Strategies for pursuing an HIV cure were a major focus of the recent International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention— a testament to how far we’ve come over the past 30 years. When HIV made its appearance in the 1980s, the research community responded with unprecedented urgency and cooperation, yielding many breakthroughs that pioneered the success we have with current HIV therapy.
Today, a diagnosis of HIV is no longer a death sentence; instead, the treatment of HIV has become a chronic, manageable condition allowing HIV-infected people to experience long and productive lives. Remarkably, by the year 2015, more than half of people living with HIV will be 50 years or older.
As the dynamics of living with HIV has changed, our research priorities have shifted to address the challenges of the changing demographics and push the frontiers of the evolving scientific landscape. We need to continue to improve treatment as we also invest in the science and investigate approaches towards the ultimate goal of curing HIV.
The Pathway To Current HIV Therapies:
Early on, it became evident that combination therapy with multiple drugs from different classes of medicines would be required to constrain the replication of the virus and prevent the development of drug resistance. To this end, scientists from around the globe invested countless hours towards understanding HIV replication at the detailed molecular level. These efforts were crucial to the development of the current armamentarium of nearly 30 licensed HIV treatments which target several distinct phases of the HIV lifecycle: entry inhibitors, protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and integrase inhibitors.
While most of these agents belong to the three drug classes identified in the earliest days of HIV drug discovery, ongoing investments in HIV research continues to be instrumental for advancing innovative medicines. With the current pipeline of therapeutic options in HIV, we are able to achieve a remarkable level of success in both treatment-naïve patients and patients who have failed therapy with multi-class drug resistance. These achievements have created a new focus for the field of HIV drug discovery with the goal of developing agents that are more optimal for managing the challenges associated with chronic therapy.
Despite these advances, we must not forget the epidemic remains in both the developed and developing world. As we seek to improve upon existing therapies, factors such as age, co-infections, interactions with other medications and resistance need to be considered. At Merck, our scientists together with collaborators are pursuing strategies to re-engineer currently available medicines to optimize outcomes for diverse patient populations by evaluating different dosing options and new delivery mechanisms. At the same time we continue to invest in new compounds that have the potential to address resistance and tolerability. In the developing world, where people are at a high risk for HIV infection and resistance, we are evaluating approaches to improve treatment outcomes and decrease new infections. As one example, the SECOND-LINE study by Kirby Institute in Australia has been exploring the use of an alternative regimen to replace the second-line therapies which carry increased risk for developing and spreading drug resistance.
The Journey To Eradication:
Despite the enormous challenge, the scientific community continues to pursue research towards the goal of eradicating HIV. The Berlin Patient, the VISCONTI cohort and the “cured” baby in Mississippi provide tantalizing hope that a “functional cure” may be possible. A “functional cure” essentially means that people can remain HIV free without the need for antiretroviral therapy. While HIV treatments are effective at controlling the active virus, HIV also persists in the body by hiding in long-lived cells (resting CD4+ memory T cells). In this state, HIV resides in a latent reservoir undetectable by the immune system and unaffected by antiretroviral treatments. Flushing latent HIV from these hiding places has been proposed as a key step towards a cure.
Merck and others are working to identify combinations of small molecules capable of seducing latent HIV out of hiding. This approach will most likely need to be combined with other approaches to either augment the immune system’s ability to recognize and eliminate such cells and/or directly kill them. Although these efforts are still very early, as in the early days of the HIV epidemic, the research community has a renewed sense of urgency and dedication to tackle the challenge of eradication. The significance of this challenge, as well as the potential impact of the opportunity, has also fostered renewed spirit of collaboration among scientists as well as the community.
While we recognize there is still a long path ahead of us, at Merck we are inspired by the progress of the past and all of the people who have contributed to this journey thus far and we are motivated by the belief that by working together a cure will someday be possible.
Dr. Daria J. Hazuda, Ph.D. is the V.P. of Early Development & Discovery Sciences Research for Infectious Disease, Merck