In this study, we describe the clinical characteristics and response to HAART among HIV-infected military personnel and beneficiaries initiating treatment over the course of twelve years (1996-2007) with an average follow-up of over 6 years. The NHS is conducted within the military medical system allowing for an evaluation of HAART response in a U.S. clinical setting with free and open access to healthcare and medications.
After stratifying patients into two HAART initiation eras, 1996-2000 (EHE) and 2000 onward (LHE), it was evident that these eras differed significantly for several reasons. First, the large majority of patients starting treatment in the EHE had prior exposure to suboptimal therapy which has been shown to compromise the response to HAART [19
]. Secondly, more potent regimens were available in the LHE. Additionally, more patients in the EHE had a prior AIDS-defining illness likely impacting response [22
]. Furthermore, those who survived the pre-HAART era long enough to initiate HAART may have intrinsic host factors which could impact outcomes [24
]. Finally, there were significant differences in the timing of HAART initiation between both eras (duration of HIV diagnosis to HAART initiation and baseline CD4 count). This likely reflects differences in treatment guideline recommendations that were followed in each era and the fact that many patients starting HAART in the EHE became infected well before the availability of HAART. Despite the challenges experienced by participants initiating in the EHE, the percent virologically suppressed was around 60% throughout the duration of follow up.
For the LHE patients in this cohort, the virologic and immunologic responses were similar to those reported by randomized clinical trials using a regimen containing either efavirenz or a boosted-PI. A meta-analysis of 20 clinical trials by Gupta et al. described a VS rate of 76% and CD4 change of 176 cells/mL at 48 weeks [25
]. The rates we observed were equivalent or slightly higher than these and were sustained for more than 5 years. Limited population and cohort studies in the U.S. have shown variable VS rates at 3 to 8 months of 50-85% and rebound at 3 years of 20-50% [26
]. Outside the U.S., several cohorts with universal access to healthcare have demonstrated a remarkable response to HAART when compared to cohorts with similar demographics in the U.S.[3
]. The Swiss HIV Cohort Study reported an overall ITT VS rate of 89% and a CD4 increase of 177 cells/mL at 12 months after HAART initiation for ARV naïve patients during this same LHE [32
]. In this same analysis, the percentage of patients having a change or discontinuation within the first year of ART for any reason was 44.3-48.8% (varying by era) which is comparable to patients in the NHS.
Although there are drug assistance programs in the U.S. for eligible individuals with HIV/AIDS, the delay before medical care becomes available can postpone HAART initiation, and even the minimal associated costs can be a significant barrier for some patients [33
]. Co-payments and fees can reduce adherence and have been shown to increase mortality [35
]. It is important to note, however, that universal access to care and free medications are insufficient to ensure that all patients will achieve treatment success. Joy et al. described a population in Vancouver, Canada that has open access to healthcare but found that poverty, unemployment and a lack of post-secondary education impacted on survival in the HAART era [38
This cohort provided an opportunity to examine the relationship between demographic and clinical factors with outcomes after HAART in a clinical setting that minimized confounding related to access to care and IDU. Previously, we and others have shown associations between both age at HAART initiation [41
] and ethnicity [17
] with treatment response. Concordant with other studies, viral load was a predictor of VF and mortality and CD4 count was a predictor of immune reconstitution, AIDS events, and mortality [44
]. The CD4 recovery was greatest for those with lower baseline CD4 counts similar to findings by Hunt et al. [47
] which likely reflects the endpoint used in this analysis (50% increase). We also showed an association between the duration of HIV infection and CD4 reconstitution [48
] in addition to increased AIDS events despite a lack of evidence for these findings in a previous prospective study [49
]. Although conflicting findings abound in the literature with respect to gender differences in HAART response [50
], in the present study, women had a longer time to AIDS as compared to men (consistent with several similar reports [51
]). Surprisingly, among all subjects the initial regimen type was not found to be a significant predictor of VF [55
]. Although this analysis did not distinguish among the NNRTIs or boosted-PIs from unboosted-PIs, the era stratification accounted for differences in drug potency. Interestingly in our study, patients with a prior STI had a lower rate of VF. This is in contrast to studies showing a higher incidence of STIs being associated with non-adherence [56
] or a negative impact on VL and CD4 count likely via increased immune activation [59
Active duty status was associated with improved survival, immune reconstitution and a lower rate of AIDS-defining events. Although a distinctive factor in our cohort, important implications related to adherence and general health can be proposed as to why individuals on active duty had improved outcomes; some of which could be translated to other settings. Factors that might improve an active duty member's medication adherence include: (1) better access to ARVs, (2) closer clinical monitoring, and (3) a more disciplined and regimented environment. Although all participants in this cohort study do have free access to the DoD healthcare system, retirees can live further from network facilities and can choose private insurance resulting in copayments for ARVs. Furthermore, active duty personnel may be more closely monitored as they are required by their supervisors to seek medical care on a regular basis. As evidence, research study visit attendance has been shown to be significantly greater for active duty vs. others [17
]. General health may be better among active duty members because of physical fitness requirements, lower rates of substance abuse, and a cultural awareness of the benefits of health and nutrition [4
]. Additional factors such as stable employment and guaranteed housing may also contribute to better outcomes. Finally, the goal of remaining on active duty itself is an incentive to stay healthy. HIV-infected military personnel can remain on active duty and continue working, but the development of an AIDS-defining illness can lead to medical separation with retention of health benefits. Although the MV analysis adjusted for several clinical factors such as previous AIDS event, it is possible that non-active duty status is a marker for poorer health. This is substantiated by the fact that 28% of non-active duty patients were retired for medical reasons prior to the start of HAART.
One limitation of this study is that medication adherence data were unavailable for most patients (adherence questionnaires were added to the data collection in 2006). The relative impact of HIV drug resistance was also not assessed in this study. Finally, a disadvantage of any cohort study is that these results cannot be readily extrapolated to other clinical settings where rates of IDU, demographic characteristics, and access to healthcare differ. However, this cohort does provide an opportunity to observe sustainable treatment success after early HAART initiation under these conditions.