Poor CD4 T cell recovery despite HIV suppression linked to increased morbidity and mortality
Richard Jefferys, TAG
A subset of HIV positive people who initiate antiretroviral therapy (ART) and achieve suppression of HIV replication experience poor recovery of CD4 T cell numbers.
Terms used to describe this subset of individuals include “discordant responders” and “immunological non-responders” (INRs). As yet, there is no universally accepted definition of INRs and a variety of CD4 T cell thresholds are cited in the scientific literature (e.g. persistently below 200, 250 or 350 cells despite HIV suppression). Depending on the definition, estimates of the proportion of people starting ART who can be categorised as INRs are typically around 5-20%. In studies conducted to date, the most consistently reported risk factors for this outcome are low CD4 T cell counts at the time of ART initiation and older age. Several published studies have also reported that INRs have a greater risk of morbidity and mortality compared to HIV-positive individuals with more robust CD4 T cell gains.
Two new papers now add to the evidence that INRs face an increased risk of illness and death.
Frederik N. Engsig and colleagues conducted what may be the largest evaluation of the clinical impact of blunted CD4 recovery on ART, using data from participants in the Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Research Europe (COHERE). The study was published on January 22nd in Clinical Infectious Diseases. 
A total of 5,550 individuals were identified who had a CD4 T cell count of less than 200 at the time of achieving viral suppression and data available for analysis after three years of follow-up. Out of this group, 835 (15%) did not experience recovery of CD4 T cells to over 200 cells. The greatest risk for this outcome was among those aged over 50 and those with the lowest CD4 T cell counts at the time when viral load was initially suppressed.
Mortality risk in this group was significantly increased compared to the participants whose CD4 T cell counts rose above 200 cells, with a hazard ratio of 2.60 (95% confidence interval 1.86-3.81) – a 2.6-fold increase in risk. The estimated 5-year cumulative mortality was 11.8% in those with CD4 counts <200 cells at the end of the follow up period compared with 4.1%, 2.2% and 2.2% in those with CD4 counts of 201-350, 351-500 and >500 cells, respectively. The researchers note that these results are in accordance with two prior smaller studies, which reported a 2.69-fold and 3.4-fold greater risk of mortality among INRs.
The second paper, published in PLoS One, involves an analysis of the EuroSIDA cohort by Alexander Zoufaly and colleagues. 
The criteria for designating INRs in this study was different, being based on the lack of a CD4 T cell increase from the baseline measurement among a cohort starting with 350 cells or less (rather than the failure to crest a specific threshold). A statistically significant, close to 2-fold increase in the risk of fatal and non-fatal non-AIDS events was documented, although when the analysis was adjusted to take into account current CD4 T cell count this was attenuated to a statistical trend suggesting a 1.43-fold increase. Notably, the researchers point out that the elevated risk did not appear to diminish with longer duration of viral suppression. The smaller difference in risk found in this study is likely related to the difference in definition of INRs, and the fact that the majority of participants were in the 200-350 CD4 T cell range at the starting point for the analysis.
The authors of both papers highlight the current lack of any interventions to reduce the risk of morbidity and mortality among INRs. Engsig and colleagues write: “since 15% of treated HIV positive individuals have CD4 count <200 cells/mm3 after long-term viral suppression, prognosis of such patients is a major concern… virally suppressed patients with low CD4 counts should be monitored closely for diseases not conventionally considered HIV-related, especially non-AIDS defining cancers and liver diseases.” On the subject of potential therapies, the Zoufaly paper adds: “to date, strategies to directly influence immune reconstitution by adding interleukin-2 or by modifying cART regimens have failed to show benefit over viral suppression alone; therefore new strategies perhaps aiming at other mechanisms to boost functional CD4 cells or decreasing the levels of immune-activation (e.g. interleukin-7, probiotics) need to be tested in people who show incomplete immune reconstitution despite sustained viral suppression.”
Unfortunately, as noted in the article on CD4/CD8 ratios (see below), a clinical evaluation of IL-7 in INRs appears unlikely to happen anytime soon due to the recent bankruptcy of the original manufacturer. TAG maintains a listing of clinical trials for people with suboptimal immune reconstitution despite HIV suppression , derived from the clinicaltrials.gov database, but currently the page offers a dismayingly limited array of options: there are a total of seven trials, and in only one case is there a smidgeon of published evidence that the intervention could be beneficial. And that intervention, umbilical cord mesenchymal stem cells, does not seem well suited to large-scale manufacturing. 
There is certainly interest in the scientific community in pursuing studies of new approaches, including a variety of anti-inflammatory/anti-immune activation strategies and probiotic/prebiotic combinations (based on promising findings in macaques ), but the current research funding environment is not helping efforts to translate these ideas into the clinic. Recent updates from the National Institutes of Health indicate that paylines for research grants are at historic lows: for established investigators, only the top 8% of grant proposals are being funded, and for new investigators, the top 12%. 
The consequences of a slowdown in scientific progress will be profound, and INRs are an example of a population with a great deal at stake.
TAG Basic Science Blog. Poor CD4 T cell recovery despite HIV suppression linked to increased morbidity and mortality. (06 February 2014).
- Engsig FN et al. Long-term mortality in HIV positive individuals virally suppressed for more than three years with incomplete CD4 recovery. Clin Infect Dis. (2014). doi: 10.1093/cid/ciu038. (22 January 2014).
- Zoufaly A et al. Immuno-Virological Discordance and the Risk of Non-AIDS and AIDS Events in a Large Observational Cohort of HIV-Patients in Europe. PLoS ONE 9(1): e87160. doi:10.1371/journal.pone.0087160. (31 January 2014).
- TAG. Clinical trials for people with suboptimal immune reconstitution despite HIV suppression. (Last updated 06 February 2014).
- Zheng Z et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AIDS (2013) 27(8);1283–1293. doi: 10.1097/QAD.0b013e32835fab77. (15 May 2013).
- TAG Basic Science Blog. Probiotic/prebiotic supplement combination shows benefits in SIV-infected pigtailed macaques. (15 March 2013).
- NIAID paylines. (Updated 28 January 2014).