient characteristics possibly associated with deviation from official treatment recommendations.

The Swiss HIV Cohort Study (SHCS) prospectively enrolls patients aged 16 years or older with HIV infection. The study design has been described in detail elsewhere (5,6). Approximately 73% of all patients with reported AIDS in Switzerland participated in the SHCS (5,7). Patients are observed in seven clinical centers (Basel, Berne, Geneva, Lausanne, Lugano, St. Gallen, and Zurich). Enrollment is independent of disease stage and degree of immunodeficiency. Information is collected according to a standardized protocol at registration and at 6-monthly follow-up visits. The follow-up questionnaire includes a detailed history of HIV-associated diseases, dates of starting and discontinuing medications, and laboratory tests' results. AIDS is defined as category C clinical conditions of the 1993 revised U.S. Centers for Disease Control and Prevention (CDC) classification system for HIV infection (8) and therefore does not consider CD4 cell counts.

Each SHCS participant presenting at one of the study centers during a 2-month period, starting on September 1st, 1997, was included in this study. The attending physician completed a pretested structured questionnaire and indicated whether the patient was receiving HAART (defined as triple therapy, a combination of one or two reverse transcriptase inhibitors with one or two PIs) or whether HAART was initiated at this visit. If a patient was not prescribed HAART, the physician specified the current antiretroviral therapy and indicated from a pre-established list, the reasons for not prescribing or for discontinuing HAART. More than one reason could be indicated for each participant. Results of laboratory tests and information on demography, presumed source of HIV-infection, social and economic background, intravenous drug use (IVDU) within the previous 6 months, and disease stage were obtained from the SHCS data base.

Prescription of HAART and the adequacy of treatment were analyzed in relation to patients' characteristics. Treatment was considered adequate if it was in accordance with the official Swiss recommendations for the treatment of HIV infection (3). These guidelines indicate that HAART should be prescribed to all HIV-infected patients unless CD4 cells count is >500/l and viremia <5000 RNA copies/ml. In addition, it is also considered acceptable to prescribe dual therapy without PI to patients with >200 CD4 lymphocytes/l and viremia <5000 RNA copies/ml.

For continuous variables, statistical comparisons of means were conducted using Student's t-test, and for categoric variables, proportions were compared using ² test. Differences in proportion between the groups that did and did not adhere to guidelines were quantified with the odds-ratio (OR) and its 95% confidence interval (CI). OR assessed the magnitude of the association between a given characteristic and the probability of receiving an inadequate treatment, that is, not conform to guidelines. The main variables of interest were gender, presumed mode of acquisition of HIV infection, age, clinical center, level of education, year of registration in the SHCS, current illicit IVDU, participation in a drug substitution program in the past 6 months, nationality, HIV disease stage, lowest CD4 cell counts, and highest viremia ever measured. Univariate comparisons and OR were first computed. Clinically and statistically relevant variables were entered in a multivariate logistic regression model to assess their independent association with the conformity of treatment with guidelines. Statistical analysis was conducted with SPSS 7.5 for Windows software (SPSS Inc., Chicago, IL, U.S.A.).

Of 3385 patients followed at the time of the survey in the SHCS, 2154 (64%) were eligible and included in the study. Survey participants and nonparticipants were similar in terms of gender, age, duration of HIV infection, date of registration in the SHCS, level of education, and distribution by disease stage, presumed mode of HIV acquisition, clinical center, and nationality. Six hundred participants (27.9%) were women. The presumed route of HIV acquisition was sex between men for 813 participants (37.7%), heterosexual contacts for 596 (27.7%), and IVDU with needle-sharing for 465 (21.6%), respectively. At the time of the study visit, 560 patients (26.0%) were in CDC disease Stage C, 119 (5.5%) had CD4 counts <51 cells/l, 553 (25.7%) had counts between 51 and 200 cells/l, and 1373 (63.7%) had counts >200 cells/l.

Most participants (1487, 69.0%) were currently receiving HAART. One quarter (541, 25.1%) had never received such treatment, and 126 patients (5.8%) had discontinued HAART. Of 667 persons who were not receiving HAART, 376 (17.5% of all patients) were receiving dual therapy, 15 (0.7%) monotherapy and 276 (12.8%) were not receiving any antiretroviral therapy. In all, 59% of patients in CDC stage A, 72.5% in CDC stage B, and 79.9% in CDC stage C were treated with HAART (p < .001). HAART was prescribed to 61.0% of patients with current CD4 counts <51 cells/l, 78.2% of patients with CD4 counts between 51 and 200 cells/l, and 65.2% of patients with CD4 counts >200 cells/l (p < .001).

Among 541 patients who had never been treated with HAART, the most common reasons indicated by the physician for not prescribing were that it was not indicated according to official guidelines (255; 47.1% of patients never treated with HAART), and the belief that the patient would not adhere to treatment (110; 20.3%). In this group of patients never treated with HAART, 18.5% refused treatment because they feared drug side effects and 18.3% because they considered that treatment was too complicated to follow (Table 1). When the decision to avoid therapy was made in accordance with the guidelines, it was most usually the sole decision of the physician (192/255, 75.3%). In this group of 192 patients, 15 patients (7.8%) were thought not to be in compliance. The decision to withhold treatment was made jointly by the physician and the patient in 63 of 255 patients (24.7%). In this smaller group, the decision was made because both parties agreed that compliance would be a problem in 14 cases (22.2%). Overall, among patients never treated, the decision not to prescribe HAART was made by the physician alone for 280 patients (51.8%), exclusively at the patient's request for 146 (27.0%), and by both physician and patient together, for 111 (20.5%). This information was not available for 4 patients.

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TABLE 1. Justification for nonprescription of HAART among patients never treated (N = 541)a

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Among 255 patients never treated for whom HAART was not indicated according to their physicians, 32.8% had had CD4 counts <500 cells/l and viremia >5000 RNA copies/ml, which therefore provided an indication for HAART according to the guidelines. Of 110 patients never treated with HAART because the attending physician believed that they would not comply with treatment, 52 (47.3%) also indicated their refusal of HAART. For the remaining 58 patients (52.7%), the decision to delay treatment was made by the physician alone.

The most common reasons for discontinuing HAART were side effects (61.1% of 126 patients), the patient's fear of side effects (25.4%), and the perception by the patient that the treatment was too complicated (23.0%) (Table 2). Patients with current CD4 counts <51 CD4 cells/l were significantly more likely to have discontinued HAART because of side effects (12.4% of patients with CD4 counts <51 cells/l) than patients with CD4 counts between 51 and 200 cells/l (3.8%) or >200 cells/l (3.0%; p < .01).

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TABLE 2. Justification for treatment interruption among patients no longer receiving HAART (N = 126)a

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Sixteen percent (345) of patients did not receive HAART or were not treated at all although their clinical condition warranted such treatment according to the official Swiss guidelines. Univariate analysis indicated that age and the highest HIV-RNA level ever measured were not associated with nonadherence to recommendations. Female gender, IV drug use as the route of HIV acquisition, lower education levels, early date of registration in the SHCS, Swiss nationality, lowest CD4 cell count ever measured, CDC disease stage C, and current IV drug use (inside or outside a drug substitution program) appeared to be significant risk factors associated with nonadherence to treatment recommendations. Multiple logistic regression analysis, however, indicated (Table 3) that the risk factors independently associated with nonadherence of the physician to treatment guidelines were patient's presumed HIV acquisition through needle sharing (adjusted OR, 1.68; 95% CI, 1.13-2.48), patients' lower education level (adjusted OR, 1.75; 95% CI, 1.16-2.64 for patients with mandatory education [9 years] or less versus more than high school), and active IV drug use outside a drug program (adjusted OR, 2.12; 95% CI, 1.38-2.26). Patients whose lowest CD4 count ever measured was <200 CD4 cells/l were less likely to receive inadequate treatment than the others.

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TABLE 3. Risk factors for inadequate antiretroviral therapy defined on the basis of official Swiss guidelines: multivariate slogistic regression (N = 2072)a

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In this cross-sectional survey of SHCS participants, 69% of patients were prescribed HAART. This proportion was greater among those who were symptomatic (80% of patients with AIDS) or had CD4 cell counts between 51 and 200/l (78%). However, prescription was less common among patients with CD4 counts <51 cells/l (61%). This was associated with an increased occurrence of side effects in this group. One-quarter of patients had never been treated with HAART, and 16% (345) were either not treated at all or not treated in accordance with recommendations (e.g., received dual therapy instead of HAART).

Only limited information is available on the use of PIs and HAART among HIV-infected patients. In the United States, of 1204 HIV-infected persons interviewed in a study in 1997, 52% were taking one or more PIs (9). In that study, logistic regression analysis showed that respondents who were not receiving PIs were more likely to be black, patients with AIDS, and to have incomes <$10,000 U.S./year. In a more recent 1997 study, 82% of participants to the HIV Outpatient Study, U.S.A., with CD4 counts <100 cells/l had a regimen containing PIs (10). Use of PIs varied widely by study site (from 40% to 95%), IVDUs were less likely than other patients to receive PIs, and patients with private insurance were more often prescribed PIs than those insured by Medicare or Medicaid. In Switzerland, at the time of this study, all officially approved antiretroviral drugs (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, saquinavir, ritonavir, indinavir, and nelfinavir) were almost entirely reimbursed by insurance companies. For this reason and because health insurance is mandatory and comprehensive, the type of insurance is unlikely to be an important determinant of treatment choice in our study population.

The most common reasons for not prescribing HAART to patients with an indication for this therapy were the physician's judgment that the patient would not adhere to treatment. This is an illustration of the importance of the physician's assessment of compliance. Although many factors affecting compliance have been described (11,12), we did not investigate how it was evaluated by physicians, and whether their judgment was adequate.

Ample evidence indicates that physicians' ability to predict adherence is rather poor (13). Treatment decisions based on subjective assessment of compliance may be somewhat arbitrary and the practice does raise complex ethical questions. In the future, strategies developed in the context of chronic conditions to assess and improve treatment adherence may be adapted and used with HIV-infected patients (2).

The patients' refusal of treatment because of fear of side effects was the second most common reason for not prescribing HAART. Patients' fear of side effects was also an important reason for stopping HAART. Because, in our study, information was provided by physicians, it may reflect their own preconception of their patients' opinions and feelings and hence may have influenced to some degree our results. The role of patients' fear should therefore be interpreted with caution.

Active IVDU outside a drug substitution program, rather than IVDU or methadone use among participants in a drug program, was associated with a significantly higher risk to receive an inadequate antiretroviral treatment. This observation lends support to the value of drug rehabilitation programs. After IVDUs have initiated treatment, their compliance may be similar to that of other patients (14).

Patients with lower education were less likely to be treated according to the official guidelines. This may reflect the complexity of current antiretroviral regimens and insufficient patients' information, or the difference in the cultural background of physicians and some of their patients.

Because the SHCS is a large community-based cohort study including most patients with reported AIDS in Switzerland (5,7), and because study participants were similar to other SHCS patients, these results are likely to represent the situation among HIV-infected patients who were observed in specialized outpatient clinics. It is, however, possible, that SHCS participants are more willing to accept HAART than the rest of the population with HIV. In addition, study participants were enrolled during a relatively short 2-month period. It is therefore probable that they were more heavily treated and sicker that other SHCS participants not included in this study. Because of these potential biases, the prevalence of HAART prescription might have been overestimated in our study. This, however, may not modify substantially the relative importance of the determinant of physician adherence to guidelines.

Most patients registered in the Swiss HIV cohort study at the end of 1997 were prescribed HAART. However, 16% of patients were not treated at all, or were "undertreated" according to the Swiss guidelines. Most often, this was because either the physician considered that the patient was unlikely to comply with treatment, or because, reportedly, the patient refused treatment and was concerned or had experienced side effects of the drugs. Because assessment of patient's compliance is so important, strategies to better predict nonadherence and facilitate drug administration are urgently needed. The physician's judgment of patients' adherence and perception of patients' fear of side effects are critical for the prescription of HAART. Physicians should address these issues to prevent unilateral withholding of treatment and to increase the proportion of patients who may benefit from current antiretroviral therapy.

The members of the Swiss HIV Cohort Study are M. Battegay (Co-Chairman of the Scientific Board), E. Bernasconi, Ph. Bürgisser, M. Egger, P. Erb (Chairman of the Group "Laboratories"), W. Fierz, M. Flepp (Chairman of the Group "Clinics"), P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011 - Lausanne), H. J. Furrer, P. Grob, B. Hirschel, (Chairman of the Scientific Board), L. Kaiser, B. Ledergerber, R. Malinverni, L. Matter, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, W. Pichler, J-C. Piffaretti, M. Rickenbach (Head of Data Center), P. Sudre, J. Schupbach, A. Telenti, P. Vernazza, R. Weber.

Acknowledgment: This study has been funded by the Swiss Federal Office of Public Health grant no. 3600.010.1.