Discordant Responders Do Well If Viral Load Remains Suppressed

HIV positive people with advanced immune deficiency are unlikely to progress to AIDS after 6 months on antiretroviral therapy as long as they maintain an undetectable viral load, even if they have trouble achieving substantial CD4 cell recovery, according to new research published in the February 1, 2011, Journal of Infectious Diseases. These findings suggests that HIV patients and their clinicians should prioritize viral suppression and do not necessarily need to change drugs due to lagging immunological response.

Effective combination antiretroviral therapy (ART) typically lowers HIV viral load to an undetectable level and then -- with little or no new replicating virus to infect them -- enables recovery of CD4 T-cells, often to near-normal levels.

Some people, however -- especially those who have more advanced disease when they start treatment -- may experience viral suppression without significant CD4 cell recovery (or more rarely, vice versa), a phenomenon known as discordant response. Various studies have found that this is the case for roughly 10% to 45% of patients, with the higher rates seen in populations that start treatment later.

Researchers do not yet full understand why discordant response occurs or what are its clinical consequences. While having a low CD4 cell count is clearly a risk factor for AIDS-defining opportunistic illnesses among untreated people, this may not be the case for people on ART with good virological response.

Alexander Zoufaly and fellow investigators with the ClinSurv Study Group analyzed data from a large multicenter cohort of more than 14,000 HIV positive people seen at 11 centers in Germany since 1999, looking at the relationship between discordant response to ART and risk for clinical events.

The analysis included data from 1318 treatment-naive patients who began ART for the first time. About three-quarters were men and the median age was approximately 40 years. About 70% were from Germany and 13% were from sub-Sahara Africa. The average nadir (lowest-ever) CD4 count before starting therapy was 80 cells/mm3 and 43% had an AIDS diagnosis.

All participants started treatment with a CD4 count < 200 cells/mm3 and achieved full, sustained viral load suppression < 50 copies/mL within 6 months. The researchers divided participants according to duration of discordant response (0-6, 7-12, 13-24, or > 24 months), or how long it took to achieve at least 1 CD4 count above 200 cells/mm3 after reaching undetectable viral load.

Results

• People with lower nadir CD4 cell counts took longer to achieve immunological recovery after viral suppression:
• Immune response within 6 months (n = 837): CD4 nadir 123 cells/mm3 (37% with prior AIDS diagnosis);
• Discordant response for 6-12 months (n = 248): CD4 nadir 40 cells/mm3 (57% with AIDS diagnosis);
• Discordant response for 12-24 months (n = 134): CD4 nadir 31 cells/mm3 (62% with AIDS diagnosis);
• Discordant response for at least 24 months (n = 99): CD4 nadir 21 cells/mm3 (65% with AIDS diagnosis)
• A total of 42 new AIDS-defining events occurred during 5038 person-years of follow-up.
• Discordant virological/immunological response was an independent predictor of new AIDS events (hazard ratio 3.10, or about triple the risk), as was prior AIDS diagnosis (hazard ratio 2.58).
• Incidence of new AIDS events was highest during the first 6 months with complete viral suppression for both immunological responders and patients with discordant response.
• During this period, participants experiencing discordant response were significantly more likely to progress to AIDS than those with both virological and immunological response (incidence rates of 55.1 vs 24.5, respectively).
• After this period, however, the likelihood of experiencing an AIDS-defining event decreased more steeply among discordant responders (65% per year) than among individuals with rapid immune recovery (41% per year), so incidence rates converged.
• After 2 years of viral suppression on ART, participants with discordant response experienced no additional AIDS-defining events.

Based on these findings, the study authors concluded, "Compared with immune responders, patients with immuno-virological discordance seem to remain at increased risk for AIDS."

However, they continued, "Absolute risk is greatly reduced after the first 6 months of complete viral suppression."

"Results from the SMART study suggest that the latest CD4+ cell count can only predict opportunistic disease in patients who are not receiving therapy," the researchers noted in their discussion. "In concert with these data, our results indicate that CD4+ cell counts are of limited use as long-term surrogates for absolute AIDS risk as long as complete virological suppression is sustained."

"Current guidelines assume a constantly elevated AIDS risk and recommend prophylaxis for several opportunistic infections as long as CD4+ cell counts remain < 200 cells/[mm3], which may contribute to additional toxicity, drug interactions, and costs," they added.

These findings suggest that people with full viral load suppression may not require prophylaxis despite lagging CD4 counts -- good news, because to date strategies intended to specifically boost CD4 cells, for example interleukin 2, have not proven effective.

Investigator affiliations: Infectious Diseases Unit/Department of Medicine 1, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Robert Koch Institute, Berlin, Germany; Department of Infectious Diseases, University Hospital, Munich, Germany; Department I of Internal Medicine, University of Cologne, Cologne, Germany; Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany; Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.

1/21/11

Reference

A Zoufaly, M An der Heiden, C Kollan (ClinSurv Study Group). Clinical Outcome of HIV-Infected Patients with Discordant Virological and Immunological Response to Antiretroviral Therapy. Journal of Infectious Diseases 203(3): 364-371 (Free full text). February 1, 2011.