Old Concept, New Hope

LifeGuide [Treatment Horizons]

Therapeutic Vaccines May Change the Treatment Landscape for the Better
by Jeannie Gibbs

Clinical development of HIV therapeutic vaccine candidate, Vacc-4x, will continue after further analysis of Phase IIb study data revealed a significant viral load decrease in patients on the Vacc-4x treatment arm. Even more substantial was the discovery that viral load set points of these patients did not rebound to pre-HAART levels, which usually occurs after antiretroviral therapy (ART) failure. Results of previous studies of Vacc-4x had been so promising that the October 1st announcement to discontinue clinical development after initial analysis determined Vacc-4x had failed to reach the trial’s primary endpoints, had left researchers and the HIV community stunned.

Initial analysis of the 135-patient, international, randomized, double-blind, placebo-controlled multi-center Phase IIb study determined that Vacc-4x had failed to meet the studies’ primary endpoints of continued cessation of ART and decreased CD4 count. However, further analysis during an in-depth review of randomized data revealed a three-times-higher viral load set point among the treatment arm compared to those given placebo. A statistically significant reduction in viral load from the pre-ART level (0.55 log, p=0.0003) was found in patients treated with Vacc-4x compared to a non-statistically significant reduction in viral load (0.08 log, p=0.89) in patients in the placebo group. Participants who received Vacc-4x had final viral loads that were twenty-eight percent of their pre-antiretroviral therapy viral loads, on average. Participants who received a placebo had final viral loads that were an average of eighty-three percent of their set-point viral loads.

These results are highly significant. Whereas ART decreases viral load to undetectable or near-undetectable levels, viral rebound is almost always seen with the discontinuation of ART. If viral set points are lowered, Vacc-4x may hold great potential for use as an adjunct to ART to maintain viral control.

According to Dr. Richard Pollard, MD, division chief of Infectious Disease, University of California Davis Center for AIDS Research, Education, and Services, who was the principle investigator for the Vacc-4x trial, “Patients starting on antiretrovirals see the viral load effectively reduced, but this is dependent on daily treatment and we know that HIV remains in the reservoirs.”

He continues: “A therapeutic HIV vaccine like Vacc-4x reducing the viral load set-point could have significant implications for future HIV management used in combination with ART. More research is needed to confirm
this hypothesis.”

Further research will also determine whether additional use of Vacc-4x in conjunction with ART could lower viral set points even further which could have an additional immense clinical benefit. Results from the analysis of the studies’ immunological data is pending.

“The full immunological analysis and long-term data will give us a better basis for evaluating the outcome and implications for the positioning of Vacc-4x as a therapeutic product for HIV-patients,” says Bionor Pharma CEO Henrik Lund. “A possible application of Vacc-4x is [as part of] a combination therapy, with repeated ART-Vacc-4x [in conjunction] with analytical treatment interruptions in order to establish a functional cure.”

Vacc-4x is presently furthest along in development of any therapeutic vaccine being studied for the treatment of HIV disease.

Recent successes, as reported at the 18th International AIDS Conference in a community forum sponsored by NAPWA and covered by international media including Nature magazine and the Financial Times, have begun to slowly reverse the lack of interest bestowed on the field of therapeutic vaccines for HIV. Although understandable when considering pre- and early HAART failures and controversies such as Remune, therapeutic vaccines conversely have come a long way with still little to no attention or outside funding. The lack of support for this important class of drug is considered an atrocity by some when viewed in light of their potential benefits, uses, and the paradigm shift in HIV treatment, global cost of care and overall change of quality and quantity of life they could bestow on people with HIV worldwide.

If therapeutic vaccines such as Vacc-4x and AGS-004 (a promising Phase IIa HIV therapeutic vaccine made by Argos Pharmaceuticals) continue to show the benefits they have thus far, it may be possible to significantly decrease the need for HIV antiretrovirals, postponing treatment, and/or reducing the amount of time spent on HAART. The benefits of this would be enormous in many aspects.

With an estimated 33.3 million HIV-positive people worldwide and with 2.6 million new infections every year, providing a lifelong supply of HIV antiretrovirals to every person with HIV is presently not a financially realistic goal. But what if we could postpone the use of antiretrovirals by a few years and then allow for extended antiretroviral-free periods with just a few injections? Even with the cost of a therapeutic vaccine used periodically, how much money would that save per patient? How many more people would that enable to initiate antiretroviral therapy? How many additional lives could be saved?

Fifteen years into the FDA approval of HIV protease inhibitors and the initiation of combination therapy, it is evident that along with their life-sustaining and improving benefits, long-term use of ART also encompasses many challenges. People with HIV on ongoing ART experience devastating effects such as cardiovascular complications, liver and kidney damage, metabolic consequences, insulin intolerance, lipoathrophic effects, mitochondrial toxicity, and many other life-altering or ending issues. A decreased use of ART may equate to a decreased expression of these distressing effects. Treatment for these side effects as well as for opportunistic infections and other illnesses that occur with antiviral drug resistance and failure and an eventual lack of further treatment options, equal billions of dollars in additional medical expenses, lost wages, and government support and, most importantly, lives.

With over twenty-five HIV antivirals to choose from, the face of HIV drug development is drastically changing. Many Big Pharma companies, who once vied for the attention of HIV physicians and patients in pursuit of utilization of their specific drugs, are now moving into other drug indications, merging with and taking on the existing pipelines of other pharmaceutical companies and partnering less with small biotechs in HIV drug development. Due to the global financial crisis, biotechnology companies (who normally take drugs through the discovery and early phases of clinical trials) are having even more difficulty in raising funds. Many biotech companies are now placing compounds on hold until a pharmaceutical partner can be found. These factors are evident in the HIV pipeline which encompasses a comparatively small number of new HIV antiretrovirals in contrast to previous years.

The HIV community is seeing a corresponding drop in funding of public education programs about existing and potential next-generation treatments. Companies no longer give away massive amounts of funding to HIV organizations, events, publications and Web sites to promote use of their specific drugs nor extend immense marketing budgets for a huge presence at HIV conference expos.

This paradigm shift will lead to fewer new HIV drugs, making therapeutic vaccines, which could extend the use of these therapies (with the exception of cure research), the most important field of drug development research for people with HIV.
Drugs such as Vacc-4x may extend the life of ART years if not decades, thus greatly prolonging the lives of people with HIV and AIDS. Government support of this research is crucial. Organizations such as The International AIDS Vaccine Initiative (IAVI), The Bill and Melinda Gates Foundation, and The Global HIV Vaccine Enterprise, who determine the direction of vaccine research, must add therapeutic vaccines to their agendas in addition to the search for a preventative vaccine. Researchers, clinicians, people with HIV, activists, and advocates must urge these organizations and our governments to support the development of therapeutic vaccines in the hope of a greater future for people with HIV and AIDS worldwide.

Jeannie Gibbs has been an AIDS treatment activist and HIV writer for over fifteen years. She lives in New York City.

March 2011