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Dolutegravir Expanded Access Begins, but Advocates Urge Caution

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ViiV Healthcare and Shionogi have opened an expanded access program (EAP) for their investigational HIV integrase inhibitor dolutegravir for treatment-experienced patients. The drug offers a new option for people with extensively drug-resistant virus, but activists caution that dolutegravir should not be used as a single active agent, as this could lead to resistance that limits its usefulness.

Studies have shown that dolutegravir (formerly S/GSK1349572) works as well as efavirenz (Sustiva) for treatment-naive people, and for treatment-experienced people it demonstrates activity against virus that has developed resistance to the sole approved integrase inhibitor, raltegravir (Isentress).

The open-label dolutegravir expanded access program (known as protocol ING114916) is for treatment-experienced adults who have detectable viral load (at least 400 copies/mL), documented resistance to raltegravir or elvitegravir (Gilead's experimental integrase inhibitor), limited treatment options, and require dolutegravir to construct a viable combination regimen.

Further information about inclusion and exclusion criteria is available online at ClinicalTrials.gov.

More information about the EAP is available at http://www.dolutegravir-eap.com.

The AIDS Community Research Initiative of America (ACRIA) and a coalition of advocates and providers recently issued a warning about the risk of starting dolutegravir as a sole new drug for people with multidrug-resistant HIV who require "salvage" regimens.

Adding dolutegravir to an existing non-suppressive regimen is effectively using the new drug as monotherapy -- or the only fully active drug in a regimen --which encourages resistance. Taimed's investigational monoclonal antibody ibalizumab is one possible additional agent that could be used along with dolutegravir to construct a regimen with at least 2 active agents.

Below is an edited excerpt from a press release describing the concern about suboptimal therapy using dolutegravir under expanded access.

Activists Caution HIV+ Patients and their Physicians About Monotherapy in Upcoming Access Program

New York -- February 9, 2012 -- AIDS activists and physician advocates welcome the news that ViiV Healthcare will be providing expanded access of dolutegravir (DTG), a new investigational integrase inhibitor for HIV patients with few remaining HIV treatment options. However, they warn patients and physicians to avoid functional monotherapy, or the introduction of dolutegravir as an "add-on" to a failing treatment regimen if the patient’s virus is resistant to all other currently available antiretroviral drugs (ARVs). Functional monotherapy has been shown to permit rapid HIV resistance to new medications, which can result in more rapid disease progression, health deterioration, and death.

Currently, the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines recommend three ARVs be given in combination to suppress HIV. But many patients have HIV that has mutated rendering their virus multi-drug resistant (MDR-HIV). Those with MDR-HIV cannot construct a viable HIV suppressive regimen with current FDA-approved and commercially available ARVs.  

"The DHHS guidelines specify that patients that have developed HIV drug resistance to all commercially available antiretrovirals require access to at least two new active drugs to maximize their chances for treatment response   However, another new drug to combine with dolutegravir will not be commercially available for at least two years, and some patients cannot wait that long", said Nelson Vergel, an activist founder of SalvageTherapies.org. "For them, access to another research drug in combination with DTG is the only hope for survival," added Vergel.

In studies to date, dolutegravir (DTG) appears to be the most potent integrase inhibitor soon to enter the HIV ARV market. Unlike Gilead's upcoming elvitegravir, DTG has been shown to be effective against HIV that has developed resistance to Merck's Isentress (raltegravir), the only FDA-approved integrase inhibitor currently on the market. 

Fortunately, another new ARV that can help patients with MDR-HIV is in active development and clinical trials. Ibalizumab, a monoclonal antibody from a small biotech firm, Taimed Biologics, may soon be available via patient participation in research studies. While ibalizumab has yet to enter phase three studies, it can also be provided to patients at risk of death via a named (or single) patient access application permitted by the FDA via a physician’s direct request to Taimed. However, it is up to the company to approve such requests for compassionate access.

There are no documented estimates of how many people have MDR-HIV in the United States who have uncontrolled HIV virus. A report in the Journal of Clinical Infectious Diseases estimates that about 260,000 patients are being treated with HIV in the United States. However, it is virtually impossible to know how many of them have run out of treatment options since no registry for those patients exists. But most experts agree that this population is probably small.

"With little immune function left and resistance to all approved HIV medications, I have tried desperately to get access to two new drugs to help save my life,” said Christopher Cacioppo, a patient with MDR-HIV in San Diego who believes he is running out of time. "But my doctor tells me that I have little choice but to wait for the dolutegravir expanded access program and some as yet unknown and unavailable second new drug."

A coalition of activists and physicians have been in coversations with Taimed and ViiV for two years to obtain compassionate access to their two active ARVs in combination for those with MDR-HIV in greatest need of new treatment options. The AIDS Community Research Initiative of America (ACRIA), a New York City-based community researchand education organization, and physicians in San Francisco have proposed solutions to overcome this "two-drug access barrier" in an effort to secure urgent access to patients across the country.

Any physician who may have a patient with MDR-HIV who is in dire need of two new unapproved ARVs may use this form.

3/6/12

Sources

Activists Caution HIV+ Patients and their Physicians about Monotherapy in Upcoming Access Program. Press release. February 19, 2012.

ViiV/Shionogi. Welcome to the Dolutegravir Expanded Access Program (DEAP) Treatment Center. http://www.dolutegravir-eap.com.

Dolutegravir Expanded Access Study (DEAP). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01536873.