Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy

Abstract

Context Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. Objective To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL. Intervention Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. Main Outcome Measures The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. Results There was no significant difference in CD8 cell activation between the 2 groups (−4.8% and −4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, −0.6%; 95% CI, −4.8% to 3.6%; P=.80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (−85 cells/μL vs −23 cells/μL at week 48; difference, −62 cells/μL; 95% CI, −115 to −8; P=.03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P=.003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P=.03). Conclusion Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. Trial Registration isrctn.org Identifier: ISRCTN30019040

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

“…34 Similar increases in plasma HIV levels had been seen in earlier studies of immunosuppressive agents: cyclosporine A, 35 prednisone, 36 and thalidomide 37 in untreated HIV infection. The mechanism whereby chloroquine enhances HIV replication is unclear.…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…In some studies this molecule was shown to reduce immune activation markers (i.e., IL-6, TNF-a and LPS) and CD8 T-cells expressing CD38CHLA-DRC and Ki-67, 158-161 while other researchers found no effect on immune-activation. [162][163][164] A possible target is also represented by TNF itself, which may be antagonized by several molecules currently in use for rheumatologic diseases. A study in rhesus macaques showed that adalimumab, a human anti-TNF monoclonal antibody, was able to reduce infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, diminishing also lymphoid tissue fibrosis; nevertheless, no effect on plasma immune activation was proven.…”

Transient Increase of Interferon-Stimulated Genes and No Clinical Benefit by Chloroquine Treatment During Acute Simian Immunodeficiency Virus Infection of Macaques

“…Surprisingly, HCQ treatment in ART-naive nonprogressors resulted in a worsening of CD4 + T cell loss. 26 A NIAID-sponsored Phase II clinical trial is currently ongoing to determine whether treatment of HIV-infected patients would reduce HIV-induced immune activation (NCT00819390).…”