Crum-Cianflone, Nancy F MD, MPH*†; Ren, Qian MS‡; Eberly, Lynn E PhD*‡; Ganesan, Anuradha MD*§; Weintrob, Amy MD*‖; Marconi, Vincent MD*¶; Barthel, RObert V MD*#; Agan, Brian K MD*; The Infectious Disease Clinical Research Program
*Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD; †Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, CA; ‡Division of Biostatistics, University of Minnesota, Minneapolis, MN; §Infectious Disease Clinic, National Naval Medical Center, Bethesda, MD; ‖Infectious Disease Clinic, Walter Reed Army Medical Center, Washington, DC; ¶Infectious Disease Clinic, San Antonio Military Medical Center, San Antonio, TX; #Infectious Disease Clinic, Naval Medical Center Portsmouth, Portsmouth, VA.
Support for this work (IDCRP-000-012) was provided by the Infectious Disease Clinical Research Program, a Department of Defense program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072.
Part of these data were presented as a poster at the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, CA.
This work is original and has not been published elsewhere.
The authors have no commercial or other association that might pose a conflict of interest in this work.
The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the National Institutes of Health or the Department of Health and Human Services, the Department of Defense or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
To the Editors:
Recently, 2 large studies found that documented HIV seroconverters are presenting with significantly lower initial CD4 cell counts during the epidemic.1,2 Trends in the initial CD4 counts may be important for health care planning because they are key markers for immune competence and initiation of highly active antiretroviral therapy (HAART).3 To further understand these trends, we examined the time to CD4 counts <500 cells per cubic millimeter after adjusting for the initial CD4 count.
We evaluated documented HIV-1 seroconverters from 1986 to 2007 as part of the US Military HIV Natural History Study.4 Active duty members are HIV negative upon service entry and undergo testing every 1-5 years, resulting in narrowly defined seroconversion windows. Participants were racially diverse and from various geographic areas within the United States.
For this analysis, participants had documented seroconverting windows of ≤4 years (mean 1.4, SD: 0.8 years). We excluded those who initiated antiretroviral therapy before the first documented CD4 count (n = 96), those without a documented CD4 count (n = 365), or a CD4 <500 cells per cubic millimeter at diagnosis (n = 1060).
Participants were evaluated at HIV diagnosis and at 6-month intervals; clinical data, including CD4 counts, were recorded. Subjects were censored at the earliest time of last observed CD4 count, 3 consecutive missed study visits, death, initiation of HAART, or after 4 years of follow-up.
The primary variable of interest was the period of HIV diagnosis. The study period was a priori divided into 1986-1990, 1991-1995, 1996-2001, and 2002-2007, similar to our previous work.2 Time zero was the date of documented HIV seropositivity. Kaplan-Meier curves and Cox proportional hazard models were utilized to estimate the hazard ratios (HR) to the first CD4 <500 cells per cubic millimeter for each time period. Models were stratified by clinical site and adjusted for age, gender, ethnicity, body mass index, seroconverting window, time from HIV diagnosis to initial CD4 count, initial CD4 count and HIV RNA level at diagnosis, and time-updated duration of single or dual-agent ART. Models were repeated among participants with narrow seroconverting dates (window ≤12 months). Analyses were conducted using SAS (version 9, Cary, NC).
We evaluated 1084 documented HIV seroconverters with a mean age of 28 (SD: 7) years; 95% were male; 48% were white, and 41% were African American. The overall mean postseroconversion CD4 cell count was 720 (SD: 205) cells per cubic millimeter and were 765, 707, 682, and 712 cells per cubic millimeter for the 4 time periods, respectively (P < 0.0001).
In the adjusted multivariate models of time to CD4 count <500 cells per cubic millimeter, the HR of a CD4 count <500 cells per cubic millimeter increased during the epidemic: 1.14 [95% confidence interval (CI), 0.92 to 1.41] for those seroconverting during 1991-1995, 1.12 (0.78 to 1.60) for 1996-2001, and 1.29 (0.91 to 1.82) for 2002-2007, compared with 1986-1990.
The analyses were repeated among participants with seroconverting windows of ≤12 months (n = 402). The HRs for the time periods were 1.09 (95% CI: 0.73 to 1.62), 1.88 (0.97 to 3.64), and 1.83 (0.95 to 3.51), respectively (Fig. 1). We performed additional analyses using a delayed entry approach (time zero was the estimated seroconversion date, but participants were not at risk until the HIV diagnosis date); similar results were noted.
In addition, analyses were repeated among participants with seroconverting windows of ≤12 months utilizing other calendar period cut-offs reflective of the literature,1 the delayed entry approach, and similar censoring (but at 2 years, not 4), stratification and adjusting variables (except for time-updated antiretroviral therapy). We found that compared with seroconverters in 1986-1990, HRs for time to CD4 count <500 cells per cubic millimeter were 1.05 (95% CI: 0.63 to 1.75) for 1991-1994, 1.67 (95% CI: 0.74 to 3.74) for 1995-1998, 2.61 (95% CI: 1.08 to 6.27) for 1999-2002, and 2.08 (95% CI: 0.91 to 4.77) for 2003-2007.
In summary, our study found that recent documented HIV seroconverters have trends for a faster time to progression to a CD4 count <500 cells per cubic millimeter after initial diagnosis than those diagnosed earlier in the epidemic. Although most HRs were not statistically significant, likely due to our sample size, they do show potentially important trends. Previous studies have suggested that HIV patients are presenting with lower initial postseroconversion CD4 counts over the epidemic.1,2 Our data extends the existing literature by examining the risk of CD4 count decline after HIV seroconversion.
Our results are concurrent to those from a European cohort, which showed that both the initial and follow-up CD4 counts are lower and declining faster, respectively, over the epidemic.1 Our findings suggest that similar trends are also occurring in the United States. The reasons for the faster progression of HIV are unclear, but some have suggested that HIV may have become more pathogenic1,2,5; further studies are needed.
Our findings have potentially important health care implications because HIV patients seem to be progressing to a CD4 count <500 cells per cubic millimeter faster over time, and recent treatment guidelines now suggest initiation of HAART at this CD4 level.3 Data on potential changes in HIV progression over time are important components of health care planning. Based on these data, we advocate future studies examining CD4 trends over time among HIV seroconverters to detect further changes in disease progression.
Nancy F. Crum-Cianflone, MD, MPH*†
Qian Ren, MS‡
Lynn E. Eberly, PhD*‡
Anuradha Ganesan, MD*§
Amy Weintrob, MD*‖
Vincent Marconi, MD*¶
Robert V. Barthel, MD*#
Brian K. Agan, MD*
The Infectious Disease Clinical Research Program
*Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD
†Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, CA
‡Division of Biostatistics, University of Minnesota, Minneapolis, MN
§Infectious Disease Clinic, National Naval Medical Center, Bethesda, MD
‖Infectious Disease Clinic, Walter Reed Army Medical Center, Washington, DC
¶Infectious Disease Clinic, San Antonio Military Medical Center, San Antonio, TX
#Infectious Disease Clinic, Naval Medical Center Portsmouth, Portsmouth, VA
1. Dorrucci M, Rezza G, Porter K, et al, and the Concerted Action on Seroconversion to AIDS and Death in Europe Collaboration. Temporal trends in postseroconversion CD4 cell count and HIV load: the Concerted Action on Seroconversion to AIDS and Death in Europe Collaboration, 1985-2002. J Infect Dis. 2007;195:525-534.
2. Crum-Cianflone N, Eberly L, Zhang Y, et al. Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007. Clin Infect Dis. 2009;48:1285-1292.
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD: Department of Health and Human Services. December 1, 2009;1-161. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
. Accessed December 7, 2009.
4. Weintrob AC, Fieberg AM, Agan BK, et al. Increasing age at HIV seroconversion from 18 to 40 years is associated with favorable virologic and immunologic responses to HAART. J Acquir Immune Defic Syndr. 2008;49:40-47.
5. Vanhems P, Lambert J, Guerra M, et al. Association between the rate of CD4+ T cell decrease and the year of human immuonodeficiency virus (HIV) type 1 seroconversion among persons enrolled in the Swiss HIV Cohort Study. J Infect Dis. 1999;180:1803-1808.
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