In two reports, American and Australian researchers have identified a group of people who, despite successful viral suppression, do not see their CD4 cell counts reach normal levels, in some cases even after a decade of HIV therapy. While the clinical impact of this incomplete immune system recovery remains unclear, the growing evidence of a link between low pre-treatment CD4 cell counts and incomplete recovery supports recent shifts towards earlier initiation of anti-HIV therapy.
CD4 cell counts often are used to determine when to start antiretroviral therapy in people living with HIV. In 2008, with mounting evidence that delaying the start of treatment until CD4 cell counts fall to below 200 cells/mm3 leads to poorer clinical outcomes, American and European HIV treatment guidelines shifted towards starting treatment at higher CD4 cell counts (below 350 cells/mm3).
Cohort analyses presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI) have highlighted the ongoing debate around whether or not starting even earlier provides additional benefit.
CD4 cell counts typically rise rapidly during the first six months following the start of HIV treatment. The rate of increase then slows but cell counts continue to rise until reaching values above 500 cells/mm3, a level considered within the normal range for HIV-negative people.
While the majority of people with HIV achieve complete immune system recovery once on therapy, some people do not attain the 500-cell threshold despite ongoing viral suppression. While this group remains incompletely characterised, studies have linked the lack of recovery with poorer clinical outcomes, including increased risk of AIDS-related diseases and non-AIDS-related conditions such as heart disease and cancer.
Some reports of immune system recovery have noted a plateau effect in which CD4 cell counts stabilise after an initial period of increase, suggesting that complete recovery may elude some people. However, most studies have reported a relatively shortened follow-up, from three to seven years, which has limited the ability to determine whether or not these people showing incomplete recovery may eventually achieve normal CD4 cell counts.
In two recent reports, investigators have identified a group of people with HIV who do not show complete immune system recovery over the short and long term despite being on successful antiretroviral therapy.
In the March 1st issue of the Journal of Acquired Immune Deficiency Syndromes, the Australian HIV Observational Database group reported on the prevalence and predictors of incomplete immune recovery in its cohort of nearly 2500 people.
The team searched its database for records of people who started combination antiretroviral therapy and showed successful viral suppression (below 400 copies/ml) but incomplete immune response after 12 to 24 months.
Of the 292 records of people who had a CD4 cell count below 350 cells/mm3 at study start, 83 (28%) did not have a count that rose above the 350-cell mark. Only baseline CD4 cell count was associated with incomplete recovery (p
When investigators looked at clinical outcomes, they saw that of the 20 deaths reported in the cohort, nine occurred in incomplete responders. The investigators hypothesised that some of these deaths may be related to immune reconstitution syndrome following therapy start. The time to AIDS or death was shorter for incomplete responders (hazard ratio 1.96) but this difference was not statistically significant (p = 0.132).
The investigators urged that longer-term analysis of clinical outcomes is necessary to better understand this preliminary observation.
In a separate report, a group of American investigators provide the longest follow-up data on immune system recovery to date.
Their report, published in the March 15th issue of Clinical Infectious Diseases drew data from five clinical cohorts in the US and analysed CD4 cell counts from 366 people with HIV who had maintained viral suppression (less than 1000 copies/ml) for at least four years. The median follow up was 7.5 years, with 81 people (22%) providing over ten years of follow-up data.
Among the 151 people in the cohort who had a CD4 cell count below 500 cells/mm3 at year four, 61 (40%) eventually saw an increase to above the 500 cell mark while the others showed incomplete recovery. Investigators also noted that about one quarter (approximately 27%) of people whose CD4 cell count was between 350 and 500 cells/mm3 at year four showed no signs of increase in their CD4 count after year four, suggesting their immune system had reached a plateau before complete recovery.
When investigators analysed CD4 cell recovery according to the baseline CD4 cell count (at year zero), almost all people (95%) who started therapy with a CD4 cell count above 350 cells/mm3 achieved complete immune recovery with a CD4 cell count above 500 cells/mm3 during follow-up.
However, among patients who started with a CD4 cell count between 100 and 200 cells/mm3, one quarter (25%) did not achieve immune recovery (above the 500 cell mark). Among patients who started therapy at an even lower CD4 cell count, below 100 cells/mm3, more than two out of every five people (44%) did not experience immune recovery over the mean follow-up of seven years.
“In conclusion,” write the investigators, “patients who delay therapy until their CD4 cell count decreases to 3 may not achieve a normal CD4+ cell count, even after >10 years of otherwise effective therapy. A clear subset of individuals who do not achieve a normal CD4+ cell count by year 4 exhibit evidence of a plateau and may not be able to achieve a normal CD4+ cell count without other interventions. These individuals likely remain at risk for developing significant non-AIDS-related events – an issue that we were not powered to address in this study.”
Of note, the definition of viral suppression used in the study was 1000 copies/ml, which was standard at the time the first data points in the study were collected but is considerably higher than the current standard of 50 copies/ml used in the developed world.
In an accompanying editorial, Julg and Walker argue that, “Maintaining a viral load
However, they add that overall this important study strongly supports the early initiation of antiretroviral therapy – a doctrine that is reflected in recent changes in the major US and European treatment guidelines.
Falster K et al. Poor baseline function predicts an incomplete immune response to combination antiretroviral treatment despite sustained viral suppression. J Acquir Immune Defic Syndr 50: 307-313, 2009.
Julg B and Walker BD The paradox of incomplete CD4+ cell count restoration despite successful antiretroviral treatment and the need to start highly active antiretroviral therapy early. Clin Infect Dis 48: 795-797, 2009.
Kelley CF et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48: 787-794, 2009.