Pre-treatment CD4 cell count is the most important factor in immune recovery following the initiation of combination antiretroviral therapy (cART), according to the results of a large observation study led by Dr Oliver Stirrup at the MRC Clinical Trials Unit, University College London. The 7,600 people included in the analysis all had an estimated date of seroconversion.
The average CD4 cell count six years post cART initiation was approximately 500 cells/mm3 for people with a baseline count of 200 cells/mm3 compared to 800 cells/mm3 for people with a baseline count of 500 cells/mm3. Surprisingly, patients with high baseline viral load (VL) also had stronger CD4 recovery. There was also evidence that starting therapy soon after seroconversion was also associated with more robust CD4 cell count gains.
“We found that the most important predictors of recovery in CD4 counts in patients with well-established dates of seroconversion following the initiation of cART are the CD4 count and VL at time of treatment initiation,” comment the authors. “The strong association of CD4 count at treatment initiation with the long-term maximum of post-treatment recovery was expected given the findings of previous research on this topic.”
Observational studies have consistently found that starting HIV therapy at higher CD4 counts is associated the greater long-term increases in CD4 count. But potential limitations of these studies include uncertainty about the time of seroconversion and reliance on a single pre-treatment CD4 count.
To overcome these limitations, investigators from the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) designed an observational study involving 7600 patients, all of whom had an estimated date of HIV seroconversion. Their analysis also included all pre- and post-treatment CD4 counts (39,255 vs 61,487, respectively). Analyses were also conducted to see if other patient characteristics influenced post-treatment immune recovery.
The patients received care between 2003 and 2014. The median calendar date of seroconversion was May 2006. Three-quarters of participants were MSM, 5% were HCV-positive and approximately two-thirds started cART a year or more after seroconversion. Median viral load at the time of treatment initiation was approximately 70,000 copies/ml. Half of patients started a cART regimen based on a ritonavir-boosted protease inhibitor, with 39% taking an NNRTI and 6% an integrase inhibitor.
CD4 cell counts improved rapidly in the first two to three months after the initiation of treatment; most patients experienced further subsequent increases for the next five years.
Baseline CD4 count was the single most important factor in long-term maximum CD4 count recovery (five year count = 800 vs. 700 vs. 500 cells/mm3, respectively, for baseline counts of 500 vs 350 vs. 200 cells/mm3).
Patients who started therapy within six months of seroconversion demonstrated a faster speed of recovery compared to patients who delayed therapy (p < 0.0001).
After taking into account baseline CD4 cell count and time since seroconversion, higher viral load at time of treatment initiation was also associated with stronger long-term CD4 cell recovery.
“There is some evidence that higher plasma VL levels are associated with sequestration of CD4 cells in lymphoid tissue, and it has been suggested that this is associated with a more rapid increase in circulating CD4 cells following the initiation of cART,” note the authors. “This may also imply that in cases with high pre-treatment VL, the baseline level of circulating CD4 cells provides a slightly pessimistic indicator of the underlying state of the immune system at treatment initiation.”
Several other factors had a small but nevertheless significant (p < 0.005) impact on CD4 count gains, including HIV risk group (MSM vs men infected via heterosexual contact), younger age (under 20 years vs over 60 years), HCV infection status (HCV negative vs HCV positive) and type of antiretroviral therapy (integrase inhibitor vs NNRTI).
In a final analysis, the investigators took into account uncertainty about the exact time of seroconversion. This showed that CD4 count recovered more rapidly if therapy was started within four months of seroconversion. But the investigators were unable to explain all the variance in CD4 count change after treatment initiation and call for more research to fully identify the factors affecting CD4 response to cART.
“These finding…provide further supporting evidence for the initiation of cART soon after HIV diagnosis, as now recommended in World Health Organisation guidelines,” conclude the authors.
Objectives: To investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. We make use of all pre-treatment CD4 counts, because analyses using only a single observation at initiation may be subject to biases.
Methods: We used data from the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) multinational cohort collaboration of HIV-1 seroconverters. We analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003–March 2014 (n = 7600 for primary analysis) using a statistical model in which the characteristics of recovery in CD4 counts are determined by multiple predictive factors. Secondary analyses were performed incorporating uncertainty in the exact timing of seroconversion to allow more precise estimation of the benefit of very early treatment initiation.
Results: ‘True’ CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. Allowing for lack of complete certainty in the date of seroconversion, CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. For other patient and drug characteristics, associations with recovery were statistically significant but small in magnitude.
Conclusions: CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid.
OT Stirrup, AJ Copas, AN Phillips, MJ Gill, RB Geskus, G Touloumi, J Young, HC Bucher, AG Babiker