Important note: Information in this article was accurate in May 2003. The state of the art may have changed since the publication date.
More From CROI…New Drugs: Full Pipeline, Steady Progress
Charles Flexner, M.D. The Hopkins HIV Report - May 2003
Despite warnings that the growing number of approved antiretroviral drugs might discourage development of new agents, presentations at the 10th CROI indicated that our anti-HIV armamentarium continues to expand. Many presentations dealt with the activity of new agents in the laboratory and even in animal models, but several described clinical activity. One disappointment was the lack of clinical data on integrase inhibitors or CCR5 blockade. But there was ample reason for optimism about other new treatments and targets.
New NRTIs
Amdoxovir (DAPD) is a nucleoside diox-alane guanosine analog that is deaminated inside cells to an active metabolite (DXG). The main interest in this compound relates to its apparent activity against multiple NRTI-resistant HIV isolates.
Melanie Thompson and colleagues reported the results of DAPD 150, a 96-week, nonrandomized, open-label trial [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 554]. In 18 heavily treatment-experienced patients with a median of 10 prior antiretrovirals and five NRTI mutations, the addition of 300 mg bid or 500 mg bid of amdoxovir produced a median viral load decline of 0.90 log10 c/mL and a median CD4 increase of 55 cells/mm3; 42% of patients achieved at least a 1.0 log10 c/mL drop in viral load. However, 10 patients were discontinued from the study: two for virologic failure, three for non-adherence, and five who developed lens opacities. Although these eye findings were not associated with changes in visual acuity, the development of this drug has slowed significantly while investigators try to understand the potential long-term impact of this finding. Lens opacities are common with aging, and do not generally affect vision. One ongoing ACTG protocol using DAPD now requires frequent eye exams. Until we get more data, the future of DAPD appears uncertain.
Racivir is a nucleoside 5-fluorocytosine analog, closely related to emtricitabine (FTC), with broad-spectrum activity against HIV and hepatitis B viruses. It has good oral bioavailability, and has a half-life allowing once-a-day administration. In the first reported treatment trial of this drug in treatment-naïve HIV-infected volunteers, racivir at doses of 200, 400, or 600 mg qd was combined with stavudine and efavirenz for 14 days [Otto, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 552]. By day 14, the mean drop in viral
load ranged from 2.02 to 2.43 log10 c/mL. All anti-retroviral drugs were stopped from Day 15 to Day 35.
Interestingly, by Day 28, viral loads remained suppressed to 2.1 to 2.6 log10 c/mL below baseline, and did not begin to increase again until Day 35. Unfortunately, the design of this study did not allow careful assessment of racivir’s contribution to anti-HIV effects, and it is not clear if the prolonged suppression of viral load is unique to racivir or simply reflects the long half-life and potency of efavirenz. The drug was well-tolerated in this short trial.
New NNRTIs
New non-nucleoside RT inhibitors continue to be developed, although the data presented at the 10th CROI focused mainly on laboratory experiments with little new clinical data. This included a new family of benzophenone NNRTIs from GlaxoSmith-Kline that retain activity against viruses with the K103N mutation [Chan, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 6].
New Protease Inhibitors
TMC-114 is a new non-peptidic HIV protease inhibitor of interest because if its lack of cross-resistance with most other PIs [Koh, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 553]. In the first clinical activity study of this compound, TMC-114 was combined with low-dose ritonavir to boost pharmacokinetics, and was given to 50 multiple PI-experienced patients currently failing a PI-containing regimen [Arasteh, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 8]. Doses of TMC-114/r were 300/100 mg bid, 600/100 mg bid, or 900/100 mg qd for 14 days. The median changes in plasma viral load at Day 14 ranged from 1.13 to 1.50 log10 c/mL in the three arms (range 0.47 log10 c/mL to 2.5 log10 c/mL); 69% to 92% of treated subjects had at least a 1.0 log10 c/mL reduction in viral load, depending on regimen. The most commonly reported side effects were gastrointestinal. Further clinical studies are in
progress.
Other PIs: RO033-4649 is a new peptidic PI being developed by Roche. In vitro, 62% of highly PI-resistant viral strains retained full sensitivity to this drug, and the remainder had intermediate sensitivity [Cammack, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 7]. The drug is currently in Phase I clinical development, and was reported to have a favorable pharmacokinetic profile. The new PIs atazanavir and tipranavir were covered in a previous article on drug resistance and treatment of experienced patients [see Gallant,
HHR;15(2):8].
Entry and Fusion Inhibitors
AMD-070: The first inhibitor of the CXCR4 chemokine co-receptor, AMD-3100, was shown at last year’s CROI to reduce viral load by more than 1.0 log10 c/mL in a patient whose HIV used CXCR4 exclusively, and caused a shift from CXCR4 to CCR5 use in the virus population of other recipients [Schols, et al. Conf Retroviruses Opportunistic Infect. 2002 Feb 24-28;9th:Abstract No. 2]. Unfortunately this drug had to be given intravenously and was associated with side effects (tachycardia and paras-thesias) at doses high enough to inhibit HIV replication. AMD-3100 is no
longer in development for the treatment of HIV, but AMD-070 is a new small molecule selective CXCR4 blocker that has good oral bioavailability in animals [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 563]. This is an interesting new approach to treatment that should not share cross-resistance with any available antiretroviral drug class. Initial clinical studies of this drug are scheduled to begin at Johns Hopkins and the University of Washington in June or July of 2003.
CCR5 inhibitors: There has been much interest in selective inhibitors of the CCR5 chemokine receptor since the first reports that one of these compounds, SCH-C, a CCR5 antagonist developed by Schering-Plough, had significant short-term anti-HIV activity in patients [Reynes, et al. Conf Retroviruses Opportunistic Infect. 2002 Feb 24-28;9th:Abstract No. 1]. Three new investi-gational CCR5 inhibitors were discussed at the 10th CROI: AK-602, a drug that has anti-HIV activity in a SCID-Hu mouse animal model [Maeda, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No.
10], TAK-220, a potent and selective CCR5 blocker that has moderate oral bioavail-ability in animals [Iizawa, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 11), and UK-427,857 [Dorr, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 12]. None of these compounds has yet entered clinical trials, and it was disappointing that there is no news on the two Schering-Plough compounds, SCH-C and SCH-D, that were reported at last year’s meeting.
Fusion inhibitors: T-1249, the second generation relative of ENF, was covered in a previous article on drug resistance and treatment of experienced patients [see Gallant, HHR;15(2):8].
Anti-CD4 antibodies: TNX-355 is a humanized monoclonal antibody that binds to a region in domain 2 of the CD4 receptor that is essential for HIV binding and entry. This agent has been around for more than a decade; it has potent antiretroviral activity in vitro and in animal models and is apparently not immunosuppressive, but until now there has been no clinical efficacy data on this antibody.
Dan Kuritzkes and colleagues presented results of the first Phase II trial of TNX-355 [Kuritzkes, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 13]. In an open-label study, five sequential cohorts of 6 infected subjects received single intra-venous doses of 0.3, 1, 3, 10, or 25 mg/kg of TNX-355. All the subjects were HAART-experienced and most entered the study on a failing regimen. TNX-355 produced mean peak decreases in viral load of 0.2, 0.68, 1.48, and 1.09 log10 c/mL for the 1, 3, 10, and 25 mg/kg dose
cohorts, respectively. Peak viral load reduction occurred at Day 21 for the highest dose of antibody, prompting the assertion that this antibody could be given once every 7 to 21 days. TNX-355 had a mean plasma half-life of 63 hours at the highest dose, and could be found still attached to circulating CD4 cells up to 27 days after a single dose. Incidentally, higher doses of the antibody caused an immediate increase in CD4 count, probably due to changes in lymphocyte trafficking. The antibody was well tolerated and no significant side effects were noted.
This is an interesting new approach to treatment, but some questions remain about long-term safety and efficacy in humans. Some patients had no drop in viral load with this antibody, even with high doses. Whether these patients have a modified CD4 protein not recognized by the antibody, or a virus that somehow resists the blocking effects was not discussed; it is also possible that some patients have unfavorable pharmacokinetics. Finally, it is likely that this product will be expensive and will have to be injected, even though it can be dosed infrequently.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in May 2003. The state of the art may have changed since the publication date.
