Does detectable CMV signal high mortality risk for older people with HIV and TB?
A study conducted in a cohort of hospitalized adults with HIV-associated tuberculosis (TB) in Khayelitsha found that having a detectable cytomegalovirus (CMV) viral load was associated with higher mortality within the first 12 weeks on TB treatment, according to Amy Ward from the University of Cape Town, who presented the findings at the 21st International AIDS Conference last month in Durban.
However, there was no clear evidence that CMV was the direct cause of increased mortality, and after adjustment for other risk factors, the strength of association with mortality was no longer statistically significant for the overall cohort. Nevertheless, among older adults (36 years old or older), both the likelihood of early mortality and CMV viremia were increased, “perhaps reflecting premature aging of the immune system,” Ward suggested.
People who are hospitalized with advanced HIV-associated TB have an extremely high mortality rate ranging from 15% to 50%, despite antiretroviral therapy (ART) and TB treatment. The reasons for this are unclear, but one idea is that active CMV infection may play a role. Autopsy studies indicate that CMV organ disease is often present in individuals dying of HIV-associated TB, leading to the hypothesis that CMV could negatively affect the immune response to either TB or HIV — for instance, perhaps by heightening inflammation.
Of note, there could be a precedent for this in other severe immune suppression conditions, such as in people who have had organ transplants, where CMV viremia is directly related to increased mortality. In that context, CMV is treated in order to reduce the risk of progression to illness and death — suggesting that if CMV plays a similar role in individuals with HIV-associated TB, it may be worth conducting a trial to see whether CMV treatment might reduce mortality.
The Study
Ward and colleagues decided to first conduct a prospective study to better characterize the association of CMV with mortality in people hospitalized with HIV-associated TB.
Adult HIV-positive inpatients with a CD4 T-cell count of 350 cells/mm3 or less and a new diagnosis of microbiologically proven or clinical TB were recruited between January 2014 and June 2015 at Khayelitsha Hospital, a large district hospital in Khayelitsha township near Cape Town.
The study included 256 participants with a diagnosis of TB and available CMV viral load data; 5 individuals were lost to follow-up. Over half the participants were women and the median age was 36. At the time of enrollment, only 35% were on ART, 44% had previously been on ART but were not at the time of hospitalization, and 21% were previously untreated for HIV. The median CD4 count was 64 cells/mm3and the median HIV viral load was 5.2 log (about 158,000 copies/mL). 40.6% had a positive blood culture for TB and 7.4 percent were rifampicin-resistant.
Blood tests, including a CMV viral load test, were performed at baseline. In addition, each participant had a clinical assessment (a full history, physical examination, and tests to confirm TB) and a fundoscopy to look for CMV retinitis (eye inflammation).
Almost a third (30.9%) of participants had a detectable CMV viral load, with a median value of 1250 copies/mL; 52% of those with detectable CMV had CMV loads of 1000 copies/mL or more. None were found to have CMV retinitis.
Follow-up was performed daily while in the hospital, and then by phone or in person at weeks 4 and 12. The primary endpoint was 12-week mortality after the initiation of TB treatment.
Mortality and Analysis
At 12 weeks, 23% of the participants had died. The researchers found that 38.0% of those with a detectable CMV viral load had died by week 12, compared to 17.8% of those without detectable CMV.
In a univariate analysis, having a detectable CMV viral load was associated with twice the risk of 12-week mortality. There was no association, however, between mortality and having a higher CMV viral load.
Other factors associated with increased mortality were increasing age, having a lower CD4 count, and lower albumin levels. When these variables, plus HIV viral load, TB blood culture results, and sex were included in a multivariate analysis, having detectable CMV was still associated with a 70% increase in mortality, though the p-value (0.077) did not quite reach significance. Only the association between increasing age and mortality remained statistically significant in the multivariate model.
In an analysis stratified by median age, participants age 36 and older had significantly higher mortality (32.8% compared to 14.1%). This did not appear to be associated with having a CD4 count below 50 cells/mm3. It was significantly associated with having detectable CMV viral loads, but only in those age 36 or older.
“This could indicate that independent of CD4 count there are other factors in this older group that are causing immune suppression resulting in an increase in both CMV viremia and mortality,” Ward postulated, suggesting that CMV viremia could be marker of premature aging of the immune system.
Even so, she concluded, “larger studies are required to address this question, as we did note a trend towards increased mortality in those with CMV viremia even after controlling for relevant co-variates.”
Reference
A Ward, D Barr, C Schutz, et al. CMV viraemia and 12-week mortality among hospitalised adults with HIV-associated TB in Khayelitsha Hospital, South Africa: A prospective cohort study. 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract WEAB0203.
Source: HIVandHepatitis.com
