Integrase Inhibitors: A New Hope

I’m Bevin English.

On October 12th, the Food and Drug Administration (the FDA) announced that it had approved a New Drug Application for a completely new kind of medication in the fight against AIDS. This drug, called IsentressTM, is the first integrase inhibitor and comes in 400 mg tablets that are taken twice daily. Produced by Merck & Co., Inc., Isentress, whose generic name is raltegravir and whose in-development name was MK-0518, has impressed many leading AIDS researchers, including Dr. Amneris Luque, medical director of the AIDS Center at the University of Rochester, who called the new drug “the road to hope for people who have failed all other AIDS medications.”

Before raltegravir’s approval, there were three oral anti-retroviral drug classes approved by the FDA: nucleoside reverse transcriptase inhibitors (also called NRTIs), non-nucleoside reverse transcriptase inhibitors (also called NNRTIs), and protease inhibitors (also called PIs). These drugs block two of HIV’s three enzymes that are necessary for infection: reverse transcriptase and protease. When HIV infects a cell, reverse transcriptase converts the viral genetic information from RNA to DNA. Integrase then inserts this viral DNA into the host cell’s genome. After the viral DNA has been translated by the host cell, protease cleaves the proteins into the functional units that come together to form protein coats for new viruses. These three classes of drugs have been used to treat HIV positive patients for many years. Nucleoside reverse transcriptase inhibitors have been used since 1987, when the FDA approved AZT. One of the most prominent non-nucleoside reverse transcriptase inhibitors, efavirenz, has been in use since 1998. And three common protease inhibitors, saquinavir, indinavir, and ritonavir, were approved by the FDA in 1996.

In Phase III clinical trials, raltegravir was administered to over 600 people who had viral loads greater than 1000 copies/mL and resistance to at least one drug in each of the three oral antiretroviral classes. In all trial groups, patients receiving raltegravir tended to have lower viral loads and higher CD4 cell counts than the control group, which consisted of patients receiving optimized background therapy (OBT) and a placebo. OBT is a personalized combination of different antiretroviral drugs that will most effectively increase an individual’s CD4 count and decrease his or her viral load; OBT is based on the patient’s history, current viral load and CD4 count, and any resistance tests. In raltegravir’s Phase III trial, the most dramatic result was seen when the drug was combined with one or two other active drugs, with 98% of patients’ viral loads below 400 copies/mL after 16 weeks. Data from on-going Phase II clinical trials show that raltegravir in combination with OBT maintains low viral loads over an extended period of time, with 64-71% of individuals achieving loads below 400 copies/mL and 46-64% of patients having loads less than 50 copies/mL after 48 weeks of the therapy.

Side effects of raltegravir were generally reported as mild to moderate and caused fewer than 2% of participants to discontinue therapy; nausea, headache, and diarrhea were the most common. Currently, there are no known drug interactions, although further studies must be conducted to investigate any possible drug interaction issues. Because of raltegravir’s efficacy, safety, and tolerability, the FDA gave this new drug priority review status, meaning that the Administration promised to review the drug within six months of their reception of the New Drug Application because it could potentially help with unmet medical needs.

However, it is important to note that “[t]he fight will not end with raltegravir,” as AIDS activist and participant in raltegravir clinical trials Matt Sharp stated to the FDA. One problem is that the drug simply has not been around long enough for scientists to understand its long-term effects in vivo. It has been less than four years since the drug was first used in humans and less than three years since it was first used in HIV positive individuals. During clinical trials, researchers observed more cases of different cancers, including lymphoma, squamous cell carcinoma, and hepatocellular cancer, among individuals who received raltegravir. Upon analysis, researchers claimed that the increase in the occurrence of cancers was not significant. However, any patient receiving raltegravir must be observed for the long-term to ensure that the drug does not lead to an increased risk of cancer.

Another important issue that must be taken into consideration is viral resistance to the new drug. In vitro data has shown that HIV can become resistant to raltegravir, but resistance generally occurs after serial passage in cell culture for several months. During clinical trials, 16% of patients were virological failures in the raltegravir group after 24 weeks. However, researchers remain hopeful that second-generation integrase inhibitors, such as Gilead’s elvitegravir, which is currently undergoing Phase II clinical trials, may help overcome resistance.

Despite the uncertainty of raltegravir’s long-term effects in vivo and the possibility of resistance, this breakthrough drug marks a milestone in AIDS treatment. The first integrase inhibitor, raltegravir, in combination with other drugs, has shown to be extremely effective in reducing viral loads and increasing CD4 counts, even in patients whose treatment options are severely limited by multi-class resistance.