Lori F.,ViroStatics Srl |
de Forni D.,ViroStatics Srl |
Katabira E.,Makerere Medical School |
Baev D.,ViroStatics Srl |
And 6 more authors.
PLoS ONE | Year: 2012
Background: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4+ T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. Methods: Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. Results: VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4+ T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3) and fewest adverse events. Conclusions: VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. Trial Registration: ITEudraCT 2007-002460-98. © 2012 Lori et al.
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.3.1-1 | Award Amount: 7.51M | Year: 2013
AIDS is one of the most serious pandemic diseases of the modern era. Although current therapies based on targeting key processes of the HIV replication cycle are potent and selective, several clinical failures are recorded due to the emergence of drug resistance. Hence, there is an urgent need for novel drugs and alternative therapeutic strategies. The objective of the THINPAD proposal is to discover and develop novel anti-HIV agents targeting the HIV nucleocapsid protein(NC), which is one of the most conserved sequence within HIV strains and is highly required for HIV replication, being therefore a primary target to overcome antiretroviral drug-resistance. The proposal originates from the successful FP6 TRIoH project and presents a multidisciplinary approach to develop anti-HIV drugs, ready for early clinical trials, that could be resistant to viral mutation since targeting a highly conserved sequence. The consortium consists of experts in the anti-HIV field which have an extensive expertise in targeting NC. Partner 1 has studied the NC dynamics and discovered small molecule NC modulators by in silico approaches. Partner 2 has developed biophysical methods to monitor the NC functions and the interaction with small molecules. Partner 3 developed a complete approach of biochemistry-, retrovirology- and microscopy-based techniques to monitor NC during HIV assembly, maturation and reverse transcription. Partner 4 is a SME founded by scientists who participated in the development of Raltegravir, which will have a leading role in the project together with Partner 5 (SME) by driving the discovery phase and pre-clinical investigation, favouring the translation of results into innovative applications for health. It is worth noting that the consortium already possesses small molecules endowed with low-micromolar inhibitory activity in cell against HIV and active against resistant strains. Notably, these molecules interact with the NC but not with the usual anti-HIV targets