Since we had collected detailed adherence data only at study visits after October 1998, we analyzed the association of adherence with both laboratory and clinical outcomes, while adjusting for race (Table 3, model 6). Among the 297 women (30.9%) with adherence data at HAART initiation, we found no statistically significant differences (P = 0.845) between adherence to therapy at HAART initiation and race (Table 1). At least 73% of each racial group reported at least 95% adherence. Higher adherence was strongly associated with favorable virologic and immunologic responses and with reduced risk of a new ADI (Table 4).
Depression reported following HAART initiation was associated with HAART discontinuation (RH = 1.40, P = 0.004). Race, however, was the stronger predictor of discontinuation, with white women less than half as likely as African American (RH = 0.43, P < 0.001) or Hispanic women (RH = 0.32, P < 0.001) to discontinue therapy independent of depression (data not shown). Thus, the higher prevalence of depression did not explain the higher rate of HAART discontinuation in African American and Hispanic women.
HIV infection, hypertension, diabetes, and trauma are responsible for most of the 6-year lower life expectancy of African Americans compared with whites in the United States.35 HIV disease accounts for 11.2% of the disparity, almost as much as ischemic heart disease (5.5%), stroke (2.8%), and cancer (3.4%) combined.35 In our study investigating the relationship of race with response to HIV-1 treatment among 961 women initiating HAART, white women had more favorable virologic, immunologic, and clinical responses to HAART. The poorer responses to HAART found in African American and Latina women, however, were explained largely by HAART discontinuation and to a lesser extent, by depression. Although discontinuation of therapy may be secondary to toxicity that results from specific genetic determinants of drug metabolism and transport, both depression and therapy discontinuation are potentially mutable. This suggests that treating depression and ascertaining and addressing reasons for treatment discontinuation could substantially improve outcomes in African American and Latina women.
Pharmacokinetics of antiretroviral agents is influenced by genetically determined factors that vary by individual ancestral history. Several studies have demonstrated that African Americans experience higher toxicity and higher rates of discontinuing therapy.8,10,11 For example, investigators have found slower clearance or higher rates of central nervous system toxicity and discontinuation of efavirenz associated with polymorphisms of the 2B6 pathway of the cytochrome P450 system.10,11 Thus, biologic mechanisms resulting in greater drug toxicity may account for the racial differences we found in HAART discontinuation.
Racial disparities in health outcomes, including HIV-1-related illness, have also been attributed to social determinants such as lower socioeconomic status, lower educational attainment, and differential access to and quality of health care services.17,18,37-43 Even in a setting of a national universal health care system, lower socioeconomic status was shown to be associated with reduced access to HAART. Among HAART recipients, however, socioeconomic status did not affect virologic response.42 Similarly, in the United States, where health care is not universally available, HIV-1-infected persons of color are less likely to receive antiretroviral therapy when indicated40,41 or to access state entitlement programs.39,40 In our study, although we focused on women who reported initiating and thus had some access to HAART, the differences in therapy continuation may be associated with more subtle and complex differences in access to and quality of care that we were unable to measure.
The association of HAART discontinuation with depression suggests that identification and treatment of depression can improve the effect of HAART. We and others have previously reported that depression predicted HAART discontinuation,44 poorer laboratory responses45 while on antiretroviral therapy, and a greater likelihood of AIDS-related deaths and that treatment of depression was associated with reduced mortality.46,47 However, the association of race with HAART discontinuation was not explained by depression, suggesting that ascertaining and rectifying the causes of discontinuing indicated therapy by women of color could also improve their response to HAART. Our current findings also support studies that have found no difference by race in immunologic48 or virologic responses.41 Adherence was associated with better responses in our study, but adherence did not vary by race. This is in contrast to some prior studies in populations mostly or exclusively male, in which white race was associated with higher rates of adherence.49-51 It is possible that our ascertainment of adherence did not completely describe differences by race or that such differences are less marked in women. Further investigation is warranted.
The Institute of Medicine Report concluded that there is “clear and convincing evidence for racial disparities in health care” in the United States.52 Some of this disparity may be attributable to difficulties in communication: whites are half as likely as Latinos in the United States to perceive difficulty communicating with their physician, and one-third less likely than African Americans.53 Latinos and African Americans are less likely to trust their provider to diagnose and choose therapy in the patient's best interest.54 These mechanisms could influence HAART discontinuation and the diagnosis and treatment of depression. An important next step will be to ascertain directly from patients their reasons for discontinuing HAART.
A limitation of our study is the low rate of HIV-related clinical outcomes after HAART initiation, particularly in AIDS deaths (16 per 1000 person-years), limiting our ability to rule out a clinically significant difference by race in clinical outcomes. A methodologic limitation of our study is that some of the exposures, specifically depression and HAART discontinuation, were ascertained at the same visit as the virologic and immunologic endpoints. In addition, HAART discontinuation could have been the result of virologic or immunologic failure, rather than the cause. The very large relative hazards, the strength of the association of HAART continuation with both laboratory and clinical outcomes, and similar findings when analyses were limited to women who continued HAART, however, suggest that some or even most of the improvement in outcomes results from the continuation of therapy. These analyses complement our other reports demonstrating the consequences of HAART discontinuation.55,56
Another significant limitation of our study, as in most studies that attempt to investigate the impact of race, is the impossibility of defining race as a biologic construct. We used women's self-classification of race and ethnicity to group them by common ancestry, comparing all women self-identifying as “black” (of African ancestry) with all women self-identifying as white (of European ancestry). In addition, there were 204 women self-identifying as Hispanic, a term that defines ethnicity and not race, but not identifying themselves as either black or white, and for whom there were some significant differences in baseline characteristics and in clinical outcomes. As reviewed recently,57 ancestrally determined differences in drug transport or metabolism may carry clinical significance, and the large majority of studies of the efficacy and tolerability of antiretroviral regimens have been performed in populations of predominantly European ancestry. The trend toward poorer outcomes in African American and Latina women, especially AIDS-related deaths, deserves further investigation with longer follow-up in this and other cohorts, to confirm that there is not a significant difference by race. Also important for HIV-1-infected African American and Latina women in the United States is the diagnosis and treatment of depression and exploration and rectification of the factors related to HAART discontinuation, as these may be contributing substantially to poorer health status, including death, among HIV-infected women of color.
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