Neurological problems related to HIV disease have long been one of the most difficult complications to diagnose and treat. Before the widespread use of highly active antiviral therapy, infections and tumors of the brain were not uncommon. While we are fortunate that these severe complications are not often seen today due to better and more effective antiviral treatment, we continue to see unexpected subtle changes in cognitive functioning that include memory loss and difficulties in concentration among otherwise healthy HIV-positive individuals.
On April 26, 2005, the prestigious Journal of the American Medical Association (JAMA) published results of a preliminary trial of a common second-generation tetracycline against immune deficiency virus. Minocycline, a common tetracycline antibiotic used to treat acne skin problems and other infections, was administered to monkeys, investigating its possible benefit in HIV infection, specifically for neurological protection. Minocycline was chosen because of its anti-inflammatory properties, its ability to penetrate brain tissue, and its proven protection in other neurologic diseases in animals, such as multiple sclerosis, ALS and Parkinson's disease.
At the conclusion of the study, the authors observed a reduction in the cytokines (cells and proteins produced by immune system cells) associated with inflammation and the reduction in immunologic response to neuro-degeneration. Also observed was a decrease in viral load levels in cerebrospinal fluid (fluid that surrounds the brain or spine) and test-tube studies revealed a reduction in virus from cultured lymphocytes and macrophages (inflammatory cells).
Because of the surprising findings of this inexpensive, safe, available antibiotic, whereas current antivirals are anything but cheap and not always effective for treating cognitive dysfunction in HIV, controversy and discussion has begun within the HIV scientific community.
The study focused on monkeys. Eleven monkeys were studied and infected with simian immune deficiency virus (SIV). SIV is a virus that is the scientific equivalent of HIV for monkeys.
Twenty-one days after infection, five monkeys were given two tablets of minocycline daily (a comparable dose used for treating humans with acne). Six other monkeys, also inoculated with SIV, were not administered the tetracycline-like treatment and were studied as a control group. During the course of the study, the monkey subjects had frequent blood tests and spinal taps for SIV testing and markers of brain inflammation. After 84 days, all monkeys were humanely sacrificed for further brain pathology testing.
Among the monkeys that got the minocycline, three out of five did not develop encephalitis, and the other two had mild encephalitis. Of the untreated controls, two had severe, three moderate and one no encephalitis. Also, when studying the CSF (cerebrospinal fluid), the minocycline-treated monkeys demonstrated lower immunologic and inflammatory cytokines and had fewer signs of brain inflammation.
The authors interpreted the decrease in these markers and cytokines to mean that less virus was getting into the brain. Surprisingly, test-tube studies showed that minocycline suppresses HIV replication itself, via a reduction in HIV (and SIV) in cultures of lymphocytes and macrophages (immune and infection-fighting cells). The number of monkeys was small, but the difference was significant in terms of disease reduction, according to the study.
Further, the authors hypothesized that minocycline may not inhibit HIV replication directly like conventional antivirals, but instead may make the cellular environment "non-permissive" for the virus to replicate in.
This proposed inhibition of viral replication is non-specific and may affect other viruses and their replication. It may also reduce the production of harmful chemicals that help mobilize cells of the immune system that cause inflammation and damage in the brain.
It would be easy to overstretch the results; however, we can't abstract data from SIV models and say that it will surely reflect HIV-infected humans. As an example, two integrase inhibitors (from Merck and from GlaxoSmithKline) that succeeded in their proof-of-concept studies in monkeys never made it past phase I or II in human HIV studies. However, the results of this well-conducted study need to be taken seriously in regards to the potential benefit for patients with cognitive problems.
HIV-positive individuals who are not on therapy but manifest brain-related signs and symptoms should begin HAART (highly active antiretroviral therapy) without delay. Postponement of treatment can result in long-term damage and irreversible impairment in neurological functioning. The effect of antiviral drugs in reducing HIV viral load correlate highly with reduction in HIV levels in the CSF.
Antiviral drugs have been effective at slowing down or halting progression to dementia in HIV disease. Cognitive and memory problems that were once more common among individuals with HIV infection have become scarce since the emergence of HAART. From experience, however, subtle neurological problems still occur despite effective HIV therapy.
We have observed individuals on long-term therapy who have undetectable viral loads with normal or high CD4 T-cell counts who experience deterioration in their cognitive abilities, including memory, concentration and learning skills, that is out of proportion to their normal aging process. A diagnostic work-up that includes comprehensive testing of the brain and blood tests to rule out a possible opportunistic complication usually fails to show any underlying cause for a patient's cognitive deterioration.
This has been especially frustrating for physicians since there is not any proven effective way to attack this problem for our patients. A switch in treatment to antivirals with better CNS (central nervous system or brain) penetration and administering certain vitamins that are associated with improving cognitive ability have met with limited success. In these individuals, it would be potentially advantageous to have effective treatment targeted towards halting the progression in downward neurologic functioning.
Thus, in these situations where patients manifest further memory loss and deterioration in mental ability, Northstar Healthcare will begin to study these findings objectively with established cognitive testing to understand the specific changes that occur within our patients. In these patients, consideration for a trial with minocycline, to see if treatment curbs or halts their neurological deterioration, will be an option discussed after a review of findings. We will begin to collect data now, because for those individuals, we don't have the luxury of time to wait for a large institution to debate the design for a study and the years it requires to fully confirm, yea or nay, any possible benefit. The waiting may cost individuals further irreversible deterioration.
This being said, close monitoring for benefits versus side effects is needed. Long-term minocycline in patients who are infected with HIV has not been studied previously, although minocycline has been safe to use for skin problems such as acne.
As a preliminary study, there is certainly a basis here for further study in HIV-infected individuals. The investigators from Johns Hopkins should be applauded for conducting this well-designed study in macaques.
This study has other implications, not only for HIV-infected individuals, but for other neural diseases. It appears that the mechanism of action of minocycline is non-specific, so that its effect may apply to other viral infections that cause brain complications.
Additionally, the observation of minocycline's effect on lymphocyte and macrophage cultures harboring HIV provokes the possibility of examining its use in patients who harbor multi-drug HIV resistance. If other clinicians begin using minocycline in clinical practice, whether for early dementia or salvage treatment, it is hoped that objective data is collected so that we can add to our scientific understanding of this agent.
Minocycline is cheap, and generics are available; sadly this poses as an obstacle for a big-money pharmaceutical company. It makes it less likely for such a company to pump investment capital into proceeding quickly with a study and development for treatment. Who will have the resources and motivation to spend the million of dollars necessary to further our knowledge regarding minocycline's potential application for HIV or any other neural disease?
This appears to be a reputable groundbreaking study, having been published in JAMA, conducted at the prestigious Johns Hopkins University and supported by grants from the National Institutes of Health. It's tantalizing that an antibiotic, cheap and reasonably safe, may have far reaching applications for treatment of HIV and its associated stigmata of the brain. Patients should not rely, however, on this information to protect themselves from HIV infection nor its progression. Further study, perhaps years of investigation, will probably be necessary to understand these potential implications.
Daniel S. Berger, M.D., is Medical Director of Chicago's largest private HIV treatment and research center, Northstar Healthcare and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He serves as medical consultant for Positively Aware and serves on the HIV Medical Issues Committee for the Illinois AIDS Drug Assistance Program, the Board of Directors for the AIDS Foundation of Chicago and the Editorial Board of Contagion: Reports, Cases, and Commentaries in HIV and Infectious Disease Research. Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.