HIV-positive people taking antiretroviral
therapy who have an undetectable viral load and a CD4 cell count above 500
cells/mm3 have a mortality risk comparable to that seen in the
general population, investigators report in the online edition of AIDS. Researchers looked at mortality
rates among participants enrolled in two large, randomised controlled trials – the
SMART and ESPRIT studies.
“We identified no evidence for a raised
risk of death compared with the general population in HIV-infected individuals
on ART [antiretroviral therapy] with an undetectable viral load, who maintained
or had recovery of CD+ T-counts to at least 500 cells/mm3,”
write the authors.
There have been significant improvements in
HIV treatment and care in recent years. Antiretroviral therapy has become more
powerful, less toxic and easier to take. Data from cohort studies suggests that
people doing well on treatment – often defined as the maintenance of an
undetectable viral load and a CD4 cell count above 500 cells/mm3 –
have a life expectancy similar to that of age- and sex-matched HIV-negative
An international team of investigators
wanted to further explore the impact of successful antiretroviral therapy on
mortality risk. They therefore examined data obtained from participants enrolled in
the SMART study (CD4 cell-guided treatment interruptions) and ESPRIT trial (HIV
therapy with or without interleukin-2, or IL-2). Both were randomised controlled
trials, meaning that mortality data were rigorously collected.
The study population involved 3280
people. To be eligible, participants were required to have a recent undetectable
viral load (below 400 copies/ml in the SMART study and below 500 copies/ml in
the ESPRIT trial) and a CD4 cell count above 350 cells/mm3. Participants from the SMART study all came from the continuous-treatment arm. Participants from the ESPRIT trial received antiretroviral therapy without IL-2.
Most participants were men (80%) and were
recruited in the United States (53%). The median age at baseline was 43 years.
As regards viral hepatitis, 4% were co-infected with hepatitis B and 8% with
hepatitis C. Injecting drug users were excluded from the study.
The participants contributed a total of 12,357
person-years of follow-up. The median length of follow-up was three years.
There were 62 deaths. This meant that the
overall mortality rate was 5 per 1000 person-years.
AIDS-related deaths were rare (n = 2, 3%).
The most common causes of death were cardiovascular disease and sudden death
(n= 19, 31%), non-AIDS cancers (n = 12, 19%), accident, suicide or violence (n
= 11, 18%), non-AIDS and non-hepatitis infections (n = 6, 10%) and liver disease (n = 5, 8%).
The investigators compared the mortality
rates seen in people with HIV to those expected in the matched HIV-negative
population to produce a standardised morality ratio (SMR). Overall, HIV was
associated with a modest increase in mortality risk (SMR = 1.24).
There were 28 deaths among participants with a
CD4 cell count between 350 and 499 cells/mm3, compared to an expected
16 in the general population (SMR = 1.77).
However, there was no evidence of an
increased mortality risk for people with a CD4 cell count above 500 cells/mm3
(SMR = 1.00).
“In our study, individuals who had current
or recent CD4+ T-cell counts above 500 cells/mm3 had no
evidence of increased overall mortality compared with the general population,”
comment the authors. “In contrast, those with CD4+ T-cell counts
between 350 to 499 cells/mm3 had evidence of higher mortality
The investigators believe that much of the
excess mortality seen in their patients would have been avoided with “timely
diagnosis of HIV and initiation of ART”.
But there was even good news with respect
to late diagnosis. The investigators found that participants with a CD4 cell count
below 200 cells/mm3 at the time of diagnosis had only a very modest
increase in their mortality risk, provided their CD4 cell count increased to
above 500 cells/mm3 while taking HIV therapy (SMR = 1.18).
There have been significant improvements in
HIV treatment since the initiation of the SMART study in 2002 and the ESPRIT trial
in 2000. This could mean that modern antiretroviral therapy reduces mortality
risk to an even greater extent than that seen in the present analysis.
However, the authors urge caution when
interpreting their findings in the context of debates about the best time to
start antiretroviral therapy. They believe this “needs to be assessed in
randomized trials, such as the ongoing START trial, which is randomizing people
with CD4+ T-cell count of at least 500 cells/mm3, to
immediate ART versus deferral to CD4+ T-cell count reaching 350