A drug developed to provide a second NNRTI option for people who fail their first NNRTI-containing regimen appears to have little durable effect in people who have accumulated a large number of non-nucleoside associated mutations, researchers reported this week at the Eighth International Congress on Drug Therapy in HIV Infection in Glasgow. Even patients with only one NNRTI mutation experienced rapid failure if they also had a high level of resistance to nucleoside analogues
TMC125, also known as etravirine, is a new non-nucleoside reverse transcriptase inhibitor being developed by Tibotec, and is already available on expanded access for highly treatment-experienced people who need the drug in order to assemble a viable treatment regimen.
Like nevirapine, TMC125 is taken twice daily, and a phase IIb study presented at the Toronto International AIDS Conference in August showed that the drug was active in highly treatment-experienced patients with both NNRTI resistance and extensive protease inhibitor resistance, producing a sustained viral load reduction of approximately 0.8-1 log after 48 weeks and a peak viral load reduction of 1.3 -1.5 log after two weeks on treatment. In this study the background regimen could include a protease inhibitor - usually Kaletra (lopinavir/ritonavir) - and could also include enfuvirtide (Fuzeon, T-20), as well as two nucleoside analogues selected by resistance testing.
However, an earlier phase IIa study had shown a less promising response in patients failing a first-line NNRTI-containing regimen. Study TMC-C227 randomised 116 patients who had been receiving a first-line NNRTI-containing regimen and who had detectable viral load above 1,000 copies/ml to receive either TMC125 800mg twice daily plus two nucleoside analogues, or to receive a ritonavir-boosted protease inhibitor (either lopinavir or atazanavir) plus two nucleoside analogues. Nucleoside analogues were chosen after resistance testing.
After two weeks viral load had fallen by approximately 1.3 log in both groups, and continued to decline in the protease inhibitor group to –2 log by week by week 16. However in the TMC-125 group almost all patients had experienced the beginning of a a viral rebound by week 16 and the study was terminated early by the Data Safety Monitoring board.
The majority of patients recruited to that study were resident in South Africa (48), Thailand (18) and Brazil (27). Almost half the Thai patients had three or more NNRTI mutations at baseline, as well as three or more nucleoside analogue mutations, as did more than a quarter of the South African patients, a much higher prevalence than other countries recruiting patients to the study.
These resistance patterns are likely to reflect several factors: the lack of drug options due to cost for patients in those countries, leading to extended periods on failing regimens, together with the lack of viral load monitoring that would warn clinicians when it was necessary to switch patients from a failing regimen.
The baseline analysis also found that more than a third of patients in the study were recycling at least one nucleoside analogue used in the past in the hope that it would have some benefit second time around. Around ten per cent were recycling two nucleoside analogues.
When the study outcomes were analysed according to baseline drug resistance patterns and by the location of participants, the researchers found:
- The rebound was greater and earlier in patients in South Africa and Thailand;
- Patients with four or more NRTI mutations at baseline had little or no virologic response to TMC125 (there was a trend towards a higher number of NRTI mutations in patients with three NNRTI mutations at baseline).
- Even in patients with just one NRTI mutation at baseline there was a trend towards a viral load rebound apparent by week 12.
- An increasing number of NNRTI mutations was associated with a smaller viral load reduction and faster viral rebound. Overall, 28% of patients in the TMC-125 arm had three or NNNRTI mutations at baseline.
There was no increased incidence of neuropsychiatric events in the TMC-125 arm when compared with the protease inhibitor arm, and although 10% of the TMC-125 group experienced rash after starting the drug, there were no grade 3 or 4 rashes. Diarrhoea was far less frequent in the TMC125 group, affecting only 3% compared to 25% in the protease inhibitor group.
The study findings suggest that TMC125 may not be approprate as a second-line drug in settings where patients have high levels of nucleoside analogue resistance, and where the drug cannot be combined with nucleoside analogues to which the patient is sensitive, as well as new drug classes such as chemokine antagonists or integrase inhibitors. This could rule out the use of TMC125 in countries like South Africa, where patients may spend lengthy periods on failing regimens before treatment failure is detected, and where the potential for coupling TMC125 with low-cost second line drugs to which the patient is sensitive will continue to remain difficult without an expansion in generic competition to make second-line products.