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Peering in the Pipeline

Summer 2009

More HIV meds could be approved next year -- some that come from new classes of drugs and some from already approved classes. Here's a brief look at a few.

Blocking the Door

Peering in the PipelineSeveral drugs are targeting HIV's entry into CD4 cells. The hope is that preventing the virus from even entering the cell will result in less damage to cells and fewer side effects.

Vicriviroc could be the second co-receptor inhibitor to receive FDA approval (the first, Selzentry, was approved in 2007). These drugs interfere with the second step in HIV's entry into a CD4 cell, by blocking the R5 co-receptor.

The VICTOR-E1 study of vicriviroc (in people resistant to other HIV drugs) found that after 48 weeks, 59% of those who added vicriviroc to approved HIV drugs had their viral load drop below 50, compared with 25% of those who took the approved drugs only. Two larger trials in people resistant to other HIV drugs are finishing soon and could report results before the end of the year.

Trials of Selzentry and vicriviroc in people who have not taken HIV meds before have found these drugs to be less effective than Sustiva, but this may have been due to the tropism test used. This test screens out anyone who has HIV that uses the X4 co-receptor, since these drugs will not be effective in those people. But looking back at studies of regimens containing Selzentry using a new, more sensitive tropism test, it was discovered that the drug was as effective as Sustiva in people screened with the more sensitive test.

Both drugs are currently in trials for people who have never taken HIV meds before, using the newer tropism test. Vicriviroc is being studied with Reyataz/Norvir but no other HIV meds. This is a new approach, since most HIV regimens include nucleosides like Truvada or Combivir. Norvir will not only boost Reyataz levels, but should also increase vicriviroc concentrations 5 to 6 times. Results from this trial could be available in 2010.

TBR-652 is another R5 co-receptor inhibitor that is just beginning its first study in people with HIV. Early studies have shown that it will likely be taken once a day, will not require Norvir boosting, is well tolerated, and may be more potent than Selzentry.

Ibalizumab (TNX-355) is different from Selzentry and vicriviroc in that it blocks the CD4 receptor on T cells rather than a blocking a co-receptor. This means it could be effective against virus that use either the R5 or X4 co-receptor. It is a genetically engineered monoclonal antibody, made by cloning a single parent cell and producing exact copies that bind to the same CD4 receptor that HIV binds to. It is currently enrolling a Phase II trial that should complete in October 2010.

An earlier study found that people who had taken HIV meds before had greater viral load drops when ibalizumab was added to approved HIV drugs. They also had greater increases in CD4 counts: a rise of 51 vs. 5 for those not taking ibalizumab. The drug is being studied as an infusion given every two weeks, so it's unlikely that a pill form will be possible. If approved, it will probably be used only in people who have become resistant to other HIV meds.

Contenders to the Throne

Sustiva is currently one of the most effective and commonly prescribed HIV meds, but that could change if newer drugs in its class (non-nucleosides) are approved.
Sustiva is currently one of the most effective and commonly prescribed HIV meds, but that could change if newer drugs in its class (non-nucleosides) are approved. About half of people who take it develop central nervous system (CNS) side effects like vivid dreams and dizziness in the first two weeks. These usually go away within a few weeks but 4 to 10% of people stop the drug because of them. It may also be linked to fat changes in the body. Intelence, the first new drug in this class in over a decade, was recently approved for people who have become resistant to Sustiva. But three new drugs in this class are worth watching.

Rilpivirine is a once-daily pill that is active against HIV that is resistant to Sustiva. In a two-year study of people who had not taken HIV meds before, it was as effective as Sustiva in lowering viral loads to below 50. But it caused less rash (9% v. 21%) and fewer CNS side effects (31% v. 48%) than Sustiva. Also, triglycerides dropped in people taking rilpivirine but rose in those taking Sustiva. There are plans to combine rilpivirine with Viread and Emtriva in a single pill, creating a competitor for Atripla (also a three-drug pill). Another study is looking at a form of the drug that is given as an injection once a month.

There are plans to combine rilpivirine with Viread and Emtriva in a single pill, creating a competitor for Atripla.
IDX899 showed strong antiviral activity in a seven-day study in 32 people with HIV who had not taken HIV meds before. In this short study, side effects were generally mild and were similar to those in people taking a placebo. It may be less prone to resistance than Sustiva (which requires only one mutation for resistance to develop).

RDEA806 is active against HIV that is resistant to Sustiva, but unlike other non-nucleosides it is not processed by the liver's P450 system, so it will most likely not interact with other medications that use this system. A small study found significant viral load drops after 8 days in people who had not taken HIV meds before. Another study found that the drug has "a high genetic barrier to resistance," meaning that HIV must create multiple mutations in order for the drug to stop working.

Blocking Integration

Researchers began looking for a drug to block HIV's integrase enzyme in the early '90s, but several of these drugs failed. Finally, Isentress was approved in 2007 for people who were resistant to other HIV meds, and that approval was expanded in July of 2009 to include those who had never taken HIV meds before. It has been shown to be a powerful drug, lowering viral load faster than other drugs while having few side effects.

Elvitegravir will likely be the second integrase inhibitor to receive FDA approval. Unlike Isentress, it must be boosted with Norvir or a similar drug, and is taken once a day. In a study of people who were resistant to some protease inhibitors, people taking elvitegravir had greater viral load drops than those who took Prezista or Aptivus.

The drug is currently being tested as part of a "quad combo" pill that combines it with Viread, Emtriva, and GS 9350 (a new boosting agent that works like Norvir). If approved, it could challenge Atripla in the "one pill, once a day" category. A study comparing the two regimens in people who have never taken HIV meds is underway.

GSK 1349572 is a new integrase inhibitor whose first results were reported at the IAS conference in July of 2009. It may lower viral loads even more quickly than Isentress or elvitegravir. In a study of people who had not taken an integrase inhibitor before, 7 of 10 people taking the highest dose of the drug (and no other HIV drugs) achieved an undetectable viral load within 10 days. Unlike Isentress, it is taken once a day, and unlike elvitegravir, it does not require a boosting agent.

Blocking the Exit

Bevirimat could be the first HIV "maturation inhibitor." Like protease inhibitors, maturation inhibitors interfere with the final processing of newly made HIV proteins, but these drugs bind to the gag protein rather than to the protease enzyme. The resulting virus particles have defects that make them unable to infect other CD4 cells.

Generally, when a first-in-class drug becomes available, few people have resistance to it. But recent studies have found that bevirimat is not effective in some people whose virus is resistant to protease inhibitors. A study that screens out people who have certain gag mutations is planned to start later this year.

While none of the above drugs appear to be major breakthroughs, they would bring us closer to the goal of effective, easy-to-take regimens that have fewer side effects. While we wait for a cure, these new meds could mean that people with HIV will find it easier to live with and control their virus.

Mark Milano is an HIV Health Educator and Editor of Achieve.

Want to read more articles in the Summer 2009 issue of Achieve? Click here.



  
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This article was provided by ACRIA and GMHC. It is a part of the publication Achieve. Visit ACRIA's website and GMHC's website to find out more about their activities, publications and services.
 
See Also
Read More Articles in the Summer 2009 Issue of Achieve
More on HIV Medications
More on Entry Inhibitors in Development
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