SUMMARY: An intensive antiretroviral therapy (ART) regimen consisting of 5 drugs from 4 different classes did not lead to better outcomes after 1 year than a standard 3-drug regimen started during acute or early HIV infection, according to study data presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) last week in Boston.

By Paul Dalton

There is growing interest in the benefits of treating HIV during the earliest phases of infection. This interest arises from observations of profound immune system injury during these early phases. Some researchers hypothesize that initiating ART within the first 6 months to a year after infection would lead to less immune depletion and better clinical outcomes.

Typical HIV drug regimens contain 3 drugs, including 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a more potent agent such as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). While 3-drug ART is largely successful, there is ongoing interest in ways to improve HIV treatment.

In an oral presentation at CROI, Martin Markowitz of the Aaron Diamond Research Center in New York City presented 48-week results from a study comparing a standard 3-drug ART regimen to an experimental 5-drug combination in people infected with HIV less than 1 year and starting treatment for the first time.

Participants were randomly assigned to take either tenofovir/emtricitabine (Truvada) plus either boosted atazanavir (Reyataz) or boosted darunavir (Prezista), or else the same 3 drugs plus the integrase inhibitor raltegravir (Isentress) and the CCR5 blocker maraviroc (Selzentry).

A total of 40 people enrolled in the study, 26 in the 5-drug arm and 14 in the 3-drug arm; 3 people in each arm dropped out, leaving 23 in the 5-drug arm and 11 in the 3-drug arm to be evaluated.

All participants were men and the average age was around 40 years. About 25% were considered to be in the acute phase of HIV infection, meaning they presented with very high viral loads and had not yet developed HIV antibodies.

Results

	Overall efficacy in an intent-to-treat analysis was 78.6% for the 3-drug arm vs 76.9% for the 5-drug arm, not a statistically significant difference.
	After 48 weeks, everyone in the 3-drug arm had undetectable viral load, as did 20 of 23 people in the 5-drug arm.
	HIV viral load dropped more quickly in the 5-drug arm, with the difference becoming statistically significant after 12 weeks; this is consistent with other research showing that raltegravir led to more rapid viral load decline compared to other antiretrovirals.
	By week 16, however, viral loads were similar between the 2 groups.
	All study participants except 1 had detectable HIV using more sensitive viral load tests.
	No differences between the groups were seen with intensive virological testing, including single cell assays, proviral DNA, and cell-associated HIV RNA.
	CD4 T-cell counts increased by an average of 300 cells/mm3 in both arms.
	There were no clinically meaningful differences between the arms in other immunologic parameters, including T-cell subsets and various markers of inflammation.
	Participants in both arms were more than 95% adherent to their assigned regimen, according to both self-reporting and random drug level sampling.

Markowitz concluded that adding raltegravir and maraviroc to a standard 3-drug ART regimen failed to provide any additional benefit in either virological or immunological parameters.

One interesting aspect of this study yet to be presented is results from gastrointestinal (GI) biopsies performed on all participants after 60 weeks. Immunologists have noted a profound loss of T-cells in the GI tract during early HIV infection, and some researchers have speculated that raltegravir and maraviroc might provide extra protection against this GI immune injury.

While this study failed to show a difference between a 5-drug versus a 3-drug ART combination after 48 weeks, further follow up is planned through 96 weeks. Promisingly, this study demonstrated that people newly infected with HIV could use either regimen successfully.

Investigator affiliations: Aaron Diamond AIDS Research Ctr, Rockefeller University, New York, NY; Rockefeller University, New York, NY; Swedish Inst for Infectious Disease Control and Karolinska Institute, Solna, Sweden.

3/11/11

Reference
M Markowitz, T Evering, M Caskey, and others. A Randomized Open-label Trial of 5-Drug vs 3-Drug Standard PI-based cART Initiated during Acute and Early HIV-1 Infection: 48-Week Results. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 148LB.