All licensed antiretroviral agents target one of two HIV enzymes and cross-resistance limits options for many treatment-exposed individuals. HIV entry involves multiple co-operative steps – attachment to CD4, recruitment of co-receptor molecules, conformation changes in gp41, and ultimately membrane fusion. T-20 and T-1249, which bind HIV gp41, are the first antiretroviral agents that inhibit HIV fusion to reach clinical development. Cross-resistance with existing agents is very unlikely. The 36-amino-acid peptide T-20 inhibits HIV replication in vitro (IC50 in the nanomolar range), with activity against R5, X4 and dual-tropic primary HIV strains, and
acts synergistically in vitro with other classes of entry inhibitor. Fusion inhibitors (FIs) provide potent suppression of HIV replication, as demonstrated by a median HIV RNA reduction of 2.0 log10 occurring after 14 days of T-20 monotherapy among four individuals who received 100 mg twice daily (bid) intravenously1. Preliminary results from an ongoing, randomised, dose-comparative trial in 71 protease inhibitor (PI)-experienced, non-nucleoside-naïve individuals (median HIV RNA 4.3 log10 copies/mL, CD4 count 232 cells/mm3) were presented recently2. Three T-20 dosages (50, 75 and 100 mg bid subcutaneously) in combination with abacavir, amprenavir, efavirenz and low-dose ritonavir were compared with oral antiretrovirals alone. At 16 weeks, 82% of
45 T-20 recipients compared with 58% of 19 controls achieved HIV suppression <400 copies/mL, with 56% and 37% of participants, respectively, <50 copies/mL (intent-to-treat). Median CD4 count changes ranged from +37 to +74 cells/mm3 in the T-20 arms and +10 cells/mm3 in controls (observed). The safety, efficacy and convenience of prolonged subcutaneous administration of T-20 (50 mg bid) in combination therapy were examined in a 48-week trial in 71 heavily pre-treated individuals with advanced disease3 (median HIV RNA 5.0 log10 copies/mL, CD4 count 90 cells/mm3). Participants had received a median of nine previous antiretroviral agents; 97% had received PIs and 79% all three classes of approved antiretrovirals. Of 41 patients completing 48
weeks, 56% showed a sustained response (>1 log10 decrease from baseline or HIV RNA <400 copies/mL), with 39% <400 copies/mL. In a questionnaire administered at 48 weeks or discontinuation, of 54 responses received, 52% found twice-daily subcutaneous injection of T-20 ‘easy’/‘very easy’ and 35% ‘not bad’. Relative to their other HIV/AIDS medications, 95% considered that T-20 did not limit moderate activities3. Preliminary results from an ongoing trial in 13 antiretroviral-experienced children show that T-20 60 mg/m2 bid subcutaneously provides potent viral suppression over the short duration of treatment currently evaluated. Ten of 13 children achieved an HIV RNA reduction of at least 0.7 log10
copies/mL within 7 days, after T-20 (30 or 60 mg/m2 bid) was added to their background regimen. Approximately two-thirds of patients in Phase I/II trials reported mild-to-moderate local injection site reactions, the most common adverse event. However, discontinuation was rarely required. Clinical and laboratory safety parameters show no consistent pattern or dose relationship. T-20, the first FI to enter clinical trials, effectively suppresses HIV replication in combination therapy in both moderately and extensively treatment-exposed patients as part of combination therapy. T-20 is well tolerated in adults and children, and twice-daily subcutaneous administration appears acceptable to most patients. Phase III studies are in progress with an
improved formulation that reduces the number of daily injections. T-1249, a rationally-designed, 39-amino-acid peptide FI, has activity in vitro against T-20-resistant viral isolates. In a 14-day monotherapy trial, 6.25–50 mg T-1249 daily was administered subcutaneously to 63 predominantly heavily pre-treated, FI-naïve individuals4. HIV RNA reductions were dose-related, with a mean change of –1.3 log10 copies/mL at 14 days for the highest dose tested. The potential for once-daily T-1249 administration was supported by pharmacokinetic analyses. T-1249 was well tolerated; mild local injection site reactions were the most frequent adverse event (40%). Higher doses are under investigation.
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