Variations in mitochondrial DNA affect CD4 gains in black patients taking successful HIV therapy

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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 Syndromes.

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.

Glossary

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

nucleotide

A building block of DNA or RNA, chemical structures that store genetic information. 

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.

sample size

A study has adequate statistical power if it can reliably detect a clinically important difference (i.e. between two treatments) if a difference actually exists. If a study is under-powered, there are not enough people taking part and the study may not tell us whether one treatment is better than the other.

confounding

Confounding exists if the true association between one factor (Factor A) and an outcome is obscured because there is a second factor (Factor B) which is associated with both Factor A and the outcome. Confounding is often a problem in observational studies when the characteristics of people in one group differ from the characteristics of people in another group. When confounding factors are known they can be measured and controlled for (see ‘multivariable analysis’), but some confounding factors are likely to be unknown or unmeasured. This can lead to biased results. Confounding is not usually a problem in randomised controlled trials. 

They comment that their study “provides insight into the contribution of mitochondrial genomics to CD4 cell recovery in individuals of non-European descent.”

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 cell dynamics.”

References

Grady B et al. Mitochondrial genomics and CD4 T-cell count recovery after antiretroviral therapy initiation in AIDS Clinical Trials Group Study 384. J Acquir Immune Defic Synr, online edition, doi: 10.1097/QAI.0b013e31822c688b, 2011 (click here for the free abstract).

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