The glucocorticoid drug prednisolone can delay the depletion of CD4 T-cells in HIV-positive people, according to a retrospective study published on 5 May 2004 in the online journal BMC Medicine. Although it acts as an immunosuppressant, the authors argue that prednisolone may slow the death of CD4 T-cells by reducing the chronic immune activation caused by HIV infection.
The authors, from Université René Descartes in Paris, showed that giving prednisolone to HIV-infected people caused the number of CD4 T-cells to increase by over 200 cells/mm3 over the first two weeks of treatment. On average, CD4 counts remained elevated for at least two years. However, a small minority of patients had raised CD4 counts for up to ten years after starting prednisolone.
Forty-four HIV-infected patients with a median of 438 CD4 T-cells/mm3 were assigned to oral prednisolone treatment. They received 0.5mg/kg of the drug daily for six months before the dose was reduced to 0.3mg/kg. Eleven of these patients were taking zidovudine (500mg per day) at the start of the study. However, all of these patients discontinued antiretroviral therapy within the first 18 months of taking prednisolone.
The control group, which did not receive prednisolone, consisted of 74 HIV-infected patients with a similar range of CD4 cell counts and viral loads to the treatment arm.
Two years after the start of the study, 43% of the prednisolone group had CD4 counts that were greater than at entry. This contrasts with 12% of the control group (p
After five years, 11% of the prednisolone group and 1% of the control group (p
None of the patients developed AIDS while taking prednisolone. In contrast, 15% of the control group developed AIDS-related dementia, cachexia or cerebral toxoplasmosis within the first two years of the study.
Despite these findings, the authors state that eleven (25%) of the patients in the prednisolone group left the study after showing decreases in CD4 counts during the first two years. Within two years of stopping prednisolone, three of these (7%) went on to develop AIDS. Unfortunately, it is not clear how the departure of these patients affected the conclusions of the study.
The effect of prednisolone therapy was greater in patients who had low viral loads (under 30,000 copies/ml). This group maintained their initial CD4 cell increase for over two years after starting prednisolone therapy. It also took longer for their CD4 counts to fall below baseline than those with higher viral loads.
Patients with higher viral loads showed a similar increase in CD4 counts in the first two weeks of therapy. However, this increase was transient, with no significant differences between the treatment and control arms after six months of prednisolone treatment.
The observed effects on CD4 counts in the prednisolone-treated patients were mirrored by decreases in the presence of markers of T-cell death (apoptosis) and activation. This leads the authors to suggest that glucocorticoids delay the loss of CD4 T-cells by reducing the activation of the immune system caused by HIV infection.
Importantly, prednisolone did not affect viral load, despite its immunosuppressant properties. The authors claim that this is due to prednisolone preventing the apoptosis of T-cells that are not infected with HIV. This strengthens their hypothesis that the depletion of CD4 T-cells is caused partly by the hyperactivity of the immune system in response to HIV infection, rather than a direct effect of HIV on the cells it infects.
Prednisolone is an inexpensive drug, which has only mild side-effects at the low doses used in this study. However, the authors suggest that a range of doses of prednisolone or other glucocorticoids should be tested in clinical trials to determine the most appropriate regimen for delaying CD4 cell decreases in HIV-positive patients.
They also propose a number of clinical trials to examine the effectiveness of glucocorticoids used alongside HAART in primary HIV infection, or to delay the progression of HIV infection to AIDS in resource-limited settings.
Reference:
Andrieu J M et al. Long-term clinical, immunological and virologic impact of glucocorticoids on the chronic phase of HIV infection. BMC Medicine 2: 17, 2004.