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Use of Efavirenz Is Not Associated with a Higher Risk of Depressive Disorders: A Substudy of the Randomized Clinical Trial ALIZE-ANRS 099

  1. Valérie Journot1,
  2. Geneviève Chêne1,
  3. Nathalie De Castro2,3,
  4. Corinne Rancinan1,
  5. Jill-Patrice Cassuto5,
  6. Christian Allard6,
  7. Jean-Louis Vildé4,
  8. Alain Sobel7,
  9. Michel Garré8,
  10. Jean-Michel Molina3,3, and
  11. ALIZE Study Group
  1. 1INSERM, U593, Bordeaux
  2. 2Assistance Publique—Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Department of Infectious Diseases, and Université Paris 7, Paris
  3. 3Faculté de Medécine, Department of Infectious and Tropical Diseases, Paris
  4. 4Faculté Xavier Bichat, Department of Infectious and Tropical Diseases, Paris
  5. 5Centre Hospitalier Universitaire de Nice, Hôpital de l'Archet 1, Department of Hematology, Nice
  6. 6Centre Hospitalier Général de Meaux, Department of Hematology, Meaux
  7. 7AP-HP, Hôpital Henri Mondor, Department of Clinical Immunology, Créteil
  8. 8Hôpital de la Cavale Blanche, Department of Infectious and Tropical Diseases, Brest, France
  1. Reprints or correspondence: Dr. Valérie Journot, INSERM U593—Case 11, 146, Rue Léo Saignat, 33076 Bordeaux Cedex, France (Valerie.Journot{at}bordeaux.inserm.fr).
 
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Abstract

Background. Efavirenz (EFV) is a highly active antiretroviral drug, use of which is associated with frequent (although transient) neurosensorial adverse reactions. Whether the use of EFV is associated with the risk of depression or suicide remains controversial.

Methods. ALIZE-ANRS (Agence Nationale de Recherches sur le SIDA et les Hépatites Virales) 099 was a 48-week randomized trial involving virologically suppressed, human immunodeficiency virus (HIV)—infected patients that compared the maintenance of a treatment regimen that contained protease inhibitors (177 subjects) with a switch to a once-daily combination of EFV, didanosine, and emtricitabine (178 subjects). We used the trial's adverse events reporting system and a self-administered Center for Epidemiologic Studies—Depression Scale questionnaire to assess depressive disorders. Determinants were studied using a multivariate proportional hazards model adjusted for antiretroviral treatment, sex, age, HIV risk factor, history of depression, hepatic disorder, alcohol abuse, and HIV-related or non—HIV-related events.

Results. Thirty cases of depressive disorder (26 cases of depression and 4 suicide attempts) occurred during treatment in 27 patients (12 patients [7%] and 15 patients [8%] in the protease inhibitor—based and EFV-based treatment arms, respectively; P = .56). In the proportional hazards model, only age (hazard ratio, 1.6 per 10 years younger; 95% confidence interval, 1.0–2.6) and a history of depressive disorder (hazard ratio, 5.0; 95% confidence interval, 2.1–12.0) were associated with a risk of depressive disorders. The proportion of depressive patients (24%), as determined on the basis of the Center for Epidemiologic Studies—Depression Scale data, was stable during the follow-up period, without difference between treatment groups. Patients with a history of depressive disorder were more frequently depressed (53%) than were those without such history (22%; P = .03).

Conclusions. The frequency of depressive disorders was high in this population, but the disorders were not related to EFV treatment. Younger age and a history of depression are important determinants for depression and should be considered for early detection and case management.

Efavirenz (EFV), a potent nonnucleoside reverse-transcriptase inhibitor with a long plasma half-life allowing convenient once-daily intake, has proved a highly active and well-tolerated component in many combination antiretroviral therapies [1]. It is well tolerated overall, although frequent CNS adverse reactions, mostly early and transient, are reported in clinical trials and clinical practice, and could lead to treatment discontinuation [2–4]. Rare acute depression and suicide ideations or attempts are also reported, more frequently among patients with a history of depression [2].

EFV is now widely used, but its association with depression or suicide remains controversial. Some studies have indicated a high prevalence of depressive disorders associated with EFV treatment and have warned about such effects [5–7], whereas other studies have concluded that there is no association between EFV use and depressive disorders [4, 8–10]. We took advantage of the experimental design of a large, controlled trial comparing the maintenance of a regimen that contains a protease inhibitor (PI) with a switch to a once-daily combination of EFV, didanosine, and emtricitabine, to determine whether EFV use is associated with a higher incidence of depressive disorders, compared with PI-containing regimens.

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Methods

Study design. The ALIZE-ANRS (Agence Nationale de Recherches sur le SIDA et les Hépatites Virales) 099 trial design is presented in detail elsewhere [11]. In brief, ALIZE-ANRS 099 was a 48-week, multicenter, randomized, open-label trial comparing the maintenance of a stable PI-containing regimen (hereafter, the “PI-based group”; 177 subjects) with a switch to a once-daily regimen of EFV, didanosine, and emtricitabine (hereafter, the “EFV-based group”; 178 subjects) in patients with controlled HIV infection.

HIV-1—infected adults were eligible for the study if they had received a combination antiretroviral therapy that had been unchanged for at least 6 months consisting of at least 1 PI plus 2 nucleoside analogues, if they had a CD4+ cell count of ⩾100 cells/mm3 and a plasma HIV-1 RNA level of <400 copies/mL for at least 6 months, and if they had never received nonnucleoside reverse-transcriptase inhibitors. A history of depressive disorder was not an exclusion criterion.

Individual clinical history was collected from patients at the time of trial entry. Patients underwent clinical and laboratory evaluations at the screening visit, at the baseline visit, at weeks 4 and 8, and then every 8 weeks thereafter up to week 48. We actively searched for errors and missing data of any type during monitoring visits on site. The trial's primary outcome was the proportion of patients with virologic success, defined as a plasma HIV-1 RNA level <400 copies/mL from baseline to week 48, with any missing HIV-1 RNA levels being considered ⩾400 copies/mL. At week 48, follow-up was extended to month 36, and patients in the EFV-based group continued to receive the same regimen, whereas willing patients in the PI-based group were switched to the EFV-based regimen.

Outcomes. Data on adverse events of any type and any severity were prospectively collected during the follow-up period, and events were coded using the MedDRA dictionary, version 3.0 [12, 13]. Types of depression were selected using the following MedDRA entries: the high level group term “depressed mood disorders and disturbances,” the preferred term “adjustment disorder with depressed mood,” or the preferred term “adjustment disorder with mixed anxiety and depressed mood.” No completed suicide occurred during the trial, so suicide attempts were selected using the following MedDRA entry: high level group term “suicidal and self-injurious behaviors not elsewhere classified.” We scanned the entire list of adverse events to check that this selection rule was exhaustive for our data. We considered any treatment-related or non—treatment-related depression or suicide attempt of any severity to be a depressive disorder. Similarly, hepatic disorders, alcohol abuse, and HIV- or non—HIV-related events were selected through MedDRA from the adverse events table.

The validated French translation of the Center for Epidemiologic Studies—Depression Scale (CES-D) questionnaire was self-administered by patients at weeks 0, 24, and 48 [14]. Patients were asked how frequently during the past week they had experienced moods described in 20 sentences dealing with the main components of depression. The frequency was scored as 0 for “rarely or none of the time” to 3 for “most or all the time.” Patients were regarded as having depressive symptoms when their cumulative CES-D score was ⩾17 for men or ⩾23 for women [14].

With use of the same self-administered questionnaire, patients were asked every 8 weeks after baseline how frequently since their prior visit they had experienced moods expressed by the sentences “I felt depressed” or “I had suicidal ideations.” Frequency scoring was as for CES-D; scores of 1, 2, and 3 were pooled because of the low frequency of scores of 1 and 2.

Finally, we searched the database for data on use of antidepressant medications at baseline or during follow-up. All outcomes were available up to week 48 for both treatment groups and up to month 36 for the EFV-based group.

Statistical analysis. We described the nature and severity of depressive disorders reported before baseline and of those occurring on treatment (i.e., before treatment discontinuation, defined as the first administered dose of EFV in the PI-based group and as permanent discontinuation EFV in the EFV-based group). We estimated the incidence density as the number of depressive disorders that occurred during treatment divided by the cumulative duration of follow-up (in years) during treatment. The probability of a first depressive disorder during treatment was estimated by the Kaplan-Meier product-limit method, and treatment groups were compared with a log rank test.

Determinants of the first depressive disorder on treatment were studied using a proportional hazards model. Covariates of interest were sex, baseline age, HIV risk factor, history of depressive disorder, history of or time-dependent hepatic disorder (because the liver is the main metabolic pathway of EFV), history of or time-dependent alcohol abuse, history of or time-dependent HIV- or non—HIV-related events other than depressive disorders (as an approximation of stressful life events), treatment group, and history of any antiretroviral treatment (nature and cumulative duration, before baseline or during follow-up). Covariate selection consisted of univariate selection at a 25% significance level, followed by multivariate backward selection at a 5% significance level. As sensitivity analysis, we also conducted an intent-to-treat analysis, using all available data up to week 48 (i.e., even after treatment discontinuation).

The proportion of patients with depressive symptoms, as determined on the basis of CES-D data, the proportion of patients having experienced depressive feelings or suicide ideations since the prior visit, and the proportion of patients taking at least 1 antidepressant medication during follow-up were reported on treatment, and treatment groups were compared using a χ2 test. Statistical tests were 2-tailed, with a 5% significance level. SAS software, version 8.2 (SAS Institute), was used for all calculations and statistical analyses.

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Results

Characteristics of patients and follow-up. As reported elsewhere [11], treatment groups did not differ according to sex, age, or any HIV-related characteristics (table 1). The proportion of patients who were taking antidepressant medication at the time of study entry was similar in both treatment groups (5%). A history of depressive disorders, mostly depression, was reported in 9% of patients; the proportion was similar in both treatment groups (table 1).

Figure 1
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Figure 1

Probability of first depressive disorder on treatment, estimated using the Kaplan-Meier product-limit method, according to treatment group (top) and history of depressive disorder (bottom). Data are from the ALIZE-ANRS 099 trial. EFV, efavirenz; PI, protease inhibitor.

Figure 2
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Figure 2

Proportion of patients reporting depression symptoms, as defined using the Center for Epidemiologic Studies—Depression Scale score, during follow-up, according to treatment group (top) and history of depressive disorder (bottom). Data are from the ALIZE-ANRS 099 trial. EFV, efavirenz; PI, protease inhibitor.

Table 1
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Table 1

Baseline characteristics and dispositions at week 48 for patients, depending on treatment group, from the ALIZE-ANRS 099 trial.

Virologic success was achieved in 89% of patients, and the rate was similar for both regimens [11]. Ninety percent of patients continued on treatment up to week 48 (95% and 85% in the PI-based and EFV-based groups, respectively; P = .002). This difference was mostly explained by early CNS adverse reactions to EFV, leading to treatment discontinuation in the EFV-based group (table 1). One suicide attempt occurred at time of treatment discontinuation in the PI-based group, but this was not considered to be related to combination antiretroviral therapy. No depressive disorder led to treatment discontinuation. The cumulative duration on treatment was 90% of what was expected from the protocol.

Depressive disorders. Altogether, 30 cases of depressive disorder, including 26 incidents of depression and 4 suicide attempts, occurred among 27 patients (12 patients [7%] and 15 patients [8%] in the PI-based and EFV-based groups, respectively; P = .56) (table 2). The severity of these disorders was mild for 6 events, moderate for 17, severe for 5 (4 in the PI-based group and 1 in the EFV-based group), and life-threatening for 2 (1 in each treatment group). Five events led to hospitalization (3 in the PI-based and 2 in the EFV-based group).

Table 2
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Table 2

Description of depressive disorders on treatment, according to treatment group, in the ALIZE-ANRS 099 trial.

The overall incidence density of depressive disorder (table 2) was 10 cases per 100 patient-years (95% CI, 6–13 cases per 100 patient-years) up to week 48. The incidence density was similar in both treatment groups (9 cases per 100 patient-years [95% CI, 4–13] and 11 cases per 100 patient-years [95% CI, 5–16] in the PI-based and EFV-based groups, respectively), but it was higher among patients with a history of depressive disorder (29 cases per 100 patient-years; 95% CI, 9–50) than among those without such a history (8 cases per 100 patient-years; 95% CI, 4–11). Likewise, there was no significant difference between treatment groups (P = .47) with regard to the probability of a first depressive disorder occurring on treatment (figure 1), but this probability was significantly higher for patients with a history of depressive disorder than for those without such a history (P < 10-3). Interestingly, in the EFV-based group, the probability of a first depressive disorder increased by 9% (95% CI, 5%–14%) during the first year of treatment (i.e., from baseline up to week 48) and by only 4% (95% CI, 8%–18%) during the 2 subsequent years (i.e., from week 48 to month 36). A total of 114 patients (64%) were still at risk at month 36.

In the univariate step of the proportional hazards model, different transformations of covariates were compared, and those with the lowest P values are shown in table 3. Treatment group was not selected but was forced into the model. In the final multivariate model of the determinants of depressive disorders (table 3), only baseline age (hazard ratio [HR] per 10 years younger, 1.61; 95% CI, 1.04–2.50; P = .03) and a history of depressive disorder (HR, 4.97; 95% CI, 2.05–12.02; P = .0004) remained significant. The intent-to-treat analysis of all data available up to week 48 yielded similar results (data not shown).

Table 3
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Table 3

Determinants of depressive disorders on treatment, selected by a multivariate proportional hazards model with backward selection, from the ALIZE-ANRS 099 trial.

Depression evaluated by the self-administered questionnaire. The rate of missing data for the self-administered questionnaire (i.e., CES-D and the 2 additional questions) was high at baseline (33%–36%, depending on the question) (table 2) and did not differ on the basis of any patient characteristic. This rate increased by ∼10% between baseline and week 48 in the PI-based group, whereas it remained unchanged in the EFV-based group.

The proportion of patients with depressive symptoms, as determined on the basis of the CES-D findings, was close to 24% at baseline, remaining stable during follow-up (figure 2). The proportion was similar in both treatment groups (25% and 24% at week 48 in the PI-based and EFV-based groups, respectively; P = .65). However, patients with a history of depressive disorder experienced depressive symptoms more frequently than did those without such a history (53% and 22% at week 48, respectively; P = .03).

At baseline, 38% of patients declared having experienced depressive feelings since the prior visit in both treatment groups alike (P = .49). These proportions were stable during follow-up in both groups (41% in the PI-based group and 31% in the EFV-based group at week 48; P = .12). Patients with a history of depressive disorder felt depressed more frequently than did those without such a history, although the difference was not significant (48% and 34% at week 48, respectively; P = .22).

At baseline, 21% of patients declared having experienced suicide ideations since the prior visit, with a trend towards a higher proportion of subjects in the EFV-based group (P = .08). These proportions were stable during follow-up in both groups (22% and 24% at week 48, respectively; P = .84), but patients with a history of depressive disorder experienced suicide ideations more frequently than did those without such a history (48% and 20% at week 48, respectively; P = .005).

The proportions of patients with depressive symptoms (according to the CES-D findings) and of patients having experienced depressive feelings or suicide ideations since the prior visit remained unchanged during follow-up in both treatment groups and in patients with versus without a history of depressive disorder. In the EFV-based group, these proportions were stable up to month 36.

Antidepressant medications. Various antidepressant therapies were initiated during follow-up for 7 patients (4%) in the PI-based group and 12 patients (7%) in the EFV-based group (P = .27).

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Discussion

In this prospective, randomized trial involving virologically suppressed, HIV-infected adults with high CD4+ cell counts and undetectable plasma HIV-1 RNA levels who either continued to receive a PI-containing regimen or switched to an EFV-containing regimen for 48 weeks, we found a high incidence density of depressive disorders (10 cases per 100 patient-years). This result was confirmed by the high rates of patients with depressive symptoms determined using the CES-D questionnaire (24%) or the additional questions (39% for depressive feelings and 24% for suicide ideations). In the general population, the lifetime prevalence of depressive disorders ranges from 1% to 6% for suicide attempts [15] and from 2% to 20% for major depression [16–18]. However, depression is approximately twice as common among HIV-infected patients than it is among the general population [19, 20], and even if its prevalence seems to decrease while patients receive combination antiretroviral therapy, it remains high (14%–46%) [21–24] and is related to a higher risk of progression to AIDS and death [25–27].

As was expected, a history of depressive disorders was significantly associated with a higher occurrence of depression or attempted suicide in our population. It is a well-known risk factor for renewed onset of depression [17]: in addition to related genetic, environmental, and psychological factors, depression seems to inhibit neurogenesis in the hippocampus, which may induce its new onset [28, 29].

Younger age was also associated, although less strongly, with an increased incidence of depressive disorders. Our patients' ages ranged from 18 to 76 years, with a 10%–90% range of 32–56 years. A higher risk level for patients in their thirties is consistent with the literature [17] and is, perhaps, the consequence of a less settled way of life in this population of younger HIV-infected patients.

We found that the switch to an EFV-containing regimen did not affect the risk of depression or suicide attempt among patients with or without a history of depressive disorder and during the first 48 weeks of the study or the 36-month extended follow-up period in the EFV-based group. Rates of depressive patients, as determined on the basis of CES-D findings or the additional questions, were also higher among patients with a history of depressive disorder, but there was no difference in these rates between treatment groups (figure 2). Although noncomparative studies have indicated a high prevalence of depressive disorders during EFV therapy and have delivered warning messages about its use [5–7], comparative studies that use a non-EFV reference group, randomized or not, have showed no effect of EFV therapy on depressive disorders or symptoms [4, 9, 10]. A substudy of a randomized trial of 303 HIV-infected patients without a history of depression evaluated neuropsychological performance and symptoms and showed that there was no difference in CES-D scores between patients receiving EFV and those who were not [10]. In another study, which involved 400 HIV-infected psychiatric patients who were receiving EFV, no serious EFV-related adverse reactions were reported, and there were not many discontinuations of EFV treatment related to psychiatric adverse reactions (6%) [30].

In the univariate model, time-dependent hepatic disorders, HIV- or non—HIV-related events, and didanosine intake were associated with a higher risk of depressive disorders. However, none of these factors remained significant in the adjusted multivariate analysis. Although HIV- and non—HIV-related events may be a marker of stressful life events, we have no explanation for the role of hepatic disorders or didanosine use that should be reassessed in new studies.

However, our study had some limitations. First, there was no specific form used to collect data on depressive disorders. Nevertheless, patients' record files were intensively searched during on-site monitoring visits, so major undernotification of adverse events is unlikely. Secondly, the trial was an open-label study, and physicians may have been driven to overnotification by the current belief that EFV use induces depression. This potential bias did not, however, produce a significant effect. Third, the on-treatment analysis strategy may have induced selection bias if treatment had been interrupted because of depressive disorders. However, treatment discontinuation did not occur frequently and was not related to depressive disorders, and the on-treatment and the intent-to-treat analyses yielded identical results. Such selection bias is therefore not very likely. Moreover, the trial sample size was calculated on the basis of a virologic success criterion and may have been insufficient for secondary analysis of depressive disorders. However, the difference in product-limit proportion of depressive disorders between treatment groups was very small (<3% at week 48) and not clinically relevant. For a more clinically relevant difference (for instance, 10% in the PI-based group and 20% in the EFV-based group, which is consistent with the prevalence range found in the literature [19, 20]), the sample size should have been 296 patients instead of 355. Thus, our data set had sufficient power for this comparison. Finally, the rate of missing data for the self-administered questionnaire was high, particularly for the CES-D score. This is often the case in self-administered questionnaires, but we identified no patient characteristic related to the process of formation of missing data.

Our study was not specifically designed to answer the question regarding EFV use and depressive disorders, but it fortunately produced valid results: our study had a non-EFV comparison group, treatment allocation was randomized, the trial size was large enough, and data collection was standardized. Therefore, we believe that our results provide a high degree of evidence that EFV is not associated with an elevated risk of depression.

Contrary to the idea widely held among HIV-infected patients, physicians, and researchers, our data showed no evidence of EFV having an effect on the risk of depression or suicide attempt in the first 48 weeks of use—or even up to 36 months of use. However, a higher risk of these conditions occurred among younger patients and among those with a history of depressive disorder.

Therefore, physicians should consider depression and suicide ideations or attempts with great caution, because recurrence is not rare, and case management should be adapted accordingly. Finally, a history of depressive disorder should not be a contraindication for prescribing EFV treatment.

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Participating Centers In The Alize-Anrs Study

Hôpital Saint-Jacques, Belfort (J.-P. Faller); Hôpital Robert Debre, Reims (G. Remy); Hôpital Lagny-Marne-La-Vallee, Lagny (P. Lagarde); Hôpital Avicenne, Bobigny (M. Bentata and A. Krivitzky); Hôpital Saint-Jacques, Besançon (R. Laurent); Hôpital Jean Minjoz, Besançon (J. L. Dupond); Hôpital Saint-Louis, Paris (J. P. Clauvel, J. M. Decazes, J. M. Molina, E. Oksenhendler, and D. Sereni); Centre Hospitalier d'Annecy, Annecy (J. P. Bru); Hôpital de Bicêtre, Le Kremlin-Bicêtre (J. F. Delfraissy); Hôpital Henri Duffaut, Avignon (G. Lepeu); Centre Hospitalier General, Aix-en-Provence (T. Allegre and A. P. Blanc); Hôpital Chalucet, Toulon (A. Lafeuillade); Hôpital Raymond Poincare, Garches (C. Perronne); Hôpital Necker, Paris (B. Dupont); Hôpital Tenon, Paris (W. Rozenbaum and G. Pialoux); Hôpital Antoine Beclere, Clamart (P. Galanaud); Hôpital Bichat, Paris (J. P. Coulaud, C. Leport, J. L. Vilde, and P. Yeni); Hôpital Foch, Suresnes (O. Bletry); Hôpital Louis Mourier, Colombes (P. Vinceneux); Hôpital Henri-Mondor, Creteil (A. Sobel); Hôpital Pitie-Salpêtriere, Paris (F. Bricaire, S. Herson, and C. Katlama); Hôpital Saint-Antoine, Paris (H. Frottier, P. M. Girard, and M. C. Meyohas); Hôpital Pierre Zobda-Quitman, Fort-de-France (A. Cabie and G. Sobesky); Hôpital de la Cavale Blanche, Brest (M. Garre); Hôpital Saint-Andre, Bordeaux (J. Beylot); Hôpital Pellegrin, Bordeaux (M. Dupon and J. M. Ragnaud); Hôpital Edouard Herriot, Lyon (J. L. Touraine); Hôpital Hôtel-Dieu, Lyon (C. Trepo); Hôpital Sainte-Marguerite, Marseille (J. A. Gastaut); Centre Hospitalier General, Meaux (C. Allard); Hôpital Gui de Chauliac, Montpellier (F. Janbon and J. Reynes); Hôpital de l'Hôtel-Dieu, Nantes (F. Raffi); Hôpital de l'Archet, Nice (J. P. Cassuto and P. Dellamonica); Hôpital Bretonneau, Tours (P. Choutet); Hôpital Purpan, Toulouse (P. Massip); Centre Hospitalo-Universitaire de Caen, Caen (C. Bazin and R. Verdon); Hôpital Hôtel-Dieu, Clermont-Ferrand (J. Beytout); Hôpital du Bocage, Dijon (H. Portier and P. Chavanet); Hôpital Albert Michallon, Grenoble (C. Brambilla and P. Leclercq); Hôpital Gustave Dron, Tourcoing (Y. Mouton); Hôpital de Brabois, Vandoeuvre- Les-Nancy (P. Canton and T. May); Centre Hospitalier de Compiegne, Compiegne (P. Veyssier); Hôpital Fleyriat, Bourg-En-Bresse (P. Granier); Centre Hospitalier Sud Reunion, Saint-Pierre-La-Reunion (C. Arvin-Berod); Hôpital Beaujon, Clichy (B. Fantin); Hôpital Porte Madeleine, Orleans (P. Arsac); Hôpital La Croix-Saint-Simon, Paris (G. Raguin); Fondation Saint-Joseph, Paris (J. Gilquin); Centre Hospitalier de Noyon, Noyon (F. Grihon); and Hôpital Rene Dubos, Pontoise (L. Blum and O. Danne).

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Acknowledgments

Didanosine was provided by Bristol-Myers Squibb, efavirenz was provided by DuPont Pharmaceuticals (now Bristol-Myers Squibb), and emtricitabine was provided by Triangle Pharmaceuticals (now Gilead).

Financial support. The ALIZE-ANRS 099 trial was sponsored by the Agence Nationale de Recherches sur le SIDA et les Hépatites.

Potential conflicts of interest. J.-M.M. has received consulting and lectures fees from Bristol-Myers Squibb. All other authors: no conflicts.

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Footnotes

  • Participating centers are listed at the end of the text.

  • Received December 2, 2005.
  • Accepted February 10, 2006.
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  1. Clin Infect Dis. (2006) 42 (12): 1790-1799. doi: 10.1086/504323
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