Modulation of human immunodeficiency virus (HIV)-specific immune response by using efavirenz, nelfinavir, and stavudine in a rescue therapy regimen for HIV-infected, drug-experienced patients

Abstract

Analysis of the virologic and immunomodulatory effects of an association of efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) was performed in 18 human immunodeficiency virus (HIV)-infected and highly active antiretroviral therapy (HAART)-experienced patients who failed multiple therapeutic protocols. Patients (<500 CD4(+) cells/ micro l; >10,000 HIV copies/ml) were nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive and were treated for 10 months with EFV (600 mg/day) in association with NFV (750 mg three times daily) and d4T (30 or 40 mg twice daily). Measurement of HIV peptide- and mitogen-stimulated production of interleukin-2 (IL-2), gamma interferon (IFN-gamma), IL-4, and IL-10 as well as quantitation of mRNA for the same cytokines in unstimulated peripheral blood mononuclear cells were performed at baseline and 2 weeks (t1), 2 months (t2), and 10 months (t3) into therapy. The results showed that HIV-specific (but not mitogen-stimulated) IL-2 and IFN-gamma production was augmented and IL-10 production was reduced in patients who received EFV, NFV, and d4T. Therapy was also associated with a reduction in HIV RNA in plasma and an increase in CD4(+) cell count. These changes occurred in the first year of therapy (t2 and t3) and were confirmed by quantitation of cytokine-specific mRNA. Therapy with EFV, NFV, and d4T increases HIV-specific type 1 cytokine production as well as CD4 counts and reduces plasma viremia. This therapeutic regimen may be considered for use in cases of advanced HIV infection.

FIG. 1.

(A) Env-stimulated cytokine production (IL-2, IFN-γ, IL-4, and IL-10) by PBMC of HIV-infected individuals at different time points (before treatment [t0] and 2 weeks [t1], 2 months [t2], and 10 months [t3] into therapy). The results are shown as means ± standard errors. (B) PHA-stimulated production of the same cytokines. *, values are significantly different from those at t0.

FIG. 2.

Quantification of mRNA for IL-4, IL-10, IFN-γ, TNF-α, and TNF-β in resting PBMC of one representative HIV-infected individual before (t0) and after 10 months of (t3) therapy. The upper bands show cDNA retrotranscribed from cytokine mRNA extracted from patient PBMC; the lower bands show cDNA retrotranscribed from β-actin mRNA extracted from patient PBMC and used to normalize the PCRs.