In the United States, over one-third of individuals develop an AIDS-defining illness within one year of HIV diagnosis, and an estimated 180 000-280 000 Americans are unaware of their HIV infection [1]. The initiation of antiretroviral therapy (ART) after an AIDS-defining illness or CD4 cell decline below 200 cells/μl increases the risk of morbidity and mortality [2,3]. In earlier research, male sex and older age were associated with an increased risk of late entry into HIV care in some [4-7] but not all studies [8-11]. Although the southeastern USA reports the greatest proportion of AIDS cases and deaths [12,13], no studies on the late initiation of HIV care have been conducted in this region. Therefore, we characterized entry to HIV care and the predictors of the late initiation of care with ART indicated.
The study population included patients initiating HIV care between 2000 and 2003 at the University of North Carolina HIV outpatient clinic, which is located in a large tertiary care facility. Clinical and demographic characteristics were abstracted from medical records. The indication for ART was defined as a CD4 cell count of less than 350 cells/μl, an HIV-RNA level greater than 100 000 copies/ml, or an AIDS-defining illness [14]. We considered a number of factors affecting entry to HIV care with ART indicated, including sex, age, race, insurance, distance-to-care, rural residence, HIV exposure group, alcohol and substance abuse, and major depressive disorder. Rural residence was defined as a metropolitan statistical area with a population of less than 50 000 [15].
We performed basic bivariate analyses and fit multivariable logistic regression models to identify characteristics predicting ART indication at entry to HIV care using the SAS statistical package (version 8.2; SAS Institute Inc., Cary, North Carolina, USA). The study was approved by the UNC Institutional Review Board.
Of 348 patients initiating HIV care during this period, 63% (n = 220) had not received any previous HIV care at any facility. Thirty-five per cent (n = 77) were women, and the median age was 37 years [interquartile range (IQR) 30, 45, Table 1]. Sixty-eight per cent (n = 150) initiated HIV care within one year of their first HIV-positive test, and 16% (n = 35) delayed care for more than 2 years. Among the 35 patients aware of their HIV diagnosis for more than 2 years, the median delay was 5 years (IQR 3, 10).
At entry to care, 29% (n = 64), 21% (n = 46), 20% (n = 45), and 30% (n = 65) had a CD4 cell count of less than 50, 50-199, 200-349 and greater than 349 cells/μl, respectively. The median HIV-RNA level was 4.8 log10 copies/ml (IQR 4.1, 5.3), and 46% (n = 101) had HIV-RNA levels greater than 100 000 copies/ml. Twenty-seven per cent (n = 59) presented with an AIDS-defining illness, most commonly, Pneumocystis jiroveci pneumonia (39%), esophageal candidiasis (16%), and extrapulmonary cryptococcosis (14%). Sixteen per cent (n = 35) were referred directly from an inpatient unit, and 11% (n = 24) were diagnosed with HIV during this index hospitalization.
On initial presentation, ART was indicated for 75% of patients (n = 165) based on the CD4 cell count, HIV-RNA level, and/or an AIDS clinical condition, and for 71% (n = 156) it was based solely on the CD4 cell count. ART was indicated for 78% (117/150), 57% (20/35), and 83% (29/35) of patients entering HIV care one year or less, 1-2 years, and over 2 years from HIV diagnosis, respectively (P = 0.02). In bivariate analyses, male sex (P = 0.02) and alcohol abuse (P = 0.03) predicted an indication for ART at presentation (Table 1). Male sex remained a statistically significant independent predictor in the multivariable model. Notably, race, rural residence and distance to clinic were not predictive.
This study demonstrates that most HIV-infected patients in the southeastern USA initiate HIV care with advanced immunosuppression, and the majority with ART indicated [14]. The degree of immunological impairment in patients initiating care at our facility is among the highest reported [4-9,11,16-19]. Male sex independently predicted ART indication at the first visit, even after the exclusion of pregnant women (n = 10). These findings have been observed by others [4-7], and indicate that targeted interventions are needed among men to increase earlier HIV diagnosis. Our alcohol use findings warrant further attention, given the high rates of alcohol abuse among HIV-infected patients [20,21], particularly in the rural southeastern USA, where treatment is limited.
This is the first investigation of HIV care initiation by the place of residence, despite the fact that rural areas in the southeastern USA have experienced the largest increases in AIDS cases [12,22-24]. Rural residence was not statistically associated with the late initiation of HIV care in this study. However, the predominantly rural and semi-rural nature of the southeastern USA may contribute to an overall observed substantial delay in accessing HIV care, given the scarce medical, social, and HIV testing services, limited transportation, poverty, decreased perception of risk, and possibly greater perceived stigma and confidentiality concerns [25,26].
We noted substantial numbers of individuals with high HIV-RNA levels at entry to care. High HIV-RNA levels have been associated with an accelerated onset of AIDS-related illness and CD4 cell decline [27], and an increased risk of transmitting HIV to sexual partners [28,29]. The high HIV-RNA levels in our patients highlight missed opportunities for treatment and the prevention of further HIV transmission. Most patients were HIV diagnosed within 2 years of HIV care initiation, indicating that late entry was not related to the delay from testing to accessing care.
Our study only included patients initiating care at a single center and may not be generalizable to other populations. We were also limited by our inability to assess the effect of factors such as lack of social support, fear of discrimination or stigmatization, lack of general HIV knowledge, or low perception of HIV risk on late entry to HIV care, although these may be especially salient to HIV testing and medical care initiation.
Overall, this study indicates that patients in the southeastern USA initiate HIV care with ART indicated, reflecting advanced immunosuppression and a need for care. As ART benefits diminish with late therapy initiation, earlier access to HIV care would probably improve morbidity and mortality in this population. A prolonged interval between HIV acquisition, diagnosis, and access to care, delays transmission-reduction measures and secondary prevention strategies. Our results indicate an urgent need to increase earlier HIV diagnosis and linkage to care, especially in the southeastern USA.
Acknowledgements
The authors greatly appreciate the support of all study staff members, HIV care providers, and particularly the individuals who participated in this study.
Sponsorship: This study was supported by the University of North Carolina at Chapel Hill, the Center for AIDS Research, National Institutes of Health funded program no. P30 AI 50410 and program RR00046, funds from the US Department of Health and Human Services, HRSA, HAB, the Office of Science and Epidemiology, the Epidemiology Department at GlaxoSmithKline, SAS Institute, and the Medical Foundation of North Carolina, Inc.
References
1. Centers for Disease Control and Prevention. Late versus early testing of HIV - 16 sites, United States, 2000-2003. Morb Mortal Wkly Rep 2003; 52:581-586.
2. Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001; 286:2568-2577.
3. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119-129.
4. Gupta SB, Gilbert RL, Brady AR, Livingstone SJ, Evans BG. CD4 cell counts in adults with newly diagnosed HIV infection: results of surveillance in England and Wales, 1990-1998. CD4 Surveillance Scheme Advisory Group. AIDS 2000; 14:853-861.
5. Samet JH, Freedberg KA, Savetsky JB, Sullivan LM, Stein MD. Understanding delay to medical care for HIV infection: the long-term non-presenter. AIDS 2001; 15:77-85.
6. Castilla J, Sobrino P, De La Fuente L, Noguer I, Guerra L, Parras F. Late diagnosis of HIV infection in the era of highly active antiretroviral therapy: consequences for AIDS incidence. AIDS 2002; 16:1945-1951.
7. Klein D, Hurley LB, Merrill D, Quesenberry CP Jr. Review of medical encounters in the 5 years before a diagnosis of HIV-1 infection: implications for early detection. J Acquir Immune Defic Syndr 2003; 32:143-152.
8. Girardi E, Aloisi M, Arici C, Pezzotti P, Serraino D, Balzano R, et al. Delayed presentation and late testing for hiv: demographic and behavioral risk factors in a multicenter study in Italy. J Acquir Immune Defic Syndr 2004; 36:951-959.
9. Manavi K, McMillan A, Ogilvie M, Scott G. Heterosexual men and women with HIV test positive at a later stage of infection than homo- or bisexual men. Int J STD AIDS 2004; 15:811-814.
10. Hocking JS, Rodger AJ, Rhodes DG, Crofts N. Late presentation of HIV infection associated with prolonged survival following AIDS diagnosis - characteristics of individuals. Int J STD AIDS 2000; 11:503-508.
11. Dybul M, Bolan R, Condoluci D, Cox-Iyamu R, Redfield R, Hallahan CW, et al. Evaluation of initial CD4+ T cell counts in individuals with newly diagnosed human immunodeficiency virus infection, by sex and race, in urban settings. J Infect Dis 2002; 185:1818-1821.
12. Centers for Disease Control and Prevention. First 500,000 AIDS cases - United States, 1995. MMWR Morb Mortal Wkly Rep 1995; 44:849-853.
13. Centers for Disease Control and Prevention. Update: AIDS - United States, 2000. MMWR Morb Mortal Wkly Rep 2002; 51:592-595.
14. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington, DC: Department of Health and Human Services; 2004.
16. Samet JH, Retondo MJ, Freedberg KA, Stein MD, Heeren T, Libman H. Factors associated with initiation of primary medical care for HIV-infected persons. Am J Med 1994; 97:347-353.
17. Katz MH, Bindman AB, Keane D, Chan AK. CD4 lymphocyte count as an indicator of delay in seeking human immunodeficiency virus-related treatment. Arch Intern Med 1992; 152:1501-1504.
18. Centers for Disease Control and Prevention. HIV/AIDS surveillance report. Atlanta, GA: CDC; 2001. p. 13.
19. Wortley PM, Chu SY, Diaz T, Ward JW, Doyle B, Davidson AJ, et al. HIV testing patterns: where, why, and when were persons with AIDS tested for HIV? AIDS 1995; 9:487-492.
20. Whetten K, Reif SS, Napravnik S, Swartz MS, Thielman NM, Eron JJ Jr, et al. Substance abuse and symptoms of mental illness among HIV-positive persons in the Southeast. South Med J 2005; 98:9-14.
21. Galvan FH, Burnam MA, Bing EG. Co-occurring psychiatric symptoms and drug dependence or heavy drinking among HIV-positive people. J Psychoactive Drugs 2003; 35(Suppl. 1):153-160.
22. Lam NS, Liu KB. Spread of AIDS in rural America, 1982-1990. J Acquir Immune Defic Syndr 1994; 7:485-490.
23. Berry DE. The emerging epidemiology of rural AIDS. J Rural Health 1993; 9:293-304.
24. Holmes R, Fawal H, Moon TD, Cheeks J, Coleman J, Woernle C, Vermund SH. Acquired immunodeficiency syndrome in Alabama: special concerns for black women. South Med J 1997; 90:697-701.
25. Centers for Disease Control and Prevention. Risks for HIV infection among persons residing in rural areas and small cities - selected sites, Southern United States, 1995-1996. Morb Mortal Wkly Rep 1998; 47:974-978.
26. Crosby RA, Yarber WL, DiClemente RJ, Wingood GM, Meyerson B. HIV-associated histories, perceptions, and practices among low-income African American women: does rural residence matter? Am J Public Health 2002; 92:655-659.
27. Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126:946-954.
28. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000; 342:921-929.
29. Wawer MJ, Gray RH, Sewankambo NK, Serwadda D, Li X, Laeyendecker O, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005; 191:1403-1409.
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