People doing well on HIV therapy have a mortality risk identical to that of HIV-negative peers

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 individuals.

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 rates.”

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 cells/ mm³”.