Does HIV therapy restore TB-specific immunity? Studies give conflicting answers

Potent anti-HIV treatment boosts the immune system’s response to tuberculosis in HIV-positive children, according to a small study conducted in South Africa and published in the April 24^th edition of AIDS. However, a separate study published in the same journal has found that a year’s potent anti-HIV treatment, even if a patient has a good CD4 cell count, does not fully restore tuberculosis-specific immune responses and that HIV-positive individuals still have increased susceptibility to the infection. HIV-positive individuals who may have latent infection with tuberculosis, or are at high risk of tuberculosis infection, should be closely monitored, the investigators recommend.

HIV therapy and immune response to tuberculosis in children

Researchers from the University of Cape Town and Imperial College, London, measured mycobacterial growth in blood samples obtained from severely immune suppressed children after they started HIV therapy. They also assessed cell-mediated immune responses, and measured changes in CD4 cell count and viral load.

The twelve-month study enrolled 15 children with a mean age of seven years. Nine of the children completed the study, which was conducted between 2002 and 2003. Before anti-HIV treatment was started the children were severely immunosuppressed, having a median CD4 cell percentage of 8%, with median viral load being 200,000 copies/ml.

Blood samples were obtained at baseline and then at months six and twelve. BCG was introduced to these blood samples in a laboratory to assess the extent of antimycobacterial immune reconstitution. The blood samples were also used to measure cytokine levels, and changes in CD4 cell count and viral load.

Median CD4 cell percentage increased to 16% after six months of HIV therapy and to 14% after twelve months of treatment, a statistically significant increase (p = 0.004). At the same time, median viral load fell significantly, to 126 copies/ml at month six and to 1320 copies at month twelve (p = 0.011).

Growth of BCG decreased significantly after HIV therapy was started (p < 0.001). When the investigators looked at cytokine production, they found that levels of INF-gamma did not change significantly after the commencement of HIV therapy, but that levels of INF-alpha did fall after the initiation of HIV treatment (p = 0.02), the most significant fall occurring after three to twelve months. Levels of IL-10 also changed significantly, particularly in the first six months of HIV treatment (p = 0.002).

“In this study, we demonstrated a significant reduction in the ability of BCG to grow in the blood of HIV-infected children after only three months of highly active antiretroviral therapy”, write the investigators, “this was accompanied by a significant increase in CD4 cells as well as a significant decrease in HIV viral load.”

However, the investigators note that even with successful anti-HIV treatment, HIV-positive children and adults are still more likely to become ill due to tuberculosis than HIV-negative individuals. “HIV-infected children on [HIV therapy] might therefore benefit from additional interventions, such as vaccination”, suggest the investigators. “Strategies for boosting immune responses by vaccinating against tuberculosis can only be determined once the development of antigen-specific immune responses during [HIV treatment] is characterised in more detail”, they add. They conclude by suggesting that the technique examined in the current study “could be used to study such immune responses in detail, and has the added advantage of pathogen-specific functional read-out: the restriction of mycobacterial growth in vitro.”

Study finds conflicting results in adults

In a second study, twelve HIV-positive patients who had been taking potent anti-HIV therapy for at least a year, with a CD4 cell count above 300 cells/mm³ and an undetectable viral load, were examined for their tuberculosis-specific immune responses. Nine patients with primary HIV-infection and 15 HIV-negative controls were also recruited to the study. All the patients taking HIV therapy, five individuals with primary HIV infection, and all the HIV-negative controls had received the BCG tuberculosis vaccine.

The study’s investigators from Oxford University and Imperial College, London, found that both the individuals taking successful anti-HIV therapy and those with primary HIV infection had significantly lower levels of tuberculosis-specific CD4 cells than the healthy controls (p < 0.001; p < 0.002).

“We demonstrated…that the capacity of [tuberculosis]-specific CD4 T cells to secrete INF-gamma is significantly impaired in long-term HAART-treated HIV-1-positive individuals despite the recovery of CD4 T cells”, write the investigators, “this immunological deficit was independent of the patients’ CD4 T-cell count at the time of sampling, the duration of HAART, or the pre-HAART CD4 T-cell nadir.”

The investigators suggest that potent anti-HIV therapy may be unable to restore the central memory population of CD4 cells. They conclude, “vigilance is therefore required in following-up individuals on HAART with a high probability of latent infection [with tuberculosis] or a high risk of re-infection.”