At the 19th International AIDS Conference (AIDS 2012) in Washington D.C., the CDC reported that only 1 out of 4 HIV patients in the U.S. have HIV under control, which is defined as complete viral suppression. Warning bells should be ringing in the scientific and HIV advocacy communities. While much progress has been made in the last three decades in the treatment of HIV, tens of thousands of people living with HIV (PLWH) are currently struggling to construct viable treatment regimens or have no options left. With a growing number of patients in need of new treatment options, and new innovative therapeutics in the various early stages of development, a strategy must be developed to move new therapies forward based on merit and not money.
Whilst strategies can play a huge part in eliciting the best therapeutic responses they thus far primarily cater for those who are not treatment resistant. The previously quoted 1 in 4 treatment successes is also a bit misleading as it includes 20% of people who do not know they are HIV positive thus are not on HIV antiretroviral medication. Twenty-five percent is an extremely low percentage nonetheless and disheartening to know that so many people with HIV do not have the virus under control.
With the highly touted success of HAART, it seems surprising that the majority of HIV patients in the U.S. are unable to attain an undetectable viral load, which defines “successful treatment”. The reasons for such a high rate of people without suppressed viruses are complex.
The stigma and fear of receiving an HIV diagnosis prevents 1 in 5 people in the U.S. infected with the virus from being tested. They are often diagnosed only after becoming symptomatic, at which point HIV may have already severely damaged the immune system. Despite decades of HIV education, awareness and testing campaigns, some still believe HIV is a death sentence. In addition, many heterosexual men and woman still believe that HIV is only a “gay disease” and still others believe they are not susceptible to the disease because transmission rates have risen disproportionately in minority communities and injection drug users, communities which they are not a part of.
With recent data from the Pediatric HIV/AIDS Cohort Study study that reports 62% of the sexually active perinatally infected teens in the study have had unprotected sex and have high levels of drug resistance as well as nearly half of the worlds new HIV infections being under age 25, it is clear that HIV education and awareness are not enough to stop the spread of HIV. That being so, research and the development of new therapeutic options are vital.
The CDC also reports that only 37% of people who have been diagnosed with HIV are retained in care. Lack of health insurance, access to transportation, fear of being recognized at an HIV medical facility, mental illness and substance abuse are just a handful of barriers to seeking and continuing treatment. A new analysis of HIV positive people on Medicaid also showed that only 25% of HIV positive people on Medicaid are linked to care within one year of diagnosis.
According to the World Health Organization, drug resistance in wealthier nations has plateaued since the early 1990’s. This may be due to the ability of newer 1st and 2nd line drugs to fully suppress HIV better than older drugs. However, with the availability of HIV medications now spanning almost 2 decades, people on third, fourth and deep salvage regimens may become more and more common as they become resistant and cross-resistance to more drugs. This may be a fate that eventually awaits the large majority of people with HIV.
Although current data on the rates of HIV drug resistance is limited, HIV drug resistance in the U.S. and Britain is found to be around 10-20%. A study published in the journal Clinical Infectious Diseases in May of 2010 reported that 17 percent of people in a British study starting treatment with newer ARV regimens developed HIV drug resistance over eight years of therapy. The study also reported 28% of participants failed therapy.
In addition to the development of drug resistance in treatment experienced patients, the rates of transmitted drug resistance in treatment naïve people infected with HIV have increased significantly and continue to rise. Available data from the 2012 WHO HIV Drug Resistance Report indicates that between 10-17% of treatment naïve patients in the U.S., Europe, Japan and Australia have some level of drug resistance.
Drug resistance and cross-resistance among drug classes make it difficult for these patients to create a viable combination regimen. New drugs with unique resistant profiles as well as new classes of drugs affecting novel targets are needed to complete full regimens. There is a growing consensus in research settings that cellular targets should be considered for intervention as viruses require cellular proteins as auxiliary factors for infectivity and cellular host-defense mechanism as drug targets are of increasing interest as a means of taking advantage in innate immunity. Despite these facts, two of the last three HIV drugs approved by the FDA can currently only be used by those who are treatment naïve, and many of the drugs under clinical development are against traditional viral targets known to become drug resistant.
In addition to new drugs in existing classes that do not confer resistance to already available drugs, brand new classes of drugs are necessary to provide treatment-experienced patients practical options. Not withstanding the possibility of an eventual cure for HIV, new mechanisms of fighting HIV must be developed in order to address the issue of drug resistance to the available treatments and allow a larger majority of people living with HIV to experience viral suppression.
For instance, one new class of drugs being researched involves a cellular protein called APOBECE3G or A3G. This protein is an enzyme that resides inside cells as a guard against invading genetic material, such as HIV, and has the ability to scramble the viral genetic code. In research laboratory settings A3G causes the virus to fail. The A3G host-defense system fails in patients because HIV expresses its own defense protein known as Vif. Vif seeks out A3G in cells and tricks cells into destroying A3G like unwanted protein. Under these conditions HIV is able to replicate itself with impunity. Further research by scientists around the world has revealed how Vif interacts with A3G and a group of scientists from OyaGen, a biotechnology company in upstate New York , have used molecular engineering methods and advanced robotics to identify various chemical compounds that inactivate Vif and thereby protect the A3G host-defense. At the same time the company has identified chemical compounds that can activate A3G in anticipation of an incoming virus. A series of compounds are being explored that will inactivate Vif at several points along the entire mechanism by which Vif helps HIV take over white blood cells. These researchers maintain that Vif antagonists and A3G activators alone, or in combination with traditional HAART, represent a distinct opportunity to tackle drug resistant strains of HIV as well as provide an exciting means by which to prevent HIV infection.
This novel approach and other novel targets are vital to the continued treatment and care of HIV patients. Legislatures need to be aware that drug resistance to HIV therapies are threatening to dramatically increase the already unmanageable economics needed to treat and care for the 1.2 million (and growing) HIV positive American citizens. Without governmental intervention, the current system of drug development will continue and many new, potentially needed therapies will be lost, not due to their inability to defend the body from HIV but from an inability of their makers to raise the capital needed to complete the FDA required clinical trials.
A greater awareness of the consequences of continued HIV drug resistance and drug failure must be considered and legislative and scientific priorities set to address the support of novel therapies and salvage therapies for those already resistant to many of the available ARV’s. The federally funded AIDS clinical trial system (The AIDS Clinical Trials Group) and NIH grants must stop funding clinical trials of drugs made by Big Pharma, who can afford to finance studies themselves, and should instead support the development of innovative compounds coming out of small biotechs and Universities. Current trends have been that small biotech companies have to finance their own development and preclinical work. Especially in today’s economic climate, this puts at risk the likelihood that innovative antiretroviral drugs will enter the pipeline and reach those who need these alternatives the most.
As was once done in the past to make available the drugs people with HIV now rely on the scientific and HIV advocate/activist community must advocate for these therapies, bringing them to the attention of legislatures, and demanding mechanisms be put in place to assure the drugs needed to adequately treat people with HIV are made available.
With assistance from Rick Blake.