A French study that looked at the total amount of time since infection that people with HIV have spent with a detectable viral load has found that, contrary to some researchers’ expectations, starting therapy immediately after infection and then interrupting it conferred no advantage compared to deferring treatment until CD4 counts fell below a certain figure. Only those who started therapy early and stayed on it had a significant advantage in terms of immune recovery.
The study also found that, while most people prescribed ART eventually develop a near-normal CD4 count, only those who started treatment soon after infection, who have continued it ever since and remained undetectable stand a more-than-even chance of achieving an immune system where the balance of T-lymphocytes resembles that of a person without HIV in terms of their CD4:CD8 ratio.
The CD4:CD8 ratio
The CD4:CD8 ratio is the balance between the CD4 or ‘T-helper’ cells, which direct an important part of the immune system’s response to infections, and the CD8 or ‘T-suppressor’ cells, which actually do the work of inducing death in cells that are infected with viruses. (This ratio should be distinguished from the CD4 percentage, which is the proportion of CD4 cells within a larger group of immune-system cells – the T- and B-lymphocytes.)
In the immune system of an HIV-negative person who is well, there are normally more CD4 than CD8 cells – anything from slightly more to four times as many - meaning that the CD4:CD8 ratio is usually over 1.0 (generally in the 1.0 to 2.0 range). In people with HIV, the ratio is usually inverted. Typically, someone with HIV may have a CD4:CD8 ratio of about 0.5 immediately after acute HIV infection and this usually declines, along with the CD4 count, as disease progresses. A ratio below 0.30 is generally indicative of needing ART.
Generally, the CD4:CD8 ratio is no more predictive of needing treatment than the CD4 count, except in young children, where it is a better guide because they have more T-cells of all types. But the long-term clinical consequences of an inverted CD4:CD8 ratio are still unclear.
The French study, part of the PRIMO cohort study, looked at a cohort of 727 people with HIV who had a known date of infection. They calculated the total amount of time they had spent since infection with a viral load above 400 copies/ml. They divided the patients into three groups.
A majority (64%) had experienced significant amounts of time off-treatment. Some, numbering 244 people (34%), were those who had started treatment soon after infection – an average of 1.3 months later, researchers calculated - but had then had at least one treatment interruption before resuming it (53% had had just one interruption and 47% more than one).
The other group, of 218 people (30%), had deferred treatment – on average, for about 2.5 years since infection – and started it later.
Most of the study was devoted to comparing the immunological results in these two groups. However these were also compared to the other 36% (265 people), who had started treatment soon after infection and never stopped it, and thus had a low exposure to HIV actively replicating in their body.
Everyone in the study was on treatment now: excluded from the analysis were 77 people who were currently not on ART, and 30 people who had deferred treatment but then interrupted it after starting.
There were no large clinical differences between the people who had started treatment and then interrupted it, and the ones who had deferred treatment till later. While the latter had had a higher CD4 count at diagnosis (554, versus 471 for those on early but intermittent treatment) the current CD4 count was similar (645 in early initiators/interrupters, 654 in late initiators). ‘Cumulative HIV viraemia’ measure – expressed as the sum of the viral loads at any given viral load test multiplied by the number of years since infection – was 7.95 billion in those who started therapy immediately but interrupted and 3.16 billion in those who deferred treatment but started it later – not, in fact, a significant difference.
The total amount of time spent with a detectable viral load may have had a slight effect on current CD4 count: the one-third of patients in both of these groups with the highest cumulative viral loads had, on average, a CD4 count 54 cells/mm3 lower. This was not, however, statistically significant. However spending more time with a detectable viral load did have a significant effect on the CD4:CD8 ratio. This was 0.27 lower in the one-third of people with the highest cumulative viral loads, and this was significant.
The patients who had been on continuous therapy since soon after infection did much better. Their current count was, on average, 731 cells/mm3 – 125 cells/mm3 higher than those who had started treatment later, even when CD4 count at initiation was controlled for – and 106 cells/mm3 higher than those who had started treatment soon after infection but had had an interruption.
Their average CD4:CD8 ratio was 0.27 higher than patients who had deferred or interrupted treatment. While only 36% of patients who had started treatment early but interrupted and resumed it had achieved a CD4:CD8 ratio over 1.0 and 40% of those who deferred treatment, 64% of those who started early and stayed on treatment had a ratio over 1.0.
While the average CD4:CD8 ratio at diagnosis in all who started treatment early was 0.41, compared with 0.58 in those who deferred treatment (0.36 by the time they started treatment), the current ratio was 0.88 in those who had started treatment early but interrupted, 0.94 in those who had deferred treatment, but 1.17 in those who had started early and stayed on treatment. This is well within normal range.
This study disproved one hypothesis. Previous studies had suggested that starting therapy early – as soon as possible after infection – might offer benefit sufficient that therapy could then be stopped for a number of years and could even offer permanent advantages in terms of immune recovery, over that achievable by people who started later. This study disproves that: while it is quite clearly possible to start therapy soon after infection and then stop it, resuming it before CD4 counts sink below threshold levels, it does not in itself offer any great advantage. Only staying on therapy does that.
Seng R et al. Influence of lifelong cumulative HIV viremia on long-term recovery of CD4+ count and CD4+/CD8+ ratio among patients on combination antiretroviral therapy. AIDS, published ahead of print. Doi: 10.1097/QAD.0000000000000571. 2015.