sections include: treatment of HIV infection, central nervous system infections, AIDS dementia complex, neuropathies, research
Acquired immune deficiency syndrome, or AIDS, was first recognized 20 years ago when a cluster of unusual infections were detected in homosexual men. Within two years of this recognition, its viral cause—now called human immunodeficiency virus type 1, or HIV—was identified, and within four years the FDA licensed a test that detects infection by this virus. Through a massive research effort, we now know a great deal about how this virus is transmitted, how it persists, and how it eventually causes fatal disease. Fortunately, treatments that are effective in suppressing HIV, and in preventing or delaying the development of AIDS, have also resulted from this research.
The primary target of this virus is the immune system, and particularly one of its components, the CD4 T lymphocyte, which is critical in orchestrating defenses against certain types of infections. The gradual loss of this system leads to vulnerability to these infections, which are rare in those with intact immunity and so are called opportunistic infections. However, infection also results in damage to different tissues by other mechanisms. As a result of both opportunistic infections and these other effects of HIV, the nervous system is frequently altered by the virus, particularly in its more advanced stage, and the resultant neurological diseases are a cause of considerable disability and suffering.
Treatment of HIV Infection
Because the disease complications of HIV ultimately relate to active HIV infection, the major approach to treatment of those who have this virus is to suppress the infection. This is now accomplished by the use of combinations of antiviral drugs, usually three or more different drugs taken several times a day. The reason several different drugs are needed is that the AIDS virus replicates very rapidly and undergoes extensive mutation, which allows the selection of strains of virus that are resistant to drugs. Current drugs target enzymes that are “coded” by the viral nucleic acid and are essential to the reproduction of new virus particles. One of these enzymes is called reverse transcriptase (RT). RT allows the nucleic acid in the virus particle, which is RNA, to produce a DNA copy that is then inserted into the target cell’s DNA (a component of the human genome), where it can serve as a template for production of new RNA to be inserted into the new virus particles. The production of DNA from RNA reverses the process normally used by the cell in its own reproduction. The first effective anti-HIV drugs were RT inhibitors. There are now two classes of these drugs and within each class there are several different drugs. The other major class of drugs inhibit a second viral enzyme, the HIV protease, which is essential for production of “mature” virus particles capable of infecting other cells. There are now also several different protease inhibitors.
Several drugs are used together to decrease the rate of virus reproduction and to make it more difficult for viable mutations to develop. Because these drugs target different enzymes or different parts of these enzymes, they are said to have synergistic, rather than simple additive, effects. When taken faithfully, these drug combinations are often remarkably effective in suppressing the virus and preventing immune dysfunction or even restoring immunity in those already damaged. However, there are also a number of problems. Because of HIV’s capacity to mutate and develop resistance and because such resistance is fostered by exposure to low levels of the antiviral drugs, patients must be very careful in adhering to medication schedules. With multiple drugs available, patients can switch to a new combination when resistance develops, but with time the various options may be exhausted. These drugs are also expensive and may have undesirable side effects in some patients. Because the DNA copy of the HIV genome discussed earlier can remain in certain long-lived lymphocytes, treatment does not eradicate infection but only suppresses viral replication. There is no cure, only the prevention or delay of progression.
Despite these difficulties, the development of combination anti-HIV therapy has restored many patients to normal or near-normal activity and well-being, and has clearly reduced the death rate. Monitoring infection and treatment now involves sophisticated tools to track the infection (by measuring the number of viral particles in the blood), its effect on the immune system (by counting the number of CD4 T lymphocytes in the blood), and even the development of drug resistance. This has all brought great hope to those infected by HIV within the developed world. Unfortunately, this cannot be said of the poorer regions of the world, such as Africa and Asia, where the great majority of the world’s infected population lives without benefit of these advances of modern biotechnology.
In the developed world, the major approach to preventing neurological complications in those infected by HIV involves suppressing HIV replication with these drugs. This has clearly reduced the incidence of these disorders. However, treatment is not successful in all, and some individuals develop neurological problems without previous awareness that they harbor HIV infection. Thus these problems have not been eliminated even in the United States.
Central Nervous System Infections
The central nervous system (CNS) includes the brain and spinal cord. While HIV renders these structures susceptible to several infections late in its course, three stand out as the most common.
- Progressive multifocal leukoencephalopathy (PML) is probably now the most common of these three central nervous system infections. PML is caused by another virus, known as JC (its name is taken from the initials of the person in whom this virus was first identified). This is a virus that infects the majority of the population but is seemingly harmless, causing no clinical disease in those with normal immunity. However, in some immunosuppressed people, including those with AIDS, it can spread to the brain and destroy the cells that manufacture myelin, the layered substance surrounding axons. This demyelination causes loss of neurological function, with particular difficulties depending on what part of the brain is infected. There is currently no specific treatment for PML, but in about one half of patients the condition may stop progressing when they are started on anti-HIV medications, which are thought to help by reversing the immunosuppression and restoring the person’s ability to fight this virus.
- Primary central nervous system lymphoma is a malignant tumor that grows and compresses the surrounding brain and may be lethal. This lymphoma also has “opportunistic” characteristics and is related to infection with Epstein- Barr virus (the virus that causes infectious mononucleosis). It is treated with radiation and formerly was usually fatal within a few months; antiviral treatment of AIDS has both reduced the frequency of this tumor and prolonged the survival of those affected.
- Cerebral toxoplasmosis involves the development of brain abscesses caused by a parasite that otherwise causes serious disease almost exclusively in newborns. While it was formerly the most common brain infection in AIDS, its incidence was reduced when sulfa drugs began to be used widely to prevent a common type of lung infection. Its incidence has been further reduced by combination anti-HIV therapy. Unlike the other two common brain disorders, cerebral toxoplasmosis can be effectively treated by antibiotics.
A weakness on one side of the body, difficulty with speech, or some other neurological anomaly may serve as a first indicator of one or another of these CNS infections. An important first step in diagnosis is usually some type of imaging of the brain, frequently magnetic resonance imaging (MRI). MRI can often reveal features that are characteristic of each of these infections (or other, less common, diseases). For instance, in PML infections, MRI can help detect any loss of myelin in white matter. In both toxoplasmosis and lymphoma, it can spot mass lesions in the brain’s cerebral cortex and deep nuclei, such as the basal ganglia.
For more certainty about the diagnosis, doctors may call for other tests. To better pin down PML, for instance, they might extract spinal fluid with a lumbar puncture (spinal tap) to test for JC virus DNA. When they suspect lymphoma, doctors usually do a biopsy to confirm the nature of the brain tumor. In the case of toxoplasmosis, the standard practice is to start a person on antibiotic therapy right away, assuming that he or she has the disorder. If the lesions get smaller, then the diagnosis was correct.
AIDS Dementia Complex
AIDS dementia complex (ADC) differs from the opportunistic infections in relating in a more fundamental way to HIV itself and to brain infection by this virus. While there remain some fundamental questions about how the brain is injured, most feel that HIV infection of macrophages in the brain causes the release of toxic chemicals that secondarily damage the essential functional elements of the brain—the neurons and other supporting cells. Thus, HIV causes a characteristic neurodegenerative disorder by triggering release of these toxins, some of which are produced as part of the host’s defenses but, in excess amounts in the brain, lead to disease. Affected patients lose their capacity to concentrate and think quickly, and, in severe cases, to remember and reason. Motor function can also be affected, so that movements are also slow and walking becomes unsteady. In the early years of the AIDS epidemic, this was a common and dreaded complication of the late stage of HIV infection. However, with the widespread use of combination anti-HIV therapy it is far less common, although it still affects some patients. The diagnosis depends on careful assessment of the patient’s abnormalities on examination and of tests that may affirm the diagnosis or suggest alternatives. These tests usually include an MRI scan and often a spinal tap.
ADC is treated with anti-HIV drugs, usually given as an ‘aggressive’ combination. Some patients, particularly those with a shorter period of dysfunction, do very well with reversal of their neurological abnormalities and return to or near their previous level of function. Others with more longstanding disease and more severe impairment may obtain more modest improvement. A variety of strategies to improve the outcome of treatment, including some aimed at interfering with the toxic processes just discussed, are under active study.
HIV can also lead to abnormalities of the peripheral nervous system, with several types of neuropathy. Indeed, one type of neuropathy is quite common in people with HIV infection and AIDS. It is referred to as a distal (because it causes symptoms in territories of the longest nerves, particularly in the feet and lower legs and sometimes in the fingers) sensory (it alters sensations, causing tingling and, sometimes, pain and loss of feeling, while largely sparing muscles so that strength remains normal) poly- (many nerves are involved so that it develops symmetrically, involving the right and left equally) neuropathy. Although the condition is not fatal, in some people it can be extremely painful and interfere with their mobility and normal life.
It has been estimated that 20 percent to 40 percent of people with HIV infection experience some degree of neuropathy, though this too may be decreasing with widespread use of antiviral therapy. Although the cause of this neuropathy remains uncertain, the leading theory is that it is an indirect consequence of the HIV infection, with mechanisms similar to those causing ADC. In other words, the virus does not injure nerve fibers directly but causes the secretion of toxins that do.
Diagnosis and Treatment
In most cases the combination of HIV infection and the characteristic complaints of the patient and findings on examination by the physician are sufficient to establish a diagnosis of distal sensory polyneuropathy. One exception is when the patient is taking certain of the anti-HIV drugs that themselves can cause a very similar neuropathy. In this case the drugs should be stopped and another drug substituted that does not cause neuropathy. If there is question about the diagnosis, or certain features are not typical, special electrodiagnostic studies that assess the function of the nerves may be helpful.
Other than management of the patient’s HIV infection, treatments aim principally at reducing pain when it is part of the neuropathy. Most effective are certain anticonvulsants (including gabapentin) or tricyclic-type antidepressants, but some patients may require opiate analgesics or other measures. While these treatments do not change the course of the neuropathy itself, they can very much help patients live with this problem. Other approaches that might be of more direct benefit in restoring the altered nerves are under study.
While major problems remain, particularly in the application of tools available in the developed world to more impoverished societies, the remarkable progress made by the intense research effort devoted to HIV and AIDS provides a stunning example of the power of modern science to understand and treat disease. Work on AIDS has set many examples that are influencing other areas of medical research and treatment, including examples applicable to neurological disease. These include the integration of the newest and most sophisticated molecular diagnostics into daily clinical care, the rational design and rapid development of new drugs, and some fundamental concepts of brain degeneration. AIDS research also provides examples of the usefulness of well-informed patients and the power of advocacy groups.
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