Variations in mitochondrial DNA are associated with poorer
CD4 cell gains after the initiation of antiretroviral therapy in non-Hispanic
black patients, US investigators report in the online edition of the Journal of Acquired Immune Deficiency
Black people who had a certain cluster of variations in
mitochondrial DNA were less likely to experience an increase in their CD4 cell
count above 100 cells/mm3 after a year of HIV therapy than patients
with a differing genetic profile.
All the patients had a viral load below 400 copies. There
was no evidence of a similar influence of these variations, or haplogroups, of
mitochondrial DNA (mtDNA) on CD4 cell changes in white or Hispanic patients.
However, the investigators note that in other research involving Caucasian patients
not taking HIV therapy certain haplogroups have been associated with increased
progression to AIDS and faster falls in CD4 cell count.
They comment that their study “provides insight into the
contribution of mitochondrial genomics to CD4 cell recovery in individuals of
Measurement of CD4 cell count is the key prognostic test for
patients with HIV. Generally patients who are not taking antiretroviral therapy
experience a gradual decline in their CD4 cell count, meaning that they become
vulnerable to potentially life-threatening infections and malignancies.
The initiation of HIV therapy and suppression of viral load is
usually accompanied by increases in CD4 cell count, often to normal levels.
However, some patients do not have an increase in their CD4
cell count after starting therapy with anti-HIV drugs, even if this treatment
suppresses viral load.
Human genetic variation has been shown to play a role in CD4
cell count recovery. For example, single nucleotide polymorphisms were
associated with a decreased chance of having a recovery of CD4 cell count above
200 cells/mm3 a year after starting HIV therapy.
Single nucleotide polymorphisms in mitochondrial DNA can be
clustered into haplogroups, and investigators from the AIDS Clinical Trials
Group (ACTG) 384 study wanted to see if these were associated with gains in CD4
cell count when taking suppressive HIV therapy.
Patients’ mitochondrial DNA was characterised at baseline
and the impact of their genetics on CD4 cell gains after 48 and 96 weeks of
therapy was assessed. The primary outcome was the impact of mitochondrial DNA on
the chances of a CD4 cell count increase of at least 100 cells/mm3 a
year after starting HIV therapy. Results were adjusted to take account of other factors that can
influence CD4 cell gain.
A total of 423 patients starting antiretroviral therapy for
the first time were included in the analysis. Their median age was 36 years and
83% were men. The study population was racially diverse – 50% were white, 30%
black and 20% Hispanic.
Median baseline CD4 cell count was 278 cells/mm3
and median viral load was approximately 100,000 copies/ml.
Overall the patients had a good immunological response to
HIV treatment. The median 48-week increase in CD4 cell count from baseline was
176 cells/mm3 and the median 96-week increase was 253 cells/mm3.
CD4 cell count changes did not differ significantly according to race.
However, the investigators found that a number of
polymorphisms in mitochondrial DNA were associated with significantly poorer
CD4 cell gains in both black and white patients.
In black patients, these polymorphisms could be clustered
into three major haplogroups – L1 (25%), L2 (32%), and L3 (29%).
Analysis of the L2 haplogroup showed that it was associated
with a decreased change of a CD4 cell gain of at least 100 cells/mm3
at week 48 (OR = 0.17; 95% CI, 0.06-0.53; p = 0.002).
Moreover, black patients with the L2 haplogroup had
significantly lower CD4 cell increases at weeks 48 and 96 than individuals with
other haplogroups (96 vs. 181 cells/mm3, p = 0.01; 177 vs. 317
cells/mm3, p = 0.05).
The difference in CD4 gains at week 48 remained significant (p
= 0.001) after adjustment for potentially confounding factors such as baseline
CD4 cell count, viral load, and the ratio of naïve and memory CD4 cells.
Five major haplogroup were identified for white patients and
three for Hispanic patients. However, no significant association was identified
between haplotype and CD4 cell increase for either racial group.
“Race-stratified analysis of mtDNA variants suggests
possible associations between the African L2 haplogroup and reduced magnitude
of CD4 cell recovery during ART [antiretroviral therapy] in non-Hispanic black
participants,” comment the authors, “the association was seen in analyses of a
discrete outcome of 100 cell/mm3 increase at 48 weeks, and with CD4
count increase as a continuous variable.”
They note that their research was limited by the small
sample size and therefore conclude “further study in larger populations is
necessary to more definitively determine the role of mtDNA variation in CD4 T