Table 4 shows the odds ratios for selected factors of having an undetectable VL at 6-months post-HAART from a multivariate logistic regression model. Serum creatinine at HAART initiation and hepatitis C coinfection were not significant in the univariate analysis and were therefore not included in the multivariate model. The odds of obtaining an undetectable VL after 6 months of HAART was 0.6 for AA compared with EA [P < 0.001, 95% confidence interval (CI) 0.4-0.8] after adjusting for age and military rank at HAART initiation, sex, VL and CD4 count at HAART initiation, AIDS and ARV use before HAART, specific HAART regimen, serum hemoglobin at HAART initiation, hepatitis B coinfection, year of HAART start, STDs after HIV diagnosis, and diagnosis of major depression. Similarly, the odds ratio for AA at 12-months post-HAART was 0.6 (P = 0.002, 95% CI 0.4-0.8). The results did not significantly change when the analyses were limited to only subjects with estimated dates of seroconversion, only subjects who were not officers, only subjects who were diagnosed with HIV infection in the HAART era, or only subjects who were active duty (data not shown).
Of those AA and EA who achieved a VL < 400 c/mL 6 months after HAART initiation, there was no significant difference between AA and EA in time from suppression to virologic failure [HR (AA vs EA): 1.2, 95% CI 0.9-1.6, P = 0.18]. Of those who started HAART but did not achieve an undetectable VL until more than 6 months after HAART initiation, there was a trend toward AA experiencing virologic failure more quickly; however, this did not reach statistical significance (HR: 1.3, 95% CI 1.0-1.7, P = 0.07).
In this evaluation of over 650 AA and 650 EA initiating HAART in a military, longitudinal cohort study with open access to health care and free medications, AA had 40% lower odds of achieving viral suppression than EA at both 6 and 12 months after therapy initiation. Of AA achieving viral suppression at 6 months; however, their time to virologic failure was not significantly different than EA. Therefore, there seem to be factors that contribute to AA having decreased rates of initial virologic suppression, but those without these factors (ie, AA who achieve viral suppression at 6-months post-HAART) are able to maintain viral suppression over time similar to EA.
Several other studies have also found that AA do not have the same initial virologic response to HAART as EA.1-5 A study examining sociodemographic characteristics of persons receiving HIV-related care in the southeastern United States found that those of minority ethnicities discontinued ART more rapidly and demonstrated virologic failure more rapidly than whites. The authors noted that lack of private health insurance disproportionately affected the ethnic minorities and theorized that the reliance on state run AIDS drug assistance programs, clinical trials, or charity care programs may have made gaps in coverage more likely resulting in an inability to obtain medications.3 A study of 961 women (including 573 AA and 184 white) in the Women's Interagency HIV Study found that white women exhibited better immunologic and virologic responses to HAART and lower rates of virologic failure compared with AA. When the analysis was restricted to women who remained on ART after initiation, there were no significant differences in outcomes between the groups.1 Therefore, differential access to care or medications may explain at least part of the results of these studies.
In the current study, AA and EA had equal access to free care and medications. Approximately, 60% of both AA and EA enrolled were on active duty and therefore their command should have required them to seek medical care at regular intervals. There was no difference between active duty AA and active duty EA in the average number of visits attended per year (1.53 and 1.52, respectively). There was also no difference between nonactive duty AA or EA in the average number of visits attended per year (1.33 and 1.26, respectively) although active duty members of both ethnicities had significantly more visits than nonactive duty members. When the multivariate analysis was limited to only active duty members, the results were similar. Therefore, in this cohort, AA and EA accessed care similarly; despite this, however, there were large differences between the 2 groups in virologic response to HAART.
Besides access to care, viral suppression also depends on high levels of adherence to HAART.16-18 The DoD HIV NHS did not start collecting self-reported adherence until 2006 and we were not able to access refill information therefore we could not evaluate whether adherence differences account for the differences in virologic suppression. Other investigations into the association between ethnicity and adherence have shown mixed findings. A study of 2088 HIV-infected children and adolescents conducted by the Pediatric AIDS Clinical Trials Group did not find any association between self-reported medication adherence and ethnicity.11 Likewise, a study of 861 veterans taking HAART did not find any differences by ethnicity in adherence as measured by 3 questions taken from a validated instrument used by the Adult AIDS Clinical Trials Group.4 In contrast to these studies, a prospective, randomized, controlled trial of 3- vs 4-drug ART regimens for the initial treatment of HIV infection in 765 patients (approximately, 35% black and 40% white) found that black patients had lower self-reported adherence rates at weeks 4 and 12 post-HAART but not at weeks 24 and 48.12
Evaluating potential adherence differences between ethnicities in a population with free access to medications is important in understanding differences in HAART response but it still may not fully explain why differences exist. If virologic outcome differences disappear when adherence is adjusted for, as was seen in a study of intravenous drug users with free access to medications,19 one would then need to evaluate why there are differences in adherence between ethnicities. It may be due to differences in absorption, distribution, metabolism, or elimination of the HAART causing different side effects or toxicities in subjects of different ethnicities or it may be due to differences in beliefs about medications or differences in education received about the medications.
The largest differences in response to HAART between AA and EA were seen with protease inhibitor based regimens with or without ritonavir, and the smallest difference was seen with NNRTI-based regimens. NNRTIs have a lower genetic barrier to resistance, and therefore one might expect that if differential adherence between the ethnic groups that was not due to side effects or toxicities was the main driver of the observed difference in virologic response, that the largest difference in response would have been between subjects using NNRTI-based regimens. The majority of PIs in this study were older, less potent ones than are available today. Slight differences in absorption, distribution, metabolism, or elimination of these older regimens between ethnicities may have lead to different side effects, toxicities, or potencies and may have contributed to the differences in virologic suppression.
Having a college degree has been associated with a favorable response to HAART.20 In the military, rank is a rough surrogate for education. Although the vast majority of both AA and EA in this study were not officers, EA were significantly more likely to be officers than AA. In the multivariate model, rank was not significantly associated with viral suppression at 6 or 12 months but to ensure that rank was not contributing to the outcome, we repeated the analyses limiting the subjects to only nonofficers and the results remained unchanged.
AA in this cohort had lower CD4 counts and CD4 percentages at diagnosis compared with EA. Although non-HIV infected AA have lower total white blood cell counts than EA, in the general population there is no difference between these 2 ethnicities in percentage of total lymphocytes that would explain these findings.21-23 One study of CD4 counts within 24 months after seroconversion conducted from 1987 to 1991 did not find a significant difference in CD4 counts between ethnicities, but did in CD4 percentages.24 To further explore this, we examined the rate of CD4 decline from HIV diagnosis to HAART initiation to determine whether CD4 cells decline faster in AA. We did not find a difference in the slopes between AA and EA. There is some evidence that immune response may play a role in the virologic response to HAART.25,26 If this is true, whatever factors contribute to lower CD4 counts in AA at HIV diagnosis may also contribute to differences seen in virologic response to HAART between ethnicities. This finding needs to be confirmed with additional studies.
AA also had higher rates of hepatitis B, hepatitis C, and STDs than EA. Although these coinfections were not significantly associated with odds of viral suppression in the multivariate model and in other studies have not been found to be associated with response to HAART,27,28 they may be markers of a certain type of behavior or belief system which affects response to HAART. Another possibility is that complications of those coinfections themselves or side effects or drug interactions from their treatment, could affect HAART adherence. The DoD HIV NHS does not collect information on illicit substance use; however, because random mandatory drug testing was instituted in the military in 1992, rates of illicit drug use have remained low in the active duty population and the odds of illicit drug use do not differ between AA and EA.29 Furthermore, a study conducted in over 500 HIV-infected active duty members found that intravenous drug use was rare with a prevalence of <1%.30
Despite the large number of subjects included in this study, it is important to note that one-third of the AA and EA who started HAART were excluded from analysis because of missing VLs. The excluded individuals were diagnosed with HIV in earlier calendar years and because VL testing did not become routine in the military until 1997, this most likely explains why they did not have a VL around HAART initiation. Although excluded subjects were significantly different than those included (lower CD4 counts at HAART initiation and more PI-based regimens, both of which reflect the earlier calendar period of HIV diagnosis), the percentage of AA and EA excluded was the same and therefore it is not likely that these exclusions influenced the results of the study. Furthermore, the results of this study were unchanged after restricting the analysis to subjects diagnosed with HIV in the HAART era.
There may be additional factors that could contribute to the differences in virologic suppression between AA and EA. Perhaps physicians treat subjects of different ethnicities differently or perhaps patients respond to providers of discordant ethnic background or gender differently. The timing of HAART initiation and the regimens prescribed was not significantly different between the groups; however, there could be differences in education given to the subjects or other factors. There could be selection bias as to who was started on HAART; however, this may have lessened the chance of finding differences between the groups as physicians may have selected only those they thought would adhere to the HAART regimen.
This study adds to the body of evidence that AA do not have the same virologic response to HAART as EA. It is imperative that we understand why the HAART response rates are lower in African versus EA to optimize therapy for all HIV-infected individuals. More efforts need to be focused on psychological, social, and cultural factors and genetic differences between ethnicities and how these may impact response to therapy.
We would like to thank the patients without whom none of this work would be possible. We would also like to thank the research coordinators and support staff who diligently work on the DoD HIV NHS and the members of the IDCRP HIV Working Group (by site): National Institute of Allergy and Infectious Diseases, Bethesda, MD: M. Polis, J. Powers, J. Metcalf, E. Tramont; Naval Medical Center, Portsmouth, VA: J. Maguire, T. Lalani; Naval Medical Center, San Diego, CA: M. Bavaro, N. Crum-Cianflone, H. Chun, B. Hale; National Naval Medical Center, Bethesda, MD: C. Decker, A. Ganesan, T. Whitman; San Antonio Military Medical Center, San Antonio, TX: V. Marconi, M. Landrum, W. Bradley; Tripler Army Medical Center, Honolulu, HI: S. Fraser; Uniformed Services University of the Health Sciences, Bethesda, MD: S. Wegner, B. Agan, G. Martin, G. Quinnan; Walter Reed Army Institute of Research, Rockville, MD: L. Jagodzinski, N. Michael, M. Milazzo, R. O'Connell, S. Peel; Walter Reed Army Medical Center, Washington, DC: C. Hawkes, A. Weintrob, G. Wortmann.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
virologic response; HIV; HAART; ethnicity; African Americans; European Americans