Salvage therapy: new protease inhibitors promising

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Three new protease inhibitors appear to hold promise for people who have already suffered viral rebound with one or more PIs, according to findings presented at the Seventh Retroviruses Conference today in San Francisco.

ABT-378/r or lopinavir (just made available in the UK for people who have failed currently available PIs) suppressed viral load below 400 copies in 84% of people after 48 weeks. This group of 70 patients had previous experience with one protease inhibitor, but no prior NNRTI experience.

Patients were randomised to receive 400mg of ABT-378 and either 100mg or 200mg of ritonavir, and after fifteen days added nevirapine and changed at least one nucleoside analogue.

Glossary

cross resistance

The mechanism by which a virus that has developed resistance to one drug may also be resistant to other drugs from the same class. 

 

sensitivity

When using a diagnostic test, the probability that a person who does have a medical condition will receive the correct test result (i.e. positive). 

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

After two weeks viral load fell by an average of 1 log in all patients, regardless of which PI had been taken previously and regardless of loss of sensitivity to ABT-378 at baseline.

At the beginning of the study, eleven patients had evidence of significantly reduced sensitivity to ABT-378. After 48 weeks, 7 out of 11 had viral load below 400 copies indicating that even in people with indications of cross-resistance to ABT-378, the drug’s very high blood levels may often overcome emerging cross-resistance. ABT-378 blood levels remain 30 times higher than the critical level needed to control viral replication (the EC50), so the loss of sensitivity seen in patients who entered this study may have had little clinical relevance (Deeks; Kempf).

However, the addition of nevirapine at day 15 also made an important contribution to viral suppression, and ABT-378 will also need to demonstrate that it can maintain viral suppression in people with experience of all currently available classes of drugs if it is to fully meet the needs of people with extensive treatment experience.

Amprenavir is most likely to be effective after saquinavir or nelfinavir treatment, according to an analysis of PI-resistant virus isolates by German researchers. 155 samples were analysed, and showed high level resistance to amprenavir in 25 cases. Out of 62 samples with complete cross-resistance to all other Pis, 37% remained sensitive to amprenavir. Resistance to indinavir or ritonavir was more likely to lead to amprenavir resistance, with genotypic mutations at codons M46I/L, I54L/V, I84V and L90M especially implicated in cross-resistance. The I84V mutation or any two other mutations in this group were strongly predictive of reduced sensitivity to amprenavir, suggesting that genotypic testing may be useful in establishing if amprenavir can be used as part of a salvage regimen for people suffering viral rebound (Schmidt). Amprenavir is already available in UK and certain other European countries through a compassionate access programme for people who cannot otherwise put together a viable anti-HIV regimen.

Tipranavir, recently acquired by Boehringer Ingelheim, is able to reduce viral load by 1.5 log when dosed with 200mg of ritonavir. This dosing system increases blood levels of tipranavir fifteen-fold, and adds further value to tipranavir’s cross-resistance profile. Researchers have previously reported that 90% of virus isolates resistant to all four protease inhibitors are still sensitive to tipranavir, so the news that a small dose of ritonavir can substantially improve the drug’s pharmacokinetic profile (and reduce the daily pill burden) is certain to increase demand for European trials in PI-experienced patients to get underway as quickly as possible (Wang).

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References

Deeks S et al. ABT/378/ritonavir (ABT-378/r) suppresses HIV RNA to Abstract 532, Seventh Conference On Retroviruses, San Francisco, 2000.

Kempf D et al. Baseline genotype and phenotype do not predict response to ABT-378/ritonavir (ABT-378/r) in PI-experienced HIV+ patients at 24 and 48 weeks. Abstract 731, Seventh Conference On Retroviruses, San Francisco, 2000.

Schmidt B et al. Cross-resistance to amprenavir in PI treated patients. Abstract 726, Seventh Conference On Retroviruses, San Francisco, 2000.

Wang Y et al. The safety, efficacy and viral dynamics analysis of tipranavir, a new generation protease inhibitor, in a phase II study in antiretroviral-naïve HIV-1 infected patients. Abstract 673, Seventh Conference On Retroviruses, San Francisco, 2000.