Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Fifth International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention

Cape Town, South Africa / July 19-22, 2009

History of the ARV Arsenal

So far, the pace of antiretroviral drug development has not only been adequate to provide most patients who have multiple-drug resistant HIV with options but to identify highly active antiretroviral therapy (HAART) that is well tolerated and convenient to take. Relevant to the expanding options in the latest class of antiretroviral therapies, integrase inhibitors, both the tolerability and convenience of regimens even in experienced patients are important issues for what now appears to be lifetime treatment.

The fourth class of antiretrovirals after nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs) were the entry inhibitors, led by enfuvirtide. This drug came at a time when many experienced patients were running out of active therapies. Subsequent development of oral entry inhibitors, which work by a different mechanism, substantiated the premise of this approach but avoided daily injections, a major limitation of the first entry inhibitor.

Integrase inhibitors, the fifth drug class, appear to be following the same path. Raltegravir, the first agent, in this class was found to be highly effective for control of HIV in treatment experienced patients with combined with an optimized background (OB) regimen. Newer agents within this class, which inhibits infections by blocking an enzyme used by the virus to insert its DNA into human DNA, will be expected to build on this efficacy.

“Next generation integrase inhibitors need to show improvement in resistance profile as well as convenience in dosing. Specifically, they should aim for once-daily dosing as well as a unique resistance profile,” according to Dr. Sherene Min, Department of Medicine, University of North Carolina, Chapel Hill. Presenting new data on one of the integrase inhibitors in development, S/GSK1349572, Dr. Min maintained that initial results have been promising.

In the study presented by Dr. Min, 35 patients with a viral load of at least 5000 RNA copies/mL and >100 CD4+ cells were randomized to 2 mg, 10, mg, or 50 mg of the integrase inhibitor S/GSK1349572 or to placebo. All doses were administered q.d. Viral load reductions were measured on Day 11.

On Day 11, viral loads were unchanged in the placebo group but reduced substantially by all three doses of the integrase inhibitor, ranging from 1.51 log₁₀/copies with the 2 mg dose to 2.46 log₁₀/copies in the 50 mg dose. Dr. Min characterized the antiviral activity of this experimental integrase inhibitor as “unprecedented.” Similar short term studies conducted with the only licensed integrase inhibitor, raltegravir, or another experimental agent, eltegravir, had not previously achieved this degree of viral suppression.

On the highest dose, 70% of patients achieved a viral load <50 copies/mL despite treatment with a single agent. Even in the two lowest dose groups, 56% achieved a viral load <400 copies/mL on the single agent therapy. Except for headache, which occurred in 20% of those on the highest dose of the integrase inhibitor, the type and rates of side effects were similar in the active therapy and placebo groups.

Interest in the clinical potential of S/GSK1349572 has been encouraged by a series of in vitro studies that suggest this agent may have a high genetic barrier to resistance relative to other integrase inhibitors. It a series of experiments conducted with HIV virus capable of replicating in the presence of raltegravir at a concentration of 4,000 nM, there was a dramatic reduction in HIV replication when concentrations of S/GSK1349572 as low as 32 nM and no replication at concentrations of 160 nM. There has also been limited cross-resistance to the experimental integrase inhibitor elvetgravir in similar studies. New classes of antiretroviral agents have been milestones in the effort to achieve indefinite suppression of HIV because it is reasonably presumed that few if any HIV strains will demonstrate resistance to a type of drug to which they have not been previously exposed. This premise was reinforced first by the experience with the entry inhibitors and more recently with raltegravir. In the phase III studies conducted in highly treatment experienced patients, raltegravir plus OB achieved undetectable viral load levels (<50 copies/mL) in more than 75% of patients. In those receiving OB alone, less than 45% achieved undetectable virus.

However, the phase III raltegravir studies, called Benchmark I and II, like all previous trials undertaken in highly treatment experienced patients, once again demonstrated the importance of coupling any new agent with at least one additional agent with predicted activity against the viral strain. Due to the fact that HIV can rapidly generate mutations that produce resistance, it is now clear that two or more active agents are required to provide a sufficient resistance barrier. In the Benchmark studies, the proportion of patients who achieved undetectable viremia increased with the number of active agents in the OB.

The goal of all HAART regimens, whether in patients who are treatment naive or treatment experiences, is to achieve undetectable viremia. The premise is to bring viral levels and viral reproduction to levels low enough to reduce the risk of the chance mutations that confer resistance.

“Viral resistance is caused by the rapid turnover of HIV during the course of infection combined with a high viral mutation rate,” explained Dr. Carlo-Federico Perno, Professor of Medicine, University of Rome, Italy. He indicated that low rates of HIV turnover prevent resistance from occurring.

New drug classes generally provide the greatest opportunity to treat resistant HIV, but resistance to one agent within a given class does not necessarily mean cross resistance to others in the same class. For example, the PI tipranavir was often able to achieve undetectable viremia in patients with key resistance mutations to other PIs, and several NNRTIs in development appear to pose a low risk of cross resistance to existing NNRTIs.

However, in addition to the efficacy of the drugs in the regimen, HAART must have characteristics, such as tolerability and convenience, that promote compliance. This was a point emphasized by Dr. Wafaa El-Sadr, Director, International Center for AIDS Care and Treatment Programs (ICAP) Columbia University, New York City. She indicated that the story of HIV treatment began rather than ended when a combination of drugs was finally found to provide sustained HIV suppression.

“After the introduction of HAART in 1996, there was a decrease in death hazard by almost 95%,” Dr. El-Sadr reported, but “with the benefits there are also the risks,” which include those of loss of efficacy. For this reason, there must be continuous development of new options in regard to HIV control that include drugs which lend themselves to simple regimens or that pose a low risk of adverse events that may jeopardize compliance. With strict compliance, persistent suppression of HIV replication means a low risk of developing resistance.

Summary

The struggle to stay ahead of drug resistance may be entering a new phase as the focus shifts from introducing newer agents that not only pose a low risk of cross resistance to existing agents but may provide advantages in regard to tolerability of convenience of dosing. These latter attributes are not trivial. The effort to keep drugs viable in an infection with a strong potential for quickly generating resistant strains depends on a very strict compliance, which is influenced by both tolerability and the burden of adhering to the assigned regimen. New data on experimental integrase inhibitors promises that coming agents will expand this class by offering agents with unique characteristics including a non-overlapping resistance profile.