“These positive two-year data indicate that elvitegravir has the potential to be an important new once-daily treatment option for people living with HIV who have developed resistance to other therapies,” said Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, which is developing elvitegravir, in a press release.

“In addition, we are very excited about elvitegravir’s role as part of our new Quad single-tablet regimen, which is currently in U.S. regulatory review,” he added.

Gilead stated that based on the results, the company plans to file for approval of elvitegravir from the United States Food and Drug Administration (FDA) in the second quarter of 2012.

Gilead also submitted a new drug application for its investigational Quad pill (cobicistat/elvitegravir/emtricitabine/tenofovir) to the FDA in October (see related AIDS Beacon news).

Elvitegravir belongs to a relatively new class of antiretroviral called integrase inhibitors. Currently, Isentress (raltegravir) is the only approved integrase inhibitor. It is approved both as a first-line treatment for HIV and for people who are treatment-experienced.

Gilead previously presented 48-week results from the Phase 3 clinical trial showing that elvitegravir was comparable in safety and efficacy to Isentress (see related AIDS Beacon news). On Friday the company released the full 96-week results.

The study included 702 participants, a majority of whom (63 percent) were resistant to two or more classes of antiretrovirals at the start of the trial.

Participants were randomly assigned to receive once-daily elvitegravir (150 mg or 85 mg) or twice-daily Isentress (400 mg). In addition, participants took a Norvir (ritonavir)-boosted protease inhibitor plus another antiretroviral.

The most common background regimen was Norvir-boosted Prezista (darunavir) plus Viread (tenofovir). Participants who took Reyataz (atazanavir) or Kaletra (lopinavir/ritonavir) received a lower dose of elvitegravir, 85 mg daily instead of 150 mg.

After 96 weeks, 48 percent of patients in the elvitegravir group achieved and maintained viral loads (amount of HIV in the blood) of less than 50 copies per milliliter, compared to 45 percent of patients in the Isentress group.

Gilead reported that the rates and types of side effects were also comparable, and that discontinuation rates due to side effects were similar between the two groups.

The company had previously reported that, after 48 weeks, the most common side effects in participants taking elvitegravir were diarrhea (12 percent of participants), upper respiratory tract infection (6 percent), bronchitis (5 percent), back pain (5 percent), depression (5 percent), sinus infection (4 percent), joint pain (4 percent), nausea (4 percent), and urinary tract infection (3 percent).

Gilead stated that it would present the full clinical trial results at a scientific conference in 2012.

For more information, please see the Gilead Sciences press release.

“The most important message from the study is that dolutegravir is a safe and highly potent drug which can be given at low doses without a pharmacologic booster once daily,”  said Dr. Jan van Lunzen, a professor at the University Medical Center Hamburg-Eppendorf, in Hamburg, Germany and lead author of the study.

“Thus it has the potential to be a very attractive future component of combination antiretroviral therapy, both in antiretroviral-naïve as well as experienced patients,” he added.

Patients receiving dolutegravir also showed a more rapid decrease in viral load (amount of HIV in the blood) compared to patients receiving Sustiva. The decrease was maintained through week 48 of the study, and the rate of decrease was similar to that reported for the integrase inhibitor Isentress.

The investigators noted that this might have important implications for people with HIV who require an especially rapid reduction in viral load, for example, late-presenting pregnant women with HIV.

The investigators stated that based on their results, they selected the once-daily 50 mg dose of dolutegravir, the highest well-tolerated dose studied, for further testing in Phase 3 trials.

“Currently there are three Phase 3 studies underway in treatment-naïve populations comparing dolutegravir with either efavirenz [Sustiva], darunavir/r [Norvir-boosted Prezista], or raltegravir [Isentress]. Another Phase 3 trial is currently ongoing in experienced patients with previous treatment failure,” said Dr. van Lunzen.

The interim results after 48 weeks were first presented at the 6^th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (see related AIDS Beacon news),

Dolutegravir (S/GSK1349572) is a potential new integrase inhibitor being developed by ViiV Healthcare, a joint venture by GlaxoSmithKline and Pfizer.

Currently, the only approved integrase inhibitor is Isentress (raltegravir), which is marketed by the United States pharmaceutical company Merck. Isentress must be taken twice-daily in combination with other antiretrovirals as part of highly active antiretroviral therapy.

In recent years, the U.S. Food and Drug Administration has approved once-daily rather than twice-daily dosages of several antiretrovirals. Previous research has shown that once-daily dosing is more convenient and promotes better adherence to drug regimens. Better adherence allows for slower disease progression and helps prevent the development of drug-resistant HIV strains.

However, results from a recent study showed that Isentress once daily is not as effective as twice daily (see related AIDS Beacon news). Elvitegravir, which is another investigational integrase inhibitor that is currently in Phase 3 clinical trials, is given once daily but must be taken with a booster such as Norvir (ritonavir) or cobicistat.

According to the study authors, previous studies of dolutegravir in people have shown it to be long lasting without the need for a booster. Results of another ongoing study also indicate that dolutegravir is effective against viral strains resistant to both Isentress and elvitegravir.

The 96 week-long Phase 2 trial was designed to test the safety and efficacy of several once-daily dolutegravir dosages relative to Sustiva (efavirenz). Sustiva, when combined with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen to treat HIV.

A total of 205 previously untreated HIV-positive adults were randomly assigned to receive 10 mg, 25 mg, or 50 mg dolutegravir, or 600 mg Sustiva. Patients in each group also took either Truvada or Epzicom (abacavir/lamivudine).

Results showed that after 16 weeks, about 93 percent of patients in all dosage groups of dolutegravir had undetectable viral loads, with little difference between the dose groups. Sixty percent of participants taking Sustiva had undetectable viral loads.

After 48 weeks, 91 percent, 88 percent, and 90 percent of participants in the dolutegravir groups, respectively, and 82 percent of the participants in the Sustiva group had successfully achieved undetectable viral loads.

In addition, CD4 (white blood cell) counts increased in all three dolutegravir groups and in the Sustiva group through week 48. Average increases were larger in the dolutegravir group, 231 cells per microliter versus 174 cells per microliter in the Sustiva group.

Nearly half of participants (46 percent) experienced one or more drug-related side effects during the first 48 weeks of the study, but investigators concluded that no serious side effects were related to dolutegravir. More participants in the Sustiva group had moderate or severe drug-related side effects (20 percent, compared with 8 percent in the dolutegravir groups).

The most common side effects in participants taking dolutegravir were nausea (12 percent of participants), diarrhea (8 percent), headache (6 percent), dizziness (3 percent), fatigue (3 percent), and weakness (3 percent).

Six participants withdrew from the study: one each in the 25 mg and 50 mg dolutegravir groups due to upset stomach/indigestion and lymphatic cancer, respectively, and four in the Sustiva group due to drug intolerance, drug sensitivity, abnormal dreams, and suicide attempt.

Investigators did not identify any HIV integrase mutations in patients in the study.

For more information, please see the study in The Lancet Infectious Diseases (abstract).

“[Patients] could use elvitegravir [once daily] instead of Isentress [twice daily] in combination with a boosted protease inhibitor with the same efficacy and safety,” said Dr. Jean-Michel Molina, a researcher at the Hôpital Saint Louis and University of Paris and lead author of the study.

The study authors noted that once daily dosing as opposed to twice daily dosing might improve patients’ adherence to treatment.

Investigators previously presented the results of the study in July at the International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (see related AIDS Beacon news).

Elvitegravir, which is being developed by Gilead Sciences, and Isentress (raltegravir) are both integrase inhibitors, a relatively new class of antiretroviral. Currently, Isentress is the only approved integrase inhibitor.

In this clinical trial, researchers compared the safety and efficacy of elvitegravir to that of Isentress in 702 HIV-positive adults who had previously been treated for HIV. Two-thirds of the participants had resistance to two or more classes of antiretroviral drugs.

Half of the participants were randomly assigned to receive elvitegravir once daily and the other half Isentress twice daily. Placebo pills were used to ensure that all participants received the same number of pills daily.

All patients also took a Norvir (ritonavir)-boosted protease inhibitor and a third antiretroviral, which was either a nucleoside reverse transcriptase inhibitor, Intelence (etravirine), Selzentry (maraviroc), or Fuzeon (enfuvirtide). The most commonly used protease inhibitor was Prezista (darunavir).

Results showed that after 48 weeks, 59 percent of patients in the elvitegravir group achieved and maintained undetectable viral loads (amount of HIV in the blood), compared to 58 percent of patients in the Isentress group.

Increases in CD4 (white blood cell) counts were also similar between the two groups: an average increase of 119 of cells per microliter in participants taking elvitegravir versus 127 cells per microliter in participants taking Isentress.

Drug adherence up to week 48 of the study was determined by pill counts at every visit during the study. Adherence was similar (95 percent) in both groups.

Rates and types of side effects were similar between the two groups. The most common side effects in participants taking elvitegravir were diarrhea (12 percent of participants), upper respiratory tract infection (6 percent), bronchitis (5 percent), back pain (5 percent), depression (5 percent), sinus infection (4 percent), joint pain (4 percent), nausea (4 percent), and urinary tract infection (3 percent).

Although diarrhea was equally common in both treatment groups in the first month of treatment, diarrhea was reported more often after the first month by patients receiving elvitegravir.

One percent of patients assigned to elvitegravir experienced serious side effects, compared to two percent of patients assigned to Isentress. Two patients (0.5 percent) and eight patients (2 percent) died in each group, respectively, during the study period.

The trial will continue for an additional 48 weeks. In addition, studies are ongoing of elvitegravir as a component of the investigational single-tablet combination “Quad” (cobicistat/elvitegravir/emtricitabine/tenofovir) regimen in previously untreated HIV-positive adults.

Gilead stated in July that it plans to apply for approval of elvitegravir in the U.S. and Europe in 2012.

For more information, please see the study in The Lancet Infectious Diseases (abstract).

AIDS.gov Opens “Facing AIDS 2011” Campaign For World AIDS Day – To commemorate World AIDS Day on December 1, AIDS.gov is raising awareness through its “Facing AIDS 2011” campaign. Interested individuals are encouraged to download a “Facing AIDS” flier from the website and share why they are facing AIDS. Participants can take photos of themselves with their flier and then upload their images to the Facing AIDS website. All participants are encouraged to share their photos online with family and friends. Instructions on how to plan community events for the campaign are also available. For more information on how to participate, please see the AIDS.gov website.

Gilead Sciences Signs Agreement To Develop New Type Of Antiretroviral Drugs – Gilead Sciences has signed a licensing agreement with pharmaceutical company Boehringer Ingelheim to develop and market a new type of antiretroviral drug, initially pioneered by Boehringer Ingelheim. The new drugs are integrase inhibitors but work differently than Isentress (raltegravir) or the investigational drug elvitegravir. As a result, they are expected to be effective against HIV that is resistant to current integrase inhibitors. The agreement includes the investigational drug BI 224436, which has been tested in a Phase 1 clinical trial. For more information, please see the Gilead Sciences press release.

Theratechnologies Begins Development On New Lipodystrophy Drug – Theratechnologies announced last week that it has discovered a new potential drug in the same class as Egrifta (tesamorelin) and will begin pre-clinical testing of the new compound for treatment of lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Theratechnologies stated that the new drug candidate appears to be as effective as Egrifta but may not need to be injected, as Egrifta is. Egrifta, which was approved in the U.S. in November of last year, was the first drug approved to treat lipodystrophy. For more information, please see the Theratechnologies press release.

“Dolutegravir administered once daily…showed a rapid and sustained response at all doses explored through week 48,” said Dr. Jan van Lunzen, who presented the results yesterday at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“The drug in all dose groups was well tolerated, with fewer discontinuations occurring than in the [Sustiva] comparator arm,” he added.

Based on the results, Dr. van Lunzen stated that several Phase 3 clinical trials have been initiated with the highest dolutegravir dosage tested.

Dolutegravir (S/GSK1349572) is a potential new integrase inhibitor being developed by ViiV Healthcare (a joint venture by GlaxoSmithKline and Pfizer). Currently, the only approved integrase inhibitor is Isentress (raltegravir), which is marketed by U.S. pharmaceutical company Merck.

The clinical trial was designed to test the safety and efficacy of several dolutegravir dosages relative to Sustiva (efavirenz), which, when combined with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen to treat HIV.

The study includes 205 participants, who were randomly assigned to one of four groups. The first group is being treated with 10 mg of dolutegravir once daily, the second takes 25 mg of dolutegravir once daily, the third receives 50 mg of dolutegravir once daily, and the fourth takes Sustiva. All groups take the drugs in combination with either Truvada or Epzicom (abacavir/lamivudine).

Results showed that after 48 weeks, most participants in all four groups had successfully achieved an undetectable viral load (amount of HIV in the blood): 91 percent, 88 percent, 90 percent, and 82 percent of the participants, respectively.

Sixteen week results presented at a previous conference suggested that participants taking dolutegravir achieved an undetectable viral load faster than participants taking Sustiva. The 48 week results showed that the more rapid response to dolutegravir was sustained throughout the study period.

Participants taking dolutegravir had slightly higher increases in CD4 (white blood cell) counts after 48 weeks than participants taking Sustiva (231 cells per microliter versus 174 cells per microliter), but the difference was not large enough to be considered significant.

There were fewer moderate to severe side effects reported in the dolutegravir trial groups than in the Sustiva group (8 percent of participants versus 20 percent). Participants taking dolutegravir also had smaller increases in “bad” cholesterol levels during the course of the trial than participants taking Sustiva, with little or no increase in cholesterol levels overall.

In total, two participants stopped taking dolutegravir and four stopped taking Sustiva due to side effects.

The trial will continue for an additional 48 weeks.

Two Phase 3 clinical trials for dolutegravir are currently recruiting participants. The first trial will test the safety and efficacy of dolutegravir versus Isentress in treatment experienced patients who have not previously been treated with integrase inhibitors. The second trial will test the efficacy of dolutegravir in people who have failed therapy with Isentress.

Two other Phase 3 trials are ongoing but are not currently recruiting participants.

For more information, please see the study presentation or abstract on the IAS 2011 conference website.

Gilead also noted that the number of participants who discontinued elvitegravir due to side effects was similar to the number of participants who discontinued Isentress.

Representatives from Gilead said that the results will help the company file for approval of elvitegravir and its proposed Quad combination pill, which contains elvitegravir, as quickly as possible.

“We are very pleased to have achieved the primary endpoint in this clinical trial, as data from this study will support regulatory filings for elvitegravir as well as Gilead’s investigational Quad pill,” said Norbert Bischofberger, Executive Vice President of Research and Development and Chief Scientific Officer of Gilead Sciences, in a press release.

Elvitegravir is an experimental antiretroviral in the integrase inhibitor drug class. Currently, the only integrase inhibitor approved by the U.S. Food and Drug Administration is Isentress (raltegravir).

Gilead is testing the safety and efficacy of elvitegravir both as a stand-alone antiretroviral and as a component of its combination “Quad” pill, which also contains cobicistat, a proposed new antiretroviral drug booster similar to Norvir (ritonavir), and Truvada (emtricitabine/tenofovir).

The ongoing Phase 3 clinical trial for elvitegravir as a stand-alone antiretroviral drug includes 702 treatment-experienced participants who had viral loads (amount of HIV in the blood) of 1,000 copies per milliliter or more prior to starting the trial. Participants also must have either drug-resistant HIV or at least six months of prior treatment with two or more classes of antiretrovirals.

Half of the participants are receiving 150 mg of elvitegravir once daily. The other half receive 400 mg of Isentress twice daily. All participants are also taking a boosted protease inhibitor plus one other antiretroviral. Participants who are taking Reyataz (atazanavir) or Kaletra (lopinavir/ritonavir) receive a smaller 85 mg dose of elvitegravir.

Results after 48 weeks show that 59 percent of participants taking elvitegravir have achieved and maintained a viral load of less than 50 copies per milliliter, compared to 58 percent of participants taking Isentress.

Gilead stated that the rate and type of side effects were similar between the two groups; however, no further details were provided at this time. The most common side effects for Isentress are nausea, headache, tiredness, weakness, trouble sleeping, stomach pain, dizziness, and depression.

The trial will continue for an additional 48 weeks. Although originally intended as a 48-week clinical trial, Gilead announced in January that it had decided to extend the trial to 96 weeks to collect additional safety and efficacy data for elvitegravir (see related AIDS Beacon news).

Gilead stated that it expects to present the 48-week results in greater detail at a scientific conference later this year.

For more information, please see the Gilead Sciences press release. For more information on the clinical trial, please see the U.S. Clinical Trials registry.

“The change allows for collection of more safety and efficacy data from a longer controlled and blinded study, the first head-to-head comparison of two integrase inhibitors,” said a Gilead representative in correspondence with The AIDS Beacon. “Gilead has not been informed of any issues with the ongoing study that would cause us to halt or otherwise amend the study design.”

Gilead has said the trial extension does not affect its investigational once-daily combination “Quad” regimen, which contains elvitegravir, cobicistat, emtricitabine, and tenofovir and is also in Phase 3 clinical trials (see related AIDS Beacon news).

Gilead has also stated that it expects its clinical trials for elvitegravir to be completed by the end of the year. Assuming positive results from the trials, Gilead said that the extension should not affect its timeline for submission of elvitegravir or the “Quad” pill for approval by the U.S. Food and Drug Administration (FDA).

Elvitegravir belongs to a class of drugs called integrase inhibitors, which is a relatively new class of antiretrovirals. The only currently approved integrase inhibitor is Isentress (raltegravir), produced by the U.S. pharmaceutical company Merck.

Dr. Derrick Butler, an HIV specialist and Associate Medical Director of the To Help Everyone Clinic in Los Angeles who is not affiliated with the clinical trial, told The AIDS Beacon that as a physician he is not particularly concerned about the extension. He speculated that the FDA was simply being cautious.

“From the FDA’s perspective, based on the performance of Isentress in terms of having a lower threshold for resistance and issues around that, they probably wanted to extend this second integrase inhibitor study to get a better look at it. Probably more for durability and efficacy,” he said.

Isentress was approved in 2007 after a 48 week clinical trial. Its use in a clinical setting has since shown that HIV resistance to Isentress can develop quickly. Additionally, results from a recent clinical trial failed to show that once-daily Isentress was as effective as twice-daily dosing (see related AIDS Beacon news).

Dr. Bill Owen, an HIV specialist in San Francisco who is not affiliated with the clinical trial, expressed some disappointment over the clinical trial extension, particularly if it affects when elvitegravir will become available.

“One advantage of elvitegravir (boosted by cobicistat or Norvir (ritonavir)) is that the only currently FDA-approved member of the integrase inhibitor class, Merck & Company’s Isentress, must be taken twice a day, whereas boosted elvitegravir need only be taken once daily,” said Dr. Owen.

“I believe that any regimen which is effective, well-tolerated, and simple can greatly assist patients who have issues with compliance,” he said.

However, he pointed out that there are a variety of other promising antiretrovirals and combination treatments under development. In particular, two Phase 3 trials for GSK1349572, an investigational integrase inhibitor from ViiV Healthcare, are currently recruiting participants. GSK1349572 will also be taken once daily.

For more information, please see the Gilead Sciences SEC filing or the Associated Press news article.

The Pharmaceutical Research and Manufacturers of America (PhRMA), a pharmaceutical company lobbying group, releases a report each year on HIV treatments under development at U.S. pharmaceutical companies. The report this year includes new antiretrovirals, gene therapies, and vaccine candidates, in addition to treatments for HIV-related conditions such as Kaposi’s sarcoma and peripheral neuropathy (pain or numbness in the extremities).

Most of the new antiretrovirals are still in Phase 1 or Phase 2 clinical trials. The list includes novel drug types that work differently than current anti-HIV drugs, as well as drugs in standard antiretroviral drug classes, such as new protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs).

In addition, there are three new combination treatments under development. Combination treatments include several antiretrovirals in one pill, which simplifies treatment regimens.

New Types Of Antiretroviral Drugs

Several of the antiretrovirals in the report are novel drug types that are not part of existing antiretroviral drug classes.

A number of these treatments consist of antibodies, proteins that help the body recognize and fight viruses. These treatments usually work by attempting to stimulate the immune system so that it can more effectively recognize and kill HIV or infected cells. Nearly all of these are still in Phase 1 clinical trials, although one set of antibodies are in Phase 2 trials.

There are a few additional prospective drugs that have made it to Phase 2 trials. One of these is also a protein treatment, called Alferon LDO (interferon alfa-n3). This protein is isolated from human blood and helps fight viral infections; currently it is approved by the U.S. Food and Drug Administration to fight human papillomavirus, which causes genital warts.

Another new treatment, called CB1922, is currently in Phase 2 clinical trials. CB1922 is a drug that has mostly been investigated for treatment of high blood pressure. It works by blocking a protein on the surface of cells that normally binds to a hormone called aldosterone.

Canopus BioPharma, which makes CB1922, has found that HIV also binds to this same protein by mimicking the hormone. By blocking the protein, CB1922 appears to prevent HIV from replicating itself.

Finally, a drug from Bristol-Myers Squibb, called BMS-626529, is also in Phase 2 clinical trials. Bristol-Myers Squibb has not explained the mechanism of BMS-626529, but states that it prevents HIV from attaching to cells, which would prevent infection and virus replication.

New Drugs In Existing Antiretroviral Drug Classes

Most of the new drug candidates are in existing antiretroviral drug classes, including the following two drugs that are in or have completed Phase 3 trials: elvitegravir, which is a new integrase inhibitor from Gilead Sciences, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Tibotec Pharmaceuticals.

Integrase inhibitors, such as elvitegravir, are a relatively new class of antiretroviral; currently, the only approved integrase inhibitor is Isentress (raltegravir).

In addition to elvitegravir, there are three new integrase inhibitors under development (GSK1247303, GSK1265744, and GSK1349672). All of these are in Phase 2 clinical trials and were developed by GlaxoSmithKline.

NNRTIs, in contrast, are an older drug class that includes Sustiva (efavirenz), Viramune (nevirapine), and Intelence (etravirine). Including rilpivirine, there are seven new NNRTIs under development; four of these are also in Phase 2 clinical trials (dapivirine vaginal gel, RDEA806, UK-453061, and VRX806).

The list includes seven new NRTIs, which is the oldest antiretroviral drug class and includes drugs such as zidovudine (Retrovir) and Epivir (lamivudine). Four of the proposed new NRTIs (elvucitabine, festinavir, racivir, and amdoxovir) are in Phase 2 clinical trials.

Only two new protease inhibitors (a drug class that includes Prezista (darunavir) and Kaletra (lopinavir/ritonavir)) were included in the report, one of which, TMC310911, is in Phase 2 trials.

Finally, the report includes several new entry inhibitors, which are another fairly new class of antiretroviral that includes the drugs Selzentry (maraviroc) and Fuzeon (enfuvirtide).

Entry inhibitors work by preventing HIV from entering and infecting new cells. Most of the new treatments act the same way as Selzentry, which blocks a protein called CCR5 on the surface of white blood cells that HIV uses to attach to and invade. Two of the proposed new entry inhibitors (PRO-140 and TBR-652) are in Phase 2 clinical trials.

New Combination Drugs

Combining several antiretroviral drugs into one pill has been a growing trend, since it simplifies antiretroviral regimens for patients. There are currently three combination treatments under development.

One, called the “Quad” pill (see related AIDS Beacon news), is a combination of four drugs in one pill: Emtriva (emtricitabine), Viread (tenofovir), and the investigational integrase inhibitor elvitegravir plus a proposed new antiretroviral booster, cobicistat. Cobicistat is thought to act similarly to Norvir (ritonavir) by raising antiretroviral drug concentrations to make them more effective.

A second combination pill will include the new NNRTI rilpivirine plus Emtriva and Viread.

Finally, the third proposed combination pill will include three already approved antiretrovirals: Sustiva (efavirenz), Epivir (lamivudine), and Viread.

Gene Therapy And Vaccines

Aside from antiretroviral drugs, the report includes both gene therapies and therapeutic vaccine treatments as potential new HIV treatments.

Gene therapy treatments are experimental procedures that scientists hope will one day be able to cure HIV (see related AIDS Beacon news). They work by changing a person’s genes, for example by turning off genes that produce proteins used by HIV to infect cells.

Three gene therapy treatments are currently under development, two of them in Phase 1 trials and one in Phase 2.

Two of the treatments work by inserting genes that make genetic material that binds to and neutralizes HIV’s genetic material so that it no longer functions. One of the treatments is being developed by the biotechnology company VIRxSYS and is currently in Phase 1 trials. The second one by Enzo Biochem is currently in Phase 2 trials.

The third therapy, by Sangamo Biosciences, works by preventing cells from producing the CCR5 protein on their surface, preventing HIV from infecting the cells in much the same way Selzentry does.

Finally, there are a number of therapeutic vaccines also under development (see related AIDS Beacon news). Therapeutic vaccines enhance the body’s natural immune response, helping to control HIV in people already infected with the virus.

Most of the therapeutic vaccines are in Phase 1 clinical trials. However, there are a few that are in Phase 2.

One of these is a dendritic cell vaccine by Argos Therapeutics. Dendritic cell vaccines are made by collecting blood from patients and isolating a certain type of immune cell called a dendritic cell.

After exposing the dendritic cells to HIV proteins in the laboratory to prompt an immune response, the cells are reinjected into the study participant in hopes that the cells will now be activated and fight against HIV.

Two other therapeutic vaccines that are in Phase 2 clinical trials are the DermaVir vaccine, by the company Genetic Immunity, and Vacc-4x by Bionor Pharma (see related AIDS Beacon news).

The DermaVir vaccine is applied as a patch rather than an injection and attempts to limit virus replication. Vacc-4x, in contrast, contains protein fragments similar to those found within the HIV virus, in an attempt to enhance the ability of patients’ immune systems to recognize and kill HIV-infected cells.

For more information, please see the report from PhRMA. For more information on clinical trials, please see the United States Clinical Trials Registry.

Shionogi-ViiV Healthcare Announces Phase 3 Clinical Trials For New Once-Daily Integrase Inhibitor – Shionogi-ViiV Healthcare has announced the initiation of Phase 3 clinical trials for its new once-daily integrase inhibitor, S/GSK1349572. Integrase inhibitors are a relatively new class of antiretroviral drugs; currently, the only approved integrase inhibitor is Isentress (raltegravir). The Phase 3 trials will include two studies. One will examine the effectiveness of the drug in patients who are treatment experienced but have never received integrase inhibitor-based antiretroviral therapy. The second trial will study the drug’s effectiveness in people who are treatment naïve. Both trials will compare the tolerability, safety, and efficacy of S/GSK1349572 to that of Isentress. For more information, please see the ViiV Healthcare website.

Cytheris Announces Phase 2 Clinical Trial For New Drug Targeting Latent HIV – Cytheris, a small French pharmaceutical company, has announced the initiation of a Phase 2 clinical trial for its new drug CYT107, which targets the latent viral reservoirs in people with HIV. The study will examine the effectiveness of CYT107 in combination with Isentress (raltegravir) and Selzentry (maraviroc). CYT107 is designed to activate HIV-infected cells that are infected with latent HIV – HIV that lies dormant and can start multiplying again if antiretroviral therapy is stopped. The researchers hypothesize that once these cells are activated, the latent virus reservoirs can be reduced or eliminated by administering Isentress and Selzentry. The clinical trial will be conducted in France, Spain, Italy, and the United Kingdom. For more information, please see the Cytheris press release (pdf).

NeurogesX Plans Expansion Of Pain Drug Qutenza To Include HIV-Associated Neuropathy – NeurogesX, a small San Francisco-based pharmaceutical company, has announced plans to apply for an expansion for the use of its drug Qutenza (capsaicin) to include HIV-associated neuropathy. HIV-associated neuropathy is a neurological condition that can be caused by HIV or antiretroviral drugs that damage nerve cells, causing pain, tingling, and numbness. Qutenza is a skin patch currently approved to help with pain from postherpetic neuralgia, a lingering complication of the viral infection shingles. NeurogesX plans to submit a supplemental New Drug Application to the FDA for Qutenza early next year. The application will include clinical data from two recently completed Phase 3 studies examining the effectiveness of Qutenza in patients with HIV-associated neuropathy. For more information, please see the NeurogesX website.

Two of the studies focused on methods to completely eliminate HIV from the body. More specifically, they targeted latent HIV – HIV that lies dormant in infected cells and can start multiplying again if antiretroviral therapy is stopped.

Latent HIV is difficult to get rid of because after infection, the virus actually inserts its own DNA into a cell’s normal DNA sequence. Antiretrovirals can prevent the virus from using this DNA to make more of itself, but they can’t remove the virus DNA once it has been inserted.

As a result, HIV can hide out in an infected person’s DNA indefinitely, even if they are taking antiretrovirals. This type of HIV is called latent HIV and is the reason HIV cannot be cured with current treatments.

Two new studies presented Monday focused on targeting and removing latent HIV. In both studies, researchers created treatments that were shown in animal tests to reduce the amount of latent HIV in the body. In one case, however, the results were only temporary.

Three other studies showed positive preliminary results for new antiretroviral drugs: four new protease inhibitors, and two new integrase inhibitors. The new drugs show promise, but are still in early stages of development.

New Treatments To Remove Latent HIV From Cells

Two studies were presented showing preliminary research on new treatments to remove latent HIV from cells.

In the first study, a team of German and Swiss researchers created an artificial protein that cuts latent HIV DNA out of cells and prevents virus replication in mice.

Unlike normal antiretrovirals, the new protein is able to find virus DNA inside a cell’s DNA and cut it out of the sequence. It can also act like a regular antiretroviral and prevent the virus from multiplying.

In this study, the investigators modified either human adult CD4 (white blood) cells or human blood stem cells so that they could produce the artificial protein. They then transplanted these cells into mice to see if the protein would effectively remove latent HIV DNA or have antiretroviral activity.

The researchers found that the protein caused a substantial decrease in HIV viral loads (amount of HIV in the blood) and also protected CD4 cells in the mice, with no toxicity.

As a result of these promising results, the scientists recommend further study of the protein to see if it could be used as a novel treatment for HIV in addition to traditional antiretrovirals.

In the second study, Italian and American researchers looked at Gar1041, an experimental leukemia drug, in combination with antiretroviral therapy to see if it could reduce the amount of latent HIV DNA in monkey cells.

GAR1041 is a new type of experimental drug called an epigenetic drug. Epigenetic drugs are used to turn genes on and off and have mostly been studied in cancer cells. However, the researchers thought they might also be useful to fight latent HIV.

Within one month of treatment with Gar1041 plus antiretroviral drugs, the researchers found that the amount of latent HIV in the monkeys significantly decreased. The drop was not observed in monkeys receiving only antiretroviral therapy.

However, the concentrations of latent HIV rebounded after two months of therapy. The researchers concluded that their study shows latent HIV can be reduced using drug treatments, which is promising. However, further research would be necessary to permanently reduce latent HIV and keep it from rebounding.

Improved Therapies: Novel Protease And Integrase Inhibitors

A joint effort between Japanese and American scientists yielded four new protease inhibitors that were highly effective against drug-resistant HIV in laboratory tests.

Protease inhibitors, such as Kaletra (lopinavir/ritonavir) or Prezista (darunavir), work by blocking a virus protein called protease, which then prevents virus proteins from assembling properly.

The four new drugs developed by the Japanese-American team were found to be highly effective protease inhibitors in the laboratory. One of the drugs was more powerful than Prezista. As a result, they will be studied further as potential drugs to fight resistant HIV strains.

Another study, presented by researchers at GlaxoSmithKline, showed results for a potential new integrase inhibitor.

Integrase inhibitors are a relatively new class of drugs. They work by blocking the protein the virus uses to insert its DNA into the DNA of a healthy cell, thus preventing HIV from replicating.

In 2007, Isentress (raltegravir) was the first integrase inhibitor to receive approval from the United States Food and Drug Administration. Soon after its introduction, HIV resistance against Isentress developed.

The new integrase inhibitor, S/GSK1265744, was effective in laboratory tests against HIV virus isolated from patients showing resistance to Isentress. As a result, it could be used to treat HIV that is resistant to Isentress.

Finally, in another study, Belgian and Swiss scientists presented a new type of integrase inhibitor called LEDGINs. LEDGINs work slightly differently than Isentress and were very effective in the laboratory against Isentress-resistant HIV.

Although still in the early stages of development, the drugs show promise as new treatments for HIV. Further studies to assess their effectiveness are currently underway.

For more information, please see the AIDS 2010 conference website.