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Br J Clin Pharmacol. Jul 2011; 72(1): 116–124.
PMCID: PMC3141193

Adherence to national guidelines for initiation of antiretroviral regimens in HIV patients: a Danish nationwide study

Abstract

AIM

To determine the adherence to the national guidelines for start of highly active antiretroviral treatment (HAART) in HIV infected patients.

METHODS

We used a Danish nationwide cohort of HIV infected patients to calculate the fraction of patients who in the period 1997–2006 started HAART according to the guidelines from The Danish Society of Infectious Diseases. We used Kaplan-Meier tables to estimate time from fulfilling the criteria for start of HAART to initiation of the treatment. Cox regression and logistic regression was used to identify risk factors for delayed initiation of treatment and chance of being included in clinical trials.

RESULTS

The study included 3223 patients, 74% of whom initiated HAART in the study period. Ninety-four% fulfilled the criteria for start of HAART, with minor differences over calendar periods. Ninety-four% initiated a recommended regimen or were included in a clinical trial. Intravenous drug use predicted initiation of a non-recommended regimen and delay in start of HAART, while non-Caucasians were less likely to be included in clinical trials.

CONCLUSIONS

In a Western world setting, the adherence to national guidelines for start of HAART can be high. We suggest that simplicity of the guidelines, centralization of treatment and involvement of local clinicians in the development of guidelines are of major importance for high adherence to treatment guidelines.

Keywords: antiretroviral therapy, guideline adherence, HIV

WHAT IS ALREADY KNOW ABOUT THIS SUBJECT

  • National guidelines for start of highly active antiretroviral treatment (HAART) in HIV infected patients are available in many Western world countries. However the impact of the guidelines on clinical practice is poorly documented.

WHAT THIS STUDY ADDS

  • Adherence to the starting criteria for HAART and the choice of treatment regimen in the guidelines exceeded 90%.
  • Intravenous drug users were more likely to start HAART at a later time after fulfilling the starting criteria and starting an alternative regimen.
  • More than a third of the patients initiated HAART as a part of a clinical trial from 1998 to 2000.

Introduction

Since the introduction of zidovudine in 1987, the number of antiretroviral treatment options for HIV infection has expanded considerably. After the marketing of protease inhibitors (PI) in 1996 and use of drug combinations in highly active antiretroviral therapy (HAART), morbidity and mortality in HIV infected patients have decreased substantially [1]. In the last decade a main focus for drug development has been reduction of the pill burden by increased dosing intervals and combination of two or three antiretroviral drugs in a single tablet. Moreover, reduction of toxicity has led to improved compliance, and new drug classes have made it possible to treat HIV resistant to the classical antiretroviral drug classes. Consequently, more than 20 different drugs are currently marketed for the treatment of HIV infection, some of which are mainly recommended for second-line treatment regimens in patients harboring resistant virus or suffering from toxicity.

The impact of guidelines on clinical practice is poorly documented. Factors facilitating implementation of guidelines are physicians' awareness of and familiarity and agreement with guidelines, self-efficacy, outcome expectancy, inertia of previous practice, concrete recommendations and precise wording [2, 3]. In general practice the adherence to clinical guidelines has been reported to be up to 60% [2, 4]. Reports from HIV treatment centres in the UK and US have indicated that 60–90% of the HIV infected patients start a recommended first-line HAART regime [57]. Since 1996, the Danish Infectious Diseases Society has published and revised national treatment guidelines for start of HAART, which include recommendations for the choice of initial treatment regimens and when to start HAART. We used a Danish nationwide cohort of HIV infected patients to study the adherence to national guidelines for start of HAART.

Methods

Setting

Denmark has a population of 5.4 million and the estimated prevalence of HIV infection in the adult population is 0.07% [8]. Denmark's tax-funded health care system provides antiretroviral treatment free-of-charge to all HIV-positive residents. Treatment of HIV infection is restricted to eight specialized medical centres, where patients are seen on an outpatient basis at intended intervals of 12–16 weeks.

Danish HIV cohort study

The Danish HIV Cohort Study, which has been described in detail elsewhere, includes all HIV-infected patients treated in Denmark from 1 January 1995 to 31 December 2007 [8]. Briefly, baseline data collected from the patients files from the centres are date of birth, gender, origin, race, most likely mode and place of infection, time of HIV diagnosis, time of previous negative HIV antibody test, serological status regarding hepatitis B and C, cytomegalovirus, and toxoplasmosis. Regular updates are carried out once a year noting antiretroviral treatment, development of opportunistic infections and other AIDS-defining illnesses, pregnancies and outcome of births, and laboratory values. Use of the Danish personal identification number enables the centres to track whether the patients lost to follow-up have died or moved outside the country.

Study population

Patients were recruited from The Danish HIV Cohort Study and were included if they meet the following criteria: residency in Denmark at time of HIV diagnosis, were 18 years of age or older at time of HIV diagnosis, had at least one CD4 count and viral load data available and were alive on 1 January 1997. The patients were excluded if they were not treatment naive before starting HAART or started HAART before 1 January 1997.

HAART was defined as a treatment regimen of at least three antiretroviral drugs that included a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or a PI, and/or abacavir, or a treatment regimen with a combination of a NNRTI and a boosted PI.

Danish treatment guideline

The national treatment guidelines for first line antiretroviral therapy are published by the Danish Infectious Diseases Society and are created in a working group with representatives from the five major HIV treating centres. In the study period the national criteria for HAART initiation were presence of one of the following: acute HIV infection, an AIDS defining disease or HIV related disease, pregnancy, CD4+ cell count <300 cells µl−1, and, until 1 January 2001, a plasma HIV RNA load >100 000 copies ml−1.

The recommended HAART regimes and recommended alternative regimens are specified in Table 1. In the present study, treatment regimes not listed were considered not to be recommended as initial HAART therapy. Patients starting on zidovudine, lamivudine and efavirenz and switching to abacavir, lamivudine and efavirenz within the first 120 days after start of HAART were considered to be starting on the latter regime. To allow for early and slow adopters the validity of the guidelines were extended by 90 days before and after the dates presented in Table 1.

Table 1
Recommended antiretroviral therapy in the national treatment guidelines for first line antiretroviral therapy as published by the Danish Infectious Diseases Society

Statistical analysis

The study period was 1997–2007. Patients were considered eligible for start of HAART on the date, they fulfilled one of the following criteria: diagnosed with acute HIV infection (valid for up to 90 days after the diagnosis), had a CD4 count <300 cells µl−1, viral load >100.000 copies ml−1 (until 31 December 2001 or 1 year after the last value above the threshold whichever came first), were pregnant (estimated as 257 days before delivery) or were diagnosed with an AIDS defining disease. Initiation of HAART due to non-AIDS defining HIV related diseases was not included in the primary study outcome but was reported separately. We calculated the fraction of patients who fulfilled these criteria up to 3 months after the start of HAART stratified on year of start of HAART. We further calculated the fraction of patients who started on a preferred recommended regimen, an alternative regimen, a regimen initiated as part of a randomized study or a regimen not recommended. Pregnant subjects starting HAART were excluded from the latter analyses. Logistic regression was used to identify factors associated with starting an alternative or non-recommended regimen or being included in clinical trials. The following variables were included: gender, race, age at time of HIV diagnosis, hepatitis B and C status, HIV diagnosis before 1997, route of transmission, pregnancy at start of HAART, CD4 count (continuous variable) and viral load at start of HAART (logarithmic transformed continuous variable), acute HIV infection, time from diagnosis to start of HAART (continuous variable). Parameters that had a P value ≤25% for improvement of the model measured by change in deviance were included in a multiple multinomial logistic regression and parameters with a P > 0.05 and not substantially influencing the estimated coefficients were subsequently step-wise eliminated.

Kaplan-Meier analyses were used to construct time-to event curves. Time was calculated from the date the patients first met the criteria for initiation of HAART (for patients fulfilling the criteria before 1 January 1997 this date was used) to date of start of HAART, death or last clinical follow up only counting the time the patient was eligible for start of HAART. Three start criteria were considered reversible (acute HIV (90 days after start criteria), pregnancy (after delivery) and viral load (after 31 December 2001)) and in this case accumulation of observation time was stopped at these time points and resumed when the next starting criteria were fulfilled. Cox proportional hazard analyses were used to identify risk factors for time to start of HAART. In these analysis we included age at time of HIV diagnosis (below vs. above 40 years), gender, race, hepatitis B and C status, HIV diagnosis before 1997 and route of transmission. The delay in median time to start of HAART was calculated from the median survival time in the Kaplan-Meier analyses. The confidence intervals was calculated using a bootstrap bias-corrected accelerated interval with 19 999 samples.

Statistical analyses were performed in R, a language and environment for statistical computing (R Foundation for Statistical Computing).

Approvals and permissions

The Danish Data Protection Agency approved the establishment of the cohort study. The study was not subject to approval by the ethics committee as the collection of data did not involve direct patient contact.

Results

We identified 3 223 HIV-infected patients in The Danish HIV Cohort Study who fulfilled the inclusion criteria. The patients were mainly males and 73.6% initiated HAART in the study period. Other characteristics are shown in Table 2.

Table 2
Characteristics of the study population

In the study period 93.9% of the patients who started HAART meet the criteria defined by The Danish Infectious Diseases Society for initiation of HAART, and this fraction did not change substantially over time (Figure 1). Of the 144 who did not fulfill the starting criteria 78 (54%) had a CD4 count between 301 and 350 cells µl−1. The reasons for starting HAART for the remaining 66 patients were obtained from the patients' medical records and the main reason for start of HAAART in this group was HIV related diseases (33 patients), which in the guidelines of later years have been considered reasons for starting antiretroviral therapy (Table 3). For 12 patients (0.4%) no reason for start of HAART could be identified.

Table 3
Reason for starting HAART in the 66 patients who had a CD4 count above 350 cells µl−1 and did not meet the starting criteria as specified by the guidelines
Figure 1
Proportion of patients starting HAART, who met the starting criteria (bars indicate 95% confidence interval)

In the study period the majority (93.8%) of the patients started a recommended regimen or were included in clinical controlled trials (Figure 2). From 2003 the fraction that started on a non-recommended regimen was very low. From 1997 to 2000 a large proportion of the patients were included in controlled trials reaching 40% in 1999 and again from 2003 to 2005. The increased use of alternative regimes from 2003 was due to more patients starting a regimen including a PI (47.9% of the alternative regimes in that period), a continuous use of the combination of lamivudine and zidovudine after it was demoted to an alternative treatment regimen in 2006 and an increasing use of nevirapine (17.6% of the alternative regimes in that period) (data not shown).

Figure 2
Proportion of patients who started a recommended regimen (white), alternative regimen (light grey), a regimen as a result of inclusion in a randomized study (dark grey) or a non-recommended regimen (black)

Logistic regression analysis revealed that patients infected by intravenous drug use (IDU) had a higher risk for starting an alternative regimen (OR = 2.1, 95% CI 1.2, 3.5) and had a lower risk of being included in clinical trials when initiating HAART (OR = 0.19, 95% CI 0.04, 0.80) compared with homosexually infected patients while Caucasian patients had a higher risk of being included in clinical trials (OR = 5.2, 95% CI 2.0, 13.8). Ninety patients started a non-HAART antiretroviral regimen after the start of the study period (1 January 1997); 64 of these started in 1997. These patients were not included in the study.

Figure 3 shows Kaplan-Meier curves for time from fulfilling the criteria for initiation of HAART to start of HAART stratified by route of transmission. One year after the criteria for initiation of HAART were met 77% of the patients were started on antiretroviral drugs. Female gender, Caucasian race vs. Asian race, HIV diagnosed before 1997, IDU, hepatitis C and age below 40 years at the time of the HIV diagnosis were associated with delayed start of HAART (Table 4). After adjustment for other confounders the association with female gender, race and hepatitis C infection was no longer statistical significant.

Table 4
Relative risk (hazard ratio, HR) of starting HAART after fulfilling starting criteria for HIV treatment according to baseline characteristics
Figure 3
Kaplan Meier curves for time from the starting criteria are met to initialization of HAART stratified by routes of HIV transmission. Homosexual (An external file that holds a picture, illustration, etc.
Object name is bcp0072-0116-mu1.jpg); Heterosexual (An external file that holds a picture, illustration, etc.
Object name is bcp0072-0116-mu2.jpg); Intravenous drug use (An external file that holds a picture, illustration, etc.
Object name is bcp0072-0116-mu3.jpg); Other/Unknown (An external file that holds a picture, illustration, etc.
Object name is bcp0072-0116-mu4.jpg)

Discussion

In this study we examined the adherence with the evolving Danish HIV treatment guidelines for HAART initiation in the period 1997–2006. Overall, the choice of initial HAART regimens was in accordance with the evolving guidelines and the majority of patients starting HAART met the criteria as defined by The Danish Infectious Diseases Society. Rarely, patients were prescribed a non-recommended first-line regime, but a high proportion started the initial HAART treatment as part of a clinical trial in the period from 1997–2000. From 2003 when the number of recommended regimens was reduced and efavirenz became the only recommended ‘third’ drug in HAART, an increased use of alternative regimes was seen. This is probably attributable to the fact that PI based regimens are rather robust and therefore used in patients with potential poor compliance, that efavirenz is generally avoided in patients prone to develop neuro-psychiatric disease and the fear of efavirenz interacting with methadone treatment.

The Danish guidelines specify that HAART could be started in patients with non-AIDS defining HIV related disease but gives no unambiguous definition of non-AIDS defining HIV related disease. Thus, in order to keep transparency in the actual analysis, initiation of HAART due to HIV related diseases was not included in the primary study outcome but was reported separately (Table 3). Nevertheless, several of these conditions are generally accepted as reasons to start HAART such as thrombocytopenia and fungal infections.

The median time from meeting the criteria for start of treatment to initiation of HAART was 3.5 months. A delay in treatment was associated with transmission by intravenous drug use, HIV infection diagnosed before 1997 or age below 40 years at the time of diagnosis. This finding might reflect either intravenous drug addicts' low compliance with outpatient appointments before treatment is initiated or concern about the regimens safety and efficacy in the first part of the study period.

A major strength of this study is the high quality of data and the population-based design with long and nearly complete follow-up. To our knowledge this is the first nationwide study to examine the impact of guidelines on the initiation of HAART.

In recent years, guidelines have been used as a means to control cost by discouraging use of overly expensive treatments with limited efficacy [9]. In contrast to previous reports on hypertension [4] and diabetes [10], the present study demonstrates a consistently high adherence to national treatment guidelines despite frequent updates. Still, the use of zidovudine, which was the basis of the treatment regimes until 2006, continued even after 2006. This could be due to the fact that zidovudine was mainly discredited due to long term toxicity, primarily disfiguring lipoatrophy and that zidovudine was used in initial regimens to avoid simultaneous exposure to agents associated with rash, e.g. abacavir, efavirenz and nevirapine. Though guidelines advocated switch from zidovudine to an alternative nucleoside after 2–3 months, patients who felt well on the zidovudine containing regimens and who were impressed by the viral load drop were often quite reluctant to change from an apparently successful regimen.

The study design did not allow an analysis of specific factors impeding or facilitating implementation of clinical guidelines [2, 3]. We presume that ownership and local involvement might be important for the implementation of the Danish national guidelines. What is more the organization with centralized treatment in eight specialized centres, many of which participated in the development and revision of the Danish guidelines, may have facilitated the adherence with guidelines. Moreover, a tradition for benchmarking of the centres has been established by the use of data from the Danish HIV Cohort Study [11].

The format of the guidelines might also be of importance. In contrast to most national guidelines [57, 12], the Danish guidelines are short and recommend only a limited number of regimens. Grol et al. [2] examined different factors influencing general practitioners adherence with guidelines covering a broad range of diseases and found, that controversial and vaguely defined guidelines were the most likely not to be followed. Other studies have emphasized the importance of guidelines being specific [13, 14].

Few studies have focused on the impact and adherence to clinical guidelines in antiretroviral treatment. Using a postal survey completed by the lead consultants with response from 99 centres in England and Ireland, Brook & Johnson reported a high adherence to the British HIV Association guidelines [6]. In a study of HIV infected US veterans, Holodniy et al. reported that less than 72% initiated a ‘preferred’ or ‘alternative’ regimen as defined by the guidelines [7]. This is in accordance with a study from United States of 217 HIV infected women, 30% of whom reported to start a HAART regimen not listed in the guidelines [5].

An interesting finding in our study was that in particular before 2002, a major proportion of the patients started HAART as part of a clinical trial. Because patients and physicians are reluctant to switch medication in the absence of side effects or treatment failure, trial inclusion may have a potential long-term impact on medication use that lasts beyond the end of the trial period. As the two largest trials involving more than 20% of the patients starting HAART in 1999 and 2004 were investigator initiated, ‘seeding’ trials [15] seems to have had only a minor impact on the initial treatment regime.

Easterbrook et al. [16] studied the pattern of antiretroviral drug use and found that nonwhites were more likely to initiate treatment at a lower CD4 count. The correlation, however, was less pronounced when stratified by the initial CD4 count suggesting that the difference was due to the disease being diagnosed at later disease stages. We observed no racial differences in time to start of antiretroviral treatment from when the start criteria were met, which supports findings by Easterbrook et al. [16]. We found that Caucasian patients had a higher probability of being included in clinical trials, probably due to the fact that in order to be included in a clinical trial the patients should be able to read the informed consent in Danish.

IDU was the transmission group in which the treatment deviated most from the guidelines. Although Danish intravenous drug addicts are tested frequently for HIV and thus present with a higher CD4 count [17], intravenous drug abusers started treatment at a lower CD4 count. This finding is in line with previous studies [16, 1820] showing that the median time to treatment initiation is delayed by over 1 year compared with homo- or heterosexual infected patients. In contrast to the US [19], medication is provided free of charge in Denmark and therefore the delay in treatment in this group of patients is unlikely to be explained by financial problems but is rather due to concerns about reduced adherence leading to treatment failure [21]. Intravenous drug addicts are often co-infected with hepatitis B or C, but only recently, earlier initiation of treatment in co-infected patients to avoid progression of liver disease has been included in the guidelines.

We found that after 2003, only intravenous drug addicts had an increased risk of starting an alternative regime. It has been shown that intravenous drug users are more likely to start on a PI based regimen [16]. Considering interactions between efavirenz and methadone [22]or the aggravation of psychiatric comorbidity associated with efavirenz, this approach seems rational. Furthermore PI containing regimens seem to be more forgiving with respect to development of resistance.

This study has some important limitations. Firstly, we did not include outcome data and did not examine the clinical consequences of guideline deviations. However the high rate of adherence to guidelines may explain the low rate of triple (NRTI, NNRTI and PI) class failure [23] and the unprecedented low rate of transmitted resistance observed in Denmark [24]. Secondly, confounding due to unregistered co-morbidity may explain the use of alternative treatments. Also we did not assess the validity of the Danish guidelines.

We conclude, that adherence to treatment guidelines is high in Denmark. We suggest that simplicity of the guidelines, centralization of treatment and involvement of local clinicians in the development of guidelines are of major importance for high adherence to treatment guidelines.

Acknowledgments

We thank the staff of our clinical departments for their continuous support and enthusiasm and the NOVO Foundation as well as the Clinical Institute of Copenhagen University for financial support.

Competing Interests

N. Obel has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen-Cilag and Swedish Orphan. C. Pedersen has received research funding from Abbott, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Swedish Orphan and Boehringer Ingelheim. J. Gerstoft has received research funding from Abbott, Roche, Bristol-Myers Squibb, Mecrk Sharp & Dohme, Pharmasia, GlaxoSmithKline, Swedish Orphan and Boehringer Ingelheim. T. Petersen, S. Andersen, K. Thorsteinsson and C.S. Larsen report no conflicts of interest.

Centres in the Danish HIV Cohort Study

Departments of Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (J. Gerstoft, N. Obel) and Hvidovre (G. Kronborg), Odense University Hospital (C Pedersen), Aarhus University Hospitals, Skejby (C.S. Larsen) and Aalborg (G. Pedersen), Herning Hospital (A.L. Laursen), Helsingør Hospital (L. Nielsen) and Kolding Hospital (J. Jensen).

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