Baseline CD4 count biggest factor in long-term immune system improvements after starting HIV therapy

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 observational and modelling study published in HIV Medicine. The 7600 people included in the analysis all had an estimated date of seroconversion.

The average CD4 cell count five 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, people 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.”



The transition period from infection with HIV to the detectable presence of HIV antibodies in the blood. When seroconversion occurs (usually within a few weeks of infection), the result of an HIV antibody test changes from HIV negative to HIV positive. Seroconversion may be accompanied with flu-like symptoms.


observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


The fluid portion of the blood.

Observational studies have consistently found that starting HIV therapy at higher CD4 counts is associated with 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 people, 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 people received care between 2003 and 2014. The median calendar date of seroconversion was May 2006. Three-quarters of participants were men who have sex with men (MSM), 5% were HCV (hepatitis C virus)-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 people started a cART regimen based on a ritonavir-boosted protease inhibitor, with 39% taking a non-nucleoside reverse transcriptase inhibitor (NNRTI) and 6% an integrase inhibitor.

CD4 cell counts improved rapidly in the first two to three months after the initiation of treatment; most people 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).

People who started therapy within six months of seroconversion demonstrated a faster speed of recovery compared to people 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 Organization guidelines,” conclude the authors.


Stirrup OT et al. Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-established dates of seroconversion. HIV Med, doi: 10.1111/hiv.12567 (2017).