Abstract
BackgroundHIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.MethodsDouble-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.ResultsNo significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.ConclusionsThis study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.Trial RegistrationClinicalTrials.gov NCT01299948
Highlights
Untreated HIV infection causes a progressive loss of helper T-cells that results, after an average period of about ten years of ongoing virus replication, in immunodeficiency and AIDS
This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population
Significant effects were observed on CD4 counts, immune activation and HIV viral load
Summary
Untreated HIV infection causes a progressive loss of helper T-cells that results, after an average period of about ten years of ongoing virus replication, in immunodeficiency and AIDS. Patients with higher levels of general immune activation progress more rapidly to T-cell loss and AIDS than individuals with lower levels [1,2,3,4,5]. Long-term non-progressors, who exhibit reduced levels of immune activation, do not progress to AIDS for a long time, despite ongoing virus replication [6]. The same correlation has been observed in SIV-infected monkeys: The natural hosts of SIV, African monkeys, remain relatively unaffected by SIV infection and exhibit neither chronic immune activation nor progression to AIDS despite high-level virus replication, whereas Asian monkeys develop chronic immune activation and AIDS (reviewed in [12]). We investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients
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