CD4 count recovery: French study reaffirms why it is important to test and treat HIV early

Seven-in-ten people with HIV taking combined antiretroviral therapy for the first time recover their CD4 cell count to above 500 cells/mm³, French researchers report in AIDS. Having a higher CD4 cell count and a higher CD4/CD8 ratio at the time of starting treatment predicted CD4 recovery (strongly, for the former; to a certain extent, for the latter).  

Using the French Hospital Database on HIV (FHDH), the study’s objective was to assess CD4 recovery in people who initiated their first treatment any time between 2006 and 2014, then obtained and maintained virologic suppression throughout up to six years of follow-up. Participants had begun treatment with a CD4 cell count of less than 500 cells/mm³ and a viral load of more than 50 copies/ml. An additional criterion for inclusion in the study was having at least one CD4/CD8 ratio measurement in the six months prior to treatment initiation.

“CD4 recovery” was defined as two successive CD4 counts of at least 500 cells/mm³ after confirmation of virologic control, whereas “virologic control” referred to two consecutive viral loads of less than 50 copies/ml.

As well as those taking a triple antiretroviral combination – including integrase inhibitors, which had not been included in previous studies on this issue – people taking protease inhibitor monotherapy or dual regimens were also eligible.

Out of the 23,188 people whose data are collected in the database, 6050 met the study criteria and could therefore be evaluated.

The majority of participants were men (66%), of whom approximately one third originated from sub-Saharan Africa. When starting treatment, the median age of participants was 38.6 years; median HIV-1 viral load was 52,257 copies/ml; median CD4 count was 275 cells/mm³ and median CD4/CD8 ratio was 0.30.

Overall, 69.7% of participants had CD4 recovery after six years with sustained virological control. After accounting for deaths and individuals lost to follow-up, only 12.1% did not achieve CD4 recovery by the sixth year.

A higher CD4 count and a higher CD4/CD8 ratio when starting treatment, were positively associated with CD4 recovery:

• 87.1% of individuals with 350-500 CD4s, or 67.6% of those with 200-350 CD4s achieved CD4 recovery; whereas only 38.2% and 19.9% of individuals with 100-200 CD4s and less than 100 CD4s, respectively, achieved the same.
• 82.5% of individuals with a CD4/CD8 ratio superior to 1, and 71.7% of those with a ratio of 0.30 to 0.50 recovered their CD4s; whereas only 47.6% of individuals with a CD4/CD8 ratio of less than 0.30 achieved CD4 recovery.

The CD4/CD8 ratio is as good a marker of the immune system as the CD4 cell count. A normal ratio ranges between 1 to 4, so the closer you get to 1, the better – it has been shown that the risk of diseases such as cancer increases with a lower ratio.

The team of researchers identified several other factors that were, significantly, though moderately, associated with CD4 cell count recovery:

• Age: individuals older than 60 years had a lower probability of CD4 recovery than younger people.
• Men who have sex with men, women and heterosexual men not from sub-Saharan Africa, had a higher likelihood of CD4 recovery than women and heterosexual men from sub-Saharan Africa.
• Individuals with hepatitis B or C co-infections, or AIDS, when starting treatment, had a lower probability of CD4 recovery.
• Individuals who began treatment in more recent years were not more likely to have CD4 recovery than their counterparts who started treatment in the earlier years of the study.

The influence of antiretrovirals on the CD4 recovery outcome was also looked at. Starting with a non-nucleoside reverse transcriptase inhibitor-based triple combination instead of a protease inhibitor-based combination was associated with a lower likelihood of CD4 recovery. But there was no difference when starting with other regimens, including integrase inhibitor-based regimens (mainly raltegravir, in this study).  

The higher the viral load at cART initiation, the greater the chances of CD4 recovery. This may look surprising but has already been documented by several studies before. The phenomenon may be explained by a release in the blood, following treatment efficacy, of CD4 cells that were mobilised in lymphoid tissue, to combat intense viral replication and inflammation.

However, the time it took for the viral load to be suppressed was not associated with CD4 recovery.

In the paper that describes the study, the French investigators state that the two major CD4 recovery factors they have identified – a high CD4 count and a high CD4/CD8 ratio at cART initiation – confirm the necessity of early diagnosis and rapid treatment of HIV. As the latest data show that over a quarter of people living with HIV in France are still diagnosed at a late stage of the infection, their statement is timely.