Intergrase inhibitor trial results have potential implications for treatment strategies

An investigational integrase inhibitor can suppress replication of an HIV-like virus, preserve or restore CD4 cell count, has a high barrier to resistance, and is well tolerated, according to a study conducted in monkeys and published in the July 8^th edition of Science. The investigators also found that the drug promoted cellular immunity to HIV and suggest that this finding could have important implications for vaccine research or the timing of the initiation of anti-HIV therapy.

Integrase is an enzyme which HIV uses to insert its DNA into human cells. L-870812 is an investigational compound developed by Merck which inhibits the strand transfer stage of this process. Laboratory studies have shown this compound to target both HIV and the monkey equivalent virus, SIV.

Investigators infected rhesus macaques monkeys with simian-HIV 89.6P, a form of HIV engineered to cause an HIV-like disease course in macaques. This is characterised by accelerated disease progression with rapid depletion of CD4 cells within two weeks of infection.

The investigators wished to evaluate the value of L-870812 in both acute and chronic infection. Twelve monkeys were included in the study, equally divided into two treatment arms. One group of rhesus macaques was treated with L-870812 ten days after infection with SHIV 89.6P, and another group when chronic infection was well established at day 87. The animals were then treated with the investigational compound for 77 and 45 days respectively. Plasma viral load, CD4 cell count, cellular immune responses, availability of the drug, and resistance were monitored.

Peak viral load occurred within approximately two weeks of infection with the HIV-like virus, leading to a rapid fall in CD4 cell count. Four of the six monkeys in the delayed treatment arm experienced a decline in their CD4 cell count to below 10 cells/mm³ within two to three weeks of infection, with a median viral load of 2 x 10⁶ log.

However, in the animals treated with L-870812 starting on day ten post infection only a minimal and transient decline in CD4 cell count was recorded, stabilising above 200 cells/mm³ and remaining there for the duration of treatment (median count on day 55 being 602 cells/mm³). What’s more, in four of these six animals, viral load was suppressed below the limit of detection, and in the other two monkeys viral load was ten to 100 fold lower in the delayed treatment arm.

Good drug levels were observed in the four rhesus macaques with undetectable viral load ten hours after dosing. Although mutations occurred between 28 to 32 days of treatment, these did not lead to a rebound in viral load.

In the delayed treatment arm, median CD4 cell count at day 87 post-infection was 35 cells/mm³ and four animals had a CD4 cell count below 10 cells/mm³. After ten days of treatment with L-87812 viral load fell ten to 100 fold in all animals. CD4 cell counts increased from 3 cells/mm³ to 20 cells/mm³ in the most immunosuppressed animal and from 150 cells/mm³ to 200 cells/mm³ in the least. Treatment response was, however, less durable and more variable. Viral load rebounded in four animals within two weeks. However, the viral population in these monkeys remained wild-type.

The investigators believe that the difference in treatment response seen in the two arms was due to significant differences in viral specific cellular immunity. Early initiation of L-870812 permitted the development of persistent cellular immune responses to SHIV.

“Integrase inhibitors represent a new class of agents to treat HIV-1 infection in therapy-naïve patients and patients harboring viruses resistant to current antiretroviral agents,” comment the investigators. The investigators conclude that their study showed oral dosing of L-870812 to be well tolerated with no clinical evidence of toxicity. They add that there appears to be a high genetic barrier to resistance to the drug. What’s more, early treatment with the drug promotes cellular immunity to SHIV, which boosted CD4 cell count and suppression of viral load. “These studies therefore suggest cellular immunity may facilitate the durability of antiretroviral chemotherapy and provide evidence to support the use of vaccines to enhance and sustain the efficacy of antiretroviral therapy as well as the re-evaluation early intervention strategies for treating HIV-infection with improved antiviral regimens.”