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Prophylaxis for Human Immunodeficiency Virus–Related Pneumocystis carinii Pneumonia
Using Simulation Modeling to Inform Clinical Guidelines
Sue J. Goldie, MD, MPH;
Jonathan E. Kaplan, MD;
Elena Losina, PhD;
Milton C. Weinstein, PhD;
A. David Paltiel, PhD;
George R. Seage III, ScD, MPH;
Donald E. Craven, MD;
April D. Kimmel;
Hong Zhang;
Calvin J. Cohen, MD, MSc;
Kenneth A. Freedberg, MD, MSc
Arch Intern Med. 2002;162:921-928.
ABSTRACT
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Background Human immunodeficiency virus (HIV)-infected patients receiving highly
active antiretroviral therapy (HAART) have experienced a dramatic decrease
in Pneumocystis carinii pneumonia (PCP), necessitating
reassessment of clinical guidelines for prophylaxis.
Methods A simulation model of HIV infection was used to estimate the lifetime
costs and quality-adjusted life expectancy (QALE) for alternative CD4 cell
count criteria for stopping primary PCP prophylaxis in patients with CD4 cell
count increases receiving HAART and alternative agents for second-line PCP
prophylaxis in those intolerant of trimethoprim-sulfamethoxazole (TMP/SMX).
The target population was a cohort of HIV-infected patients in the United
States with initial CD4 cell counts of 350/µL who began PCP prophylaxis
after their first measured CD4 lymphocyte count less than 200/µL. Data
were from randomized controlled trials and other published literature.
Results For patients with CD4 cell count increases during HAART, waiting to
stop prophylaxis until the first observed CD4 cell count was greater than
300/µL prevented 9 additional cases per 1000 patients and cost $9400
per quality-adjusted life year (QALY) gained compared with stopping prophylaxis
at 200/µL. For patients intolerant of TMP/SMX, using dapsone increased
QALE by 2.7 months and cost $4500 per QALY compared with no prophylaxis. Using
atovaquone rather than dapsone provided only 3 days of additional QALE and
cost more than $1.5 million per QALY.
Conclusions Delaying discontinuation of PCP prophylaxis until the first observed
CD4 cell count greater than 300/µL is cost-effective and provides an
explicit "PCP prophylaxis stopping criterion." In TMP/SMX-intolerant patients,
dapsone is more cost-effective than atovaquone.
INTRODUCTION
PNEUMOCYSTIS CARINII pneumonia (PCP) is the
most common serious opportunistic infection among patients infected with human
immunodeficiency virus (HIV) in the United States.1-3
Initiating PCP prophylaxis at a CD4 cell count less than 200/µL has
been the standard of care for the past decade.4-5
In the past few years, however, there has been a dramatic reduction in the
rates of opportunistic infections in HIV-infected patients receiving highly
active antiretroviral therapy (HAART), prompting reassessment of the role
of prophylaxis.6-24
Several recent publications25-28
suggest a convergence of opinion in favor of discontinuing PCP prophylaxis
in patients whose CD4 cell counts have increased to greater than 200/µL
with HAART.
In conjunction with cost-effectiveness analysis, simulation modeling
has become an increasingly important tool for assisting in developing health
policy.29-30 Complementing the
information from clinical trials with such modeling is particularly useful
for HIV because clinical trials rely on intermediate surrogate markers of
outcome (eg, CD4 cell counts and HIV RNA levels), cannot evaluate all the
possible alternatives that should be considered, and cannot address all key
policy questions before decision making. With respect to primary PCP prophylaxis,
the following were among the important questions facing the 1999 US Public
Health Service–Infectious Disease Society of America Prevention of Opportunistic
Infections Working Group5: Is it appropriate
to discontinue prophylaxis in patients with CD4 increases while receiving
HAART, and, if so, at what CD4 cell count? Should the recommended agents for
second-line PCP prophylaxis be changed given new data on the efficacy of those
agents? Since publication of these guidelines,5
new data have become available. We used a comprehensive mathematical model
of HIV to inform the development of future editions of the US Public Health
Service–Infectious Disease Society of America clinical guidelines. We
assessed the cost-effectiveness of alternative CD4 cell count criteria for
stopping PCP prophylaxis in patients receiving HAART and alternative drugs
for prophylaxis in those intolerant of trimethoprim-sulfamethoxazole (TMP/SMX).
MATERIALS AND METHODS
ANALYTIC OVERVIEW
A computer-based simulation model of HIV infection was used to incorporate
changes in HIV RNA levels and CD4 cell counts with disease progression, risk
of opportunistic infections, and the effectiveness of opportunistic infection
prophylaxis and HAART.29, 31 A
Monte Carlo simulation was conducted to compare alternative CD4 cell count
criteria for stopping primary PCP prophylaxis with CD4 cell count increases
to greater than 200/µL with HAART and alternative agents (eg, dapsone,
atovaquone, and aerosolized pentamidine) for second-line prophylaxis in TMP/SMX-intolerant
patients. The target population in both analyses was a cohort of HIV-infected
patients in the United States with initial CD4 cell counts of 350/µL
who were given PCP prophylaxis after their first measured CD4 lymphocyte count
less than 200/µL. Model outcomes included total cases of PCP, lifetime
costs, life expectancy, and quality-adjusted life expectancy. Comparative
performance of alternative strategies was measured by using the incremental
cost-effectiveness ratio, defined as the additional cost of a specific strategy
divided by its additional clinical benefit compared with the next less expensive
strategy. A societal perspective was adopted, although time costs were not
included. Future costs and quality-adjusted life years (QALYs) were discounted
at an annual rate of 3%.29
SIMULATION MODEL
Progression of HIV disease was modeled as a sequence of monthly transitions
between health states, defined by a patient's current and maximum HIV RNA
levels, CD4 cell counts, time receiving HAART, and history of previous effective
and ineffective antiretroviral treatment and previous opportunistic infections.
Health states were divided into 6 CD4 strata (>500/µL, 301-500/µL,
201-300/µL, 101-200/µL, 51-100/µL, and 0-50/µL) and
6 HIV RNA strata (>100 000, 30 001-100 000, 10 001-30 000,
3001-10 000, 501-3000, and  500 copies/mL). Pneumocystis
carinii pneumonia was specified as one of several possible opportunistic
infections, which also included toxoplasmosis, cytomegalovirus, Mycobacterium avium complex, fungal infections, and other complications
of acquired immunodeficiency syndrome (AIDS). The prognosis for an individual
patient depended on previous opportunistic infections, HIV RNA levels, and
CD4 cell counts. Patients could die of an acute clinical event, chronic AIDS
(eg, wasting), or non–HIV-related causes. Further description of the
model is given in recent publications.32-34
A hypothetical cohort of 1 million individuals entered the model, 1
person at a time, in a Monte Carlo simulation, and each was followed until
death.31 Characteristics (age, sex, CD4 cell
count, and HIV RNA level) of each person were randomly drawn from distributions
derived from the Dupont 006 trial (mean CD4 cell count, 350/µL; median
log HIV RNA level, 4.8 copies/mL) for the main analysis, although secondary
analyses were conducted using data from other clinical trials.35-37
On entry into the model, patients were given zidovudine, lamivudine, and efavirenz
and were eligible for up to 4 sequential 3-drug antiretroviral regimens.35-38 The
efficacy of a regimen determined the success of HIV RNA suppression, which
in turn resulted in a CD4 cell count rise.35-38
The increased CD4 cell count corresponded to a reduction in the risk of acute
opportunistic infections and AIDS-related deaths. CD4 and HIV RNA testing
were performed every 3 months in stable patients, and decisions about prophylaxis
for opportunistic infections and further changes in antiretroviral therapy
were made based on results observed for CD4 cell counts and HIV RNA levels,
respectively. In accordance with national guidelines, we assumed that all
patients received PCP prophylaxis beginning with TMP/SMX (400 mg/80 mg daily)
after their first measured CD4 lymphocyte count less than 200/µL, and
for Mycobacterium avium complex disease with weekly
azithromycin (1200 mg) after the first measured CD4 lymphocyte count less
than 50/µL.5
We made the following assumptions: (1) immune function with CD4 cells
regenerated via effective antiretroviral therapy was similar to that predating
the CD4 cell count decline; (2) virologic failure was defined as a 0.5-log
increase in HIV RNA levels in each of 2 consecutive months during HAART; (3)
among patients with virologic failure, CD4 cell counts would not start to
decline for at least 6 months39; (4) among
patients who were still responding to therapy, a specific HAART regimen ceased
to confer benefit after 5 years40; (5) the
efficacy of subsequent antiretroviral regimens among patients who did not
respond to an initial regimen was represented as a reduction in the efficacy
of the first-line regimen; (6) antiretroviral toxic effects were modeled as
drug specific and triggered a switch to an alternative agent within the same
class; and (7) the duration of viral suppression depended on adherence and
the development of resistance, both of which were assumed to be included in
the efficacy estimates derived from the intention-to-treat analyses of data
from clinical trials. These assumptions were tested in sensitivity analysis.
CLINICAL DATA
Selected values and plausible ranges for the analysis are given in Table 1.33, 35, 41-58
The monthly decline in the CD4 cell count, primary opportunistic infection
incidence, acute mortality associated with an opportunistic infection, and
chronic mortality in the absence of HAART were based on data from the Multicenter
AIDS Cohort Study using methods described previously.33, 42-43,59-61
The efficacy of prophylaxis was modeled as a percentage reduction in the monthly
incidence of an opportunistic infection.44-46,50, 57-58
Rates of toxic effects in the model were defined according to the AIDS Clinical
Trial Group criteria62: minor toxic effects
included grades 1 and 2 toxic effects that did not require discontinuation
of therapy; major toxic effects included any grade 1 to 4 toxic effects that
required discontinuation of therapy and crossover to a second- or third-line
agent for prophylaxis. Pneumocystis carinii pneumonia
prophylaxis could be initiated or discontinued at any CD4 cell count.
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Table 1. Model Variablesa
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We used a weight to determine the risk of PCP and other clinical events
in patients receiving HAART and referred to it as "fraction of benefit."63-64 A fraction of benefit of 1.0 means
that the risk of opportunistic infections was based on the actual new CD4
cell count (ie, the risk of PCP was similar to that in HAART-naive patients
with the same CD4 cell count); a fraction of benefit of 0.0 means that these
risks were based on the lowest-ever CD4 cell count; and a fraction of benefit
of 0.5 means that these risks were based on the mean of the lowest-ever and
current CD4 cell count. Recent data suggest that CD4 cell function with successful
virologic suppression is associated with protection against PCP.11-24
However, lower CD4 cell count nadirs may be associated with a greater risk
of opportunistic infections, and we explored the implications of a lower fraction
of benefit in patients with a CD4 cell count nadir less than 50/µL.27, 65 We also explored the effects of a
fraction of benefit greater than 1.0 (implying a risk of PCP with CD4 cell
count increases during HAART that was lower than the risk of PCP in the average
untreated patient with that same CD4 cell count).
Trimethoprim-sulfamethoxazole is the preferred choice for PCP prophylaxis,44-45,47, 62, 66-70
but intolerance often limits its use.44, 70-71
Alternative prophylactic agents include dapsone, aerosolized pentamidine,
and, most recently, atovaquone.50, 68, 72
Based on data from a randomized trial comparing atovaquone (1500-mg suspension
daily) and dapsone (100-mg tablet daily) for PCP prophylaxis in TMP/SMX-intolerant
patients, El-Sadr et al50 reported similar
rates of efficacy, tolerance, and survival in both groups. Because results
for drug tolerance when stratified by dapsone use at baseline differed significantly,
we explored these data in a sensitivity analysis (Table 1).
The efficacy of first-line antiretroviral therapy was based on the best
3-drug arm (zidovudine, lamivudine, and efavirenz) of the Dupont 006 trial
(70% suppression at 48 weeks)35; second-line
efficacy was based on the 3-drug arm (zidovudine, lamivudine, and indinavir)
of the AIDS Clinical Trial Group 320 (60% suppression at 24 weeks)36; third-line efficacy was based on the intervention
arm of the Community Program for AIDS Research Clinical Trial 046 (34% suppression
at 12 weeks); and fourth-line efficacy was based on the control arm of the
previously mentioned study (22% suppression at 12 weeks).37
The methods used to derive transition probabilities using these clinical trial
data are described elsewhere.33
Costs of prophylaxis and antiretroviral agents were obtained from the
1999 Red Book.47 Other medical costs were derived
from the AIDS Cost and Services Utilization Survey dataset using methods described
previously,33, 48-49
although upper and lower bounds for sensitivity analyses were chosen to include
other published estimates for the cost of HIV care.56, 73
All costs were converted to 1999 dollars using the Medical Care component
of the Consumer Price Index.51
Data linking perceived health status to the states defined in the model
were obtained from AIDS Clinical Trial Group protocols 019, 108, 154, and
204 by approximating a preference-based measure of health status, as described
previously.33, 53 Although these
weights were not derived using the preferred techniques of the standard gamble
or time tradeoff, they were similar to utilities reported by others using
these methods.54-56
RESULTS
CRITERIA FOR STOPPING PCP PROPHYLAXIS WITH CD4 CELL COUNT INCREASES
DURING HAART
In HIV-infected patients with initial CD4 cell counts of 350/µL
(who were given PCP prophylaxis after their first measured CD4 lymphocyte
count <200/µL), we considered different strategies to guide the decision
to stop or continue PCP prophylaxis once CD4 cell counts increased to greater
than 200/µL during HAART. In the base case analysis, we assumed that
the risk of PCP was based on the actual new CD4 cell count (ie, fraction of
benefit of 1.0). A CD4 cell count stopping criterion greater than 200/µL
provided 3.6 months of quality-adjusted life expectancy and cost $5100 per
QALY compared with no prophylaxis (Table
2). Discontinuing prophylaxis with a CD4 cell count greater than
300/µL prevented an additional 9 cases of primary PCP per 1000 patients
at a cost of $9400 per QALY.
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Table 2. Costs, Clinical Impact, and Cost-effectiveness of Using Difference
CD4 Cell Count Criteria for Stopping PCP Prophylaxis in Patients Receiving
HAART*
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The clinical benefits of a CD4 cell count cutoff value greater than
300/µL compared with greater than 200/mL were sensitive to assumptions
about the immune function that accompanied CD4 cell count increases higher
than 200/µL in patients receiving HAART. When the true underlying risk
of PCP was reflected by an individual's historical CD4 cell count nadir (fraction
of benefit of 0.0), continuing prophylaxis once the CD4 cell count increased
to greater than 200/µL became increasingly cost-effective, reflecting
the longer duration of substantial risk of PCP with more years of life to
be saved. When we assumed a fraction of benefit of 0.0 only in patients who
had a CD4 cell count nadir less than 50/µL, or only in those with HIV
RNA levels greater than 30 000 copies/mL, the results were unchanged.
When we assumed that the fraction of benefit was greater than 1.0 (ie, the
risk of PCP was even lower than the risk in an average untreated patient with
the same CD4 cell count), a lower CD4 cell count stopping criterion became
more efficient. For example, with a fraction of benefit of 1.5, stopping prophylaxis
when the CD4 cell count was greater than 200/µL vs greater than 300/µL
was more effective and less costly, dominating the latter strategy and costing
only $2300 per QALY.
For patients starting with lower CD4 cell counts and in the later stages
of HIV disease, the clinical benefits of waiting until the CD4 cell count
was greater than 300/µL vs greater than 200/µL were much greater.
For example, in patients similar to those in the AIDS Clinical Trial Group
Protocol 320 (initial mean CD4 cell count, 87/µL), delaying discontinuation
of prophylaxis until the CD4 cell count was greater than 300/µL prevented
an additional 34 cases of primary PCP per 1000 patients compared with stopping
at a CD4 cell count greater than 200/µL. The cost-effectiveness ratio
of this strategy, at $8200 per QALY, was more attractive than the cost-effectiveness
ratio of stopping at a CD4 cell count greater than 200/µL, thereby dominating
the latter strategy.74 In contrast, in a cohort
of patients starting with earlier HIV disease (mean CD4 cell count of 500/µL),
delaying discontinuation of prophylaxis until the CD4 cell count was greater
than 300/µL prevented only 5 additional cases of primary PCP per 1000
patients.
SECOND-LINE AGENTS IN TMP/SMX-INTOLERANT PATIENTS
We evaluated 7 possible strategies for PCP prophylaxis in patients intolerant
of TMP/SMX and found that dapsone followed by aerosolized pentamidine and
then atovaquone if toxic effects developed (dapsone aerosolized pentamidineatovaquone)
increased quality-adjusted life expectancy by 2.7 months and total lifetime
costs by $1000, for an incremental cost-effectiveness ratio of $4500 per QALY
compared with no prophylaxis (Table 3).
All strategies that began with aerosolized pentamidine were less effective
and more costly than dapsoneaerosolized pentamidine atovaquone.
Compared with dapsoneaerosolized pentamidine atovaquone, the strategy
of starting with atovaquone followed by dapsone and then aerosolized pentamidine
provided only 2.7 extra days of life expectancy and cost $1.8 million per
year of life gained. Unless the monthly cost of atovaquone was decreased by
approximately 90% (equivalent to an annual cost of $962), the cost-effectiveness
ratio for any strategy beginning with atovaquone remained greater than $100 000
per QALY.
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Table 3. Cost-effectiveness of Second-Line Prophylaxis for Patients
Intolerant of TMP/SMX*
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We determined the plausible bounds for the efficacy and toxicity of
dapsone and atovaquone based on data from the randomized trial of dapsone
vs atovaquone using the confidence intervals from the intention-to-treat analysis,
the subgroup analysis of the dapsone-naive patients, and the on-treatment
analysis.50 Despite the intentional bias against
dapsone resulting from the latter 2 approaches, the cost-effectiveness ratio
for a strategy that started with atovaquone was never less than $300 000
per QALY.
COMMENT
Pneumocystis carinii pneumonia prophylaxis
was the most important improvement in the standard of HIV care during the
first decade of the HIV epidemic, and it played a major role in reducing the
rate of progression to AIDS before the availability of other opportunistic
infection prophylaxis and HAART.1-3
Its low cost makes it the least expensive HIV medication, and its cost-effectiveness
suggests that it offers substantial clinical value for the resources spent.32 There is a convergence of opinion in favor of discontinuing
PCP prophylaxis in patients whose CD4 cell counts have increased to greater
than 200/µL with HAART.11-28
In HIV-infected patients with initial CD4 cell counts of 350/µL who
started PCP prophylaxis after their first measured CD4 lymphocyte count less
than 200/µL, stopping prophylaxis when the CD4 cell count increased
to greater than 300/µL with HAART provided a small additional clinical
benefit (eg, 9 cases of primary PCP averted per 1000 patients) compared with
stopping at 200/µL. However, the additional costs are so low that continued
prophylaxis has an attractive cost-effectiveness ratio nonetheless. For patients
with more advanced disease, such as those in AIDS Clinical Trial 320 (CD4
cell counts of 87/µL), the incremental benefits of stopping prophylaxis
at a CD4 cell count greater than 300/µL rather than greater than 200/µL
are much greater (eg, 34 cases of primary PCP averted per 1000 patients).
Lower CD4 cell count nadirs may be associated with a greater risk of opportunistic
infections in patients with CD4 cell count increases during HAART.65 However, even when we assumed a fraction of benefit
of 0.0 in those with CD4 cell count nadirs of less then 50/µL, the overall
cost-effectiveness results were unchanged.
For patients intolerant of TMP/SMX, we found that the most cost-effective
strategy for PCP prophylaxis was to use dapsone followed by aerosolized pentamidine
and then atovaquone in the event of toxic effects. This was the case even
when the relative risks of failure and toxic effects with atovaquone use were
assumed to be 50% of the base case. In fact, when the relative risk of stopping
atovaquone therapy because of toxic effects was 0.42 compared with dapsone
(recently reported in the subgroup analysis of dapsone-naive patients),50 starting with atovaquone in TMP/SMX-intolerant patients
still had a cost-effectiveness ratio exceeding $500 000 per QALY. Given
the current annual wholesale cost of atovaquone of $9600, this would pay for
not only dapsone for PCP prophylaxis but also for 10 months of zidovudine,
lamivudine, and efavirenz for an individual patient. With limited available
resources for costly HIV therapy,75 using atovaquone
before a trial of dapsone does not make policy sense.76
There are several limitations to this analysis. First, we did not incorporate
the additional benefit of TMP/SMX in preventing bacterial infections, and
we did not consider the possible impact of the development of TMP/SMX resistance
with lifelong use. Second, the input data for efficacy and toxicity were based
on multiple studies of varying size, design, and quality, although, when possible,
we used data from randomized controlled trials. We did not include secondary
PCP prophylaxis because there are fewer data, although thus far discontinuation
with CD4 cell count increases seems safe.13, 77-78
Estimates of costs reflect practice before HAART; however, we modified these
costs to reflect newer drug costs and HIV RNA testing, and we conducted extensive
sensitivity analyses on costs with little impact on the results. Finally,
although cost-effectiveness analysis can help illustrate the tradeoffs with
different policy alternatives, it serves as only one input to decision making.29 There may be important qualitative considerations
when developing guidelines, such as the potential psychological benefit of
discontinuing treatment.26
Our results, in large part, support recent clinical guidelines.5 The 1999 US Public Health Service–Infectious
Disease Society of America Working Group suggested that stopping prophylaxis
when the CD4 cell count has been greater than 200/mL for at least 3 to 6 months
may be reasonable based on early data showing an extremely low risk of PCP
in patients treated successfully with HAART. The analysis we conducted to
address this issue involved the critical review of all published studies supporting
safe discontinuation in patients with CD4 cell count increases with HAART;
in most of these studies, the mean CD4 cell count at the time of discontinuation
was greater than 300/µL.11-24
Because these clinical studies described the immune status of their study
populations using the mean CD4 cell count, we elected to use an absolute CD4
cell count rather than duration of time at a particular CD4 cell count for
our primary prophylaxis discontinuation criterion. In fact, the clinical guidelines
and our results are quite similar—whether there will be a clinically
meaningful difference between "a CD4 cell count greater than 200/µL
for at least 6 months" and "a measured CD4 cell count of at least 300/µL"
is a question for future research.
The results of this analysis support the following conclusions: (1)
Despite the relatively low risk of PCP in patients successfully treated with
HAART, waiting to stop primary PCP prophylaxis until an observed CD4 cell
count is greater than 300/µL will prevent PCP cases, is cost-effective,
and provides an explicit and easily understandable PCP prophylaxis stopping
criterion for patients and providers. (2) Regimens using atovaquone in TMP/SMX-intolerant
patients have cost-effectiveness ratios that are much higher than those of
well-accepted clinical interventions, and dapsone should be the initial choice
for prophylaxis in these patients. These conclusions can be used to refine
the optimal approach to PCP prophylaxis as treatment for HIV disease continues
to evolve in this era of effective antiretroviral therapy.
AUTHOR INFORMATION
Accepted for publication August 23, 2001.
This study was supported by grants U64/CCU 114927 and U64/CCU 119525-01
from the Centers for Disease Control and Prevention and by grant R01-AI42006
from the National Institute of Allergy and Infectious Diseases, Bethesda,
Md.
We thank Wafaa M. El-Sadr, MD, MPH, for providing data and helpful comments
on the analysis; Lisa Sullivan, PhD, Debra L. Hanson, PhD, Yazdan Yazdanpanah,
MD, MSc, and Bruce Schackman, PhD, for their helpful input during the analysis;
and the advisory board members for the Cost-Effectiveness of Preventing AIDS
Complications project (Samuel A. Bozette, MD, PhD, Judith Currier, MD, Roy
Gulick, MD, Scott M. Hammer, MD, Diane Havlir, MD, Kenneth H. Mayer, MD, William
Powderly, MD, and Albert W. Wu, MD, MPH) for their valuable input during the
development of the model and their helpful comments on the analysis.
Corresponding author and reprints: Sue J. Goldie, MD, MPH, Center
for Risk Analysis, Department of Health Policy and Management, Harvard School
of Public Health, 718 Huntington Ave, Second Floor, Boston, MA 02115-5924.
From the Center for Risk Analysis, the Departments of Health Policy
and Management (Drs Goldie, Weinstein, and Freedberg) and Epidemiology (Dr
Seage), Harvard School of Public Health, Boston, Mass; the Division of HIV/AIDS
Prevention, Centers for Disease Control and Prevention, Atlanta, Ga (Dr Kaplan);
the Department of Epidemiology and Biostatistics, Boston University School
of Public Health (Drs Losina, Craven, and Freedberg); the Department of Epidemiology
and Public Health, Yale University School of Medicine, New Haven, Conn (Dr
Paltiel); the Division of General Medicine and Partners AIDS Research Center,
Massachusetts General Hospital, Harvard Medical School, Boston (Drs Losina
and Freedberg, Ms Kimmel, and Mr Zhang); and the Community Research Initiative
New England, Brookline, Mass (Dr Cohen).
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