Aspects of HIV-1-treatment: an exploration of the positive and negative physiological aspects of host-directed treatments for HIV-1-infection

The theme of this thesis is an exploration of some of the physiological aspects, both positive and negative of two host-directed therapies, recombinant interleukin-2 (rIL-2) and small molecule blockers of the chemokine-receptor-5 (CCR5). The cytokine, IL-2, an immunomodulating agent, has been the subject of more than two decades of research culminating in the negative results of the Phase III clinical endpoint studies. The CCR5-receptor antagonists have been a focus of research for 15 years, following the recognition of the CCR5-receptor as critical for human immunodeficiency virus (HIV) virus entry into CD4+ T-cells (and other immune cells). As this class of anti-HIV agent blocks a host receptor there is the potential to impact on normal physiology by so doing. The introductory Chapter presents a review of the recombinant interleukin-2 and small molecule blockers of CCR5 as HIV therapeutic agents. Next, two physiological aspects of rIL-2 therapy in the setting of the Phase III study, Evaluation of Subcutaneous Proleukin in an International Trial (ESPRIT) study are presented. First, an exploration of CD4+ T-cell change and clinical events (i.e. Progression of Disease events (AIDS)/death, all cause mortality and Serious Non-AIDS events (SNA)) in ESPRIT participants receiving a protease inhibitor (PI) based regimen vs. a non-nucleoside reverse transcriptase (NNRTI) based regimen and whether any interaction between PI and rIL-2 existed. Next, the incidence of first episode bacterial pneumonia, the most commonly reported infection reported in ESPRIT, was explored in order to better understand the temporal relationship between the inflammatory surge induced by rIL-2 and risk of bacterial pneumonia. In the second half of the thesis, data on the safety, efficacy and pharmacokinetic profile of a novel CCR5-receptor blocker, SCH532706 is presented. Having established an antiviral effect of this agent, the immunological changes in cells expressing CCCR5 (T-cell subsets and plasmacytoid dendritic cells) and the changes in antigen-specific cells during sequential exposure of the same group of patients to monotherapy with the CCR5-receptor blocker, a no therapy period and combination antiretroviral therapy (cART) was explored

Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study

Background. Alternative combination antiretroviral therapies in virologically suppressed human immunodeficiency virus (HIV)-infected patients experiencing side effects and/or at ongoing risk of important comorbidities from current therapy are needed. Maraviroc (MVC), a chemokine receptor 5 antagonist, is a potential alternative component of therapy in those with R5-tropic virus. Methods. The Maraviroc Switch Study is a randomized, multicenter, 96-week, open-label switch study in HIV type 1-infected adults with R5-tropic virus, virologically suppressed on a ritonavir-boosted protease inhibitor (PI/r) plus double nucleoside/nucleotide reverse transcriptase inhibitor (2 N(t)RTI) backbone. Participants were randomized 1: 2: 2 to current combination antiretroviral therapy (control), or replacing the protease inhibitor (MVC + 2 N(t)RTI arm) or the nucleoside reverse transcriptase inhibitor backbone (MVC + PI/r arm) with twice-daily MVC. The primary endpoint was the difference (switch minus control) in proportion with plasma viral load (VL) <200copies/mL at 48 weeks. The switch arms were judged noninferior if the lower limit of the 95% confidence interval (CI) for the difference in the primary endpoint was <-12% in the intention-to-treat (ITT) population. Results. The ITT population comprised 395 participants (control, n = 82; MVC + 2 N(t) RTI, n = 156; MVC + PI/r, n = 157). Baseline characteristics were well matched. At week 48, noninferior rates of virological suppression were observed in those switching away from a PI/r (93.6% [95% CI, -9.0% to 2.2%] and 91.7% [95% CI, -9.6% to 3.8%] with VL <200 and <50 copies/mL, respectively) compared to the control arm (97.6% and 95.1% with VL <200 and <50 copies/mL, respectively). In contrast, MVC + PI/r did not meet noninferiority bounds and was significantly inferior (84.1% [95% CI, -19.8% to -5.8%] and 77.7% [95% CI, -24.9% to -8.4%] with VL <200 and <50 copies/mL, respectively) to the control arm in the ITT analysis. Conclusions. These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r