Two non-nucleoside reverse transcriptase inhibitors (NNRTIs) active against HIV resistant to efavirenz and nevirapine may provide a second-line NNRTI option, according to results presented on Monady at the Ninth Annual Retroviruses Conference in Seattle.
DPC 083
DPC 083 is a new NNRTI under development by BMS Pharma that may be active against HIV that is resistant to nevirapine and efavirenz. Nancy Ruiz reported week 8 results from a study of DPC 083 in people who have experienced failure of an NNRTI-containing regimen.
Fifty one patients (mean age 40, 94% male) with mean baseline viral load of 3.85 log (around 7,000 copies /ml) and 473 CD4 cells/mm3 were randomized to receive either 100mg or 200mg of DPC 083 once daily.
Baseline resistance profiles were available for 48 individuals; 94% had at least one NNRTI resistance mutation, including mutations at positions 101 (44%), 103 (52%), 181 (17%), and 190 (25%). Fifteen patients had at least two NNRTI resistance mutations.
The pooled (100 and 200 mg) on-treatment (OT) response rate at week 8 (
DPC 083 was also tested in treatment-naïve patients in a study comparing the efficacy of various doses plus two NRTIs against efavirenz plus two NRTIs.
134 patients with mean baseline viral load of 33,113 copies were randomised to receive either 50mg, 100mg or 200mg of DPC 083 or efavirenz. All participants received Combivir (AZT plus 3TC). After 24 weeks, the proportion of patients with viral load below 50 copies (undetectable) was similar in each arm (79% (50 mg), 67% (100 mg), 72% (200 mg), and 78% (EFV).
However, there was a trend towards higher discontinuation rates in the efavirenz group and in those who received the highest DPC 083 dose. Premature discontinuation rates were 14% (50 mg), 17% (100 mg), 24% (200 mg) and 22% (EFV) (p > 0.05). The most frequent side effects were dizziness and rash. Dizziness was less frequent with DPC 083 (11-18%) than with EFV (32%). The frequency of rash was 15% (50 mg), 33% (100 mg), 53% (200 mg), 38% (EFV).
The 50mg is now likely to be carried forward for studies in treatment-naive patients, but the dose for NNRTI-experienced patients remains to be defined.
TMC 125
TMC 125 is a new NNRTI developed by Tibotec-Virco that is active against HIV resistant to currently available NNRTIs.
Prof. Brian Gazzard of London’s Chelsea and Westminster Hospital reported results from a seven day study designed to test whether TMC 125 is active in people who have experienced failure of an NNRTI-containing combination, and who have measurable resistance to existing NNRTIs.
For this phase IIA study 16 individuals with resistance to EFV (defined a 10-fold or greater reduction in susceptibility assessed by VirtualPhenotype and/or Antivirogram) received 900 mg TMC125 twice daily for 7 days, substituting the failing NNRTI, while they continued taking their NRTIs (unchanged). After day 7, treatment with TMC125 was terminated and replaced with another drug.
The average reduction in efavirenz susceptibility was 111-fold, and nevirapine susceptibility was reduced by at least 35-fold. Participants had a mean baseline viral load of 10,753 copies/ml, and also had at least one nucleoside analogue resistance mutation.
After 7 days of treatment, the median decrease in viral load was 0.9 log from baseline. Viral load continued to decrease on day 8. 12 patients (75%) had a decrease in viral load of at least 0.5 log10; in 7 patients (44%) a decrease >1 log10 was observed. There was no relationship between response and genotypic or phenotypic resistance. Eleven patients reported grade 1 (mild) adverse events. Diarrhoea (n=5) and headache (n=4) were most common.
No relationship between drug concentration and treatment response was seen in this study.
In a separate study in treatment-naïve patients, a team from the University of Amsterdam reported that TMC125 alone appears to be just as potent as a five drug combination using drugs from all three currently licensed classes (AZT, 3TC, abacavir, indinavir and nevirapine). The researchers calculated the rate of virus clearance from plasma over the first seven days of treatment by taking frequent viral load measurements, and compared data from two studies in which treatment-naïve patients had similar characteristics at baseline. Viral load in the TMC125 group fell by -1.92 log in the first 7 days of treatment, compared to -1.55log in the five drug group.
Gazzard B et al. TMC125, a Next-Generation NNRTI, Demonstrates High Potency after 7 Days Therapy in Treatment-Experienced HIV-1-Infected Individuals with Phenotypic NNRTI Resistance. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 5, 2002.
Ruiz N et al. Study DPC 083-203, a Phase II Comparison of 100 and 200 mg Once Daily DPC 083 and 2 NRTIs in Patients Failing a NNRTI Containing Regimen. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 7, 2002.
Ruiz N et al. Study DPC 083-201: A Phase II Double-Blind (DB) Comparison of 3 Once Daily Doses of the NNRTI DPC 083 vs 600 mg Efavirenz (EFV) in Combination with 2 NRTIs in HIV Anti-Retroviral (ARV) Treatment Naïve-Patients. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 7, 2002.
Sankatsing S et al. TMC125 Monotherapy for 1 Week Results in a Similar Initial Rate of Decline of HIV-1 RNA as Therapy with a 5-Drug Regimen. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 6, 2002.