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CCR5 Chemokine Receptor blocker: first report of anti-HIV effect in HIV-infected people
Written by David Margolis, MD, University of Texas Southwestern Medical Center, Dallas VA Med Ctr
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Pozniak and colleagues reported on the short-term antiviral activity of Pfizer's CCR5 antagonist UK-427,857 (abstract H-443). HIV requires a second receptor in addition to CD4 to enter cells. Drugs that effectively block this interaction are hoped to add a new and highly potent class of antivirals to our armamentarium. Of the two most-often used chemokine receptors, CCR5 is the receptor primarily used by most HIV strains dominant in HIV-infected people, both during the initial process of infection, and throughout the course of disease. This receptor is therefore a therapeutic target of great potential, particularly as some immunologically healthy humans are born with the functional absence of CCR5. Blockade of CCR5 by a drug might therefore be well tolerated.
24 asymptomatic, untreated HIV positive patients with CD4 counts >250 cells/mm3 and plasma viral load >5000 copies/ml were treated with UK-427,857 for 10 days. Volunteers were given 25mg once a day, 100mg twice a day or placebo for 10 days and were followed for 30 days after drug was stopped.
Prior to dosing, patients were selected for this study that had predominant circulating viral populations that used the CCR5 receptor, rather than the other major co-receptor CXCR4 (seen most often in individuals with advanced AIDS). A concern is that blockade of CCR5-using viruses will lead to the selection and outgrowth of X4-using viruses, which might result in more rapid disease progression.
UK-427,857 was well-tolerated with no severe or serious adverse events. EKG abnormalities, seen with some prior chemokine blocker candidates, were not found. Although the Pfizer team had hoped to develop a drug without food restrictions, plasma levels were much higher when the drug was taken in the fasted state. Drug levels were also much higher and more stable at the 100 mg bid dose, rather than the 25 mg qd dose.
However, the 100mg bid dose of UK-427,857 yielded an impressive mean decrease in viral load of 1.42 log10 in only 10 days, with a mean decrease of 0.42 log10 at the 25mg QD dose. It was discovered that one patient harbored a mixed population of X4 and R5 viruses. This subject responded poorly to UK-427,857 monotherapy, and although viral load did not increase the proportion of circulating X4 virus increased roughly 10-fold.
Recent laboratory studies suggest that R5 receptors are a limiting factor for HIV entry, and that multiple R5's are need for the entry of a single viral particle. Currently, it appears that Pfizer must define the optimal dose for UK-427,857, and whether high levels of drug that saturate available R5 receptors are necessary, or whether sub-saturating doses will be equally clinically effective. However, the initial potent antiviral effects seen in short-term monotherapy are very encouraging. An important new antiretroviral may not be too far off.
Benzophenones: a new kind of NNRTI still under development
Hazen and co-workers from GSK added to the story of this new drug class (abstr. H-445), as first reported at CROI '03. GW8248 is a benzophenone and a potent NNRTI. A prodrug form of GW8248 with increased bioavailability and solubility is also under development. Like other NNRTIs, GW8248 inhibits HIV in the low nanomolar range. It is of great interest as it is active against a wide variety of NNRTI-resistant strains, including Y181C and K103N. GW8248 exhibited additive activities with other NNRTIs (NVP, DLV and EFV), was additive or synergistic with the activity of nucleosides, and generally synergistic with the activities of PIs.
To pose a very challenging laboratory test to GW8248, Hazen and colleagues tried to evolve a GW8248-resistant virus in the laboratory, starting with a K103N NNRTI pan-resistant virus. After 8 serially passages of K103N-infected cells in the presence of sub-inhibitory concentrations of GW8248, GSK scientists were able to grow out a virus encoding new mutations at V106I, P236L and E138K that was 50-fold resistant to GW8248. This is a glass half-full, as while this experiment shows that resistance can develop, the fact that 8 passages and 3 new mutations are required is encouraging.
Stronger is not Better? Abacavir is non-inferior to zidovudine
DeJesus (abst. H-446) reported the findings of a large phase III, international, multi-center, randomized, double-blind, study that compared the virologic response to abacavir to zidovudine when given with 3TC and efavirenz (Abstr. H-446). HIV-1 infected, ART naïve adults with baseline median HIV-1 RNA 4.79 log10 copies/mL, and median CD4+ cell count was 264 cells/mm3 were followed for 48 weeks. 39% of patients had baseline vRNA >100,000 copies/mL. Of the 649 subjects who received therapy, 70% vs. 69% of subjects in the ABC vs. the ZDV groups, respectively, achieved vRNA < 50 copies/mL by week 48. Virologic failure was infrequent and comparable between the treatment groups. It was reported that subjects receiving ABC group had a significantly better CD4 cell increase at week 48 (ABC, +209 CD4+ cells/mm3; ZDV, +155 CD4+ cells/mm3, p=0.005), despite the fact that the virological responses were similar. It is unclear if this is a meaningful or reproducible result.
As might be expected, the safety profiles were comparable over 48 weeks of randomized treatment, and both regimens were generally well tolerated. ABC hypersensitivity led to discontinuations, as did characteristic GI and other toxicities of AZT.
Hypotheses were put forth to explain why ABC, clearly a more potent drug in monotherapy studies than AZT, and known to maintain activity in the presence of more mutations than AZT, did not outperform AZT. A simple explanation would be that ABC toxicities led to more discontinuations or interruptions of therapy. However, these findings recall Gilead 903 in which tenofovir did not outperform D4T, and a viral dynamics study reported by the Aaron Diamond group last winter in which despite the use of >3 potent agents initial viral decays were not more rapid than standard therapy. Clearly, virological outcome is driven by multiple factors, and we do not understand all of these. Nevertheless, ABC/3TC is clearly another option as a dual nucleoside backbone.
How much punch is left? the activity of DDI in experienced patients
To define the antiviral efficacy of DDI in antiretroviral-experienced patients, Molina and colleagues (Abstr. H-447) performed a 4-week study called Jaguar. Patients on stable therapy with plasma HIV RNA between 1000-100,000/ml were randomized (2:1) to add DDI (Videx EC qd 400 mg or 250 mg according to weight) or placebo to their regimen for 4 weeks. 168 patients received either DDI (n= 110) or placebo (n=58). At baseline, median HIV RNAlog10 was 3.8, median CD4 count was 378 cells/mm3. Median HIV RNA decrease from baseline in DDI and placebo arm were respectively -0.5 and -0.02 log10 at week 2 (p< 0.0001); - 0.59 and +0.07 at week 4 (p<0.0001).
Viral load dropped significantly despite the presence of up to 4 NRTI mutations, or 3 thymidine analog RT mutations. Although the numbers were small (17 subjects) a non-significant trend towards DDI effect was seen when 5 NRTI mutations were present, but not when 4 TAMS were seen. However, DDI retains significant antiviral activity in treatment-experienced patients with moderate RT resistance. This is clinically important information to use when trying to construct a salvage regimen.
Basta means enough is enough
Maggiolo (Abstr. H-448) reported the interim findings of a treatment interruption study called "BASTA." Patients durably suppressed to HIV-RNA < 50 copies/ml with stable CD4 > 800 cells/mcl were randomized (2:1) to either interrupt or to continue their ongoing treatment. Therapy was to be restarted if CD4 count <400 cells. Of 114 patients enrolled, 76 stopped therapy while 38 continued it. At roughly 20 months, ca. 25% of patients assigned continuous therapy had stopped therapy, presumably due to fatigue or toxicity. Multivariate analysis found that only the CD4 nadir value of predicted CD4 cells (P< 0.001). 50% of subjects with nadirs <200 CD4 cells has restarted therapy within 5 months, whereas 50% of subjects with nadirs 200-350 remained off therapy for 12 months. Of the subjects with CD4 nadirs > 350 cells, more than 75% were still off therapy at up to 22 months. This adds to the findings of previous clinic cohort observational studies that suggest that if one does not need HAART when HAART was started, it is safe to stop. Additional biomarkers that could aid in the identification of patients at low or high risk of progression off therapy are needed.
Weird viruses: NNRTI resistance is not always predicted genotype
Chris Petropoulos (Abstract H-451) reported the rare discovery of viral isolates with high-level resistance to HIV-1 NNRTIs when assayed by Virologics phenotype despite the absence of known NNRTI resistance mutations. In a dataset of 18,034 samples, 48 isolates were identified that exhibited >10-fold resistance to at least one NNRTI in the absence of well-characterized NNRTI mutations (98G, 101E, 103N/S, 106A/M, 225H, 230L, 236L, or any mutation at position 100 181, 188, 190 or 227). Of these 10 encoded K101P and 13 the combination of K103R and V179D. The remainder of isolates contained other changes that have not yet been associated with NNRTI resistance. While this phenomenon is rare, it is useful to remember how much we have still to learn about the resistance of HIV to our drugs, and an illustration of the use of the phenotype assay to identify resistance not reported in a genotype assay. The reverse could also rarely occur, as it is conceivable that rare isolates clinically resistant may not demonstrate significant fold resistance in phenotype assays. |
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