Important note: Information in this article was accurate in 2003. The state of the art may have changed since the publication date. In addition to providing data on new antiretroviral agents in existing classes, the 10th Conference on Retroviruses and Opportunistic Infections (CROI) also featured information on novel therapeutic agents. All but one approved drugs for treating HIV currently target one of two viral enzymes (reverse transcriptase and protease); data was presented on new classes of agents that target other viral processes as well.
The first new class to arrive since 1996 is the fusion inhibitor class. Data presented on enfuvirtide (Fuzeon), formerly known as T-20, showed that the drug is well tolerated with the main exception being injection site reactions due to a local reaction to the drug. However, it was also shown that like the other classes of antiretrovirals (ARVs), resistance to enfuvirtide can develop, so it should be used with other active ARV agents. Fuzeon was granted FDA approval on March 13; see Inside News (page 7).
Data on the second-generation fusion inhibitor, T-1249, were also presented. When given to 25 patients who failed enfuvirtide, they experienced a significant reduction in viral load. This suggests that T-1249 could be used to rescue enfuvirtide-resistant strains of HIV. Phase 2 studies will begin later this year. Enfuvirtide is expected to be approved by the FDA within the month.
Another novel class of agents known as CCR5 antagonists was presented. CCR5 antagonists block the binding of HIV to the CCR5 receptor on the surface of the T lymphocyte, thereby blocking entry of HIV. In vitro data on three compounds - AK602, TAK-220, and UK-427,857 - were presented. Unlike fusion inhibitors that are given as a subcutaneous injection, these agents will be given orally. All appeared to be potent inhibitors of CCR5 and should be entering Phase 1 trials this year.
Finally, data on approximately 24 HIV-positive patients given a single IV infusion of TNX-355 were presented. This agent is an anti-CD4 antibody that works by blocking the interaction of HIV with the CD4 receptor on T cells by coating the receptor. Significant viral load reductions were seen as far as 21 days after a single infusion. This promising data support further studies using multiple doses.
In the existing class category, we heard about a new Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and two new PI (Protease Inhibitor) candidates that have the potential to overcome preexisting resistance. The data on the GlaxoSmithKline NNRTI and the Roche PI were from in vitro studies, but the Tibotec TMC-114 PI given to 50 patients with multi-PI-resistant HIV produced a significant decline in viral load in the first two weeks of therapy.
There were data presented on atazanavir, which is expected to be approved by the FDA this year. This once-a-day PI has been found to be kinder and gentler to lipids than its classmates. In a continuation of a previously-reported study comparing two doses of atazanavir combined with stavudine (d4T) + lamivudine (3TC) versus a combination of the same nucleosides and nelfinavir (NFV), subjects on NFV were switched to atazanavir while those originally assigned to atazanavir continued on this agent. To participate in this study continuation phase, subjects had to have a viral load less than 10,000 copies/mL after 48 weeks on their originally assigned regimen. Overall, the rates of maximal viral suppression were not as impressive as in some recent studies. Approximately 40% to 50% of subjects initially randomized to atazanavir had viral loads below 50 copies/mL after a year of treatment - no different from NFV. However, among those with low viral loads entering the study rollover, switching from NFV to atazanavir resulted a year later in improved suppression of viral load below 50 copies (a small jump from 44% to 49%) and increased CD4+ cell counts by about 35 cells/mm3. Importantly, LDL cholesterol, HDL cholesterol and triglycerides all improved significantly after the switch.
A catch for this convenient, lipid-friendly PI is its own brand of toxicity. Hyperbilirubinemia somewhat greater than that seen with indinavir (IDV) is very common in persons taking this drug and frank jaundice can be expected in 10% to 20% of patients. The elevated bilirubin is unconjugated (due to inhibition of bilirubin glucuronidation) and importantly does not reflect chemical hepatitis.
Data regarding the development of resistance to atazanavir suggest this agent will serve best as a first PI rather than as a salvage agent because prior PI experience and resistance is associated with cross-resistance to atazanavir. Development of atazanavir resistance in the ARV-naïve patient with its characteristic I50L mutation actually increases susceptibility to a number of other PIs, which should appears to retain susceptibility to the other available PIs. The combination of this data suggests that atazanavir will be best used as part of an initial PI-containing regimen. It is also likely that in patients receiving PIs who have dyslipidemias and risk factors for cardiovascular disease but limited evidence of PI resistance, substitution with atazanavir will become a popular alternative to lipid-lowering therapy.
* Speaker's Bureau: BMS, GSK, Merck, Roche, Gilead. Grant/Research support: BMS, GSK, Roche, Merck, Trimeris, Boehringer-Ingleheim, Chiron, Pfizer, and Gilead.
** Speaker's Bureau: GlaxoSmithKline, Gilead, Merck, Roche, and Abbott. Grant support from Roche.
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