Where Are We in The Search for an HIV Cure?
It has been 33 years since the first case reports of what would later become known as Acquired Immunodeficiency Syndrome, 27 years since the first drug was FDA-approved for treatment of the AIDS virus (Human Immunodeficiency Virus, or HIV) and the formation of the AIDS Coalition to Unleash Power (ACT-UP), 18 years since we developed the earliest “cocktails” that effectively suppress HIV (also known as Highly Active Antiretroviral Therapy, or HAART), 14 years since we learned that individuals need to take over 95 percent of their HAART for it to be most effective and prevent resistance to these drugs from developing, eight years since the FDA-approval of the first fixed-dose combination (FDC, or one pill/once daily) regimen to improve patient adherence and HIV suppression (by this summer, we will have four FDCs from which to individualize patient treatment), three years since we learned that taking effective HAART reduces HIV transmission by 96 percent (leading to “Treatment as Prevention”), and two years since we begin recommending HAART for everyone as soon as possible after diagnosis and regardless of one’s CD4 cell count. These are all major milestones I have witnessed and participated in to shape the modern history of HIV/AIDS.
So why do we need a cure for HIV when lifelong HAART can essentially halt the spread of it? First, there are an estimated 1.25 million Americans infected with HIV, 1 million with known HIV infection and 250,000 with unidentified HIV infection. You would think that in the land of entitlements where everyone known as HIV-positive has full access to HAART that nearly everyone would and should be “undetectable” for HIV (defined as not being able to detect HIV at the lowest limits of the viral load test being used, e.g. less than 200 or 50 or 20 copies of HIV) and therefore have a 96 percent reduction in risk for HIV transmission. Our harsh reality check shows that, sadly, partly due to continued HIV stigma, less than 30 percent of these one million individuals are “undetectable” (or, conversely, approximately 700,000 HIV-positive patients still can infect others), as patients fall out of care, stop taking HAART, become resistant to HAART, or are not on HAART for many other reasons.
Second, our youth are being devastated by the “second wave” of this epidemic. Of the 250,000 individuals with undiagnosed HIV infection, again in great part due to HIV stigma, over 90 percent of these individuals are 13 to 34 years old. Additionally, if you were 10 years old in 1996 when HAART was developed, you are 28 today and have never witnessed the “death and dying” of our brave brethren who succumbed to AIDS complications in the ‘80s and ‘90s and may feel “it is no big deal to get HIV” or “nobody dies from HIV anymore” or, my favorite, “all I have to do is take one pill a day.”
Third, that one pill a day can cost over $25,000 per year and may cause kidney failure and/or osteoporosis, and other antiretroviral agents can cause liver problems, elevated cholesterol and triglycerides, diabetes, diarrhea, and many other toxicities. Fourth, do you really want to be infected with a virus that still can be a fatal infection, or, at the least, can cause rapidly advancing aging conditions such as stigmatizing lipodystrophy (loss of fat in the face and/or fat accumulation in the belly), low testosterone in up to 66 percent of men and women, heart attacks, cancers, liver and kidney failure, and varying degrees of brain impairment?
And, lastly, in 2012 alone, the U.S. Federal Government spent $27.7 billion in research, services and treatment of the disease.
So, where are we in developing “the cure?” At this year’s just-completed Conference on Retroviruses and Opportunistic Infections (CROI), we inched several optimistic steps closer to developing a cure. It is true that a second baby born to an HIV-positive mother, who was not undetectable at the time of her baby’s birth, was quite possibly “cured” of HIV by administering HAART almost immediately after birth, leading to a future controlled clinical trial that will take approximately two years to prove and, inevitably, still unrealistically require the 250,000 babies born with HIV worldwide to access and take expensive and potentially toxic HAART for a year or so. Let’s not lose sight of the fact that, in the U.S., we have less than 200 babies born with HIV annually because HAART, when administered to an HIV-positive pregnant woman before her third trimester, reduces mother-to child HIV transmission to less than 1 percent. But these great statistics still require lifelong HAART.
We certainly know Timothy Ray Brown, the “Berlin patient,” is the first person in the world to have been cured of HIV. But Tim first developed leukemia, failed standard chemotherapy, underwent whole-body radiation therapy with toxic chemotherapy followed by two expensive bone marrow transplantations with stem cells (BMT) from a rare donor who was genetically immune to HIV (we know approximately 1 percent of Caucasian Northern Europeans, Europeans, and Ashkenazi Jews carry a gene mutation, technically referred to as “CCR5 delta-32/delta-32 homozygotes,” that makes them immune to HIV, meaning they carry a gene mutation of their CCR5 gene so their T cells don’t have the CCR5 protein, or receptor, that opens the door for HIV to enter and infect their T cells). At CROI, two HIV-positive patients, who also underwent BMT without whole-body irradiation and with different chemotherapy than Timothy and who were initially thought to be “cured,” rebounded with HIV at three and eight months, respectively.
This finally brings us to gene therapy as a possible method to achieve a “functional cure,” whereby an individual would, in the ideal world, no longer need HIV medications and would remain undetectable, despite having virus hiding in various places in their body, known as “reservoirs.” I reported at CROI on results from a clinical trial, SB-728-1101, investigating Sangamo Biosciences’ promising SB-728-T, a gene therapy that involves removing some CD4 T cells from HIV-positive individuals, using Sangamo’s proprietary zinc finger nuclease (ZFN) technique to “edit” the CCR5 gene of the CD4 cells to create a mutation on the gene for the CCR5 receptor, similar to that found in nature in those 1 percent described above, and, after growing billions of the new cells outside the body, intravenously infusing 10 to 40 billion of these newly created gene-modified cells followed by stopping HAART.
The new genetically modified CD4 cells, referred to as SB-728-T, have mutated CCR5 receptors that make them resist HIV infection by the most common form of HIV (these are the HIV viruses that use the CCR5 receptor to infect the CD4 cell and are called “R5”-tropic viruses; less common viruses use the other receptor known as CXCR4 and are called “X4”-tropic viruses, or use one or both receptors and are referred to as dual or mixed [“D/M”]-tropic viruses). We are investigating using a chemotherapeutic agent, Cytoxan or cyclophosphamide (CTX), before the infusion of SB-728-T to improve the chances of developing genetically altered CD4 cells that will be immune to and resist HIV infection and will flourish in the HIV-positive individual. The hope is that enough of these immune CD4 cells will grow to allow the individual to control their virus without the need for HAART, thus achieving a “functional cure.” Please keep in mind, however, that these are early FDA Phase 1/2 clinical trials aimed at finding the ideal dose of CTX and evaluating its safety, toxicity, and early effectiveness.
In summary, 12 HIV-positive individuals with CD4 cells of at least 500 received one of three doses of CTX, followed one to three days later with infusions of 8 to 36 billion SB-728-T CD4 cells and discontinuation of HAART 6 weeks later. Individuals remain off HAART for at least 16 weeks or more if their CD4 cell counts remain over 500 and their viral loads decline to less than 10,000. The highest doses of CTX showed better “engraftment” of the genetically modified CD4 cells with the greatest increases in CD4 cell counts. One of 3 individuals on the highest CTX dose dropped his viral load by almost 99 percent and remains off HAART, along with a second individual remaining off HAART with a detectable but lower and stable viral load. These gene modified cells have been shown to survive much longer in the presence of HIV when compared to those not gene modified. The CTX was found to be generally safe and well-tolerated with expected and controllable nausea with anti-nausea medications. I also reported that one of my patients from an earlier study of SB-728-T, given without CTX to individuals who carry one of the two genes needed to naturally express the CCR5 gene mutation, remains off HAART with an undetectable viral load for 31 weeks now. We are making enormous progress in understanding how best to deploy this gene therapy, showing significant increases in CD4 cells, prolonged survival of the gene modified cells, significant reductions in viral load as well as the HIV reservoirs, all of the factors necessary to provide “functional” control of HIV. The story continues to unfold and more results will continue to be presented at future meetings. Soon we will find out whether or not SB-728-T is capable of creating a “functional cure” in certain individuals, leading to further studies in larger numbers of individuals and utilizing other techniques to genetically modify the CD4 cells. Stay tuned.
About the Author
Dr. Gary Blick is the Co-Founder and Chief Medical Officer of The World Health Clinicians, a 501(c)(3) non-profit humanitarian organization. He is also Medical & Research Director of CIRCLE CARE Center, and Medical Director of BEAT AIDS Project Zimbabwe, both of which are WHC entities. He is a doctor of Internal Medicine and an HIV Specialist certified by the American Academy of HIV Medicine. Dr. Blick is an internationally known HIV/AIDS clinician, clinical researcher, lecturer, and humanitarian. His career in healthcare spans more than 30 years. Originally planning to become a plastic surgeon, Dr. Blick studied at the University of Miami Medical School. But after witnessing the tragic and heart-wrenching effects of the early AIDS epidemic he quickly changed his educational direction. Thirty years later, Dr. Blick remains on the cutting edge of HIV/AIDS care, having provided medical treatment to over 3,500 individuals living with HIV/AIDS. He has been the Principal Investigator in more than 110 clinical research trials, and has authored or co-authored more than 155 medical manuscripts and scientific presentations regarding therapies and treatments for those with HIV/AIDS. His work has been published in the Journal of Infectious Diseases, Journal of AIDS, AIDS, Clinical Infectious Diseases, Journal of the American Medical Association, Lancet, and many other peer-reviewed medical journals.