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 categorized 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/μl 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 yesterday in the post on CD4/CD8 ratios, 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 certainly 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.
Clin Infect Dis. (2014) doi: 10.1093/cid/ciu038
First published online: January 22, 2014
Frederik N. Engsig1,2, Robert Zangerle3, Olga Katsarou4, Francois Dabis5, Peter Reiss6, John Gill7, Kholoud Porter8, Caroline Sabin9, Andrew Riordan10, Gerd Fätkenheuer11, Félix Gutiérrez12, Francois Raffi13, Ole Kirk1,14, Murielle Mary-Krause15, Christoph Stephan16, Patricia Garcia de Olalla17, Jodie Guest18, Hasina Samji19, Antonella Castagna20, Antonella d'Arminio Monforte21, Adriane Skaletz-Rorowski22, Jose Ramos23, Giuseppe Lapadula24, Cristina Mussini25, Lluís Force26, Laurence Meyer27, Fiona Lampe28, Faroudy Boufassa29, Heiner C. Bucher30, Stéphane De Wit31, Greer A. Burkholder32, Ramon Teira33, Amy C. Justice34,35, Tim R. Sterling36, Heidi Crane37, Jan Gerstoft1, Jesper Grarup14, Margaret May38, Geneviève Chêne5, Suzanne M. Ingle38, Jonathan Sterne38, Niels Obel1, The Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Research Europe (COHERE) in EuroCoord
Background. Some HIV infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after three years of sustained viral suppression and (2) the association of achieved CD4 count with subsequent mortality.
Methods. We included treated HIV infected adults from two large international HIV cohorts, who were virally suppressed (≤500 HIV-1 RNA copies/ml) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality.
Results. Of 5550 eligible individuals, 835 (15%) did not reach CD4 count >200 cells/µL after three years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998 and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after three years of viral suppression had substantially increased mortality (adjusted hazard ratio 2.60; 95% confidence interval 1.86-3.61) compared to those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death.
Conclusions. Virally suppressed HIV positive individuals on cART who do not achieve CD4 count >200 cells/µL have substantially increased long-term mortality.
PLoS ONE 9(1): e87160. doi:10.1371/journal.pone.0087160
Alexander Zoufaly, Alessandro Cozzi-Lepri, Joanne Reekie, Ole Kirk, Jens Lundgren, Peter Reiss, Djordje Jevtovic, Ladislav Machala, Robert Zangerle, Amanda Mocroft, Jan Van Lunzen, EuroSIDA in EuroCoord
Published: January 31, 2014DOI: 10.1371/journal.pone.0087160
The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated.
Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4<350 cells/µl and viral load (VL)>500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models.
2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37–2.81, p<0.001) in unadjusted analysis and 1.43 (0.94–2.17, p = 0.095) after controlling for current CD4 count. ID was not associated with the risk of AIDS events (aRR 0.76, 95% CI 0.41–1.38, p = 0.361).
Compared to CD4 responders, patients with immuno-virological discordance may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID, strategies to directly modify CD4 count response may be needed besides the use of ART.