Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA Cohort
Dieleman, Jeanne P.a; Jambroes, Mariellec,d; Gyssens, Inge C.b; Sturkenboom, Miriam C. J. M.a; Stricker, Bruno H. Ch.a,h; Mulder, Wilhelmina M. C.e; de Wolf, Frankg; Weverling, Gerrit-Janf; Lange, Joep M. A.c,d; Reiss, Peterc,d; Brinkman, Kees*; on behalf of the ATHENA Study Group
From the the aPharmaco-Epidemiology Unit, Departments of Internal Medicine, and Epidemiology & Biostatistics, and the bDepartments of Microbiology & Infectious Diseases, and Internal Medicine, Erasmus University Medical Centre Rotterdam, the cNational Aids Therapy Evaluation Centre, Amsterdam, the dDepartment of Infectious Diseases, Tropical Medicine and AIDS, the eDepartment of Clinical Pharmacology and Pharmacotherapy, the fDepartment of Clinical Epidemiology and Biostatistics, and the gDepartment of Human Retrovirology, Academic Medical Center, Amsterdam, the hDutch Inspectorate for Health Care, The Hague and iOnze Lieve Vrouwe Gasthuis, Department of Internal Medicine, Amsterdam, the Netherlands. *See the Appendix for members of the ATHENA Study Group.
Requests for reprints to: J. P. Dieleman, Pharmaco-Epidemiology Unit, L-448, Depts of Internal Medicine and Epidemiology & Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
Received: 6 July 2001;
revised: 9 November 2001; accepted: 13 November 2001.
Sponsorship: the ATHENA-project is funded by the Dutch Health Insurance Council, Amstelveen, the Netherlands. J. P. Dieleman was supported by a grant from the Dutch Inspectorate for Health Care, The Hague, the Netherlands.
Background: Toxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit–risk ratio of HAART, guidelines for toxicity management are needed.
Objective: An observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression.
Methods: Patients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was ≤ 500 copies/ml (n = 775). One-year cumulative incidences of subsequent toxicity-driven switches and adjusted relative risks (RR) for potential determinants were calculated.
Results: The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24% [95% confidence interval (CI), 21–28], mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch (RR, 2.5; 95% CI, 1.7–3.5). Switching from PI to nevirapine while continuing the other antiretroviral drugs was more protective against a subsequent switch because of further toxicity than changing to another PI-containing regimen (RR, 0.2; 95% CI, 0.1–0.6).
Conclusions: As for first-line HAART, toxicity is responsible for the majority of switches during second-line HAART. Prior switching for toxicity increased the risk of having to switch the subsequent regimen for toxicity, but this risk is reduced when switching to nevirapine rather than to an alternative PI. The latter should be taken into account when designing toxicity-management guidelines.
The burden of toxicity resulting from highly active antiretroviral therapy (HAART) is of concern as it constitutes a threat to sustained success of HIV treatment [1,2]. The high frequency of toxicity [3,4] results in a high rate of treatment switches [5–7]. In fact, 44–58% of switches on initial HAART regimens and 56% of switches on subsequent regimens have been attributed to toxicity, which makes toxicity the most important reason for premature switching of antiretroviral treatment [6,8,9]. The impact of toxicity on the benefit–risk ratio of HIV treatment may become even more pronounced as sustained virological suppression becomes more feasible because of the availability of potent antiretroviral regimens [10–12].
Obviously, risk factors for developing HAART-associated toxicity include the specific antiretroviral drugs used . However, underlying conditions and patient characteristics, including pharmacokinetic parameters such as high drug absorption, low distribution volume and low metabolic clearance, may cause increased susceptibility to toxic effects of certain classes of drug [13–16]. Accordingly, patients who switch first-line HIV protease inhibitor (PI)-containing treatment because of toxicity are at an increased risk of a similar switch on a subsequent PI-containing regimen . As yet, there is no information to suggest that switching to another class of drug can reduce this risk. In addition, information on the influence of other factors on the risk of recurrent toxicity-driven switches is scanty, despite the high incidence of such switches.
The present study was conducted within the ATHENA cohort to estimate the incidence of treatment switches because of toxicity in a population of patients who had switched first-line PI-containing HAART despite successful viral suppression. In order to obtain more insight into toxicity-driven switches, determinants of the renewed need to switch treatment were identified.
Subjects and methods
The ATHENA cohort is a multicentre clinical cohort of HIV-infected individuals in the Netherlands, who are or have been treated with one or more of the antiretroviral medications that became generally available as of July 1996 (lamivudine, stavudine, the PI drugs and non-nucleoside reverse transcriptase inhibitors). All 22 Dutch hospitals that provide treatment to HIV-infected patients participate in this cohort study, with approval of their local ethical committees. Patient enrolment, for which informed consent is obtained, effectively started in May 1998 and continues to date.
According to the national guidelines for HIV treatment in the Netherlands, patients receiving antiretroviral treatment visit the outpatient clinic at approximately 3-monthly intervals for regular follow-up . Data for the ATHENA cohort are abstracted by treating physicians and trained research assistants from medical records onto standardized forms. This is done retrospectively for the period prior to having obtained participants’ informed consent, and prospectively thereafter. The resulting database contains anonymous information on patient characteristics (e.g., age, gender, date of birth, date of death, height and weight), HIV infection (e.g., HIV type, HIV-related events, route of HIV transmission, CD4 cell count and plasma HIV-1 RNA load), detailed treatment data (e.g., antiretroviral and prophylactic medications against opportunistic infections, dose frequencies, start and stop dates and reasons for treatment switch) and adverse events. Adverse events recorded include certain drug-associated events, which are preprinted on the data collection forms (e.g., hepatitis, lipodystrophy, nephrolithiasis, neuropathy) and which are recorded at the discretion of the treating physician. In addition, other events resulting in a treatment switch, as well as laboratory values outside prespecified ranges, are recorded. Reasons for treatment switch are categorized into mutually exclusive groups, consisting of toxicity [referring to the adverse event(s)], treatment failure (increase in viral load and/or decrease in CD4 cell count and/or clinical disease progression), patient request, pharmacological indication, dose escalation, other (with specification) and unknown. Treating physicians are requested to indicate a single primary reason for the switch.
The source population for the present study comprised all patients who started a first HAART regimen consisting of at least one PI and two nucleoside analogue reverse transcriptase inhibitors (NRTI) or the combination of ritonavir and saquinavir, with or without stavudine as used in the Prometheus study . The current study cohort included all patients from the source population who had a switch of their first PI-containing HAART regimen without having virological failure in order to select a population of patients for whom toxicity was of a potential concern. To achieve this, patients were excluded if their plasma HIV-1 RNA at the time of treatment switch was > 500 copies/ml. In addition, patients were excluded if treatment data were missing, no information on a subsequent regimen was available, or if their treatment was interrupted for more than 7 days, in order to reduce the chance of an increased viral load being present at the start of the second-line HAART regimen.
The date of switch of the first HAART regimen was considered as the baseline date for the current cohort study. Switches were defined as any change in composition of the regimen, dose adjustments other than the standard dose escalations (coded as dose escalation) or adjustments in frequency of administration of drugs.
The primary outcome measure was a toxicity-driven switch, defined as a switch of the second-line regimen because of toxicity, as indicated by the treating physician. A secondary outcome measure was switch of the second regimen for reasons other than toxicity. Follow-up lasted from the date of switch of the first HAART regimen until the date of switching the second regimen, the end of the 1-year period, or the end of follow-up, whichever came first. A 1-year period was chosen to ensure an equal follow-up time for various regimens.
The cumulative incidence of a switch while on the second-line HAART regimen was estimated by Kaplan–Meier survival analysis. The proportion of patients with HIV-1 RNA > 500 copies/ml at the end of follow-up was calculated. Risk factors for toxicity-driven switches were analysed by means of univariate and multivariate Cox regression analysis. Factors included in the analysis were calendar time of switch, route of HIV transmission, Centre for Disease Control and Prevention (CDC) classification of HIV disease (classified as C and non-C) , antiretroviral treatment experience prior to the first HAART, duration of the first HAART, CD4 cell count at switch, reason for switch and the type of treatment switch. As proxies for underlying conditions or characteristics, age, gender, nationality (classified as Dutch or non-Dutch), body mass index and lean body mass were included. All factors that were univariately associated with toxicity-driven switch at a P value of 0.1 were included in the multivariate analysis. Subsequently, variables were excluded from the multivariate analysis in a stepwise manner if the P value was > 0.1. Results were expressed as relative risks (RR) with 95% confidence intervals (95% CI).
All analyses were performed using SPSS for Windows version 9.01 as the statistical software package.
Among the 2470 patients in the ATHENA database who were available for analysis, 2096 (85%) used at least one PI with two NRTI or a Prometheus-trial regimen  as the first HAART regimen, and 1573 (75%) of these patients had ever switched from this regimen. From the population of switchers, 696 (45%) patients were excluded because of an HIV-1 RNA level > 500 copies/ml, nine (0.6%) patients because of missing treatment data, 41 (3%) patients because there was no information on a subsequent regimen, and 52 (3%) patients because of a treatment interruption of more than 7 days. Therefore, the final cohort consisted of 775 patients, who entered the study between June 1996 and December 1999.
Baseline characteristics of the study cohort are summarized in Table 1. The median date of cohort entry (i.e., the date of having switched a first-line HAART regimen) was March 1998. The majority of patients were homosexual males of Dutch nationality with a median age of 40 years. Most patients had asymptomatic or mildly symptomatic HIV disease with a median CD4 cell count of 365 × 106 cells/l. Approximately half of the patients were antiretroviral treatment-experienced prior to initiating their first HAART. The most frequent reason for switching the first HAART regimen with HIV-1 RNA < 500 copies/ml as indicated by the treating physician was toxicity and the most frequent type of treatment switch was replacement of PI drugs by another PI without changing the NRTI. The various PI drugs used in HAART regimens are summarized in Table 2. The most common PI and NRTI combinations in both the first and second regimens were indinavir with zidovudine and lamivudine (data not shown). The only non-nucleoside analogue reverse transcriptase inhibitor used in second-line regimens was nevirapine (n = 122;Table 1).
Incidence of toxicity-driven switches of the second HAART regimen
Within 1 year, 373 (48%) patients had a switch of the second regimen, with toxicity being the most common reason (n = 142) (Tables 1 and 3). Table 3 summarizes the incidence of the different reasons for switching second-line HAART, as well as the detectability of HIV-1 RNA (below or above 500 copies/ml) at the end of follow-up. The 1-year cumulative incidence of toxicity-driven switch on second-line HAART was 24% (95% CI, 21–28). The overall 1-year cumulative incidence of switching a second-line HAART regimen was 53%, indicating that approximately half of the switches was attributable to toxicity. Switching treatment for toxicity usually did not coincide with virological failure.
In a subgroup analysis among patients who had switched the first HAART regimen because of toxicity (n = 270), 77 (representing more than 10% of the current study cohort) subsequently had another toxicity-driven switch. The 1-year cumulative incidence of such subsequent toxicity-driven switches was 37% (95% CI, 30–44), indicating a higher risk of switching for toxicity for patients who had previously changed treatment likewise as a result of toxicity compared with patients who had not (Fig. 1).
Factors associated with toxicity-driven switches of the second HAART regimen
After univariate analysis and stepwise multivariate analysis, four factors were identified that were associated with toxicity-driven switching of second-line HAART (Table 4). First, there was a risk reduction over calendar time. Second, women appeared to have a higher risk of toxicity-driven switches than men. Similarly, patients who switched the first HAART regimen because of toxicity had a 2.5-fold increased risk (95% CI, 1.7–3.5), relative to patients who switched because of other reasons, for toxicity-driven switch of the second regimen. Finally, among the various types of switch, switching from PI to nevirapine without changing the NRTI appeared to be protective against a subsequent switch for toxicity reasons (adjusted RR, 0.2; 95% CI, 0.1–0.6). Conversely, switching from PI to nevirapine with a concomitant change of NRTI was not favorable. Within the subgroup of patients who previously switched first HAART because of toxicity (Table 4, column 3), switching to nevirapine without changing the NRTI was equally favorable, whereas switching to nevirapine and concomitantly changing NRTI tended to increase the risk.
Body mass index and lean body mass as well as other baseline characteristics, such as nationality, route of HIV transmission, antiretroviral treatment experience prior to first HAART and duration of first HAART, did not significantly influence the incidence of toxicity-driven switch on the second regimen (data not shown). Stratification by hospital, in order to explore whether results may have been influenced by being under the care of a specific treatment centre, did not alter the conclusions (data not shown).
Types of toxicity leading to toxicity-driven switches
Table 5 summarizes the different types of clinical toxicity that were specified as the reason(s) for switching treatment. No significant difference in the distribution of toxicities was observed between initial and subsequent HAART regimens. For both the first and second regimen, the most common types of toxicity resulting in a treatment switch were gastrointestinal events and peripheral neuropathy.
After having switched the first HAART because of gastrointestinal toxicity (n = 100), the 1-year risk of a recurrent toxicity-driven switch because of gastrointestinal toxicity was 26% (95% CI, 15–37), representing a 5.1-fold (95% CI, 2.1–12.1) increased risk relative to patients who switched the first HAART because of other toxicity reasons (n = 170). Out of 100 patients who switched the first HAART for reasons of gastrointestinal toxicity, 22 patients switched to nevirapine without changing NRTI. Only one of those had a recurrent switch because of gastrointestinal toxicity on the second regimen, suggesting a general improvement of gastrointestinal toxicity among patients who switched to nevirapine.
After having switched the first HAART because of neuropathy, the 1-year risk of another toxicity-driven switch because of neuropathy on the second regimen was 21% (95% CI, 5–37), yielding a RR of 12.8 (95% CI, 3.2–51.3) compared with patients who switched the first regimen because of other toxicity reasons. The small number of patients did not allow a distinction between the type of switch regarding the risk of neuropathy-driven switches on the second regimen.
Differentiating between those who concomitantly changed NRTI during the first switch and those who did not resulted in RR values for a recurrent switch because of neuropathy on the second regimen of 8.2 (95% CI, 1.5–45.1) and 19.2 (95% CI, 1.7–212.7) for these two groups of patients, respectively. These results suggest that changing the NRTI along with PI can reduce the risk of a neuropathy-driven switch. The fact that recovery from neuropathy is a time-consuming process might explain that the increased relative risk did not disappear.
In this cohort study, more than half of the patients who switched initial treatment for reasons other than virological failure again switched treatment within 1 year. Toxicity accounted for approximately half of these second switches and mostly involved gastrointestinal events and peripheral neuropathy. In line with previous reports, patients who switched a first HAART regimen for reasons of toxicity had a greater than twofold increased risk of a subsequent switch because of toxicity . This implies that a subgroup of patients may exist, including at least 10% of all patients, who are particularly prone to the development of HAART-associated toxicity. There was a slight reduction in risk of toxicity-driven switch over calendar time, which may reflect improved toxicity management as the experience of a physician evolves.
The proportion of toxicity-driven switches has previously been reported to be high for both first-line (26% within 1 year) [5,6] and second-line PI-containing HAART regimens (33% during a median of 483 days) . These findings, however, were based on the first regimen only and a relatively small single-centre patient population respectively. In a much larger and multicentre patient sample, we observed a 24% 1-year cumulative incidence of switching second-line regimens for toxicity. This figure may be slightly higher than for the entire population on second-line HAART, given that patients were selected who had a prior switch of treatment in the absence of virological failure and, therefore, may have been at potentially higher risk of a subsequent toxicity-driven switch. However, selecting such a population allowed us to investigate various types of switch, including switches between classes of antiretroviral drug, without the choice of subsequent regimens being influenced to any important extent by concerns of antiviral potency and cross-resistance between drugs.
An interesting observation was that switching to nevirapine, without concomitantly switching the NRTI, was associated with a fivefold lower risk of a subsequent toxicity-driven switch. The favourable effect of switching to nevirapine has been described before, albeit in small series of patients with a limited follow-up or a limited reference group [20–23]. Unfortunately, we were not able to study the effect of switching to other non-nucleoside analogue reverse transcriptase inhibitors, such as efavirenz and delavirdine, since these drugs were not licensed in the Netherlands during the period covered by the current analysis. Remarkably, combining the switch to nevirapine with a change in concomitant NRTI annihilated the advantageous effect of switching to nevirapine, possibly indicating the additional toxicity of the newly introduced NRTI. None of the other types of switch, including switching between different PI and changing NRTI at the same time, significantly influenced the risk of a subsequent toxicity-driven switch.
No associations were found between lean body mass or body mass index and the incidence of treatment switch for toxicity, suggesting little influence of distribution volume on toxicity risk for any of the drugs. Toxicity-driven switches occurred independently of patient nationality, which might suggest that cultural differences do not play a major role, but this association needs further substantiation. Women seemed to be more susceptible to toxicity. This may be attributable to sex-dependent pharmacokinetics or adherence leading to higher plasma concentrations of PI in particular . Alternatively, women may be more sensitive to toxicity or report toxicity more easily than men, resulting in a reporting bias.
Since this was an observational cohort study, results may have been confounded. For example, as guidelines for switching primarily focus on virological failure rather than toxicity [12,17,25], the decision to switch and how to switch was dependent of the treating physicians. They were also asked to indicate the primary reason for switching. As a consequence, the observed effects for the type of switch might in fact have been confounded by physician's preference. However, stratification by hospital did not alter the results, which to some extent reduces the likelihood of physician confounding. As we were able to adjust for the potential confounding effects of other determinants for toxicity-driven switches, the effect of residual confounding is assumed to be minimal.
In conclusion, toxicity continues to be a cause of major concern in the treatment of HIV-1 infection. It was deemed responsible for the majority of recurrent treatment switches among patients who had initially switched first-line HAART while having reasonable virus suppression, particularly among patients who had also switched their first-line HAART for toxicity. Switching to nevirapine rather than to an alternative PI, without concomitantly switching the NRTI, was associated with a significantly lower risk of again having to switch the new regimen for toxicity, even in patients with prior toxicity. These findings may provide guidelines for how to minimize the risk of renewed toxicity when managing patients with toxicity during PI-based HAART.
The authors thank the patients, physicians, nurses and data collectors participating in the ATHENA project and the ATHENA project team for their contribution to this study. We are grateful for the critical comments from the ATHENA Toxicity Working Group.
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Clinical and Epidemiological Working Group (*site coordinating physicians): W. Bronsveld, Medical Centre-Alkmaar; H. Weigel*, K. Brinkman and P. Frissen, Onze Lieve Vrouwe Gasthuis; J. ten Veen*, M. Hillebrand and S. Schieveld, Onze Lieve Vrouwe Gasthuis-Location Prinsengracht; J. Mulder*, E. van Gorp and P. Meenhorst, Slotervaart Hospital; A. van Eeden, J. van Goyen Kliniek; S. Danner*, F. Claessen* and R. Perenboom, Academic Hospital Vrije University; J. K. Eeftinck Schattenkerk, E. Gisolf, M. Godfried, J. van der Meer, J. Nellen, D. Notermans, K. Pogany, T. van der Poll, M. van Praag, J. Prins, P. Reiss, M. Reijers, Th. Ruys, M. van der Valk, A. Verbon and F. Wit, Academic Medical Centre, Amsterdam; C. Richter* and R. van Leusen Hospital Rijnstate, Arnhem; R. Vriesendorp, Westeinde Hospital, The Hague; R. Kauffmann* and E. Kogger, Hospital Leyenburg, The Hague; B. Bravenboer, Catharina Hospital, Eindhoven; C. ten Napel*, Medisch Spectrum Twente-Enschede; H. Sprenger* and G. Law, University Hospital, Groningen; R. W. ten Kate, Kennemer Gasthuis, Haarlem; M. Leemhuis, Medical Centre, Leeuwarden; F. Kroon* and E. Schippers, Leiden University Medical Centre; G. Schrey*, S. van der Geest and A. van der Ven, University Hospital, Maastricht; P. Koopmans*, M. Keuter and D. Telgt, University Hospital, Nijmegen; M. van der Ende*, I. Gyssens and S. de Marie, Erasmus University Medical Centre, Rotterdam; J. Juttmann* and C. van der Heul, St Elisabeth Hospital, Tilburg; M. Schneider*, J. Borleffs, I. Hoepelman and C. Jaspers, University Medical Centre, Utrecht; W. Blok, Hospital Walcheren,Vlissingen.
Subworking groups (*chair). Working Group on Cost-effectiveness: J. Tijssen*, G. Bonsel, M. Dijkgraaf and S. Heisterkamp, Academic Medical Centre, Amsterdam; Clinical Working Group: J. Lange*, M. Jambroes and G. J. Weverling, Academic Medical Centre, Amsterdam; Dutch HIV Patient Association: M. Mulder; Toxicity Working Group: J. Dieleman and I. Gyssens, Erasmus University Medical Centre, Rotterdam; K. Brinkman, Onze Lieve Vrouwe Gasthuis; P. Koopmans and H. ter Hoffstede, University Hospital, Nijmegen; P. Reiss*, G. J. Weverling and M. Jambroes, Academic Medical Centre, Amsterdam; Medical Psychology Working Group: M. Sprangers* and P. Nieuwkerk, Academic Medical Centre, Amsterdam; Pharmacology Working Group: D. Burger*, R. Aarnoutse and P. Hugen, University Hospital, Nijmegen; R. Hoetelmans*, R. van Heeswijk and A. Veldkamp, Slotervaart Hospital,Amsterdam; Virological Working Group: P. Rietra and K. Roozendaal, Onze Lieve Vrouwe Gasthuis; W. Pauw and A. van Zanten, Slotervaart Hospital; B. von Blomberg and P. Savelkoul, Academic Hospital Vrije University; F. de Wolf*, J. Goudsmit, L. van der Hoek and S. Jurriaans, Academic Medical Centre, Amsterdam; L. Nohlmans, Hospital Rijnstate, Arnhem; C. Jansen, Westeinde Hospital, The Hague; P. Franck and A. Lampe, Hospital Leyenburg, The Hague; E. Boel and A. Janz, Catharina Hospital, Eindhoven; R. Hendriks, Regional laboratory Twente, Enschede; J. Schirm, Regional laboratory, Groningen; H. Storm, Medical Centre, Leeuwarden; D. Veenendaal, LVF, Leeuwarden; A. Kroes*, Leiden University Medical Centre; C. Bruggeman and V. Goossens, University Hospital, Maastricht; J. Galama, University Hospital, Nijmegen; A. Osterhaus* and H. Niesters, Erasmus University Medical Centre, Rotterdam; A. Buiting, St Elisabeth Hospital, Tilburg; C. Boucher*, N. Back and R. Schuurman, University Medical Centre, Utrecht.
Steering Committee (*chair): J. Ruitenberg*, C. Boucher, D. Burger, S. Danner, R. Hoetelmans, R. W. ten Kate, R. Kauffmann, F. Kroes, J. Lange, A. Osterhaus, J. Tijssen and F. de Wolf.
Coordinating Centre: J. Lange, J. Tijssen, F. de Wolf (project leaders); M. Jambroes, E. van der Ven (project coordination); S. Brouwer, M. Overveld, R. van Boxtel (clinical research associates).
Data collection assistants: R. Runia and N. Wijdenes, Medical Centre, Alkmaar; N. Troost and R. Regez, Onze Lieve Vrouwe Gasthuis; M. Beerepoot, Onze Lieve Vrouwe Gasthuis-Location Prinsengracht; E. Oudmaijer, Slotervaart Hospital; J. Troon, Jan v. Goyen Kliniek; A. van Diggelen, Academic Hospital Vrije University; J. Ruijs and L. Veenenberg, Academic Medical Centre, Amsterdam; N. Langebeek, Hospital Rijnstate, Arnhem; M. Groot and S. Wildebeest, Westeinde Hospital, The Hague; A. de Haas, Hospital Leyenburg, The Hague; W. van Schaik and N. Slegers, Catharina Hospital, Eindhoven; H. Heins and T. Lansink, Medisch Spectrum Twente, Enschede; A. Bakker and S. Moolenburgh, University Hospital, Groningen; E. Kloosterhuis and M. Schoemaker, Kennemer Gasthuis, Haarlem; J. de Groot and A. Ketser, Medical Centre, Leeuwarden; W. Dorama, Leiden University Medical Centre; Ch. Leenders, University Hospital, Maastricht; M. Meeuwissen and B. Zomer, University Hospital, Nijmegen; T. Royaards, Erasmus University Medical Centre, Rotterdam; R. Santegoets and B. van der Ven, St Elisabeth Hospital, Tilburg; F. Bär, University Medical Centre, Utrecht; S. Baas and C. Ruissen, Hospital Walcheren, Vlissingen. Cited Here...
HAART; toxicity; treatment switch; cumulative incidences; risk factors; highly active antiretroviral therapy
© 2002 Lippincott Williams & Wilkins, Inc.
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