- Category: HIV Treatment
- Published on Friday, 13 April 2012 00:00
- Written by Liz Highleyman
People with HIV who respond well to antiretroviral therapy (ART) and achieve undetectable viral load and a CD4 T-cell count above 500 cells/mm3 can have a mortality rate similar to that of HIV negative people, but this is not the case for those with 350-500 cells/mm3, according to a study presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last month in Seattle.
Effective combination ART has dramatically lowered mortality among people with HIV since the mid-1990s. A growing body of evidence suggests that even low-level viral load can contribute to higher risk of non-AIDS chronic conditions such as cancer and cardiovascular disease, but outcomes among people with well-preserved immune function have not been well studied. Recently updated U.S. treatment guidelines now recommend that all people diagnosed with HIV should consider ART, up from the previous threshold of 500 cells/mm3.
In the current analysis, Alison Rodgers from University College London and colleagues looked at mortality rates among participants in 2 large multinational studies that collected extensive data about morbidity and mortality: the SMART treatment interruption trial and the ESPRIT study of interleukin 2 (IL-2).
In the SMART study, 5472 HIV positive participants were randomly to either start ART immediately and stay on treatment, aiming to maintain viral suppression, or else to defer or stop treatment while CD4 counts were above 350 cells/mm3, resuming when they fell below 250 cells/mm3. Although some experts at the time hypothesized that spending less time on ART might be beneficial, in fact people who interrupted treatment not only had a higher risk of progression to AIDS or death, but also higher rates of non-AIDS conditions including heart, liver, and kidney disease.
In ESPRIT, 4112 people with CD4 counts above 300 cells/mm3 were randomly assigned to receive ART alone or ART plus IL-2, to see if adding the cytokine would help raise CD4 cells; it did not do so significantly.
The analysis presented at CROI looked at the control groups in both studies, those who received uninterrupted ART without IL-2. The 3280 participants included were 20-70 years old (median 43 years) and about 80% were men. They had low viral load (below 400 or 500 copies/mL) and CD4 counts above 350 cells/mm3. About half were from North America and 40% from Europe. About 13% were coinfected with hepatitis B or C. Injection drug users were excluded, as this group is at higher risk of death due to causes unrelated to HIV.
The researchers calculated standardized mortality ratios, comparing death rates among study participants versus general population death rates in the same country among people of the same sex and age.
- A total of 62 deaths occurred during follow-up, for an overall mortality rate of 5.02 per 1000 personyears.
- The most common causes of death were cardiovascular disease or "sudden death" (31%), non-AIDS cancers (19%), "unnatural deaths" such as accidents or suicides (18%), infections other than HIV or hepatitis (10%), and liver disease (8%); only 2 deaths (3%) were due to AIDSrelated causes.
- Looking at standardized mortality ratios in the primary analysis, the overall SMR was 1.24, meaning people with HIV had a 24% higher risk of death than the population at large.
- Broken down by CD4 count, HIV positive people with 300-500 cells/mm3 had a significantly higher risk of death (SMR 1.77, or 77% higher).
- However, among HIV positive people with 500 cells/mm3 or more, the risk of death was the same (SMR 1.00).
- Mortality rates were also similar when looking only at the most recent CD4 count and viral load measurements.
Based on these findings, the researchers concluded, in the SMART and ESPRIT trials "in (non IDU) HIVinfected patients on ART, with an undetectable viral load, who maintained or had recovery of CD4 counts to > 500 cells/[mm3] there was no evidence for a raised risk of death compared to the general population."
"[T]hose who had CD4 counts between 350500 cells/[mm3] had evidence of higher mortality rates," they continued, but "the potential balance between the risks and benefits of starting ART at CD4 counts above 350 cells/[mm3] needs to be assessed in randomized trials, such as the ongoing START trial."
"Studies have consistently found that markers of inflammation are elevated even among ART treated individuals...and strongly associated with subsequent morbidity and mortality," they added. "It might be expected that inflammation might remain elevated even in those with viral suppression and high CD4 cell counts (> 500 cells/[mm3]) and emerging data from the study of human aging suggests that the cumulative harm associated with persistently low-level inflammation may only become apparent as people enter their sixth and later decades of life. It therefore remains a distinct possibility that excess morbidity and mortality among optimally treated adults may hence only become apparent as the current generation of treated individuals age."
A Rodger, R Lodwick, M Schechter, et al. Mortality in Patients with Well-controlled HIV and High CD4 Counts in the cART Arms of the SMART and ESPRIT Randomized Clinical Trials Compared to the General Population. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 638.