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Neuropathogenic Manifestations of HIV Infection and Its Therapy: report from CROI
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Written by Justin C. McArthur, MBBS, MPH, Johns Hopkins University Medical School
11th Annual Retrovirus Conference
Feb 8-11, 2004, San Francisco
Source: www.medscape.com
Since the introduction of potent combination antiretroviral regimens in the 1990s, there have been significant declines in the incidence rates of both HIV-associated dementia (HIV-D) and central nervous system (CNS) opportunistic infections among HIV-infected patients. Highly active antiretroviral therapy (HAART) regimens have improved survival in HIV/AIDS, and have led to decreases of 40% to 50% in the incidence of HIV-D. Nonetheless, HIV-D remains the most common cause of dementia worldwide in persons under the age of 40, and recent studies have shown that HIV-D and its less severe form, minor cognitive-motor disorder, remain very prevalent among HIV-infected individuals with CD4+ cell counts < 200 cells/mcL, with an approximate combined prevalence of 30%. The temporal progression of HIV-D appears to have been altered by HAART, with most patients now presenting with less severe or attenuated forms of dementia, and disease is slowly progressive or even reversible with therapy. No treatments, except HAART, have proven useful for HIV-D.
HIV-related sensory neuropathies (HIV-SN) are presently the most common neurologic disorders associated with AIDS, and include a length-dependent sensory neuropathy triggered by HIV itself (distal sensory polyneuropathy, or DSP) and peripheral nerve injury associated with the use of specific nucleoside agents (antiretroviral toxic neuropathy, or ATN). The incidence of neuropathies in advanced HIV/AIDS exceeds 20% annually, and is thought to be higher among patients with prolonged exposure to neurotoxic antiretroviral drugs.
Thus HIV-D and HIV-SN will develop in a significant proportion of individuals with HIV/AIDS, affecting function, quality of life, and medication adherence. Furthermore, infected macrophages within the brain may represent a sequestered reservoir of incompletely suppressed HIV. Aberrant immune activation and oxidative stress within the CNS and peripheral nervous system (PNS) play a major role in the development of these disorders, yet we know little about the genetic determinants of dementia or neuropathy.
Several presentations and posters addressed some of the major unanswered questions in neuro-AIDS:
- What are the latest trends in the epidemiology of neurologic diseases?
- What are the latest clues to the pathophysiologic mechanisms underlying dementia and sensory neuropathies?
- What are the predictors or determinants for these disorders, and what are the most precise diagnostic studies for their early recognition?
- What treatments have been proven effective, and what clinical trials are under way?
- How will neurologic complications of HIV infection and its therapy affect the developing world as antiretroviral treatment initiatives roll out?
At Monday's Neuropathogenesis session, several presenters reviewed key issues related to sensory neuropathies:
- David Simpson, MD,[1] of the Mount Sinai School of Medicine in New York delivered a mini-lecture on peripheral neuropathy associated with HIV infection and antiretroviral therapy.
- The diagnosis of sensory neuropathies can be complicated by confounding illnesses, eg, diabetes mellitus, alcohol abuse, and vitamin deficiency. Recent studies have demonstrated that up to 71% of neurologist-confirmed cases of DSP or ATN are not recognized by HIV clinicians. Sensitive and specific screening measures have been developed and tested within the AIDS Clinical Trials Group (ACTG); for example, the Brief Peripheral Neuropathy Screening Instrument has been validated with a sensitivity of 46% and specificity of 91% against a neurologist's examination.[2]
- Despite observations that hepatitis C may be associated with cognitive dysfunction and sensory neuropathies of various types, to date there has been no convincing evidence that hepatitis C virus (HCV) accelerates or triggers sensory neuropathies in coinfected individuals. In fact, in a cohort study based in Baltimore and Melbourne, Australia, there was no added effect of HCV coinfection on either the development of sensory neuropathies or the morphology of epidermal nerve fibers.[3]
- The pathophysiology of the sensory neuropathies remains enigmatic, although it appears more convincing that HIV proteins may have a specific toxicity within the nerves. One study detected HIV DNA in the peroneal nerves of 7 of 12 subjects, but HIV RNA was detected in only 1 subject, suggesting that viral replication is limited in the PNS.[4] In the same study, however, in vitro experiments with recombinant viruses derived from those found in the nerves were discovered to damage the processes of the neurons. This suggests that HIV may produce toxicity within the peripheral nerves without direct infection. This line of work was extended in a separate study,[5] which demonstrated that the HIV envelope glycoprotein gp120 is neurotoxic in picomolar concentrations, and produces programmed cell death (apoptosis) and a dying-back of the neuronal processes.
- Finally, with respect to treatment, Dr. Simpson reviewed recent trials of symptomatic pain-modifying treatments, and confirmed the potential usefulness of the anticonvulsant lamotrigine for ATN. Other agents under clinical investigation in the United States include: a novel regenerative and analgesic agent, Prosaptide (ACTG5180), and a placebo-controlled trial of a high-concentration capsaicin patch, Capreve.
References
- Simpson D. Peripheral neuropathy associated with HIV and ARV: Update on diagnosis and management. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 34.
- Ellis R, Robertson K, Moo L, et al. NARC007: Clinical validation of the AATCG NeuroScreen. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 493.
- McArthur JC, Creighton J, Skolasky R, et al. Risk factors and determinants for HIV-associated sensory neuropathies: Is hepatitis C a modifier? Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 27.
- Jones G, Zhu Y, McArthur JC, et al. Peripheral nerve-derived HIV-1 is both CXCR4 and CCR5 dependent and reduces neurite outgrowth in dorsal root ganglia cultures. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 465.
- Keswani S, Polley M, Hoke A. Nociceptive neurons are particularly vulnerable to gp120 neurotoxicity. Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 463.
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