Neurologic Complications of HIV Infection - From Head to Toe: risk factors include viral load, cd4s

     Written for NATAP by David Alain Wohl, MD, Clinical Assistant Professor, University of North Carolina School of Medicine

"My brain! That's my second favorite organ" - Woody Allen

Soon after it enters the body HIV colonizes the brain and other nerve tissues. Within the 'compartment' of the nervous system, the virus remains, often at high concentrations and with time can lead to a spectrum of problems spanning from localized disease of the brain to distal peripheral neuropathy. At the 8th CROI in Chicago, a plenary presentation by Justin McArthur of Johns Hopkins and an entire oral session was dedicated to discussion of the neurologic complications of HIV infection. Given the hoopla regarding fusion inhibitors, structured treatment interruptions and other novel approaches to treatment, the conference organizers are to be commended for dedicating significant time to focus on problems that 20 years into the epidemic continue to plague persons living with HIV.

Peripheral Neuropathy - What we know, what we don't; risk factors; certain HIV meds

In a presentation that can only be described as elegant, Dr. McArthur reviewed the current understanding of the clinical features, pathogenesis and treatment of peripheral neuropathy. As affected patients and their clinicians know well, neuropathy appreciably reduces quality of life, limits choice of antiretroviral therapy and threatens adherence. Additionally, neuropathy accompanying HIV infection is generally under treated. Typically, neuropathy is experienced as pain and/or parasthesias (pins and needles) in the soles of both feet. The major types of peripheral neuropathy occurring in persons with HIV infection include an HIV sensory neuropathy caused by the virus itself and a similar problem that is a side effect of certain medications. In one study conducted by David Simpson, Director of the Mount Sinai Neuro-AIDS Research Center in New York, of 300 patients with HIV associated peripheral neuropathy 139 had reasons other than HIV infection to have neuropathy. These included HIV medications such as ddI, d4T and dapsone as well as other diseases and alcohol use. HIV viral load also seems to play a role in development of peripheral neuropathy as those with HIV RNA levels above 10,000 have a much higher risk (about 25% over 10 years) of being diagnosed compared to those with lower viral burdens. Other risk factors include increased age, wasting syndrome (the original wasting syndrome - not lipoatrophy), and low CD4 count.

Dr. McArthur detailed what is known about the cause of peripheral neuropathy. In series of impressive photographs, he demonstrated how the number of nerve fibers in skin biopsies of the leg was reduced in patients with neuropathy compared to controls. These images also support the hypothesis that blood macrophages are activated during HIV infection to produce substances causing inflammation and a reduction of the small nerves. These effects are not restricted to just the nerve endings but are also evident in the dorsal root ganglion near the spinal cord. It was once believed that only adults experienced the neuropathy but similar skin biopsy findings have been described in symptomatic children. How HIV drugs cause peripheral neuropathy is not clear. The 'd' drugs (d4T, ddI, ddc) are well known culprits, especially when combined with each other or hydroxyurea. Use of one of these agents alone is associated with about an 8% risk of neuropathy compared to an astounding 20% with a combination of two and 26% when ddI, d4T and hydroxyurea are combined. It is theorized that (like most anything that goes wrong with HIV treatments) mitochondrial toxicity is at work. The ability of each of the nucleoside analogues to inhibit the DNA polymerase gamma enzyme of human mitochondria in the lab correlates closely with the risk of developing neuropathy for each of these drugs. In a presentation by Bruce Brew from Australia here at the conference, peripheral neuropathy in 73 patients was strongly associated with having elevation of venous blood lactate (Abstract 9). In that study 90% of the 20 patients with d4T related peripheral neuropathy had elevated lactate levels (mean lactate = 3.16) compared to 15% of the 20 patients on d4T without neuropathy (mean lactate 1.68) and 10% of the 10 patients with HIV-related neuropathy (mean lactate = 1.8). Both lactic acidosis and neuropathy are seen more often in d4T and ddI users - adding further support for the hypothesis that these drugs may do their dirty work via mitochondrial damage.

Treatment

As far as treatment is concerned, despite neuropathy being a problem identified early in the HIV epidemic, we have a long way to go. The workhorse of neuropathy treatment has been amitriptyline, also known as Elavil (Dr. Glen Treisman, a psychiatrist at Johns Hopkins, is an advocate of using nortriptyline instead of Elavil as it is more potent and, since drug concentrations in the blood can be measured, the dose can be adjusted for each patient until a target level is reached.) Amitiptyline has been compared to acupuncture in a randomized study with no difference seen. Ditto for a comparative study of the drug versus a lidocaine derivative, mexiletine. More hopeful results were found in studies of the anticonvulsant lamotrigine and recombinant human nerve growth factor (rhNGF). The latter was found to significantly improve pain scores after 12 weeks of therapy. However, industry support for this drug has evaporated and its future appears dim (call Genentech Inc. at 650-225-1000 to share your thoughts regarding the need for rhNGF to be further developed). Clearly, more work needs to be done to study peripheral neuropathy and develop strategies to prevent and treat this complication. Challenges, however, exist including the difficulty of teasing out HIV-related from drug-induced neuropathy, the need for large numbers of patients to demonstrate treatment differences and the long-term nature of studying this disease. Dr. McArthur proposed a clever model for the rapid evaluation of neuropathy treatments in which nerve fibers in skin are depleted intentionally with capsaicin, a red pepper derived compound. The rate of recovery of these nerves in the presence of candidate therapeutic agents can be compared easily over the course of several weeks.

This is your Brain on HIV - Lots of Questions

In an oral slide session data were presented which characterized the changing epidemiology of HIV-related neurologic disease with the advent of HAART and the pathogenesis of neuro-dysfunction. The bottom line for many of these reports was that HAART helps most of the neurologic complications of HIV infection but not completely. Unfortunately, little new information regarding prevention and treatment of neurologic complications of HIV was reported.

Neurologic Disorders

A report from the Italian Register Investigative NeuroAIDS (IRINA) indicates that while the nature of HIV associated neurologic diseases has changed over time - with a decrease in all opportunistic infections of the brain - HAART recipients are not completely protected from the ravages of HIV on the central nervous system (Abstract 8). Data from 311 patients with neurologic disorders were collected from the many medical centers contributing to the registry. Among the patients, who were mostly men (70%), 62% were antiretroviral experienced and 42% were receiving HIV treatment at the time their neurologic disease was diagnosed. Median CD4 cell count was 51 cells/cu mm. Overall, the prevalence of toxoplasmosis was 27%, progressive multifocal leukoencepahlopathy (PML) 15% and cryptococcocal meningitis 13%. CMV neurologic disease and primary central nervous system lymphoma were very rare. Among the patients receiving HAART, most of the opportunistic infections occurred within 6 months of starting antiretrovirals. In those who had been on HAART for more than 6 months there was an increased prevalence of "non-determined leukoencephalopathy", an ill-defined term the investigators appear to be using to describe abnormalities of the brain seen on radiographic imaging in the presence of symptoms but of unclear etiology. If it exists, could this be an immune related phenomenon? Or is this undiagnosed PML? Hopefully, the investigators will conduct follow-up studies to better define this apparently HAART associated entity.

PML

In a retrospective Spanish study, the effect of HAART on PML in 118 patients was examined (Abstract 10). The diagnosis of PML was clinical (i.e. PCR for JC virus was not required). At diagnosis of PML the median CD4 cell count was 85/cu mm and viral load was 4.78 log10 copies/mL. Prior to the availability of HAART, the average length of survival following the diagnosis of PML was on the order of 2 to 4 months. In this cohort mean survival was 4 years. Almost half of the patients were characterized as being cured or improved. Of the 43 that did die, 3 succumbed to PML. Importantly, 44 patients received cidofovir therapy, an antiviral that has been demonstrated to improve survival in patients with PML (DeLuca A, et al. [Abstract TuPeB3128] 13th International AIDS Conference; July 9-14, 2000; Durban, South Africa.) although in a poster presented by Christine Marra here in Chicago (Abstract 596, see below) cidofovir did not improve survival in 24 patients with PML and had significant toxicity. Factors associated with survival in the Spanish study were baseline CD4 count above 100/cu mm and cidofovir therapy. Age, gender, risk group and viral load were not associated with survival. Therefore, although median survival was extended dramatically, almost a third of patients still died - usually from PML. Clearly, the protection afforded by HAART is not absolute.

AIDS Clinical Trials Group (ACTG) study 363, the cidofovir study mentioned above, evaluated the use of cidofovir at 5 mg/kg at baseline, week 1 and every 2 weeks thereafter (Abstract 596). As described, results were fairly abysmal. Of the 24 patients enrolled, five experienced protocol defined toxicities (1 proteinuria, 4 decrease in intraocular pressure). Fourteen subjects (58%) stopped therapy by week 12. At baseline 71% were receiving HAART, yet half the patients in this study died, 11 from PML and one from aspiration pneumonia. Only CD4 cell count was associated with survival. Clearly, PML is a challenging condition to treat. The limited data available suggest that HAART plus cidofovir may offer the best chance for survival but that the toxicity of cidofovir can be substantial. Lower dose and/or less frequent of administration of cidofovir is worth studying.

It is clear that HIV establishes residence in the brain soon after HIV infection, yet how the virus in the central nervous system responds to HAART is not well defined. The levels of HIV in the cerebral spinal fluid (CSF) in patients starting HAART were examined in two separate studies. Researchers from Germany compared the levels of the virus in the CSF and the blood of 38 patients, 27 with previously treated opportunistic infections, nine with HIV-related dementia and 2 with acute HIV infection (Abstract 1). In general, CSF levels of the virus were higher than those measured in blood plasma. With HAART, there tended to be a lag in clearance of HIV from the CSF relative to the blood which was most evident in those with advanced HIV infection. This slower clearance of the virus from the CSF was not correlated to levels of the drugs in the CSF or blood or genotypic resistance. In a study of the dynamics of HIV levels in the blood and CSF of patients with acute HIV infection, researchers from the University of North Carolina and Duke University obtained blood and CSF specimens from 7 patients with new HIV infection receiving HAART therapy (Abstract 3). Patients had detectable HIV RNA and/or p24 antigen but a negative HIV ELISA and no more than two positive bands on the Western blot test. Five of the six with CSF available had an abnormal CSF cell count. This was mostly represented by an increase in lymphocytes. All five patients with acute HIV had detectable virus in the CSF at baseline compared to 27/49 controls patients with chronic HIV infection who were not receiving therapy. Compared to chronically infected controls, patients with acute HIV had higher CSF levels of HIV but these tended to decrease with HAART.

CD4s & Viral Load & Neuropathy: When To Begin Therapy

(Editor's Comments: Some protease inhibitors do not enter the brain or CSF. But since HAART appeared there has been a great decline in the incidence of HIV related neurological problems, particularly dementia. Its been suggested that HAART improves immune function which in some way improves HIV related neurological problems such as dementia. Possibly HAART immune improvement affects cytokines in a positive way which in turn sets off an effective cytokine or immune response. The control of a neurological problem or the prevention of problems appears to be associated with CD4 & plasma viral load levels, so this relates to When To Begin Therapy. It's possible that deferring therapy til cd4s are low or viral load too high may increase risk for the development of neuropathy or other neurologic HIV-related disorders. Of course, the question is what cd4 count is too low and what viral load is too high so as to increase risk of neuropathy. Wohl refers to increased risk when plasma viral load is > 10,000 copies/ml.. I assume that as viral load in plasma increases and as cd4decreases risk may increase. Abstract 613 at Retrovirus reports findings seen previously, that the magnitude of plasma viral load reduction & using drugs that cross the blood brain barrier increases the magnitude of viral load reduction in the CSF. Drugs known to cross the BBB include nevirapine, efavirenz, d4T, indinavir, amprenavir, abacavir, AZT, and 3TC probably less so).

In the opening session McArthur talked about using an experimental skin biopsy procedure in helping to determine development of peripheral neuropathy and evaluating if an HIV medication was increasing neuropathy. You can read about it in previous highlight I wrote from Retrovirus. You can go to NATAP web site and access Retrovirus Highlights Section, or here is direct link to article:

http://www.natap.org/2001/feb/retroconf/neuropathy020701.htm