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A Randomized Study of Serial Telephone Call Support to Increase Adherence and Thereby Improve Virologic Outcome in Persons Initiating Antiretroviral Therapy

  1. Ann C. Collier1,
  2. Heather Ribaudo2,
  3. A. Lisa Mukherjee2,
  4. Judith Feinberg3,
  5. Margaret A. Fischl4,
  6. Margaret Chesney5,a and
  7. for the Adult AIDS Clinical Trials Group 746 Substudy Teamb
  1. 1University of Washington School of Medicine and Harborview Medical Center, Seattle;
  2. 2Harvard School of Public Health, Boston, Massachusetts;
  3. 3University of Cincinnati, Cincinnati, Ohio;
  4. 4University of Miami, Miami, Florida;
  5. 5University of California at San Francisco, San Francisco
  1. Reprints or correspondence: Ann C. Collier, UW AIDS Clinical Trials Unit, Harborview Medical Center Box 359929, 325 9th Ave., Seattle, WA 98104 (acollier{at}u.washington.edu)
 
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Abstract

BackgroundAdherence to antiretroviral therapy is difficult, and methods to increase it are needed

MethodsWe tested the impact of supportive telephone calls in an adherence substudy of a treatment trial. Subjects initiating antiretroviral therapy received either each site’s usual adherence support measures or usual support measures and scripted serial telephone calls (16 calls during 96 weeks)

ResultsA total of 282 subjects enrolled: 140 in the usual support measures group and 142 in the calls group. A total of 75% of expected calls were completed. Virologic failure occurred in 97 (34%) subjects: 52 (37%) of those in the usual support measures group and 45 (32%) of those in the calls group; time to virologic failure was not different (P=.32). In each group, >72% of subjects reported ⩾95% adherence, with no difference between groups. Independent predictors of higher rates of virologic failure were <95% adherence, receiving the 4-drug regimen with nelfinavir, and female sex; older age was associated with decreased likelihood of virologic failure. Receiving the 4-drug regimen with nelfinavir, higher stress scores, older age, and higher call completion rates were independently associated with higher adherence

ConclusionsSerial telephone calls did not improve virologic outcome but had an impact on self-reported adherence

Combination antiretroviral therapy is associated with a delay in disease progression and a prolongation of survival in persons with HIV infection [1, 2]. However, many patients receiving antiretroviral therapy are unable to achieve optimal virologic suppression [3–5]. A consistent factor associated with an inadequate virologic response is the inability to adhere to a regimen [6–8]. Studies of protease inhibitor–containing regimens have suggested that adherence rates of ⩾95% may be necessary to achieve optimal virologic suppression [6, 7]

Predictors of low adherence include patient characteristics such as active substance abuse, attitudes and beliefs about antiretroviral therapy, level of education, depression or anxiety, relationships between patients and health care providers or health care systems, and complex regimens (reviewed in [9, 10]). Characteristics such as male sex, older age, higher income, and race have been associated with high adherence in some studies [11–17]

There is no standardized approach to increase adherence (reviewed in [18]). Pilot studies have suggested that watch alarms, medication-taking skills development, motivational interviewing, other behavioral interventions, peer support, personalized cues with financial compensation, case management, and directly observed therapy may increase adherence [19–27]. Randomized studies have shown that some interventions increase adherence, but improvement in virologic outcome has been rare [28–31]. A randomized study of a cognitive behavioral intervention in 60 patients showed that it led to increases in some measures of adherence over the course of 1 year but did not affect virologic outcome [28]. In a randomized study of 170 patients, receiving individualized advice about taking the antiretroviral drugs led to an increase in adherence over the course of 24 weeks but did not increase the likelihood of having an HIV RNA level below the limit of detection [29]. A randomized study of 244 subjects showed that receiving 3 counseling sessions by nurses led to an increase in adherence and was associated with a modest decrease in HIV RNA level; there was no difference in the proportion of subjects with undetectable HIV RNA levels at 6 months [30]. A psychoeducational intervention in 116 patients led to an increase in self-reported adherence and the proportion of patients with HIV RNA levels <400 copies/mL in an as-treated analysis but not in an intent-to-treat analysis [31]. These data suggest that additional studies of interventions to increase adherence and thereby increase virologic suppression are needed. Because of the time constraints that providers and patients have, simple interventions would be particularly beneficial

We hypothesized that increased communication between patients initiating combination antiretroviral therapy and study staff members in a treatment trial would increase adherence and thereby improve virologic outcome. The purpose of the study was to determine the impact that the addition of scripted serial telephone calls to each study site’s usual adherence support measures had on adherence and plasma HIV RNA levels

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Subjects, Materials, and Methods

Study designThis adherence intervention study (Protocol 746) was a substudy of AIDS Clinical Trials Group (ACTG) Protocol 388, a randomized, open-label study comparing 2 different 4-drug regimens with a standard 3-drug regimen in subjects with advanced HIV infection who were initiating antiretroviral therapy [32]. ACTG 388 and 746 were conducted in the United States, Puerto Rico, and Italy. All subjects provided written, informed consent. The study was approved by each study site’s institutional review board. The regimens used were zidovudine, lamivudine, and indinavir with either efavirenz or nelfinavir versus zidovudine, lamivudine, and indinavir. Three hundred milligrams of zidovudine and 150 mg of lamivudine were given as a fixed-dose combination tablet (Combivir). Four 200-mg capsules of indinavir (total, 800 mg/dose) were given 3 times daily in the 3-drug regimen, and five 200-mg capsules (total, 1000 mg/dose) were given 3 times daily in the 4-drug regimen with efavirenz. In the 4-drug regimen with nelfinavir, 1000 mg of indinavir (five 200-mg capsules) was initially given twice daily, but each dose was increased to 1200 mg (six 200-mg capsules) when data about a pharmacokinetic interaction became available [33]. Six hundred milligrams of efavirenz (three 200-mg capsules) was given daily. Stavudine could be substituted for zidovudine if a subject was intolerant of the drug. The duration of the study was 96 weeks after enrollment of the last subject. Subjects were monitored in a standardized fashion for safety and efficacy of the drugs. If subjects met the study criteria for virologic failure, they could switch to alternate antiretroviral drugs

Subjects in the substudy were randomized at entry to receive either each study site’s usual adherence support measures (usual support measures group) or each study site’s usual adherence support measures and scripted serial telephone calls from study site staff members (calls group). Study site staff members (mostly nurses) followed a standardized script for telephone calls and received training by the study team by conference call before the study started. The training included script review and written materials with guidelines for the appropriate approach to take during the telephone calls. Spanish and Italian translations of the English script were provided. Additional training occurred via periodic telephone calls to study sites by a clinical social worker trained and supervised by one of the authors (M.A.C.). The telephone calls focused on each subject’s medication-taking behavior, and study site staff members identified barriers to adherence and developed individualized strategies to increase adherence. During the telephone calls, the study site staff members also provided social support and assistance with the management of side effects. The telephone calls were to be made at specific times: 1–3 days after the initiation of the study regimen and at weeks 1, 2, 3, 6, 12, and every 8 weeks thereafter, as long as the subject continued to receive the assigned study regimen, for a maximum of 16 telephone calls over the course of 96 weeks. For each telephone call, a study site staff member attempted to contact the subject at least twice before leaving a counseling or general message. Telephone calls were noted as being completed if the study site staff member was able to contact the subject and cover the topics described above. If the study site staff member talked with the subject but was unable to complete the script, the telephone call was categorized as being partially completed. Study subjects completed a baseline standardized adherence questionnaire and a follow-up questionnaire evaluating medication-taking behavior during the preceding 4 days at weeks 8, 16, 24, 48, 72, and 96 and if they had confirmed virologic failure [34]. At baseline, subjects also completed the Center for Epidemiologic Studies (CES) 7-item depression and 15-item perceived stress scales [35]

Adherence toolsSubjects were provided with plastic laminated cards showing pictures of their pills to be taken at each time of day and brief instructions in English, Spanish, or Italian. Fact sheets about the antiretroviral drugs used in the study regimens were available to subjects. The usual adherence support measures included an average of 35 minutes of in-person counseling, typically provided by a study site nurse or pharmacist, at the start of treatment. According to a study site survey, 67% of study sites reported that they provided written materials to study subjects as part of their usual adherence support measures. In addition, 41% of study sites reported making at least 1 telephone call to selected subjects (who were judged by study site staff members as being at high risk for low adherence) as part of their usual support measures; telephone calls were made to a minority of subjects, the number of telephone calls per subject was limited, and the content was not standardized

Study populationAll subjects had to have ⩽200 CD4+ T cells/mm3 or >80,000 HIV RNA copies/mL of plasma at screening, no or limited previous antiretroviral therapy (no previous use of lamivudine, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors), hemoglobin ⩾9.1 g/dL (for men) or ⩾8.9 g/dL (for women), ⩾850 neutrophils/mm3, >65,000 platelets/mm3, hepatic aminotransferase levels <5 times the upper limit of reference values, and amylase levels <1.5 times the upper limit of reference values, and they could not be pregnant or breast-feeding [32]

Statistical analysesThe primary measure of antiretroviral drug activity was time to virologic failure. Virologic failure was defined as (1) having ⩾200 HIV RNA copies/mL of plasma at or after week 24 or (2) having an increase of >1.0 log10 above nadir levels or an increase to or above baseline levels before week 24 or (3) having 2 consecutive HIV RNA levels ⩾200 copies/mL at any time after having 2 consecutive HIV RNA levels <200 copies/mL. The primary objective of ACTG 746 was to assess the impact that the adherence intervention had on the risk of virologic failure. This was evaluated using Kaplan-Meier analysis, log-rank tests, and Cox proportional hazards models. All analyses were intent-to-treat and were stratified by ACTG 388 regimen and whether the study site provided primary care. Analyses were censored at the permanent discontinuation of the study regimen

For the baseline standardized adherence questionnaire, it was decided a priori to dichotomize the 4-point responses into 2 categories (never/somewhat vs. often/very often). The CES depression and perceived stress scales were analyzed as continuous variables; high scores reflected greater depression or stress. For the follow-up questionnaire, subjects who missed <1 dose during the preceding 4 days were considered to have ⩾95% adherence. Adherence measures for each subject were summarized over time and were modeled longitudinally using logistic regression analyses and generalized estimating equations with an autoregressive order–1 working correlation structure with SAS Proc Genmod (versions 6 and 8; SAS Institute) [36]. In addition, other potential predictors of adherence selected a priori were considered in the models. A metric for the proportion of expected telephone calls that were completed was included in the multivariate model; this was the number of completed telephone calls made since the last adherence evaluation divided by the number of telephone calls that were supposed to have been made during this period. The metric was defined as 0 for all subjects in the usual support measures group. For analyses investigating relationships between self-reported adherence and risk of virologic failure, analyses were performed with time-dependent covariates reflecting current self-reported adherence, were adjusted for covariates associated with virologic failure in the ACTG 388 final analyses (ACTG 388 regimen, age, and sex), and assumed that the subject’s self-reported adherence in the interval constructed around each measurement of adherence was assessed. Missing adherence evaluations were categorized as “unknown.”

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Results

SubjectsA total of 282 (55%) of the 517 ACTG 388 subjects entered the adherence substudy (ACTG 746) at 1 of 30 participating sites. All but 2 sites participating in ACTG 388 enrolled subjects in ACTG 746. A total of 140 subjects were randomized to receive the usual adherence support measures (usual support measures group), and 142 were randomized to receive the usual adherence support measures and scripted serial telephone calls (calls group). Table 1 compares characteristics of subjects in ACTG 746 with those of 235 subjects enrolled in ACTG 388 who did not participate in ACTG 746 and with those of the overall ACTG 388 population. ACTG 746 subjects reflected the overall ACTG 388 population, with similar assignments in study regimens and characteristics. There were no significant differences in characteristics of subjects between the usual support measures and calls groups

Figure 1
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Figure 1

Time to virologic failure in the usual support measures group and the calls group

Figure 2
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Figure 2

Proportion of subjects reporting ⩾95% adherence with the study regimens over time

Table 1
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Table 1

Study regimens and subject characteristics in adherence substudy AIDS Clinical Trials Group (ACTG) 746 and main study ACTG 388

Factors that might impact adherence are shown in table 2 and were similar in the 2 groups. The CES depression and perceived stress scores had a wide range in both groups, although median scores for each assessment were fairly low. Approximately one-half of subjects reported current alcohol use, with 9% of the usual support measures group and 4% of the calls group reporting heavy drinking. The majority of subjects had at least a high school education

Table 2
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Table 2

Baseline factors of interest related to adherence

Of the 282 enrollees, 239 (85%) completed ACTG 746, 35 (12%) prematurely discontinued ACTG 388 (and, thus, ACTG 746), 6 (2%) died, and 2 (<1%) discontinued for other reasons. The categories were similar between the groups. The median follow-up period for ACTG 746 was 96 weeks

Completion of telephone callsOverall, of the expected telephone calls, 1300 (75%) were completed, 41 (2.4%) were partially completed, and 111 (6.4%) messages were left. Weeks 0–76 had 75%–82% of the telephone calls completed at each time point. Telephone call completion rates decreased to 69% and 62% at study weeks 84 and 92, respectively. Reasons for the 290 uncompleted telephone calls included telephone calls made but no contact made with subject (28%), subject without a telephone who did not call as planned (14%), no record of attempts to make telephone calls (20%), subject discontinued study regimen (12%), and miscellaneous reasons, such as disconnected telephone, subject out of town, and study site staff member forgot to make telephone calls (26%)

Impact of telephone calls on virologic failureThe majority of subjects had suppression of plasma HIV RNA while receiving antiretroviral therapy [32]. A total of 97 (34%) ACTG 746 subjects—52 (37%) in the usual support measures group and 45 (32%) in the calls group—had virologic failure. This was comparable to the virologic failure rate of 32% in ACTG 388 subjects who did not participate in ACTG 746. Although there was a consistent slightly lower risk of virologic failure throughout the study in the calls group, there was no statistically significant difference between the usual support measures group and the calls group in time to virologic failure (P=.32, log-rank comparison) (figure 1). No significant differences were seen for the impact of the intervention when virologic failure rates were compared with those in the usual support measures group by ACTG 388 regimen, location of subject’s primary care provider (ACTG unit or not), or sex

Adherence analysesA total of 253 (86%) subjects completed at least 1 adherence assessment. During year 1 of the study, completion rates were 68%–80% per time point, with lower rates during year 2 of the study. Self-reported adherence was high in both groups, with >72% of subjects in each group reporting ⩾95% adherence (missing <1 dose in the preceding 4 days). Figure 2 shows these data for each group by time point. There was no evidence of a difference in self-reported adherence between study groups (odds ratio [OR], 0.86 [95% confidence interval {CI}, 0.57–1.29]; P=.46)

Several factors were associated with self-reported adherence in multiple regression analyses (table 3). These included study regimen (lower adherence was associated with the 4-drug regimen with nelfinavir), female sex (lower adherence), age (higher adherence was associated with older age), and telephone call completion rate (higher adherence was associated with a higher telephone call completion rate). For each 10-year increase in age, the odds of nonadherence decreased by 30% (OR, 0.7 [95% CI, 0.56–0.88]; P=.003). Of the potential baseline predictors of adherence, only the CES perceived stress score was associated with the level of adherence (lower adherence with higher stress score). For each 5-point increase in the perceived stress score, there was a 3% increase in the odds of nonadherence (OR, 1.03 [95% CI, 1.0–1.06]; P=.04). Subjects in the calls group who received a higher proportion of telephone calls had a lower likelihood of low adherence (OR, 0.46 [95% CI, 0.23–0.90]; P=.02)

Table 3
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Table 3

Multiple regression analyses modeling the probability of <95% self-reported adherence

Additional analyses investigated whether there was an interaction between the adherence intervention and the study regimen or the location of the subject’s primary care provider. There was no effect of the telephone calls on adherence in the 3-drug regimen or the 4-drug regimen with efavirenz, but there was evidence of a positive effect in the 4-drug regimen with nelfinavir. Subjects in the calls group had a lower risk of reporting <95% adherence, compared with those in the usual support measures group (OR, 0.47 [95% CI, 0.25–0.91]; P=.02). There was no interaction between the adherence intervention and the location of the subject’s primary care provider

Predictors of virologic failureSingle variable models and multiple regression analyses investigated predictors of virologic failure by use of Cox proportional hazards models with time-dependent covariates for current adherence. Predictors of virologic failure in the multiple regression model adjusted for current adherence are shown in table 4. Less than 95% adherence, assignment to the 4-drug regimen with nelfinavir, and female sex were associated with an increased risk of virologic failure; older age was associated with a decreased risk of virologic failure. These results were similar to the findings in the main ACTG 388 study. For each 10-year increase in age, the risk of virologic failure decreased by 4% (hazard ratio, 0.96 [95% CI, 0.93–0.99]; P=.01). Sensitivity analyses that imputed all unknown adherence time points as either <95% adherence or ⩾95% adherence gave similar results

Table 4
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Table 4

Multiple regression analyses modeling the hazard of virologic failure

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Discussion

This large, randomized adherence study failed to show that the addition of scripted serial telephone calls to each study site’s usual adherence support measures was associated with an improvement in virologic outcome in subjects initiating antiretroviral therapy. Although there was a modest consistent decrease in the risk of virologic failure throughout the study in the calls group, compared with that in the usual support measures group, this difference was not statistically significant. In addition, we were unable to identify any subgroups that appeared to benefit virologically from this intervention, although there was limited power for these analyses. However, self-reported adherence was higher in subjects receiving a higher proportion of telephone calls. Overall, these data suggest that increasing adherence through the use of scripted serial telephone calls may be possible, but a more intensive approach than we used is needed, or the telephone calls should be targeted to a different patient population. The study enrolled a large number of demographically diverse subjects from 30 different study sites in the United States, Puerto Rico, and Italy, and the majority of these study sites were primary care providers to study subjects. However, studies published elsewhere have suggested that HIV treatment study participants may differ from patients in routine clinical care [37, 38]. We must be cautious about the generalizability of the results of the present study to other treatment settings, especially because the regimens we studied are more complex than most initial regimens used at present

We hypothesized that individualized meetings with patients in which medication-taking was discussed, barriers to adherence were identified, strategies to address these barriers were devised, and advice about managing side effects was offered would impact favorably on adherence. Lack of support and antiretroviral drug–induced symptoms have been associated with low adherence [7, 10, 12, 39–41]. The intervention was designed to provide support and assist with the management of side effects and other impediments to optimal adherence and to be easy to implement in the context of a busy clinic. There are a number of possible reasons that differences between the usual support measures group and the calls group were not observed. First, the same study site staff members were counseling subjects in both groups. All study sites indicated that subjects who were anticipated to have problems with adherence received counseling. It is possible that the approach used for the usual support measures group may have been influenced by the additional support measures used for the calls group if study site staff members inadvertently used counseling strategies they learned from the standardized script. Second, it is possible that the training of the study site staff members was insufficient to ensure optimal communication and problem-solving approaches when subjects did report barriers to adherence. A third possibility is that the usual adherence support measures were effective enough that a much larger study would be needed to show additional improvement in virologic outcome. Last, our data suggest that, when completed in accordance with the protocol, telephone calls had the intended favorable impact on adherence. Thus, strategies to enhance the telephone call completion rates might have led to an improvement in virologic outcome. Additional studies of telephone communication strategies should provide more extensive training for the staff members who make the telephone calls, use separate staff members to provide the usual adherence support procedures and any intervention, monitor the staff members who provide the intervention, and increase the telephone call completion rates. In addition, incorporating specific strategies for stress management into the intervention would be useful, because this was found to predict lower adherence

The intervention of supportive telephone calls did not increase the overall self-reported adherence, except in subjects receiving the most telephone calls. Subjects in the usual support measures group reported high rates of adherence to the study regimens. This high rate may have made it difficult to detect an increase in adherence that was caused by the telephone calls. Targeting interventions to patients likely to have lower adherence may be a more useful approach. Adherence self-report measurements may overestimate adherence to study regimens, compared with more objective measurements, such as pill counts or medication-event monitors [42–44]. However, there has been a high correlation between self-reported and objective adherence measurements, and lower adherence by self-report has been correlated with lower virologic responses [43–48]. In addition, in some patient populations, medication-event monitoring is not feasible [49]. The adherence questionnaire used in the present study is the standard self-report measurement used in multiple ACTG studies and has been found to yield adherence rates that are related to virologic outcome [7, 34]. It was developed to provide an easy and relatively low-cost tool that could be implemented in large multisite studies

In the present study, factors associated with <95% adherence (4-drug regimen with nelfinavir and female sex) were similar to factors associated with virologic failure in the main ACTG 388 study as well as to factors associated with nonadherence in other studies. Increased complexity in the drug regimen has been frequently associated with difficulty in adherence and increased risk for virologic failure [10, 11, 15, 50]. The 4-drug regimen with nelfinavir was the most complex regimen used in the present study, with a high pill burden of 11 pills/day [32]. By contrast, a minority of other studies have associated female sex with lower adherence [7, 51]. One possible explanation for the association is the lack of a sufficient number of women in many studies examining adherence; a few studies have evaluated adherence specifically in women, so cross-sex comparisons could not be made [14, 52]. The main ACTG 388 study did not use any specific assessments of mental health, but other studies have noted the association between psychological disturbances and suboptimal adherence [6, 13, 39, 40, 53, 54]

Despite the strengths of its randomized study design and size, the present study had limitations. Although the study site staff members received initial training in the procedures to be used for the telephone calls, only intermittent training was provided during the course of the 2-year study. The telephone calls were not monitored, and we relied on study site staff members to accurately report information about the telephone calls. At some study sites, a few telephone calls were made to selected subjects as part of the usual adherence support measures, and this procedure could have decreased the potential differences between the study groups. However, such telephone calls were not made systematically and occurred at only a subset of study sites with a minority of patients. Because each study site’s usual adherence support procedures were not specified by the protocol, we cannot eliminate the possibility that, during the study, adoption of the counseling strategy for use in the usual support measures group during clinic visits increased. In summary, our strategy of scripted serial telephone calls cannot be recommended as a routine approach to increase adherence in antiretroviral-naive adults initiating complex regimens in the context of a clinical trial. However, investigation of this approach and other strategies to optimize adherence is an important area for further study

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Adult AIDS Clinical Trials Group 746 Substudy Team Members and Adult AIDS Clinical Trials Group Units

Center for Prevention Studies, University of California at San Francisco, Mark Shiner; Social and Scientific Systems (Silver Spring, MD), Barbara Brizz; Instituto Superiore di Sanità (Rome, Italy), Marina Giuliano, Liliana Weimer, and study sites under their supervision: University of Brescia (Brescia, Italy), Ospedale S. M. Annunziata (Florence, Italy), University of Milan (Milan, Italy), University of Rome (Rome, Italy), Spendali Civili (Brescia, Italy), and University of Genoa (Genoa, Italy); University of North Carolina (Chapel Hill), Joseph J. Eron, Jr., and Cheryl J. Marcus; Northwestern University (Evanston, IL), Ruth M. Davis (Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL) and Joanne Despotes (Cook County Hospital, Chicago, IL); Ohio State University (Columbus), Michael Para and Kathy Watson; University of Puerto Rico (San Juan), Jorge L. Santana-Bagur and Olga I. Mendez-Flores; University of Miami (Miami, FL), Jacqueline Clerville and Nancey Bathurst; Indiana University (Indianapolis), Jean Craft and Helen Rominger; University of Alabama at Birmingham, Greg Smith and Robert Hill; University of Colorado (Denver), Sally Canmann; University of Hawaii at Manoa, Joanne Frederick and Debra Ogata-Arakaki; Washington University (St. Louis, MO), William Powderly and Michael Klebert; New York University Medical Center/Bellevue (New York, NY), Charles Gonzalez and Karen Cavanagh; University of Cincinnati (Cincinnati, OH), Tammy Powell and Sharon Kohrs; University of California at Los Angeles, Mallory Witt and Sandia Shaik; Tulane University (New Orleans, LA), Juan J. L. Lertora and Rebecca Clark; University of Minnesota (Minneapolis), Christine Fietzer and Frances Van Meter; University of Pennsylvania (Philadelphia), Janet Hines and Karen McGibney; University of Rochester (Rochester, NY), Jane Reid and Tammy O’Hara; University of Texas at Galveston, Monica Pickthall and William A. O’Brien; Johns Hopkins University (Baltimore, MD), Ilene Wiggins and Dorcas Baker; Beth Israel Medical Center (New York, NY), Donna Mildvan and Gwendolyn Costantini; Cornell Clinical Trials Unit and Chelsea Clinic (New York, NY), Todd Stroberg and Brenda Greenhill; University of Washington (Seattle), Beck Royer, Joanne Stekler, and N. Jeanne Conley; Case Western Reserve University (Cleveland, OH); University of California at San Diego, Linda Meixner and Joanne Santangelo; San Francisco General Hospital (San Francisco, CA), Mark Jacobson; Beth Israel Deaconess Medical Center (Boston, MA), Mary Albrecht and Carol DeQuattro; Stanford University (Palo Alto, CA), Pat Cain and Sylvia Stoudt; and Howard University (Washington, DC), Robert Delapenha and Lisa Alexis

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Acknowledgments

We are indebted to the study subjects

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Footnotes

  • ↵Presented in part: 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 24–28 February 2002 (abstract 540-T)

    Potential conflicts of interest: none reported

    Financial support: National Institute of Allergy and Infectious Disease, National Institutes of Health (grants AI27664, AI25897, and AI27675); National HIV/AIDS Research Program, Instituto Superiore di Sanità, Rome, Italy. Merck, DuPont Pharmaceuticals, Agouron Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb, provided the study medications

  • ↵Present affiliation: National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland

  • ↵Study team members are listed after the text

  • Received December 14, 2004.
  • Accepted May 25, 2005.
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  1. J Infect Dis. (2005) 192 (8): 1398-1406. doi: 10.1086/466526
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