The 3rd IAS, set this year at Brazil’s RioCentro conference center, included a substantial amount of information pertaining to the treatment of antiretroviral therapy (ART)-experienced patients, although much of it had been presented in earlier forms elsewhere. There was specific emphasis on new antiretroviral agents, many of which show promise for the treatment of patients with resistance to currently available drugs.

New Drugs

TMC114 is an investigational protease inhibitor (PI) with novel protease-binding properties that attracted considerable attention as a salvage drug at this year’s Conference on Retroviruses and Opportunistic Infections [Conf Retroviruses Opportunistic Infect 2005 Feb 22-25;12: Abstract 164LB, see Lucas G, HHR 2005;17:1]. At CROI pooled results from two trials were presented. At IAS 24- week results from one of those studies, POWER 1, were reported [Katlama C, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd (Abstract WeOaLB0102)].

A total of 318 subjects, with an average of 9 years of ART exposure and a median of 8 protease resistance mutations, received an optimized background regimen and were randomized to 1 of 3 ritonavir (RTV)-boosted doses of TMC114 or to investigator-selected PI(s). The median viral load was 4.5 log₁₀ c/mL, and the median CD4 count was 172 cells/mm³ at enrollment. Enfuvirtide (ENF) was used by about 45% of participants overall. The TMC114/r arms performed substantially better than the comparison arm (Table 1).

In a separate report on the safety of TMC114, the rates of grade 3 or 4 adverse events were 24% and 29%, and the rates of discontinuation for adverse events were 5% and 6% in the combined TMC114 and control arms, respectively [Grinsztejn B, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WePeLB6.2C01]. Additionally, a pharmaco-kinetic study [Sekar V, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WePe3.3C13)] reported that gastric acid-reducing drugs (omeprazole and ranitidine) had no effect on the pharmacokinetic parameters of TMC114/r, in contrast to the reductions that acid-reducing drugs are known to cause in plasma concentrations of boosted and unboosted atazanavir.

GW695634 is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against resistant isolates that is under development at GlaxoSmithKline. Results from a 7-day, dose-finding, monotherapy study were presented at IAS [Becker S, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WePe6.2C03)]. Forty-six participants with previous failure on an NNRTI-containing regimen were randomized to placebo or 100, 200, 300 or 400 mg of GW695634. Sixtyone percent of participants had =1 NNRTI mutation identified at baseline, and the remainder had past evidence of NNRTI resistance. At 7 days the median viral load change in the placebo group was +0.14 log₁₀ c/mL compared -1.1 to -1.6 log₁₀ c/mL in the GW695634 groups, with no evidence of a dose-response relationship. Rash was observed in some subjects, and appeared to be more common at higher doses.

D-d4FC (Reverset) is a novel fluoro-cytidine NRTI, which appears to have activity against NRTI-resistant HIV strains. It is being codeveloped by Pharmasset and Incyte. Results from the RVT-203 study were presented, in which 199 treatment-experienced participants added placebo, 50, 100, or 200 mg of D-d4FC to a failing regimen for 2 weeks [Cohen C, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WeOaLB0103)]. At two weeks, the background regimen could be modified at the discretion of the treating physician, and participants were followed to week 16. At the end of the 2 week add-on phase, the average changes in viral load from baseline were 0, -0.4, -0.3, and -0.7 log₁₀ c/mL in the placebo, 50 mg, 100 mg and 200 mg D-d4FC groups, respectively (all D-d4FC groups were significantly different from placebo). Patients who took D-d4FC with ddI were more likely to have lipase elevations, and 3 developed overt pancreatitis. The two-week response to the highest dose of the drug, 200 mg qd, was best among patients with TAMs, including the 41L/210W combination that causes high-level cross-resistance among most NRTIs. Response was somewhat diminished among those with TAMs plus M184V or with the K65R or L74V mutations. Interestingly, patients who took D-d4FC along with 3TC or FTC had a diminished response to therapy, which may be due to an intracellular pharmacokinetic interaction similar to that observed with SPD754, another NRTI.

• There are now 3 CCR5 inhibitors in clinical stages of development, each of which now has a new generic name that conjures up images of drug therapy in the Flintstone era. Maraviroc is the Pfizer drug, formerly known as UK-427857. Aplaviroc is the GSK drug, formerly known as GW873140. Vicriviroc is the Schering compound, formerly SCH- 417690, or Schering D. Data were presented on maraviroc and vicriviroc in Rio. Phase 1 and 2a studies have demonstrated excellent tolerability and viral load reductions associated with short-term use at all therapeutic doses of maraviroc [van der Ryst E, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuOa0204)]. Patients who received 300 mg bid had viral load reductions of 1.84 log₁₀ c/mL at 10 days. Orthostatic hypotension was a doselimiting side effect, observed with doses of 600 mg or greater. Selection of R5/X4-dual-tropic virus, presumably pre-existing, has occurred in two patients treated with 10 days of maraviroc monotherapy. The virus in one patient reverted to R5 tropism several days after discontinuation of the drug, while dual-tropic virus persisted in the other. In 14-day monotherapy studies with vicriviroc, HIV-infected subjects experienced dose-related 1.0- 1.6 log₁₀ c/mL reductions in viral load [Raffi F, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuOa0205)]. This drug also appears to be well tolerated in early studies. It has a long half-life (>24 hours), and there is a post-antiviral effect of 2 to 3 days following discontinuation. Since vicriviroc a substrate of the CYP3A4 enzyme system, drug levels are increased markedly by ritonavir (RTV) and by LPV/r. Coadministration with EFV reduces drug levels, but this interaction is more than offset by use of RTV boosting [Saltzman M, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuPe3.1B05)]. Binding to the CCR5 coreceptor may also be inhibited in other ways: PRO 140 is a humanized IgG4 anti-CCR5 monoclonal antibody that is synergistic with CCR5 inhibitors as well as entry inhibitors [Pevear D, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract TuOa0206)].

Existing Drugs

• George Hanna from Abbott presented pharmacokinetic data on the new tablet coformulation of lopinavir/ritonavir (LPV/r), which is currently FDA-approved in a gel-cap formulation [Awni W, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WeOa0206)]. The gel-cap formulation requires refrigeration and is administered as 3 capsules bid with food (133 mg of LPV and 33 mg of RTV per capsule). The new tablet formulation will reduce the pill burden to 2 tablets bid (200 mg of LPV and 50 mg of RTV per tablet) and need not be refrigerated. In an open-label, randomized crossover study in healthy volunteers, the LPV maximal concentration (C_max) and area-under-the-concentration-time- curve (AUC) were 24% and 18% higher with the tablet than the gel-cap formulations, respectively. Importantly, the overall pharmacokinetic variability was reduced with the tablet formulation compared to the gel-cap formulation, and administration with food was not necessary to optimize absorption. LPV/r has now been approved for once-daily administration by the FDA, but once-daily dosing will become much more feasible with approval of the new tablet formulation, which is anticipated to occur this fall.

• Additional 24-week data from the RESIST 1 and 2 trials of RTV-boosted tipranavir (TPV) were presented at IAS by Valdez [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WeOa0205)]. Selected 24-week results from this trial were reported earlier this year at CROI [Lucas G, HHR 2005;17:1]. The IAS presentation addressed the association between the TPV inhibitory quotient (IQ), ENF use, and viral suppression at 24 weeks. Baseline phenotypic resistance testing and trough TPV concentrations were performed in a random subset of subjects in the RESIST trials at weeks 2 and 4. A TPV IQ was calculated from the susceptibility and plasma concentration results. IQ results were stratified as <60 or ≥60, the latter indicating a more favorable drug concentration/baseline resistance relationship. Concomitant use of ENF and a TPV IQ ≥60 were associated with a higher likelihood of achieving viral suppression at 24 weeks (Table 2).

• The near absence of PI-associated resistance mutations after failure of a LPV/r-based regimen [J Infect Dis. 2004 Jan 1;189(1):51-60] or a RTV-boosted fosamprenavir regimen [AIDS. 2004 Mar 5;18(4):651-5] have been published previously. Similar findings were reported at this year’s IAS for RTV-boosted saquinavir (SQV)-based therapy [Ananworanich J, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: (Abstract WePe4.4C12)]. Treatment-naïve participants in the Thai Staccato trial (n-258) were treated with 1600 mg SQV/RTV 100 mg once daily plus NRTIs. Virologic failure occurred in 10 participants after a median of 30 weeks. None of the 10 patients developed a major PI-associated mutation; 7 of 10 had minor mutations or polymorphisms (protease codons 10, 20, 36, 63), and in 4 of these 7 the mutations were present at baseline.

Conclusions

TMC114 and GW695634 are promising agents in the pipeline for salvage of PI-resistant or NNRTI-resistant virus, respectively. Dd4FC appears to have more modest activity against NRTI-resistant virus. Three CCR5 inhibitors are currently in clinical phases of development, and demonstrate promising activity. A new tablet formulation of LPV/r is expected to simplify the use of this drug, and will make once-daily dosing more feasible.

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