CASCADE analysis finds antiretroviral treatment benefits are evident below CD4 count of 500, uncertain above this level

Starting antiretroviral therapy with a CD4 cell count between 350 and 500 cells/mm³ reduces the likelihood of HIV disease progression and death relative to initiation below 350 cells/mm³, according to findings from the large CASCADE study presented on Thursday at the Eighteenth International AIDS Conference in Vienna. Starting treatment with more than 500 cells/mm³ did not appear to confer additional benefit, but this analysis did not take into account non-AIDS-related conditions.

Numerous randomised trials have demonstrated the benefits of starting antiretroviral treatment before significant immune system damage occurs; that is, before the CD4 cell count falls much below 350 cells/mm³ and certainly before it hits 200 cells/mm³.

The benefits and risks of starting treatment above 350 cells/mm³ are less clear. Randomised trials to address this question are underway, but in the meantime a growing body of data from observational studies suggests starting earlier may lead to better outcomes, particularly with regard to non-AIDS-related conditions such as cardiovascular disease. Ongoing immune activation and chronic inflammation due to low-level HIV may contribute to problems throughout the body even while CD4 cell count remains high, some experts believe.

Joseph Eron from the University of North Carolina presented the latest findings from CASCADE, a collaborative natural history study of HIV seroconverters from more than two dozen clinical cohorts in Europe, Australia and Canada, followed since the advent of highly active antiretroviral therapy, or HAART.

The 9455 participants in the CASCADE 'When to Start' analysis were enrolled between January 1996 and May 2009. At the time of enrolment they were at least six months past seroconversion, free of AIDS and had not yet started antiretroviral therapy.

Just over three-quarters were men and a majority (56%) were gay/bisexual. The average age at the time of seroconversion was 30 years and the estimated duration of infection was 1.3 years.

Participants were analysed as 161 sequential nested cohorts of people enrolled during one month. The researchers measured time between the end of the prior month and the occurrence of an AIDS-defining illness or death. Participants who remained alive could join the next monthly cohort, so some individuals were members of multiple cohorts.

Researchers recorded whether participants started HAART (defined as any three-drug antiretroviral regimen) and collected information about demographic and disease-related factors including sex, age, history of injecting drug use, hepatitis B or C co-infection, CD4 cell count and HIV viral load. Eron described the study as "intent-to-treat in spirit".

Participants were divided into five categories according to CD4 cell count: 0 to 49, 50 to 199, 200 to 349, 350 to 499 and 500 to 799 cells/mm³. Only 183 people fell into the lowest category, whilst the three highest categories each had more than 4000 participants. The researchers did not include people with more than 800 cells/mm³ because there were too few events for a statistically meaningful analysis.

Participants were followed for nearly five years on average, contributing a total 52,268 person-years of data. Overall, 812 people (8.6%) progressed to AIDS during the study period and 544 participants (5.8%) died.

Importantly, the analysis did not include occurrence of non-AIDS-defining conditions of the type reported more frequently in HIV-positive people with well-preserved immune function, for example heart, liver and kidney disease. Eron said the causes of death in this analysis were unknown, though presumably recorded by investigators for the specific cohorts.

Being an observational study, outcomes amongst people who started therapy and those who deferred treatment cannot be directly compared since participants were not randomly assigned to one strategy or the other.

On the whole, people who started treatment had better prognosis in some respects (including being less likely to have a history of injecting drug use or to be co-infected with hepatitis B or C) but poorer prognosis in others (including higher viral load and a slightly lower CD4 cell count on average).

The benefits of starting treatment were clear in the three lower CD4 count categories. Amongst people with 0 to 49 cells/mm³, for example, the rate of AIDS or death was 55 per 1000 person-years for those who started treatment, compared with 193 per 1000 person-years for those who deferred treatment, or about a 70% risk reduction. In the 200 to 349 cells/mm³ group, the rates were 19 per 1000 person-years for those who started and 29 per 1000 person-years for those who waited, about a 40% reduction.

The advantages of treatment initiation were less evident in the two higher CD4 count groups. The rate of AIDS or death in the 350 to 499 cells/mm³ category rose from 17 per 1000 person-years for those who started to 21 per 1000 person-years for those who deferred, a 25% reduction after adjusting for other factors.

In the 500 to 799 cells/mm³ category, AIDS or death rates were 15 and 19 per 1000 person-years for starters and deferrers, respectively – essentially no change in risk in the adjusted analysis. These patterns were similar overall when looking at death alone.

The researchers calculated that they would have to treat only three people with 0 to 49 cells/mm³ to prevent one case of progression to AIDS or death within three years. The number needed to treat rose to 21 for the 200 to 349 cells/mm³ category and to 34 for the 350 to 499 cells/mm³ category.

They were unable to calculate a figure for AIDS or death in the 500 to 799 cells/mm³ category but, looking at death alone, they determined that 239 people would have to start treatment in order to prevent a single death.

The researchers concluded that starting antiretroviral therapy with a CD4 count below 500 cells/mm³ "appears to reduce risk compared to deferring at baseline". However, at CD4 counts of 500 to 799 cells/mm³, there was "no apparent benefit to [treatment] initiation for the larger population of patients with CD4s in this range".

These findings support current US treatment guidelines recommending initiation of therapy when CD4 cell count falls below 500 cells/mm³ and suggests that the World Health Organization's threshold of 350 cells/mm³ may be too low. 

Jonsson Funk M et al. HAART initiation and clinical outcomes: insights from the CASCADE cohort of HIV-1 seroconverters on 'When to Start'. Eighteenth International AIDS Conference, Vienna, abstract THLBB201, 2010.

View abstract and slides from this session on the official conference website.