The Path to a Cure
The Pathway to an HIV Cure and Other Treatments in the Pipeline
Is curing HIV possible? I believe that the answer is a resounding YES! The proof of concept for a cure is derived from the famous Berlin patient, Timothy Ray Brown, who many now believe has been "cured." Also, at least two small pharmaceutical companies are researching gene therapy, of which the upshot may be to mimic the same effects observed in Mr. Brown.
At the time of this writing, it has been more than five years since Brown's bone marrow transplant and he continues to demonstrate clearance of HIV from blood and other tissues. The transplanted cells were from a donor who harbored the delta 32 variant gene. Moreover, there are some individuals who already have this rare genetic alteration; they do not need a "cure" because they were born with and harbor this same delta 32 genetic variant. These individuals cannot become infected by exposure to HIV.
To be clearer, HIV requires bonding at two sites in order to gain entry into human cells: the CD4 receptor site and a chemokine receptor site, most commonly CCR5. When a person has both genes (homozygous) carrying the delta 32 variant, it results in a deletion of the gene that, under normal circumstances, selects for the CCR5 chemoreceptor. In other words, it results in them lacking CCR5, a protein on the surface of immune cells that HIV uses to gain entry. In this situation, HIV is disabled from gaining entry or infecting human cells. Roughly 1% of Northern Europeans possess this abnormality. Other individuals that are heterozygous and have the genetic modification in only one gene are not protected.
At least two pharmaceutical companies are involved in looking at gene therapy. Their focus is to mimic the individuals who are naturally born with this genetic variation by causing the deletion of the gene that selects for CCR5. While this may be merely a sketch of the possible pathway to a cure, it is certainly a new road of research for HIV disease treatment.
Brown suffered from a leukemic disease as well as HIV. When treating leukemia, patients often undergo stem cell transplants after all their diseased cells are destroyed by chemotherapy. This form of chemotherapy is dangerous, wiping out many immune system cells as well, and carries with it a 50% mortality rate due to severe infections that can arise with a severely crippled immune system. However, during the post-chemo phase, where there should be no evidence of host cell disease, donor stem cells are infused into the patient with the hope of repopulating and replacing the cell lines with the new healthy donor cells. Five years ago, Mr. Brown's physician had the vision to treat his HIV and leukemia at the same time by using donor cells from someone with the delta 32 variant. Timothy Ray Brown is currently the only living example of a possible HIV cure.
Enter a new possible approach to treating HIV: gene therapy being researched by Sangamo Biosciences which collaborated with Sigma Life Science, a company which has made zinc finger technology widely available. Other scientists are looking at Sangamo's example of how to best use this technology for creating new cell lines and new proteins to help fight additional disease states. Sangamo, with a viral vector (carrier), has created a method of using zinc finger nucleases to clip both strands of DNA that selects for the CCR5 co-receptor. In HIV-positive individuals, replacing genes with this deletion could potentially prohibit any HIV from infecting those cells. The altered CD4 cells that lack the co-receptor, known as SB-728-T, are multiplied in a laboratory and infused back into the same patient.
Recent data from Sangamo's trial were presented at the 51st ICAAC in Chicago in September. Cohorts from the West Coast (nine patients) and East Coast (six patients) had undergone the procedure of altering the cells to become SB 728-T-modified CD4 cells during a Phase 1 trial.
The nine patients from the West Coast had baseline undetectable viral loads and median CD4 counts of 384 cells/mm3 (384 cells are felt to be suboptimal CD4 recovery after ART). The study participants, median age of 50 years, had been HIV-positive for an average of 20 years. Results showed that the modified cells persisted for a median of 337 days, with the maximum duration being 561 days. The presence of the CCR5 deletion was shown in 25% of the patients and all had CD4 increases of an average of 163 cells. Also, the CD4 cells had normal migrating properties. Side effects were minimal and short lived, with flu-like symptoms occurring for 24 hours after their infusion.
The East Coast cohort underwent a 12-week ART interruption starting four weeks after receiving SB-728-T-modified CD4 cells. The subjects with CCR5-deleted genes who also had higher CD4 values showed lower viral loads and as much as a .08 to 2-log viral load drop. One of the subjects who had the heterozygous form of the delta 32 gene achieved undetectability during the treatment.
Sangamo is now considering investigation into treating patients by adding small doses of chemotherapy prior to infusing the zinc finger (SB-728-T)-modified CD4 cells, with the aim of achieving a higher turnover towards CCR5-deleted CD4 cells and thus further progress at arriving at a functional cure.
New Single-Pill Cocktails
Let's move on to a discussion of two new single-pill regimens, each containing triple drug therapy in one pill. Complera, recently approved, contains the new non-nuke rilpivirine (Edurant) plus Truvada (Viread plus Emtriva). Another pill, nicknamed the Quad, is undergoing Phase 3 studies but has filed a New Drug Application (NDA) with the Food and Drug Administration (FDA) for approval. If successful, it may become available by April 2012. The Quad contains the integrase inhibitor elvitegravir boosted by cobicistat, plus Truvada.
Since approval, clinicians have been switching selected patients to Complera. This occurs more commonly when patients have been enduring side effects from Atripla, containing Sustiva (such as sleep disorders, morning lethargy, and anxiety), but also when side effects of some protease inhibitor regimens persist. Also, some patients are being transitioned to Complera merely for the sake of treatment simplification.
Some clinicians have been more reserved, not confident of Complera's potency due to higher failure rates observed in naïve patients of the Phase 3 trials, who had baseline viral loads greater than 100,000 copies/ml. Thus, physicians are split between using Complera now, vs. waiting for the Quad to become approved. However, in present real-world situations, patients who have already reached undetectability, being stable on other regimens, are undetectable at this baseline when switching; concerns regarding the effectiveness of Complera should at least be on par with the overall data of non-inferiority compared to the standard of care, Atripla. Of note is that higher levels of rilpivirine are achieved within the single pill Complera than were observed in the original Phase 3 trials, in which rilpivirine was administered as a separate pill. Of course, prior to any switch, clinicians should review their patients' previous genotypic history, ensuring that no underlying rilpivirine and Truvada resistance is present.
During the ICAAC conference, new data on Complera were presented by Dr. Tony Mills. In this study, 49 patients who were undetectable on Atripla switched to Complera. All 49 patients remained undetectable at 12 weeks.
Also, two more studies are ongoing to better define Complera's use. In one trial, Complera is being pitted against Atripla in a study of nearly 800 treatment-naïve patients. The second, which enrolled approximately 500 patients, is studying treatment-experienced patients on boosted protease inhibitors, who were randomized to either stay on their original regimen or be switched to Complera. I currently serve as principle investigator for all three trials at Northstar Healthcare, while seeing many of our patients on these studies. It gives me great pleasure to be observing patients improve their quality of life while contributing to research and our knowledge base as they are offered these new advances in treatment.
Newest Nuke, GS-7340
GS-7340 is a pro-drug of tenofovir (Viread) (pro-drugs get metabolized within the body, or in vivo, which improves bio-availability). 7340 has been thought to have great antiviral activity at low doses, also penetrating tissues at 20-100 times that of other drugs. At Northstar, we have recently completed a Phase 1 dose-finding, 10-day monotherapy study, comparing several low doses of the drug. We expect data to be released from this study in the near future. Also, Gilead has reported that they plan to formulate yet another single-tablet regimen, to contain GS-7340 plus Emtriva and the cobicistat-boosted integrase inhibitor elvitegravir.
2012 is expected to be an exciting year for development of HIV therapeutics. Various single-pill regimens will eventually overtake older regimens where previous treatment-naïve patients were started on quantities of three or four pills. Many treatment-experienced patients will also be eligible to have treatment simplified towards one-pill therapy. Further down the road, a completely new approach in treatment is underway -- one that may have the potential to be a functional cure of HIV infection. However, challenges still remain in the attempt to retard the premature development of complications associated with the aging HIV population.
Dr. Daniel S. Berger is a leading HIV physician in the U.S. and is Clinical Associate Professor of Medicine at the University of Illinois at Chicago. He is founder and medical director of Northstar Healthcare, has published extensively in such prestigious journals as The Lancet and The New England Journal of Medicine, and currently serves as principle investigator at Northstar Healthcare. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award. Dr. Berger can be reached at DSBergerMD@aol.com and www.Nstarmedical.com.
This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.
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