Experimental drugs at IAS

 Several studies focused on experimental treatments at the recent International AIDS Society Conference in Sydney. Comparisons with efavirenz, the recommended non-nucleoside reverse transcriptase inhibitor (NNRTI) for those starting HIV therapy for the first time, were more than abundant as trials aimed to determine whether benefits would be seen in those new to treatment or reserved for those with more experience.

Benefits of a new NNRTI

An analysis of side-effect data from a clinical trial of TMC-278, Tibotec’s experimental NNRTI, indicates that it causes fewer changes to lipid (fat) and glucose (sugar) levels than efavirenz. The new data suggest that the drug may have a potential safety advantage over efavirenz.

Study C204 is a 96-week trial comparing TMC-278 to efavirenz, in combination with Truvada (tenofovir plus emtricitabine) or Combivir (zidovudine plus lamivudine). Data from the trial, reported at the 14th Conference on Retroviruses and Opportunistic Infections earlier this year, have already demonstrated that TMC-278 has comparable efficacy to efavirenz.

Maraviroc reserved for treatment experienced?

While Pfizer's CCR5-blocking entry inhibitor, maraviroc (Celsentri), has proven safe and effective in clinical trials involving treatment-experienced patients, new data have found it inferior to the standard-of-care, efavirenz, when used by people starting HIV treatment for the first time.

The MERIT study randomised participants to receive either efavirenz or maraviroc combined with Combivir (zidovudine plus lamivudine). Sixteen weeks into the study, those using once-daily maraviroc showed inferior responses in terms of viral load reduction.

Maraviroc blocks the use of CCR5, one of two coreceptors HIV can use to enter the CD4 cell. Upon entering the study, participants were required to have CCR5-tropic virus (HIV using the CCR5 coreceptor to gain entry to the CD4 cells as apposed to the CXCR4 coreceptor) to ensure benefit from maraviroc.

During the study, 11.9% of those taking maraviroc stopped due to treatment failure, compared to 4.2% in the efavirenz group.

Update on Merck's integrase inhibitor

Results from an ongoing clinical trial of raltegravir, Merck's experimental integrase inhibitor, have suggested comparable efficacy to efavirenz after 48 weeks of treatment. Encouraging 24-week data has already been seen at the 14th Conference on Retroviruses and Opportunistic Infections (CROI) in February.

The study enrolled 198 HIV-positive people new to treatment who received either raltegravir (at varying doses) or efavirenz, along with a backbone tenofovir and lamivudine.

After 48 weeks of therapy, 83 - 88% of those in the varying raltegravir dosing groups saw their viral loads reduced to less than 50 copies/ml. In the efavirenz group, approximately 87% experienced viral load reductions to less than 50 copies/ml. The differences were not statistically significant, meaning that the variations could have been due to chance. Raltegravir and efavirenz also did equally well at raising CD4 cell counts. In addition, 3% of patients experienced treatment failure (failed to achieve an adequate viral load response) in both groups.

More news from the 4th International AIDS Society Conference

According to a late-breaker presentation at IAS, switching from an antiretroviral regimen that is currently controlling your viral load to Kivexa is more likely to result in toxicity-related treatment failure than switching to Truvada. Switching from a successfully suppressive antiretroviral regimen may be necessary for several reasons, including the possibility of long-term side-effects. 

Truvada and Kivexa are fixed-dose combination pills, each of which combines two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) into a single-tablet formulation. Kivexa contains 3TC (lamivudine) and abacavir; Truvada is a combination of FTC (emtricitabine) and tenofovir.
The Spanish “Bicombo” trial compared the safety and efficacy of Truvada and Kivexa after 48 weeks.

Virological failure was uncommon in all participants, occurring in 2.4% patients taking Kivexa and none of those taking Truvada. CD4 cell counts increased by 44 cells/mm³ in the Kivexa group, while falling by 3 cells/mm³ in those taking Truvada.

However, more people in the Kivexa arm discontinued therapy prematurely. Whilst nine (5.4%) of those taking Truvada stopped due to adverse events, 17 (10.2%) did so in the Kivexa group.

The majority of adverse events in the Kivexa group were attributed to abacavir hypersensitivity reaction. Participants were not pre-screened for genetic susceptibility to abacavir hypersensitivity (see this issues upfront on page 3). If clinicians were to use genetic screening test to exclude patients who are prone to abacavir hypersensitivity, Kivexa and Truvada might have shown comparable effectiveness.
Some participants changed from individual drugs to the combination pill that contained the same agents (for example, from separate FTC and tenofovir to Truvada), so strictly speaking these patients did not switch therapy.

Switching to Kivexa or Truvada?