A New Intensification Trial Launched to Study Residual HIV Replication on Effective HAART: the IntensHiv study
Researchers at Toulon General Hospital, France, have announced the first inclusion in a new HAART intensification trial aimed at analyzing residual HIV disease and reservoirs. Named 'IntensVih' in French (ClinicalTrials.gov Identifier: NCT00935480), this trial will study the 'Impact of Therapy Intensification by an Integrase Inhibitor +/- a CCR5 Inhibitor on the Lymphoid Reservoir for HIV-1 in Chronically Infected Patients'
Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. HAART intensification trials conducted over the last few years have provided conflicting results. Consequently, it is not yet clearly established if low-levels of ongoing HIV replication persist in patients successfully treated, and if yes, where this takes place.
Most trials failed to show any effect of HAART intensification by adding one new drug (either an nNRTI, a PI, or raltegravir) on the low level viremia (plasma HIV RNA between 1 and 49 copies/ml) which persists in treated patients. However, if these very low levels were a consequence of ongoing viral replication, their dynamics would be very slow and could not have been influenced by a few weeks or months of intensification. In the IntensHiv trial, HAART intensification will last for 12 months.
Two trials found either an increase in episomes in blood (Buzon et al), suggesting persistent HIV replication, or HIV RNA changes in the gut (Yukl et al). As gut-associated lymphoid tissue is supposed to be the greatest viral reservoir in treated patients, investigating this tissue compartment in trials is of utmost importance.
The IntensHiv trial will test durable intensification both at the blood and tissue levels. It will also combine in the intensification cocktail two new antiretrovirals acting differently: Raltegravir, an HIV integrase inhibitor, and Maraviroc, a CCR5 (coreceptor) inhibitor.
Thirty six HIV-infected patients on effective HAART including a boosted PI will be randomized within the next 12 months to either the intensified regimen or the control arm. Intensified patients will receive raltegravir for 12 months in addition to their usual regimen, plus Maraviroc if CCR5 HIV tropism is found on proviral DNA by genotyping. The evolution of the HIV reservoir will be followed in these patients both in plasma, peripheral mononuclear cells and gut biopsies.
This study will provide data on the nature and origin of persistent HIV RNA on effective therapy, ont the role of tissue reservoirs, on immune changes with Raltegravir/Maraviroc combination and will establish if 2 RTI + boosted PI + Raltegravir + Maraviroc is the correct background regimen to use in future eradication trials.
This protocol is sponsored by Toulon General Hospital in collaboration with Abbott and Merck laboratories.
Key words: cure, eradication, gut, hiv, maraviroc, raltegravir, reservoirs