Middle-aged and elderly suffer if ART delayed

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Delaying antiretroviral therapy (ART) may have especially serious consequences for middle-aged and elderly HIV-positive people, according to new research. US investigators found that patients aged between 45 and 65 years who started treatment at lower CD4 counts – 350 or 200 cells/mm3 – had higher mortality rates compared to patients who started treatment when their count was around 500 cells/mm3.

“Among patients who entered care aged between 45 and 65 years, delaying ART had profoundly deleterious effects,” comment the authors. “Delaying ART until CD4 count dropped below 200 cells/mm3 increased 10-year mortality from 19% (had patients initiated ART when CD4 counts first dropped below 500 cells/mm3) to 28%.”

Most treatment guidelines now recommend either immediate ART or the initiation of therapy at a CD4 cell threshold of 500 cells/mm3. Delaying treatment has been shown to increase mortality risk. Moreover, early ART also has public health benefits, in some circumstances effectively eliminating the risk of transmission.

It’s already well known that age is a risk factor for poorer outcomes in untreated HIV-positive patients, and the diseases of ageing are an increasingly important cause of death among patients taking ART. But it’s currently unclear if there is an association between older age and poorer outcomes with delayed ART initiation.

To remedy this knowledge gap, investigators from the US Centres for AIDS Research Network of Integrated Clinical Systems (CNIS) monitored ten-year mortality rates according to age and CD4 counts at the time of ART initiation in 3,532 patients. The patients entered care between 1998 and 2013, and all had a baseline CD4 count above 500 cells/mm3. Mortality rates were compared according to CD4 counts at the time ART was started: 500 cells/mm3 or above; 350 cells/mm3; 200 cells/mm3. Comparisons were also conducted for each CD4 cell threshold according to age at ART initiation: 18 to 34 years; 35 to 44 years; 45 to 65 years.

Most (82%) of the patients were male, a third were black and 67% were men who have sex with men. Median CD4 count at study entry was 646 cells/mm3. The ten-year mortality rate was 13% (n = 165). As expected, there was a relationship between CD4 counts at ART initiation and mortality rates. Starting treatment with a CD4 count of 500 cells/mm3 or higher was associated with the lowest mortality (11%); mortality increased to 12% for patients who delayed treatment to a CD4 count of 350 cells/mm3 (RR = 1.08; 95% CI, 1.00-1.16) and increased further to 14% among patients who started treatment with a CD4 count of 200 cells/mm3 (RR = 1.25; 95% CI, 1.08-1.44).

Patients in the 45 to 65 years age group had the highest mortality rates at all CD4 thresholds. Starting therapy with a CD4 count of at least 500 cells/mm3 was associated with ten-year mortality of 19%; this increased to 22% when treatment was delayed to the 350 cells/mm3 threshold (RR = 1.12; 95% CI, 1.01-1.25) and 28% when therapy was started with a CD4 count of 200 cells/mm3 (RR = 1.45; 95% CI, 1.21-1.71).

The impact of delaying ART to 350 cells/mm3 for younger patients (18 to 34 years) in terms of mortality was unclear. “Our findings suggest that for younger patients entering HIV medical care with high CD4 counts, there may be less urgency in initiating ART from the standpoint of individual health outcomes,” suggest the authors. “These results contribute a new layer of evidence by describing the variable individual-level benefits of more immediate ART initiation according to age.”

However, for middle-aged and older patients, the findings were clear. “The striking increase in 10-year mortality under delayed ART initiation for adults over 45 years stresses the heightened importance of early ART initiation in this group,” conclude the investigators.

The authors of an editorial endorse this conclusion, writing “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.”

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/mm 3 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/mm 3 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/mm3threshold 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. 

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Clinical Infectious Diseases abstract
Clinical Infectious Diseases editorial


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