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Age-Old Questions: When to Start Antiretroviral Therapy and in Whom? COMMENTARY....... Age at entry into care, timing of antiretroviral therapy initiation, and 10-year mortality among HIV-seropositive adults in the United States
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Download the pdf here
Download the pdf here
"The current report by Edwards et al. must be considered preliminary. This modeling study was based on retrospective and observational data, with many potential confounders. This modeling study was based on retrospective and observational data, with many potential confounders. The younger patients were more likely to be male, men who had sex with men (MSM), and Hispanic, whereas the older population was more likely to be injection drug users (IDU) with higher competing morbidities and to have an AIDS diagnosis on entry. In addition, causes of death and co-morbidities were not recorded, and loss to follow-up was high."
original study - "The effect of delaying ART initiation on 10-year mortality was not homogenous among age groups. For patients who entered care at a CNICS site between ages 18 and 34, delaying ART until CD4 cell count dropped below 200 cells/mm3 had little effect. The effect of delaying ART was slightly more pronounced among patients who entered care between ages 35 and 44. However, among patients who entered care between ages 45 and 65, delaying ART had a profoundly deleterious effect: delaying ART until CD4 cell count dropped below 200 cells/mm3 increased 10-year mortality from 19% (had patients initiated ART when CD4 cell count first dropped below 500 cells/mm3) to 28%."
from Jules: Again the benefits of early ART are not only associated with mortality but also the development of comorbidities & earlier ART has been shown to delay or prevent comorbidities as the longer you wait to start ART the damages accrues to the immune system & often this damage is not reversible.
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Age-Old Questions: When to Start Antiretroviral Therapy and in Whom? COMMENTARY
Clinical Infectious Diseases Advance Access published June 16, 2015
Rochelle P. Walensky, Martin S. Hirsch
From the Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Two seemingly unrelated themes have emerged in HIV research over recent years. One relates to the increasing evidence that early introduction of antiretroviral therapy (ART) in infected individuals is preferable to delayed therapy, and the second to the interactions between HIV and aging in our population. An article by Edwards et al. in this issue of Clinical Infectious Diseases [1] suggests that these themes may be closely related.
When to start ART has been controversial since the 1980s, and recommendations from different guideline committees have fluctuated widely, even within the same groups over time (Figure). The most widely used US guidelines currently recommend treating virtually all HIV-infected persons, regardless of CD4 cell count [2, 3], whereas other guidelines draw rather arbitrary CD4 cell limits for ART initiation (<500 or <350 cells/μl) because of the paucity of clinical endpoint data from randomized clinical trials supporting early therapy. Until recently, data to support when to start have come largely from cohort studies that suggest higher death rates are associated with deferred ART [4-6]. Some studies have also utilized non-clinical endpoints to suggest that early ART is preferable to deferred therapy [7, 8]. In addition, one important randomized clinical trial indicated that in a study of discordant couples (one HIV-infected, one not), early ART was associated with a 96% reduction in HIV transmission to the uninfected partner [9]. Thus, early therapy may not only benefit the individual patient, but may have public health advantages as well.
Two recently and preliminarily reported randomized controlled trials have further informed the when to start question. In February 2015, results of the seven-year Temprano trial were presented. In this four-arm factorial design study enrolling 2,056 participants with CD4 cell counts >500/μl in Cote d'Ivoire, the investigators examined both the benefit of early ART and that of early antituberculosis chemoprophylaxis. Results demonstrated that ART started at CD4 cell counts >500/μl reduced the risk of serious infection and death by 44% compared to ART initiation performed according to current World Health Organization guidelines [10]. In May 2015, the preliminary results of the START trial were announced [11]. Like the TEMPRANO study, the START trial compared initiation of ART in HIV-infected individuals whose CD4 cell counts were >500/μl (early group) with ART initiation when CD4 cell counts declined to 350/μl (deferred group). The study enrolled 4,685 participants, and after approximately three years of follow-up, an interim analysis by a Data Safety Monitoring Board found that the risk of the combined clinical outcome, which included AIDS related events, serious non-AIDS events, or death, was reduced by 53% by early compared with deferred treatment (41 vs 86 events). Findings were consistent across geographic regions, and the benefits of early treatment were similar for participants from low-, middle- and high-income countries. Collectively, these two studies offer solid support for starting ART in all HIV-infected individuals as soon as they enter care, irrespective of CD4 cell count. Full publication of both trials is anticipated.
Regarding the aging theme, we also know that the population of HIV-infected individuals is aging. Approximately 30% of HIV-infected persons in the US are now over 50, and this proportion is expected to increase steadily over time; moreover, HIV disease progression appears to be more rapid among older individuals [12], and the reasons for this are likely multi-factorial. Older individuals often have co-morbid conditions involving multiple organ systems [13, 14]. In addition, older age may affect susceptibility to, and transmission of, HIV, either physiologically by reducing immunologic or mucosal barriers (e.g., via atrophic vaginitis), or behaviorally, such as by reduced condom use because of less concern for pregnancy [3]. Finally, HIV itself may affect the biology of aging by mechanisms yet to be determined [15].
The novel findings by Edwards et al. begin to elucidate whether there are different age subgroups within the population of HIV-infected individuals in whom the benefits of early ART initiation are more apparent [1]. In their study, 10-year mortality rates were determined using the parametric g-formula to compare 3,532 US patients in three different age groups (18-34y; 35-45y; 45-65y) who entered care between 1998 and 2013. Overall, projected 10-year mortality increased from 11% when ART was initiated at a CD4 cell count threshold of 500/μl to 14% when treatment was initiated at a threshold of 200/μl. However, the effect of delaying ART was age-dependent, with the greatest benefit of early ART projected in the oldest age group studied. Although there was little effect of early therapy on the youngest age group studied, the effects of early ART on the oldest age group were profound.
Despite these impressive results, today it is difficult to optimally implement early ART in older patients. Data from 2007 note that the median CD4 count at the first test performed after an HIV diagnosis was 135/μl in patients 55-64 years, compared to 313/μl for patients 15-24 years [16]. As of 2010, only 37% of persons aged 45-64 years had ever had an HIV test, compared to 57% of persons aged 25-44 years [17]. In addition, linkage to HIV care rates are among the worst for older patients [18]. These markers for delays to care might be attributable to fewer devoted resources because of lower anticipated rates of infection; however, this is not borne out by available data. In a recent Centers for Disease Control and Prevention testing report, newly identified HIV positivity rates were equal in the age categories of 20-29 years and >50 years (0.5%) and were highest among those 40-49 years (0.7%) [18].
The current report by Edwards et al. must be considered preliminary. This modeling study was based on retrospective and observational data, with many potential confounders. The younger patients were more likely to be male, men who had sex with men (MSM), and Hispanic, whereas the older population was more likely to be injection drug users (IDU) with higher competing morbidities and to have an AIDS diagnosis on entry. In addition, causes of death and co-morbidities were not recorded, and loss to follow-up was high. However, the results are intriguing and do suggest that although the urgency to initiate ART may be less for younger HIV-infected individuals, the need for early ART intervention in older individuals is great. It will be of considerable interest to see whether the age-associated risks of deferring ART are confirmed on closer analysis of the two trials (TEMPRANO and START) mentioned above.
If the findings by Edwards et al. are further confirmed in other cohort or trial-based analyses, what does this mean for policy? In the US, reverting from the current "treatment at any CD4" guidelines is unlikely among any age group. However, the intersection of these new results with current case identification rates and treatment failures in older patients could serve as a critical alarm. If patients over 45 years are to capitalize on the potential benefits of early ART, it is time to redouble national efforts to ensure that early treatment is truly viable. Testing, linkage, ART initiation and retention are key; most importantly, we need to remember that aging -- while putting one at risk for many other things -- does not protect one against infection with HIV.
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Age at entry into care, timing of antiretroviral therapy initiation, and 10-year mortality among HIV-seropositive adults in the United States
Clinical Infectious Diseases Advance Access published June 16, 2015
"......patients who entered care between ages 45 and 65 experienced the highest 10-year risk of mortality under all treatment plans. Under the 500 cells/mm3 threshold for ART initiation, the 10-year mortality was 19%. The 10-year risk of mortality increased to 22% under the 350 cells/mm3 threshold for a risk ratio of 1.12 (95% CI: 1.01, 1.25) or a risk difference of 2.30% (95% CI: 0.23, 4.37). If patients in this group waited to initiate ART until CD4 cell count was below 200 cells/mm3, 10-year mortality was 28%, yielding a risk ratio of 1.45 (95% CI: 1.21,1.71) and a risk difference of 8.78% (95% CI: 5.89, 13.90). Figure 2 depicts the 10-year mortality under the 3 dynamic treatment plans stratified by age, demonstrating more dramatic effects of delayed ART initiation among older patients. The p-value for trend in the risk differences by age group was 0.0498 comparing the 350 and 500 thresholds and 0.2230 comparing the 200 & 500 thresholds."
[from Jules: its important to bear in mind this study examines mortality NOT development of comorbidities, many studies show delaying ART tip CD4s are lower damages the immune system & encourages the onset of comorbid diseases - neurologic function deterioration, CVD, bone disease etc. As well, this study can be deceptive, sure patients 18-34 are going to have longer lifespans & this study appears to be an estimate/projection of mortality, which is difficult to do: "We estimated the 10-year cumulative incidence of mortality......we model the probability of treatment, time-varying confounders, and mortality at each time point conditional on covariates in the observed data. Then, we use these conditional probabilities to estimate the risk of mortality"]
"The effect of delaying ART initiation on 10-year mortality was not homogenous among age groups. For patients who entered care at a CNICS site between ages 18 and 34, delaying ART until CD4 cell count dropped below 200 cells/mm3 had little effect. The effect of delaying ART was slightly more pronounced among patients who entered care between ages 35 and 44. However, among patients who entered care between ages 45 and 65, delaying ART had a profoundly deleterious effect: delaying ART until CD4 cell count dropped below 200 cells/mm3 increased 10-year mortality from 19% (had patients initiated ART when CD4 cell count first dropped below 500 cells/mm3) to 28%."
Abstract
Background. The goal of targeted antiretroviral therapy (ART) initiation is to minimize disease progression among patients with HIV while also minimizing the therapeutic burden on these patients. Here, we examine whether the effect of delaying ART initiation from 500 cells/mm3 to 350 or 200 cells/mm3 is modified by age at entry into care.
Methods. We used the parametric g-formula to compare 10-year mortality under 3 CD4 cell count thresholds for treatment initiation among 3532 patients who entered care at 1 of 8 sites in the United States between 1998 and 2013. Results are reported separately for patients between 18 and 34, 35 and 45, and 45 to 65 years of age at study entry.
Results. In the observed data, 10-year mortality was 13% (165 deaths). 10-year mortality increased from 11% under ART initiation at 500 cells/mm3 to 12% at 350 cells/mm3 (risk difference [RD]: 0.87; 95% confidence interval [CI]: 0.56, 2.17), and 14% at 200 cells/mm3 (RD: 2.71; 95% CI: 1.79, 5.38). The effect of delaying ART became greater with age: RDs comparing the 350 cells/mm3 threshold with the 500 cells/mm3 threshold ranged from -0.03 (95% -0.15, 1.76) for patients between 18 and 34 to 0.99 (95% CI: -0.27, 1.98) for patients between 35 and 44 and 2.30 (95% CI: 1.29, 5.42) for patients between 45 and 65.
Conclusions. Delaying ART increased 10-year mortality in the full cohort. Subgroup analysis highlights that patients entering care at older ages may be more vulnerable to the consequences of delayed ART initiation than younger patients.
Here we report age-stratified 10-year mortality in the CNICS cohort [9] under several possible CD4 cell count treatment thresholds.
Key points (40/40): The deleterious effect of delaying antiretroviral therapy initiation is stronger among patients over age 45 at entry into care than among younger patients. These results stress the importance of improving timely linkage to HIV medical care in this population.
As expected, this study illustrates that delaying ART increases 10-year mortality. Subgroup analysis highlights that adults entering care between ages 45 and 65 are more vulnerable to the consequences of delayed ART initiation than younger adults. While current guidelines recommend early ART initiation for all adults to improve both individual and population-level health outcomes, the striking increase in 10-year mortality under delayed ART initiation for adults over 45 stresses the heightened importance of early ART initiation in this group. Increasing early ART initiation among adults over 45 will require both the clinical guidelines already in place as well as a renewed commitment to improving timely diagnosis and linkage to HIV medical care in this population.
Table 2 compares the 5- and 10-year cumulative incidence of mortality for the eligible patients under no intervention and the 3 dynamic treatment plans for each age group. Overall, 10-year mortality was elevated if patients initiated ART within 6 months of CD4 cell count dropping below 350 cells/mm3 (mortality = 12%) compared to if all patients initiated ART within 6 months of CD4 cell count dropping below 500 cells/mm3 (mortality = 11%), for a risk ratio of 1.08 (95% CI: 1.00, 1.16) and a risk difference of 0.87% (95% CI: 0.07, 1.67). Ten-year mortality was further elevated to 14% if patients waited to initiate ART within 6 months of CD4 cell count dropping below 200 cells/mm3, for a risk ratio of 1.25 (95% CI: 1.08, 1.44) and a risk difference of 2.71% (95% CI: 0.92, 4.50). Figure 1 illustrates the cumulative incidence of mortality over 10 years for each of the treatment plans.
Table 2 also compares the estimated mortality under each treatment plan by age group. Patients who entered care between ages 18 and 34 had the lowest estimated 10-year mortality for each treatment plan. In these patients, mortality was similar regardless of the CD4 cell count threshold used as a trigger for ART initiation.
The 10-year mortality for patients entering care between ages 35 and 44 was 11% under ART initiation within 6 months of CD4 cell count dropping below 500 cells/mm3. Mortality increased slightly under the 350 cells/mm3 threshold (RR: 1.09; 95% CI: 0.99, 1.20; RD: 0.99%; 95% CI: -0.13, 2.11) and the 200 cells/mm3 threshold (RR: 1.19; 95% CI: 1.98, 1.45; RD: 2.15%; 95% CI: -0.39, 4.69).
As expected, patients who entered care between ages 45 and 65 experienced the highest 10-year risk of mortality under all treatment plans. Under the 500 cells/mm3 threshold for ART initiation, the 10-year mortality was 19%. The 10-year risk of mortality increased to 22% under the 350 cells/mm3 threshold for a risk ratio of 1.12 (95% CI: 1.01, 1.25) or a risk difference of 2.30% (95% CI: 0.23, 4.37). If patients in this group waited to initiate ART until CD4 cell count was below 200 cells/mm3, 10-year mortality was 28%, yielding a risk ratio of 1.45 (95% CI: 1.21,1.71) and a risk difference of 8.78% (95% CI: 5.89, 13.90). Figure 2 depicts the 10-year mortality under the 3 dynamic treatment plans stratified by age, demonstrating more dramatic effects of delayed ART initiation among older patients. The p-value for trend in the risk differences by age group was 0.0498 comparing the 350 and 500 thresholds and 0.2230 comparing the 200 & 500 thresholds.
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