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Immune Status at Presentation to Care Did Not Improve among Antiretroviral-Naive Persons from 1990 to 2006

  1. Jeanne C. Keruly and
  2. Richard D. Moore
  1. Johns Hopkins University School of Medicine, Baltimore, Maryland
  1. Reprints or correspondence: Dr. Richard D. Moore, Johns Hopkins University School of Medicine, 1830 E. Monument St., Ste. 8059, Baltimore, MD 21287 (rdmoore{at}jhmi.edu).
 
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Abstract

Background. Human immunodeficiency virus (HIV) prevention initiatives to improve access to HIV services have increased over time. Despite this, >250,000 cases of HIV infection in the United States are undiagnosed, and many infected persons do not present for care until their HIV infection is advanced. Late presentation may increase the risk of HIV transmission and make HIV infection more difficult to treat effectively. With more effective HIV therapy, it was hoped that patients might present earlier in their disease course.

Methods. To assess immune status and time of HIV diagnosis in patients who newly presented for care, we analyzed data for the period 1990–2006 from patients who were antiretroviral naive at presentation to the Johns Hopkins HIV Clinic in Baltimore, Maryland. We compared CD4+ cell count and time from HIV diagnosis at presentation by demographic characteristics at enrollment.

Results. The median presenting CD4+ cell count decreased from 371 cells/mm3 during 1990–1994 to 276 cells/mm3 during 2003–2006 (P < .01) overall and decreased within individual demographic groups. There was also a decrease in the median time from HIV diagnosis to presentation for care (271 days in 1990–1994 to 196 days in 2003–2006; P < .01). Multivariate analysis revealed that, in addition to CD4+ cell count at presentation, male sex was associated with lower CD4+ cell counts (-93 cells/mm3), as was black race (-71 cells/mm3) and older age (-20 cells/mm3 per 10 years).

Conclusions. There has been a decrease in time from diagnosis of HIV infection to presentation for care, coupled with an increase in the severity of immunocompromise at time of presentation, over the past 16 years in Maryland. New strategies to provide earlier HIV testing and referral into care are urgently needed.

Innovative care models to improve access to HIV services along with HIV prevention initiatives in the United States have evolved over time to address the medical needs of HIV-infected persons and the public health need to contain the spread of the virus. In 1990, the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act was federally legislated to support the unmet health needs of HIV-infected persons by funding primary health care and support services to uninsured or underinsured persons [1]. Programs receiving such funds are required to develop clinical services that are medically appropriate and comprehensive with an emphasis on ease of accessibility, because services are targeted to poor, minority, and disenfranchised populations. In 1998, the Minority HIV/AIDS Initiative (MAI) was enacted. This $156 million federal initiative was implemented to enhance effective HIV/AIDS health efforts targeting minority communities. Two goals of the MAI initiative are to increase access to HIV prevention and care and to build community linkages that would enhance HIV prevention among minorities [2]. These HIV health care and prevention enhancements were simultaneously implemented at a time when the Centers for Disease Control and Prevention (CDC) revised their guidelines for HIV counseling, testing, and referral in 2001 [3].

Despite these efforts, by the end of 2003, approximately one-quarter of the 1.0–1.2 million persons estimated to be living with HIV infection were unaware of their HIV infection [4]. Persons who are unaware of their HIV status are unable to benefit from the advances made in HIV treatment, which include decreased HIV-related morbidity and mortality associated with initiation of antiretroviral therapy [5,6,7–8] and prophylaxis against opportunistic infections [8, 9]. Persons who undergo testing late in their disease course are more likely to be black or Hispanic and to have been exposed through heterosexual transmission [10].

Baltimore, Maryland, has been the recipient of Ryan White CARE Act funds since 1990; this eligible metropolitan area was also awarded MAI funding when it was made available in 1998. Additionally, Baltimore benefits from several counseling and testing centers throughout the city that are supported by both CDC funding and state funding. The Johns Hopkins AIDS program is the largest HIV care provider in Maryland, has an adult HIV program that receives both Ryan White and MAI funding, and has strong linkages with community agencies offering HIV counseling and testing. Given the efforts to improve access to care, coupled with the improvements that have occurred in HIV therapy, we wished to assess whether patients presented for HIV care earlier in the course of their HIV infection over time in a large urban center.

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Methods

Study design and population. All patients are part of the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients in primary HIV care in Baltimore and from 6 suburban and Maryland county HIV practices operated by the Johns Hopkins HIV service. This service provides longitudinal primary and subspecialty care for a large proportion of HIV-infected persons in the Baltimore metropolitan area and throughout Maryland. The Johns Hopkins HIV Clinical Cohort was established in 1990, and enrollment into the cohort coincides with the date of the first HIV clinic visit. After the subjects provide informed consent, information is collected by trained medical record technicians and is obtained electronically from a variety of sources, including outpatient and inpatient medical records, the Johns Hopkins Health System automated databases, supplemental medical records from outside facilities, and vital records. Fewer than 1% of patients have refused consent. Comprehensive demographic, clinical, laboratory, and pharmaceutical data are collected and summarized at times corresponding to enrollment and at 6-month intervals thereafter. The details of the database design and follow-up have been described elsewhere [11].

Inclusion criteria and variables of interest. The population for this study consisted of HIV-infected patients who were newly enrolled in the cohort from January 1990 through June 2006 and who were antiretroviral naive at the time of presentation to the clinic. Patients were stratified into 4 groups on the basis of year of enrollment at the clinic: 1990–1994, 1995–1998, 1999–2002, and 2003–2006 (data extend to June 2006). This stratification was selected a priori, so that the calendar time would be approximately equivalent among strata, with no selection of calendar strata based on any post hoc analyses. Information obtained at baseline included the patient's self-report of the date that he or she was first known to be HIV infected and HIV transmission risk behavior. The baseline CD4+ cell count was the value obtained closest to—but not after—the initial visit for clinical care. To be used for this analysis, the measurement had to have been made within 30 days of the initial clinic visit. Seventy-nine percent of the measurements occurred on the day of initial clinic visit. Other variables of interest included age, sex, self-reported race, and diagnosis of an AIDS-defining illness [12].

Analysis. We determined the median absolute CD4+ cell count at presentation and the number of days from when the patient first learned of his or her HIV-positive status (HIV diagnosis) and presentation for care, stratified by the 4 time periods specified above. This analysis was done for the entire sample and separately by sex, race (white or black), and HIV transmission risk group (injection drug user [IDU], men who have sex with men [MSM], and heterosexual). If there was both an IDU and sexual risk category reported concurrently, the patient was categorized as IDU for the analyses. Univariate statistical comparisons of demographic and clinical characteristics of the sample across calendar dates was done by the Cochran-Armitage trend test for categorical variables (sex, race, HIV transmission risk, and AIDS diagnosis) or by Cuzick trend test for continuous variables (age, CD4+ cell count, and number of days to presentation). Univariate statistical comparisons of CD4+ cell count and time (in days) to presentation, by demographic strata, were done by the Cuzick trend test. By multivariate least-squares linear regression analysis, we analyzed covariates associated with CD4+ cell count at presentation. An initial analysis included all covariates. A final multivariate model was computed using a backward stepwise approach, starting with all variables and retaining only those variables that were statistically significant (P < .05). All analyses were done using SAS, version 9 (SAS Institute) or STATA, version 8 (Stata).

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Results

A total of 3348 antiretroviral-naive patients met the inclusion criteria. The number and characteristics of these patients, stratified by years of enrollment, are shown in table 1. The patients were predominately male and of black race. Over time, the median age of the sample increased from 34 years (1990–1994) to 40 years (2003–2006). Transmission risk also changed over time, with fewer IDU and greater heterosexual transmission reported (P < .01). In all but 1 stratum (1995–1998), patients presented to care within 1 year of learning that they had HIV infection. There was a significant decrease in the median CD4+ cell count over calendar time (P < .01). Figure 1 shows the median CD4+ cell count for each calendar year from 1990 to 2006.

Figure 1
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Figure 1

Plot of CD4+ cell count in antiretroviral-naive persons at presentation for HIV care, by calendar year

Table 1
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Table 1

Characteristics at enrollment of antiretroviral-naive patients in a study assessing when in relation to diagnosis is care for HIV sought.

Table 2 shows the median CD4+ cell count and time from diagnosis of HIV infection to presentation for care, stratified by calendar year of presentation and by demographic and HIV risk characteristics. The median CD4+ cell count at presentation decreased over time in both women and men and in black patients (table 2). The CD4+ cell count also decreased over time in heterosexual and IDU HIV transmission subgroups but not in the MSM transmission subgroup. The time between HIV diagnosis and presentation for care decreased in men, in persons of white race, and in patients who had MSM as their HIV transmission risk. Notably, time from diagnosis of HIV infection to presentation was >2 years for patients with IDU risk after 1995. The shortest time interval between diagnosis of HIV infection and presentation was in MSM, with a significant decrease in time to presentation from 1990–1994 (215 days) to 2003–2006 (87 days).

Table 2
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Table 2

CD4+ cell count and time to presentation from HIV diagnosis, stratified by demographic characteristics.

Multivariate analysis (table 3) revealed that the presenting CD4+ cell count was significantly lower in all calendar year strata than in 1990–1994, with estimates ranging from -57 cells/mm3 in 1995–1998 to -78 cells/mm3 in 2003–2006, compared with the 1990–1994 group. Other covariates associated with a decrease in CD4+ cell count included older age (-20 cells/mm3 per 10 years), male sex (-93 cells/mm3), and black race (-71 cells/mm3). IDU transmission risk was associated with a higher CD4+ cell count at presentation (+61 cells/mm3), although heterosexual transmission and the duration of time from diagnosis of HIV infection to entry into care were not associated with CD4+ cell count (P = .48 and P = .27, respectively).

Table 3
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Table 3

Multivariate analysis of factors associated with CD4+ cell count.

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Discussion

Over the past 16 years, Maryland has been fortunate to have good resources for clinical care and HIV counseling and testing. Regional mandates for providers receiving Ryan White CARE Act funding and recommendations from the CDC for counseling and testing sites emphasize the need for coordination of services and referral to primary care [3]. One would hypothesize that, in this scenario, patients would present earlier in the course of disease. Instead, our data indicate that patients are presenting later for care than in earlier years, with lower CD4+ cell counts, a small increase in those who have AIDS, and no improvement in the time between HIV diagnosis and presentation for care for women or those with heterosexual transmission.

Although this analysis included only patients who were antiretroviral naive, we do not know whether some of these patients had presented previously for care elsewhere before first presenting for HIV care with us. However, because the median time from diagnosis of HIV infection to presentation was only 6–12 months throughout time, and because the natural history of the decrease in the CD4+ cell count was only an average of ∼50 cells/mm3 per month [13], our data would still indicate that presentation to care is late and has not improved over time.

Others have found that patients present late in the course of infection. Krawczyk et al. [14] found that, among 1209 patients who newly presented for care in an ambulatory infectious diseases clinic in Alabama, infection in 41.2% had already progressed to CDC-defined AIDS. Similar to our findings, more than one-half of patients received their HIV diagnosis in the year preceding entry to care [14]. Delay in diagnosis can affect survival. In one study it was shown that 40% of persons in the United States have their first HIV serological test within 1 year of an AIDS-defining complication and that delayed initiation of treatment reduces the survival benefit of antiretroviral therapy by 5.1 years [15].

Over time, among antiretroviral-naive patients presenting for care, differences emerged that reflect the changing demography of the HIV epidemic in Maryland and in the United States [16,17–18]. There has been an increase in the proportion of women with HIV/AIDS and an increase in the age of patients. In Maryland, the primary risk factor for HIV transmission has also changed, with a decreasing proportion of IDUs and an increase in heterosexual transmission. In most demographic and HIV risk groups, the CD4+ cell count at presentation decreased over time. In 1998, guidelines for the use of antiretroviral therapy recommended that therapy should be offered at a CD4+ cell count of 500 cells/mm3 [18]. In 2002, guidelines were revised to recommend that therapy could be delayed until the CD4+ cell count was in the 200–350 cells/mm3 range [19]. Although it is possible that the 2002 revision of the guidelines could have influenced time of presentation for patients who presented in 2003–2006, we doubt that this was a major influence on when patients presented because of the lateness of HIV diagnosis over time.

These data came from a single large clinical practice in Maryland. Therefore, they may not generalize to other locations in the United States or to other industrialized countries. However, we suspect that they may generalize, because recent data from the North American AIDS Cohorts Collaboration on Research and Design, which represents >90,000 HIV-infected persons in the United States and Canada, indicated that the presenting CD4+ cell count at the initiation of HAART was only ∼200 cells/mm3 after calendar year 2002 (Richard D. Moore, personal communication), and data presented recently at the Conference on Retroviruses and Opportunistic Infections also showed a CD4+ cell count of only ∼200 cells/mm3 at the time of initiation of therapy in 2003–2005 in North America and Western Europe [20]. Nevertheless, we do not know how our results on time from diagnosis of HIV infection to presentation compare with data from other areas, because we are not aware of any data by which to compare. We suspect that our results are most likely to generalize to HIV-infected populations in which the demographic characteristics are most similar.

Although our data are from one metropolitan area, it is an area with a significant HIV/AIDS epidemic. Maryland has the third-highest AIDS case rate (28.5 cases per 100,000 population) of any US state. The Baltimore metropolitan region has the second-highest AIDS case rate (40.4 cases per 100,000 population) of any metropolitan region in the United States [21], and Maryland has the third-highest annual AIDS case report rate (28.5 cases per 100,000 population) of any state and the District of Columbia. It is also notable that our clinical practice provides care not only in the city of Baltimore, but also at 6 sites in suburban and rural Maryland, through county health departments. Statewide data based on reported cases of HIV infection and AIDS from all county and city health departments to the Maryland State AIDS Administration show that, of the persons living with HIV infection or AIDS, 65% are men, and 82% are African American; 55% have IDU as the risk factor for HIV transmission, and 67% are aged 30–49 years. These statewide demographic characteristics [21] are almost identical to the demographics of our sample. Of note, the State AIDS Administration has been reporting the demographic data for the HIV epidemic in Maryland since the 1980s, and the changing demographic characteristics of our cohort have reflected the demographic data for the epidemic in Maryland over time. A final caveat is that self-reporting of the date of first HIV diagnosis is subject to recall bias. This is not an inception cohort, so we do not have serial HIV serotesting. However, we have no reason to believe that recall would be any worse or better over time, so we believe that it is likely that trends in our data are valid.

A delay in presentation for treatment not only increases the chance of clinical disease progression for that patient; it may increase the risk of ongoing transmission, because there is a delayed opportunity for effective antiretroviral treatment, which can lower circulating HIV-1 RNA levels [22, 23]. There is clearly a need for early diagnosis and intervention. HIV testing is entering a new era as practice guidelines have recently changed to address the need for increased testing and earlier testing with linkages to care. In September 2006, the CDC released Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings [24]. These new recommendations advise routine HIV screening of adults, adolescents, and pregnant women in health care settings in the United States. These revised guidelines also call for the removal of a separate informed consent for HIV testing, because this is seen as a barrier to early diagnosis of HIV infection [25, 26]. The guidelines suggest that general consent for medical care should be considered sufficient to encompass consent for HIV testing. To adopt these recommendations into practice, state laws will need to be changed in 14 states that require HIV-specific written informed consent and in another 14 states that require specific consent, either written or verbal, for HIV testing [27]. In addition, public health officials, hospital administrators, and clinicians will need to change policies and practice to ensure that more persons are screened and referred for early treatment if we are to make any impact on improving the health of HIV-infected persons and reducing the spread of the virus.

During the past 16 years in Maryland, there has been no improvement in getting patients into care earlier in the course of their disease. Patients present with AIDS, and a high proportion with symptoms of an AIDS indicator condition, potentially complicating the initiation of treatment. Demographic disparities in when patients present to care continue. These data provide compelling evidence that implementation of new strategies for HIV testing and entry to care, recommended by the CDC, are urgently needed.

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Acknowledgments

Financial support. National Institutes of Health (R01 DA-11602, K24 DA-00432, and R21 AA-105032).

Potential conflicts of interest. R.D.M. has received research funding from Gilead Pharmaceuticals and has served as a consultant for Bristol-Myers Squibb; J.C.K.: no conflicts.

  • Received June 1, 2007.
  • Accepted July 17, 2007.
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