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.
