To the Editor:
The optimal timing of highly active antiretroviral therapy (HAART) initiation for chronic HIV-1 infection is an issue of ongoing debate. Observational studies have shown an increased risk of mortality when HAART is initiated in patients with CD4 cell counts less than 200/μL compared with initiation at higher levels.1,2 At which CD4 cell count greater than 200/μL therapy should be initiated remains unclear, however, because evidence is inconsistent.1-4 Arguments in favor of initiating HAART earlier in the course of HIV infection comprise preservation of immune function, earlier control of viral replication, and prolongation of disease-free survival. In previous years, increased recognition of long-term adverse effects of HAART and difficulties with adherence to therapy have outweighed arguments in favor of extremely early treatment.
The timing of HAART initiation may also influence patients' quality of life (QoL). Previous studies have shown a positive effect of HAART on patients' QoL because of the delay of disease progression.5 At the same time, HAART can have a negative effect on patients' QoL because of the toxicities and inconveniences associated with most regimens.6 The extent to which these potential negative effects of HAART on QoL are outweighed by positive effects may depend on the timing of HAART initiation. Our objective was to investigate patients' QoL after starting HAART at different CD4 cell counts.
Between May 1998 and December 2000, consecutive adult HIV-1-infected patients from 22 hospitals in The Netherlands who were starting or already receiving HAART were enrolled in an observational cohort study called the ATHENA project.7 In a subset from the entire ATHENA population, the ATHENA 600 group, questionnaires on QoL were administered to patients with sufficient literacy to complete Dutch or English self-report questionnaires. Questionnaires were completed at inclusion in the ATHENA project and every 6 months thereafter until December 2000. After receiving additional funding, the data collection on QoL was restarted between April 2002 and November 2003 and ended in June 2005. For the present report, we selected patients who commenced HAART after enrollment in the ATHENA project and who completed a QoL questionnaire at the start of HAART and at least 1 questionnaire thereafter. The study was approved by the institutional review boards of all participating centers. All patients gave written informed consent.
QoL was assessed by the Medical Outcomes Study Health Survey for HIV (MOS-HIV), a widely used 35-item questionnaire of QoL in HIV/AIDS with established reliability and validity.8 Responses to items of the MOS-HIV can be aggregated into physical and mental health summary scores. Summary scores are transformed to a standard score with a mean of 50 and an SD of 10, with higher scores indicating better QoL.9
Patients were categorized into those starting HAART with <200 CD4 cells/μL, 201 to 350 CD4 cells/μL, and >350 CD4 cells/μL. We investigated whether there was a different pattern of change over time in physical and mental health among the 3 groups using mixed linear models, more specifically, growth curve models with random intercepts and slopes. P values <0.05 were considered to indicate statistical significance. Data analysis was conducted using the SPSS Software Package for Windows, version 12 (SPSS, Chicago, IL).
A total of 265 of 566 patients enrolled in the ATHENA 600 group as of December 2000 started HAART after enrollment in the ATHENA project. A total of 239 (90%) of these 265 patients completed a QoL questionnaire at the start of HAART and at least 1 questionnaire thereafter. These 239 patients completed a total of 1439 questionnaires (average of 6 per patient).
The number of patients starting HAART with <200 CD4 cells/μL, 201 to 350 CD4 cells/μL, and >350 CD4 cells/μL was 106, 65, and 68, respectively. The median (interquartile range [IQR]) CD4 count at the start of HAART in the 3 groups was 70 (20 to 140), 271 (230 to 320), and 450 (390 to 635) cells/μL, respectively. The median (IQR) plasma HIV RNA load at the start of HAART in the 3 groups was 5.2 (4.8 to 5.5), 5.0 (4.5 to 5.3), and 4.8 (4.4 to 5.0) log10 copies/mL, respectively. The percentage of male subjects in the 3 groups was 96%, 88%, and 93%, respectively. The mean (SD) age in the 3 groups was 39.4 (7.7), 40.3 (10.2), and 40.4 (8.4) years, respectively. The median (IQR) duration of follow-up in the QoL study in the 3 groups was 4.2 (2.1 to 5.3), 4.4 (1.9 to 5.4), and 4.8 (4.0 to 5.6) years, respectively.
Patients who started HAART with <200 CD4 cells/μL had significantly worse baseline physical health than patients who started HAART with 201 to 350 cells/μL or with >350 CD4 cells/μL (Fig. 1A). We found a statistically significant different pattern of change over time in physical health among the 3 groups. Patients who started HAART with <200 CD4 cells/μL had significantly more improvement in their physical health than patients who started HAART with 201 to 350 CD4 cells/μL or with >350 CD4 cells/μL (P = 0.001 for group by time interaction 200 vs. 201 to 350 CD4 cells/μL; P = 0.002 for group by time interaction 200 vs. >350 CD4 cells/μL). We found no difference in change over time in physical health between patients who started HAART with 201 to 350 CD4 cells/μL versus with >350 CD4 cells/μL (P = 0.85 for group by time interaction 201 to 350 vs. >350 CD4 cells/μL). There was no different pattern of change in mental health among the 3 groups, with mental health significantly improving over time (P = 0.013 for time effect) irrespective of CD4 cell count at the start of HAART (see Fig. 1B). Adjustment for baseline plasma HIV RNA concentration, age, gender, and calendar year of HAART initiation did not significantly affect the comparison of QoL among the 3 groups (data not shown).
In conclusion, QoL improved more among patients who started HAART with <200 CD4 cells/μL than among those with >200 CD4 cells/μL. We found no difference in the impact of HAART on QoL between patients who started HAART with 201 to 350 CD4 cells/μL versus those who started HAART with >350 CD4 cells/μL. Although QoL should be taken into account when deciding about HAART initiation in the individual patient,10 it is not likely to be a decisive factor on a group level among patients with >200 CD4 cells/μL.
The authors thank the participants in this study. This study was supported by grant 6003 from the AIDS Fund, Amsterdam, The Netherlands.
Pythia T Nieuwkerk, PhD*
Milly E. Hillebrand-Haverkort, MD, PhD†
Robert Vriesendorp, MD, PhD‡
P. H. Jos Frissen, MD, PhD§
Frank de Wolf, MD, PhD*∥
Mirjam A. G. Sprangers, PhD*
for the ATHENA Study Group
*Academic Medical Center University of Amsterdam Amsterdam, The Netherlands
†Medisch Centrum Alkmaar Alkmaar, The Netherlands
‡Medisch Centrum Haaglanden Den Haag, The Netherlands
§Onze Lieve Vrouwe Gasthuis Amsterdam, The Netherlands
∥HIV Monitoring Foundation Amsterdam, The Netherlands
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