Suppressed HIV Virus may cause Neuropathy

Another interesting article first published in 2003, from Neurology Today (see link below) discusses what is now an accepted, if uncomfortable truth: that the longer you live with HIV, the more likely it is that you will suffer from neurological problems. It's a frightening thought that even though your viral count may be undetectable, the much-reduced virus may well be hiding in spinal fluid and negatively influencing the nervous system and the brain. The article claims that serious work was being done to investigate how much this has to do with neuropathy and other neurological problems. If any reader knows of articles relating to outcomes of this research, please use the Contact button.

It goes further to look at various treatments for neuropathic pain but these must be seen in the context of an article written in 2003. Similarly, Dr Schifitto and his group's conclusion that rates of nerve damage were dropping thanks to HAART, has been proved to be wrong over the longer term, lending more support to the theory that the virus itself plays an important role. However, even if the virus is proved to be acting as a sniper, it's difficult to see what can be done about it. Neuropathy may end up being one of the prices we have to pay for survival.

Longer Hiv-AIDS Survival Raises Likelihood of Neurological Problems
Samson, Kurt: July 2003

The dramatic impact of combination therapy against HIV/AIDS carries a neurological postscript. Even as the incidence of AIDS-related dementia declines with highly active antiretroviral therapy (HAART), researchers are concerned that longer survival may mean a steadily growing population with neurological complications.

Opportunistic infections, side effects from potent medications, and the ability of the virus - even in a diminished state - to affect the brain and central nervous system (CNS) over time mean that neurologists will be treating more and more HIV-AIDS survivors.

Scientists are gaining insight into the pathology of HIV-AIDS on the brain and CNS, but the uncertainty that marks and propels AIDS research in general also applies to neurological studies.

The growing number of people living with AIDS may be neurologically vulnerable, with the cerebrospinal fluid serving as a sanctuary or reservoir for partially suppressed HIV replication, said Ned Sacktor, MD, Assistant Professor of Neurology at Johns Hopkins University in Baltimore, MD.

In an effort to better understand and treat the neurological aspects of the disease, clinical trials are being conducted under the auspices of the National Institute of Allergy and Infectious Diseases (NIAID) through the Neurologic AIDS Research Consortium (NARC) and the AIDS Clinical Trials Group (ACTG).

HIV COMPLICATIONS

HIV infection can damage the brain and spinal cord, causing encephalitis, meningitis, nerve damage, AIDS dementia complex, painful peripheral neuropathies, behavioral changes, poor circulation, headache, and stroke. Cancers and opportunistic infections frequently seen in HIV-AIDS patients can also affect the nervous system. Neurological symptoms may be mild in the early stages of AIDS, but may become more severe as the disease progresses.

Complications include cerebral toxoplasmosis, which is a common opportunistic infection in AIDS and one that can cause ataxia, apraxia, seizures, and sensory loss. Progressive multifocal leukoencephalopathy affects the cerebrum and cerebellum, and may cause visual loss.

Some experimental treatments appear promising for neurological complications. For example, anti-dementia drugs may relieve confusion and slow mental decline while infections may be treated with more powerful antibiotics. Radiation therapy may be necessary for AIDS-related cancers in the brain or spinal cord, while HAART cocktails can reduce dementia and opportunistic infections.

STATE OF HAART

Last year Dr. Sacktor and fellow Hopkins researcher Justin C. McArthur, MPH, MBBS, Professor of Neurology, published the results of one of the largest studies of the impact of HAART on the incidence of AIDS dementia. They compared the incidence of dementia and cognitive impairment in 500 AIDS patients, half of whom developed the disease prior to the advent of HAART (J Neurovirol 2002;8(2):136-142).

We found no difference between the two groups, so it is unclear whether HAART has changed the frequency of specific cognitive abnormalities, said Dr. Sacktor. However, we are seeing patients living longer with less severe dementia, and HIV-associated cognitive impairment continues to be a major clinical problem among people with advanced infection.

Although comprehensive data are sparse, anecdotal reports suggest that HAART protects against dementia just as it does against opportunistic infections, and some studies have charted a gradual drop in dementia since HAART became available (Neurology 2001;56(2):257-260).

Estimates of the incidence of HIV-associated dementia vary, depending on the definition used, noted Dr. Sacktor. The Hopkins scientists estimate that 15 percent of HIV-infected people may develop dementia and that 30 percent may show some signs of neurological impairment (Semin Neuro 1999;19:129-150).

Dr. Sacktor acknowledged that HAART is a major advance because it can reduce the viral load in the CNS, allowing patients to live longer lives. But while cases of severe dementia decline, less advanced cases - those with chronic cognitive deficit - are rising. There is a high prevalence of dementia among patients who have had the disease for years, but we're seeing lesser severity. Where dementia once led to death in AIDS patients in three to nine months, suppression of the viral load lets patients live years longer. Co-author Dr. McArthur added that HAART also may result in metabolic disturbances that can cause nerve damage and peripheral neuropathy.

This is a moving target, he said. We anticipate an increase in neurological problems as patients live longer. There are also the toxic effects of the antiretroviral drugs on the peripheral nervous system, and drugs to treat them can't be used in some patients, notably diabetics.

He added that HAART also raises the risk of atherosclerosis in patients who experience higher cholesterol and triglyceride levels.

Some studies suggest accelerated rates of heart attacks and strokes in patients on HAART, and our techniques for cardiovascular observation and intervention are not what they should be. While patients may be put on statin therapy, and remain on it for their entire lives, these drugs can also cause muscle damage.

Giovanni Schifitto, MD, Associate Professor of Neurology at the University of Rochester Medical Center in Rochester, NY, is principal investigator for a NARC-ACTG clinical trial of transdermal selegiline in treating HIV cognitive impairment.

The trial, which began in the fall of 2001, is evaluating transdermal selegiline for treatment of HIV-related motor cognitive disorder. This study, jointly sponsored by NARC and the ACTG system, is assessing the safety and efficacy of selegiline (Deprenyl) patches, following up on an earlier, smaller study that suggested efficacy in treating AIDS dementia.

PERIPHERAL NEUROPATHIES

Finding treatments for painful peripheral neuropathies is a major research goal for NARC and ACTG. As many as 20 percent of AIDS patients suffer neuropathies, which may be exacerbated by the neurotoxicity of several drugs commonly used to treat HIV, including didanosine (ddI), zalcitabine (ddc), and stavudine (d4T).

Peripheral neuropathy develops primarily in advanced disease in patients with low CD4 counts. The viral infection itself typically causes a symmetric, painful, distal sensory neuropathy, often manifesting with the loss of sensation in the feet, and painful paresthesias in the feet and up the legs.

In a trial by consortium researcher David Simpson, MD, of Mount Sinai Medical Center in New York, the anticonvulsant lamotrigine (Lamictal) has shown promise in treating the pain of the distal sensory neuropathy (DSP).

Lamotrigine blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. In May, Dr. Simpson's team reported that lamotrigine was well tolerated and effective for HIV-associated neuropathic pain in DSP patients receiving neurotoxic antiretroviral therapy (Neurology 2003;60(9):1508-1514).

In the double-blind study, patients were randomized into two groups, those who were currently using a neurotoxic antiretroviral therapy (ART) and those who were not. Ninety-two patients received ART - (62 lamotrigine, 30 placebo) - and 135 (88 lamotrigine, 47 placebo) did not. While little difference was observed in baseline scores for average pain between lamotrigine and placebo, the drug offered greater improvement in pain intensity and also in the ratings of change by patients and clinicians.

A trial of nerve growth factor (NGF) for painful neuropathy found that NGF relieved pain, even though sensory testing did not demonstrate improved peripheral nerve function at the end of the 18-week study (Neuro-logy 2000;54:1080-1088).

Neuropathic pain is difficult to treat under the best of circumstances, noted Russell Bartt, MD, Assistant Professor of Neurology at Cook County Hospital-Rush Presbyterian St. Luke's Medical Center in Chicago, IL. He is co-chair of a pilot study launched in 2002 to evaluate the safety, toxicity, and tolerability of acetyl-L-carnitine (ALC) in treating peripheral neuropathy. It will include 36 HIV patients with mild to moderate peripheral neuropathy currently taking ddI, ddc, or d4T.

Some studies showed striking improvement in painful AIDS neuropathies, as well as histological improvement, even some nerve regeneration, with ALC, said Dr. Bartt (AIDS 2001;15(16):2207-2208; Neurology 2002;58(1):115-119). We're seeking a number of patients for the trial not only to evaluate their physical response but also to document histological changes in nerve function.

NEUROPATHY RATES DROPPING

Dr. Schifitto is lead investigator for a just-completed study that he said strongly suggests that the incidence of neuropathies has fallen since the advent of HAART. The study, by four leading research hospitals, found a significant decrease in pre- and post-HAART neuropathies among 400 HIV/AIDS patients. The results have been submitted in abstract form to the American Neurological Association for the upcoming meeting in October.

Unlike the data showing an increase in dementia cases as patients live longer on HAART, the neuropathy numbers look encouraging. But these conditions are not going away.

There are two important points, Dr. Schifitto said. First, with increased survival there is a greater incidence of neuropathies in patients receiving HAART. Second, the incidence may be lower now, but it is going to increase, as will the incidence of other chronic neurological disorders, in the next ten to twenty years.

Neurologists must be prepared to see more patients with chronic neuropathies in the future, although I suspect these will be less severe, Dr. Schifitto continued. The number of HIV-AIDS patients with severe, life-threatening dementia will be small, but we're going to see a lot more chronic cognitive impairment that will impact patients in different ways, such as limiting their ability to work at some jobs.

Dr. Schifitto agreed that the reported decrease in the incidence of severe dementia does not mean long-term survivors will not suffer cognitive impairment.

Just the opposite, he said. The longer they survive, I believe, the greater the likelihood of some degree of impairment. They will still be able to function, but they will be impaired to some degree.

In addition, even with aggressive treatment, some patients will gradually become more and more resistant to the current HAART medications, he added. In terms of numbers, it will be a catch-up game until there are alternative treatments available. We can't declare any victory here.

http://journals.lww.com/neurotodayonline/Fulltext/2003/07000/Longer_Hiv_AIDS_Survival_Raises_Likelihood_of.14.aspx