Raltegravir may act against HIV in a manner quite distinct from existing antiretrovirals, allowing for the drug to remain effective against HIV for a period much longer than the actual metabolic half-life of the drug itself. The primary and secondary HIV mutations conferring resistance to raltegravir are also becoming well-characterised.
Raltegravir (Isentress) is the first drug to be approved in the relatively new class of HIV integrase inhibitors. Recent reports from phase II and phase III studies have provided very encouraging efficacy and safety data on raltegravir. This presentation to the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy by investigator Daria Hazuda described the first in-depth analysis of raltegravir resistance, along with emerging insights into the drug's mechanism of action.
Data were drawn from Benchmrk 1 and 2, ongoing phase III studies in highly pre-treated patients with triple-class resistant HIV. The successes of raltegravir in treating this population have been reported elsewhere.
In patients who failed virologically during raltegravir treatment in the Benchmrk trials, resistance was evaluated by phenotyping (by Monogram PhenoSense) and genotyping. Out of 462 patients, virologic failure (viral load > 400 copies/ml) occurred in 105, and genotypic data showed a difference between baseline and at the time of failure for 64 of these. These 64 patients were the subject of the remaining analysis.
Longitudinally, resistance mutations were seen to accumulate over time: while 30% of patients had only a single resistance mutation at the first genotype analysis after failure, that number declined to 8% in subsequent genotypes while the percentage of people with multiple (two or more) mutations increased.
Viruses with mutations in the integrase gene were found in the majority of patients with virologic failure. Three distinct genetic pathways predominated and were defined by signature mutations at N155, Q148, or Y143. The N155 mutation was the most common at first (45%), but Q148H emerged as the more dominant mutation over time, regardless of the resistance pattern seen at first.
The N155 mutation alone reduced raltegravir sensitivity approximately tenfold. However, additional secondary mutations nearly always emerged. These had a dramatic effect, reducing sensitivity by roughly one hundredfold overall.
Mechanism of action
During this session, new insights into raltegravir's mechanism of action were also discussed. In test tube studies, raltegravir appears to suppress HIV replication for a much longer time than its already long active half-life within cells would predict.
Also, raltegravir response is largely not dose-dependent. Normally, drug concentrations must be constantly maintained above the minimum concentration needed to suppress the virus from replicating. (This is the reason for the emphasis on drug adherence.) However, in patients whose trough (lowest-concentration) levels of raltegravir have been seen to fall below that minimum, outcomes have been as good as in other patients.
This appears to be due to a feature that may be unique to raltegravir (or possibly to integrase inhibitors as a class, although this is not yet known). After the reverse transcriptase enzyme converts HIV RNA into DNA, the DNA must be integrated into the host cell nucleus. This is accomplished by the integrase enzyme, which cuts the host cell’s genome and inserts the viral genetic material (DNA).
However, before being integrated, this viral DNA exists in a form which has a limited life-span. It appears that raltegravir is able to bind itself to this viral DNA in a way that permanently inactivates it. Dr Hazuda described cells exposed to raltegravir as being "essentially irreversibly marked so as to inhibit HIV integration".
If this is the case, then raltegravir could continue to be active against HIV in a cell that has been exposed to the drug, even if concentrations fall to very low levels thereafter.
In fact, test tube studies showed that, 48 hours after infection, HIV was still not replicating in cells that had been exposed to raltegravir, even after they were "washed" clean of active drug.
In conclusion, this study provides the first comprehensive analysis of raltegravir resistance as seen in Benchmrk studies 1 and 2. These analyses suggest three distinct resistance pathways marked by primary mutations at 143, 148, and 155, with the 148 mutation as the preferred mutation.
Hazuda DJ et al. Analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from the Benchmrk 1 and 2. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H-898, Washington, 2008.