Important note: Information in this article was accurate in March 2002. The state of the art may have changed since the publication date.
There is concern that the growing list of approved antiretrovirals will discourage pharmaceutical and biotechnology companies from investing in the discovery and development of new drugs. The short list of new investigational agents in the antiretroviral classes at the 9th CROI seems to confirm that fear. However, there were several important advances.
In order to infect human cells, HIV must bind to the CD4 receptor plus one of several co-receptors, all of which normally function as receptors for chemokine proteins. The two most common HIV co-receptors are CXCR4, used to infect T-lymphocytes, and CCR5, used to infect macrophages. Three presentations at this conference provided the first evidence that small molecule inhibitors of CXCR4 and CCR5 have activity in HIV-infected patients and could play a role in future treatment.
• AMD-3100: Investigators from Johns Hopkins and five other U.S. sites reported the results of the first Phase II trial of AMD-3100, an inhibitor of HIV binding to the CXCR4 chemokine receptor [Hendrix, Abstract 391-T]. In this study, HIV-infected inpatients received a continuous intravenous infusion of AMD3100 and no other antiretroviral drugs for up to 10 days. A total of 40 subjects received infusion rates of 2.5 to 160 µg/kg/hr of drug. At the end of the study, only a single subject (with SI phenotype) receiving the highest dose of AMD-3100 experienced a 1.3-log drop in viral load; no other subjects had a significant change in viral load.
However, when virus from these subjects was examined for co-receptor usage, there was a shift in peripheral virus populations from CXCR4 usage to CCR5 usage, presumably driven by exposure to AMD-3100 [Abstract 2]. Nine of 19 subjects had a mixed CXCR4-CCR5 usage at baseline, but all 19 had predominately CCR5 virus at the end of the study. Only 2 of 40 patients had predominately CXCR4 usage at the end of the study, and one of these received the lowest possible dose of drug.
High dose AMD-3100 is probably too toxic for chronic use. But based on the results of these studies, the shift in co-receptor usage indicates that CXCR4 blockade could drive a patient’s virus population to the more benign CCR5-type. The long-term clinical benefit is unknown, but combining a CXCR4 inhibitor with a CCR5 inhibitor (see below) might be an exciting future approach to anti-HIV therapy.
• Schering C (SCH C): For several years, Schering Plough has been developing orally absorbed small molecule inhibitors of the CCR5 chemokine receptor. Two of these, Schering C (SCH C) and Schering D have been in clinical trials in HIV-infected patients. A small Phase II trial of Schering C produced a significant drop in viral loads in patients with NSI phenotype treated with a 25 mg BID dose for 10 days [Reynes, et al. Abstract 1]. The mean viral load drop in 12 patients was 0.6 logs, with a range of 0 to -1.5 logs. Of note, most patients had a small (<0.3 log) increase in viral load in the first 72 hours of treatment, presumably related to CCR5 blockade and a reduction in HIV clearance.
Unfortunately, the drug was associated with cardiac toxicity, producing QT interval prolongation of about one-tenth of a second by Day 10. The long-term safety of this drug is a concern, especially if higher doses need to be used. There were also no data presented on whether SCH C promoted a shift from CCR5 use to CXCR4 use, which would be the anticipated opposite of the AMD-3100 effect. Nonetheless, this study represents proof-of-concept that blocking a chemokine receptor can predictably lower viral load.
Fusion of the HIV virus membrane and the T-cell membrane is mediated by interactions between CD4 and HIV gp160 and is essential for infection. This step in virus entry is blocked by T-20 and related peptide-based fusion inhibitors.
Investigators from Bristol Myers-Squibb reported developing the first small molecule, non-peptidic inhibitor of HIV mediated membrane fusion [Lin, Abstracts 9 and 10]. This molecule, BMS-806, competes with CD4 for HIV envelope binding, and blocks fusion by targeting a part of the HIV envelope also targeted by T-20.
Unfortunately, BMS-806 is HIV-1 selective and has no activity against HIV-2 or SIV. Several clade B isolates of HIV-1 were also resistant to BMS-806 prior to exposure to the drug. Not surprisingly, resistance can develop quickly in vitro, with two mutations in the gp41 fusion domain of the HIV envelope conferring >1000-fold resistance. This drug will therefore have to be used as a component of a multi-drug regimen in order to avoid resistance, and its clinical utility remains to be proven.
Investigators from Shinogi in Japan reported developing a small molecule HIV integrase inhibitor, S-1360, which is both potent and selective [Yoshinaga, Abstract 8]. This chemical inhibits NRTI-, NNRTI-, and PI-resistant HIV isolates in vitro. HIV can become resistant to this drug by mutating its integrase active site. No human studies have been conducted yet. In vitro results with S-1360 look similar to an integrase inhibitor developed by Merck. Merck’s compound has reportedly been through Phase I trials, but there are still no data on anti-HIV activity in people for any integrase inhibitor.
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