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Missing Doctor Visits Can Reduce Survival, CD4 Count & Affects Viral Load: Retention in Care: A Challenge to Survival with HIV Infection
 
 
  Clinical Infectious Diseases June 1, 2007;44:1493-1499
 
Thomas P. Giordano,1,2 Allen L. Gifford,3,4,5 A. Clinton White, Jr.,1,a Maria E. Suarez-Almazor,1,2,a Linda Rabeneck,7 Christine Hartman,1,2 Lisa I. Backus,6 Larry A. Mole,6 and Robert O. Morgan1,2
 
1Baylor College of Medicine and 2Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, Texas; 3Center for Health Quality, Outcomes, and Economic Research, Bedford Veterans Affairs Hospital, Bedford, and Departments of 4Health Services and 5Medicine, Boston University, Boston, Massachusetts; 6Center for Quality Management in Public Health, Department of Veterans Affairs, Palo Alto, California; and the 7University of Toronto and Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada
 
The study found a clear delineation between patient clinical outcomes of CD4 count, viral load reduction, and deaths in relationship to the number of patient visits to their clinic. Patients who visited the clinic once in each quarter (every 3 months) did better in each category, those with 3 of 4 quarterly visits did less better, those with 2 of 4 visits did worse compared to those with 3 of 4 visits, and patients who visited 1 in 4 quarters did the worst.
 
An Editorial by Laura Cheever, HRSA follows at the end of this report.
 
Background. Patients with human immunodeficiency virus (HIV) infection need lifelong medical care, but many do not remain in care. The effect of poor retention in care on survival is not known, and we sought to quantify that relationship.
 
Methods. We conducted a retrospective cohort study involving persons newly identified as having HIV infection during 1997-1998 at any United States Department of Veterans Affairs hospital or clinic who started antiretroviral therapy after 1 January 1997. To be included in the study, patients had to have seen a clinician at least once after receiving their first antiretroviral prescription and to have survived for at least 1 year. Patients were divided into 4 groups on the basis of the number of quarters in that year during which they had at least 1 HIV primary care visit. Survival was measured through 2002. Because data were available for only a small number of women, female patients were excluded from the study.
 
Results. A total of 2619 men were followed up for a mean of >4 years each. The median baseline CD4+ cell count and median log10 plasma HIV concentration were 228 _ 106 cells/L and 4.58 copies/mL, respectively. Thirty-six percent of the patients had visits in <4 quarters, and 16% died during follow-up. In Cox multivariate regression analysis, compared with persons with visits in all 4 quarters during the first year, the adjusted hazard ratio of death was 1.42 (95% confidence interval, 1.11-1.83; P < .01), 1.67 (95% confidence interval, 1.24-2.25; P < .001), and 1.95 (95% confidence interval, 1.37-2.78; P < .001) for persons with visits in 3 quarters, 2 quarters, and 1 quarter, respectively.
 
Conclusions. Even in a system with few financial barriers to care, a substantial portion of HIV-infected patients have poor retention in care. Poor retention in care predicts poorer survival with HIV infection. Retaining persons in care may improve survival, and optimal methods to retain patients need to be defined.
 
Although it may seem intuitive that persons who remain in medical care will live longer than persons who do not, that relationship has not been demonstrated for HIV infection or, for that matter, for other chronic diseases. We used the VA registry to study retention in care after starting antiretroviral therapy, hypothesizing that poor retention in care would be associated with adverse clinical outcomes, including death.
 
Cohort and baseline characteristics. The registry included 4752 patients entered into the database in 1997 and 1998 with HIV and outpatient visit data. Of these patients, 3691 (78%) were first prescribed an antiretroviral medication on or after 1 January 1997 and had a VA primary care visit on or after the date of their first antiretroviral prescription. There were 255 patients who died within 1 year after the index primary care visit, leaving 3436 patients. Baseline CD4+ cell count results were available for 2673 (78%) of these remaining patients. Of the 2673 patients, 54 were women; these women were dropped from further analysis because of the small sample size. The remaining cohort of 2619 men included 55% of the original sample. The 2133 patients not included in the study were also nearly all men (male sex, 95%), but compared with the study cohort, they were a mean of almost 1 year older and were more likely to have missing data for race/ethnicity. The final analysis cohort of 2619 men represents HIV-infected male veterans who used the VA health care system and who started antiretroviral therapy during the defined study interval with a baseline CD4+ cell count result available who survived for at least 1 year.
 
Baseline differences were found between the 4 groups with respect to known predictors of HIV disease survival, including age, race/ethnicity, CD4+ cell count, plasma HIV concentration, HAART use, and hepatitis C virus coinfection (table 1). In general, the persons with better retention in care had more-advanced disease, were older, and had received HAART slightly more often. They also had less hepatitis C virus coinfection, less alcohol use, and less hard illicit drug use. There were no differences in the prevalence of non-HIV-related comorbidities or socioeconomic instability.
 
Outcomes. CD4+ cell count and plasma HIV concentration data after 1 year of antiretroviral therapy were less often available for patients with worse retention in care. However, even for patients with available data, poor retention in care was associated with less improvement in CD4+ cell count and less reduction in plasma HIV level at 1 year (table 2).
 
Table 2. Clinical outcomes 1 year after starting antiretroviral therapy in a cohort of HIV-infected men who initiated antiretroviral therapy at a US Department of Veterans Affairs hospital or clinic, stratified by number of quarters in the first year during which an HIV primary care visit occurred. There is a clear delineation between patient clinical outcomes of CD4 count, viral load reduction, and deaths in relationship to the number of patient visits to their clinic. Patients who visited the clinic once in each qurarter did better in each category, those with 3 of 4 quarterly visits did less better, those with 2 of 4 visits did worse compared to those with _ visits, and patients who visited 1 in 4 quarters did the worst.
 

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Deaths after 1 year occurred in 425 patients (16% of the sample population). The unadjusted death rates trended higher with worse retention in care (P = .06). Kaplan-Meier results for >4 years of follow-up show that the group with visits in 1 of 4 quarters had the worst survival, whereas the group with visits in 4 of 4 quarters had the best survival (P = .02; figure 1).
 
Multivariate analysis adjusted for potential confounders to the relationship between retention in care and survival (table 3). The model included the entire analysis cohort and adjusted for age, race/ethnicity, baseline CD4+ cell count, receipt of HAART, hepatitis C virus coinfection, non-HIV-related comorbidity score, alcohol abuse, hard illicit drug use, and socioeconomic instability. After adjustment, poor retention in care was associated with poorer survival, with a dose-response relationship. Compared with persons who had visits in all 4 quarters, the adjusted hazard ratio of death was 1.42 (95% CI, 1.11-1.83; P < .01), 1.67 (95% CI, 1.24-2.25; P < .001), and 1.95 (95% CI, 1.37-2.78; P < .001) for persons with visits in 3, 2, and 1 quarter, respectively. Lower baseline CD4+ cell count, older age, a greater number of non-HIV-related comorbidities, and hepatitis C virus coinfection were also associated with increased risk of death.
 
In this cohort study of persons with HIV infection who were enrolled in care during the HAART era and who had a provider visit, a baseline laboratory assessment, and prescription of antiretroviral therapy, 36% were out of VA care for at least 3 months beginning in their first year of antiretroviral therapy. Approximately one-half of this 36% were out of care for at least 6 months. Patients out of care for as little as 3 months beginning in the first year of therapy had worse survival after adjusting for age, CD4+ cell count, plasma HIV concentration, hepatitis C virus coinfection, and other comorbid conditions. To our knowledge, this study is the first to demonstrate that poor retention in care for HIV infection (or, for that matter, for any chronic disease) has a negative impact on survival. The survival reduction associated with the poorest retention in care (i.e., associated with having a health care provider visit in only 1 of 4 quarters) was quite large, approaching that associated with having a baseline CD4+ cell count <200 X 106 cells/L. Patients with poor retention in care also had less improvement in CD4+ cell count and plasma HIV concentration in response to antiretroviral therapy at 1 year.
 
HIV-infected patients who miss clinic visits may also miss taking their antiretroviral medications [25, 26]. Patients who are poorly adherent to physician visits are less likely to receive HAART in the first place, are more likely to develop an infection with resistance to HAART, and are less likely to achieve HIV suppression [27-29]. Indeed, we constructed a measure of adherence to the initial antiretroviral therapy over the first 3 months of care [30] and found mean adherence percentages of 59%, 68%, 74%, and 79% in the groups with visits in 1, 2, 3, and 4 quarters, respectively (P < .001). We did not adjust for adherence to antiretroviral medication in the survival analyses, because it is likely that adherence or nonadherence to antiretroviral medication is on the causal pathway to the outcomes. Persons who are not retained in care cannot receive adherence-support interventions. The results of this study, even if largely driven by adherence to antiretroviral therapy, confirm that retention in care should be a goal of HIV care.
 
Reduced adherence to HAART, however, may not be the only important reason for high mortality among those with poor retention in care. Comorbid diseases other than HIV infection are common causes of disability and death, and they require active management [14, 31]. Worse outcomes in this cohort may well have been attributable to missed opportunities for treating substance use, psychiatric diseases, hepatitis C, diabetes, or heart disease, in addition to missed chances for antiretroviral therapy and prophylaxis against opportunistic infections. Because data on the cause of death are not available in these databases, we could not explore these possibilities.
 
The data from the present study provide objective support for HIV treatment guidelines that recommend that patients be seen every 3-4 months while receiving HAART [13]. They also confirm that policies and programs designed to improve retention in care, especially for those who are younger and less immunocompromised, are urgently needed. Little is known about how to retain patients in care. Provider continuity has been demonstrated to be important in general medical care [32]. Cross-sectional and nonrandomized studies of HIV-infected persons in care have shown that case management, access to social services, and flexible clinic hours are associated with better retention [33-35]. One randomized prospective trial demonstrated that a case-management intervention at the time of diagnosis of HIV infection helped people to engage and remain in care, but even with the intervention, more than one-third of the patients were not retained in care for >1 year, and the intervention was not effective for crack cocaine users [23]. The high rates of interruption in care over 1 year observed in that study and the present study are alarming when one considers that patients with HIV infection must remain in care for many years or even decades. Further research is clearly needed.
 
This study demonstrates that retention in care for HIV infection after starting antiretroviral therapy is often poor, even in a system with relatively few financial barriers to care. Patients with poor retention in care did not achieve the same CD4+ cell count, plasma HIV concentration, and survival benefits as those who were retained in care. Strategies to retain persons in long-term care need to be developed, tested, and implemented to maximize the benefit from currently available medical care.
 
EDITORIAL
 
Engaging HIV-Infected Patients in Care: Their Lives Depend on It

 
Laura W. Cheever
 
Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau, Rockville, Maryland
 
The HIV infection epidemic in the United States continues to expand to communities of color and poor populations, which have traditionally been medically underserved, and the health disparities associated with the HIV infection epidemic continue to increase. Up to one-quarter of HIV-infected individuals in the United States are unaware of their infection [1]. Without knowledge of their HIV infection status, patients will not enter into treatment programs and may unknowingly continue to spread the virus. Almost one-half of patients will undergo testing late in the course of HIV disease and will receive a diagnosis of AIDS within 1 year after receiving a diagnosis of HIV infection. [2] One-quarter of individuals who receive a diagnosis of HIV infection will remain outside of care [1]. As a result, only 56% of those who are eligible for antiretroviral treatment in the United States actually receive it [3], which is an appalling statistic, given the survival benefit associated with therapy.
 
Last year, the Centers for Disease Control and Prevention released new guidelines for HIV testing that challenge medical providers to make HIV testing routine [4]. This ambitious plan to improve the identification of infected individuals further challenges providers to link individuals with newly diagnosed infection to HIV care and to subsequently retain them in care, so that they may benefit from advances in HIV treatment.
 
Although HIV-positive patients who fully engage in care reap the maximum benefits, the term "engagement" in care describes a spectrum of patient care, ranging from initial diagnosis to full engagement in care. The Health Resources and Services Administration represents this continuum as outlined in figure 1. Patients can move in both directions across the spectrum. In some cases, patients who become fully engaged in care may go on to drop out of care for months or years at time [5, 6].
 
Even though researchers have focused a tremendous amount of resources during the past decade on projects concerning adherence to antiretroviral medication, relatively few projects have focused on the predictors of retention in care, the barriers that patients face that prevent full and continuous engagement in care, and the interventions that improve retention. Few statistics exist to portray the extent of the problem. Current research documents that, consistent with Maslow's hierarchy of needs, a patient's need for food, shelter, and other essentials can interfere with the ability to prioritize health care [7, 8].
 
In this issue of Clinical Infectious Diseases, Giordano et al. [9] use data from the Veterans Administration (VA) HIV Immunology Case Registry to demonstrate a dose response relationship between quarterly medical visits and reduced mortality-a seemingly obvious relationship, given the enormous survival benefit associated with receipt of HAART. However, these are the first data to demonstrate the survival advantage of regular HIV care. Interestingly, this improved mortality rate persisted, even though patients with more frequent visits had more-advanced HIV disease. The article [9] has several of the limitations associated with data obtained from a VA cohort: (1) the VA health care system is unique among health care systems in the United States, and the results, therefore, may not be generalizable; (2) information on care received by these patients at other health care facilities is not available; and (3) because of the small number of female subjects, women were ultimately excluded from the analysis. Given the integrated model, lack of financial barriers within the VA, and findings from several studies indicating that women have more barriers to care than men, the estimates are likely to be conservative. In fact, the impact of health care retention on mortality was amplified in the analysis that excluded those patients who had undetectable viral loads at the first visit; these patients had presumably received prior care elsewhere.
 
The data from this article [9] should serve as incentives for both researchers and health delivery systems to devote additional attention and resources to the problem of engagement in care. Further research is needed to better understand the barriers encountered across the spectrum of engagement (including the impact of service and health system design on retention) and to design cost-effective interventions that improve engagement. HIV care programs should examine their retention rates, identify those individuals who are at risk for loss to follow-up, and intervene both with patients at risk and with those who have not been retained in care. Quality-management programs should include retention in their portfolios of quality measures, both for new patients and for those followed longitudinally.
 
Giordano et al. [9] also found racial disparities between patients who were retained and patients who were not retained in care. This finding may partially explain the racial and sex disparities that occur in antiretroviral use that, in turn, correlate with kept health care provider appointments [10-12]. Improving retention may lessen disparities in antiretroviral use and use of other HIV services by underserved populations.
 
With limited staff-related and financial resources available for the care of the expanding population of medically underserved individuals living with HIV infection, we must invest wisely in reaching these patients. For that reason, the Health Resources and Services Administration has supported and continues to support a variety of engagement and retention interventions through Special Projects of National Significance initiatives. Many of our programs, which are largely based in clinics, have difficulty identifying those who have truly never been in care. This identification and linkage to care is effective when done at the time of HIV testing. Valuable interventions are being developed to target individuals at that time.
 
One such intervention, the Antiretroviral Treatment and Access Study, demonstrated that, for patients who have received a new diagnosis, as few as 2 case-management visits could significantly improve linkage to and retention in care [13]. A total of 78% of intervention participants attended 1 clinic visit; only 64% attended clinic visits twice within 1 year. In addition, crack cocaine users did not benefit significantly from the intervention. This and other studies [14, 15] document case management as an important intervention for some patients, but further work is needed to improve retention rates and to effectively reach illicit drug users. Furthermore, getting patients to walk through the clinic doors once does not ensure that they will return for a second clinic visit. Patients need to be engaged in care at their first clinic visit if they are to return a second time.
 
Our largely clinic-based programs, funded by the Ryan White Program, have attained a higher degree of success through outreach to patients who are lost to follow-up and who, therefore, are already "known" to the medical programs. The health systems have the names and often have the addresses or other contact information of such individuals. Our Special Projects of National Significance grantees have succeeded in finding those patients who are lost to follow-up by creating linkages with other community-service organizations. Medical programs often have existing relationships with these organizations and need only to start to use them differently.
 
Although networking often enables health care facilities to track their clients, programs must also commit to these clients' sustained engagement in care. Key concepts like "meeting clients where they are" have been implemented with impressive results. "System navigators"-guides that take a variety of forms-have helped clients to navigate our complex health care and social service system and to get the assistance that they need. In another successful strategy, peers and near-peers coach patients; for example, they rehearse patient appointments in advance, assist in the processing of information received during appointments, and role play responses to health care barriers.
 
In addition to targeting those individuals who are lost to care, programs have improved retention rates by targeting newly engaged patients, including both those who have received recent diagnoses and those who are returning to the clinic after a prolonged period without care. Using data from their programs, health care providers have developed risk assessments to identify those at risk of nonretention and to concentrate their resources on those patients who are most vulnerable. Interventions have focused both on navigating the health care system and on intensively fortifying relationships between patients and health care providers.
 
As well as analyzing data to assess those patients at risk for nonretention, grantees have looked at their own clinic populations and data to understand and address specific barriers to client engagement. For example, the barriers to care for Hispanic immigrant populations in Portland, Oregon, can differ from those for single-room occupancy hotel residents in New York City. To improve HIV care delivery in the United States' fragmented health care system, we must implement the important lessons that our outreach grantees and other researchers have learned.
 
As we move forward, we must continue to balance our provision of interventions and support services intended to help patients engage in initial care with those that are intended to help them remain in care. Multiple studies have shown that patients who access case management, transportation, mental health support, drug treatment, and other supportive services are more likely to be retained in care than are those who do not [16-18]. Interventions that assist patients to develop and maintain a positive relationship with health care providers [19-23] and to improve their knowledge of HIV infection and dispel negative health beliefs [24, 25] also improve outcomes.
 
Providers of the health care safety net in the United States have done a remarkable job in reaching the medically underserved by developing models of HIV care that integrate mental health and substance abuse treatment. Engagement and retention in care is also critical in those 2 areas, in which outcomes are associated with the length of time that the patient is in treatment. To continue to provide excellent health care services and reduce HIV-related health disparities-thereby diminishing the HIV infection epidemic-we must use our limited resources to develop, study, and adopt innovative strategies to engage and retain HIV-infected patients in care.
 
 
 
 
 
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