Friday, October 26, 2007

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.

Integrase Inhibitor Isentress Provides a New Way to Treat AIDS Patients

Welcome to this installment of The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I’m Mike Neri.

In this podcast, I will talk about the optimism surrounding the recently FDA approved AIDS drug Isentress, including how it works, what step in the HIV replication cycle it affects, and what preliminary data show about the drug’s effectiveness and side effects. Ever since the discovery of HIV as the causative agent of AIDS, scientists have searched for weaknesses in its life cycle that they can exploit. As early as 1990, scientists had identified 13 pathways in the life cycle of HIV where the virus was susceptible to treatment. Unfortunately, due to the years of trial and error necessary to produce safe and effective drugs, new AIDS medications are developed slowly, and often have many side effects.

But optimism is high after the new drug Isentress showed very promising results when acting on a novel pathway to inhibit HIV replication. Isentress, also called Raltegravir, was developed by the Merck Corporation. It’s the first drug in a new line of AIDS medications called integrase inhibitors. As the name suggests, these drugs target an enzyme called integrase that the virus brings with it into an infected cell. Integrase, along with two other enzymes called reverse transcriptase and protease, is essential for HIV’s replication within the host. Therefore, scientists believe that if they can find a compound that stops integrase, they may be able to stop HIV from replicating.

After HIV has entered the cell by fusing with the membrane of its target cell, the virus dumps its genetic material and enzymes inside. It then makes copies of its own genetic material and uses integrase to insert them into the DNA of its host. This allows the virus to replicate its genome using the host’s machinery, and essentially take over the infected cell for its own reproductive purposes. The goal of integrase inhibitors is to prevent integrase from working correctly, therefore keeping the HIV genetic material out of the host’s genome and hindering viral replication. Previously, there had been only four pathways that drugs target in the HIV life cycle, and none of them had targeted integrase. However, integrase is an attractive target molecule for drug development for a number of reasons. First of all, integrase does not resemble any known human proteins, meaning the chances of side effects are reduced. In addition, by going after a new viral pathway for infection, doctors can combine integrase inhibitors with drugs targeting different pathways, which prevent the virus from becoming resistant to an entire class of drugs.

Scientists have long wanted to develop an integrase inhibitor, but the road to creating an effective drug and gaining FDA approval for it is a long one. According to Merck’s website, research into integrase inhibitors began in 1993 and eventually resulted in the identification of a class of compounds that could impede the function of the enzyme. These compounds work by binding to the active site of the integrase, thus preventing it from binding and cutting the host DNA, which prevents the viral genome from being inserted. After this discovery, researchers worked with these compounds in the lab to create the best integrase inhibitor, and tested it in virus cultures and animals. The use of animals allowed them to get an idea of the severity of the side effects and an approximate idea of the appropriate drug dosage. The final product of this drug testing was named Isentress. After emerging from the laboratory phase, Isentress was put through three phases of clinical studies involving groups of healthy and sick people. Results from the studies of Isentress given with a combination of other AIDS drugs were compared to a placebo given with the same drugs. From these data, researchers were able to get an idea of the effectiveness of the drug in treating the virus and fine-tune dosage information, all while closely monitoring side effects. At the end of this process, Merck submitted the data from all of the tests and clinical studies to the FDA for it to decide whether the drug was safe to be offered on the market. And on October 12, 2007, Isentress was officially approved by the FDA for treatment in AIDS patients, specifically those with HIV strains resistant to all other drugs. Most of the optimism surrounding the approval and release of the drug comes from the data obtained in the clinical studies. In the later phases of these trials, Isentress and a standard combination of other drugs were given to the most drug-resistant patients and compared to a placebo group. After 16 weeks, the Isentress treatment reduced the viral load to almost undetectable amounts in nearly 80% of patients, compared to only 43% in the placebo group.

While questions concerning Isentress still remain, such as whether the drug will work over longer periods of time and what the long term side effects might be, the preliminary results suggest that Isentress will have a significant impact on the treatment of AIDS immediately. As mentioned before, Isentress is initially expected to be used in patients who have exhausted all other drug treatment options. However, the overwhelming success of the drug so far has medical professionals wondering whether it can eventually be used as a front-line treatment against HIV. The true impact of Isentress cannot be known until it has been used by all types of AIDS patients over long periods of time. Nevertheless, the approval of Isentress is a sure sign for optimism in the AIDS community and a great success for the drug and pharmaceutical companies that have spent years producing and testing it.

I’m Mike Neri, and thanks for listening.

Sunday, October 21, 2007

HIV/AIDS: The Brazilian Response

In the arena of HIV/AIDS prevention and treatment, Brazil has become a beacon of hope, particularly among developing countries. Countries around the globe are now looking towards their system of universal AIDS care for guidance.

In the early 90’s it was estimated that within a decade, the number of HIV+ people in Brazil would be near 1.2 million. Instead, recent estimates suggest that only half that amount (about 660,000 people) are infected. How have they been so successful in limiting the spread of this deadly disease? With a three pronged government program focusing on prevention, treatment, and reducing the stigma associated with AIDS patients.

The first aspect of Brazil’s plan hopes to prevent the spread of HIV, particularly among the highest risk groups. After a brief stint of abstinence education failed early in the epidemic, the government looked towards other alternatives. Surprisingly, even in a country that is dominated by the Catholic Church, promoting condoms has proven very effective. The government has plans to distribute millions of condoms through local clinics, particularly to those involved in the commercial sex industry. Condom distribution is intensified during Carnival, a lively celebration before Lent where “free condoms are passed out like candy.” They have even encouraged the adult films industry to incorporate condoms into their films, and have produced prime time TV ads promoting condom usage in homosexuals. Additionally, a government funded needle exchange program hopes to slow down the spread among IV drug users.

A particularly intriguing aspect of Brazil’s treatment program has been their ability to supply anti-retroviral drugs to any AIDS patient needing them. As of September 2005, over 170,000 patients who required treatment were receiving it for free from the government. On a recent visit, the head of Uganda’s Parliamentary Committee on HIV/AIDS affirmed that “being able to provide the same standards of care to all citizens irrespective of their status in society is something to emulate.” This program, which began in 1997 as the first of its kind in the developing world, has lead Brazil to seek cheaper prices in order to keep costs down. A government sponsored company produces generic forms for many of the most widely used drugs. They have even broke patents on some of the newer drugs as costs have continued to skyrocket. Under fear that the Brazilian government will bypass the patent system, many companies have opted to cooperate and lower their prices. Even still, treatment makes up about 80% of their AIDS budget.

Contrary to many aspects of the US AIDS program, the Brazilian government has worked to gain the support of many of the most at risk groups. In 2005, Brazil rejected over $40 million from the United States because they would have had to pledge that they oppose commercial sex work; having the support of the sex industry has been integral in their fight against AIDS. Additionally, focusing on treatment instead of solely on prevention has encouraged testing and reduced stigma for those suffering with AIDS.

The model system that Brazil has implemented is envied by many countries around the world. Even the United States could learn from Brazil’s focus on condom distribution and treatment, as well as their support for constructive dialogue about the disease.

For more information about the current status of HIV/AIDS in Brazil, go to Brazil’s page of the UNAIDS website.

I’m Ben Young, thanks for listening.