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Cruising the Internet Columns

Each month the International Association of Physicians in AIDS Care reviews and responds to HIV/AIDS-related queries on the Internet. The responses are written by internationally acknowledged experts in the applicable disciplines of HIV disease management. Here is a selection of the inquiries and responses from the past months.

July '96

The scoop on HIV mutations

Q. I heard a talk by Robert Gallo the other day in which he said that each HIV base mutated "several times per day." While this sounds like hyperbole, I understand that the mutation rate is very high, and this fact has been cited by some as the reason that the immune system has difficulty fighting HIV. Could someone point me toward a quantitative analysis of the mutation rate in HIV?

A. Calculations are simple, but they don't tell the whole story. Current estimates1-3 are that some 109 cells are infected every day by HIV in an infected individual and survive for 1-2 days, releasing virus that goes on to infect new cells. Since the mutation rate has been estimated at 3 x 10-5 per base per genome per replication cycle4 (on average), each and every possible single base mutation appears in the population some 30,000 times each day.

Why isn't this the whole story? Because this feature alone does not explain the unusual properties of HIV infection. All RNA viruses, not only retroviruses, but other familiar viruses like influenza, common cold viruses, polio-virus, and many others have similar mutation rates (in the range of 10-5 to 10-4) and can replicate to similar population sizes. Infection with these viruses, however, is readily handled by the immune system and the virus is eliminated within a fairly short time. Thus, there is nothing inherent in high mutation rates, rapid replication and large population sizes that the immune system cannot deal with, and we must look elsewhere for the special features of HIV that allow it to persist for many years as a stable, steady state in the face of a competent immune response. Although there is good evidence that immune escape variants do occur in HIV infection, there is considerable debate among workers in the field as to their importance to the overall course of infection. My own opinion is that the situation would not be very different if they did not occur at all, but the issue still awaits a critical experimental test. What is it about HIV that makes it so different and so able to mount very long-term persistent infection? There are several possibilities, themselves not mutually exclusive:

  1. The nature of the target cell (CD4+ cells) and the site of replication (lymphoid tissue);
  2. The "phased" nature of the replication cycle, which is divided into early and late events, possibly allowing a measure of protection from the cellular immune system;
  3. The structure of the envelope glycoproteins (gp120 plus gp41) may hide it from the immune system perhaps by coating their surface with a layer of carbohydrate, and thus making the key protein components essentially invisible.5

Although genetic variation may or may not be necessary for persistent virus replication, it has one extremely important consequence: resistance to antiviral therapy. So far, the virus has always been able to generate mutants making it resistant to all therapies attempted. The problem is that not only are many mutants generated each day, but (since replication is sequential), they accumulate in the population so that large numbers of even multiply-resistant viruses can be already present in the population even before therapy starts. 6

To date, the only antiviral therapies that give promise of complete long term suppression of virus replication are those which require a half-dozen or more mutations simultaneous in the virus genome for resistance. Even with these therapies, the risk of resistance is always present. If, for example, the dose of drug is reduced, then preexisting mutants with fewer mutations will be allowed to grow and evolve to greater resistance. Indeed, were it not for the extensive genetic variation exhibited by HIV, infection by this virus would have long ago become a manageable problem, at least in countries sufficiently wealthy to afford therapy. -- John M. Coffin, PhD

John M. Coffin, PhD, is professor of molecular biology and microbiology at Tufts University School of Medicine, Boston, Massachusetts.

References

  1. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV infection. Nature 1995;373:123-126.
  2. Wei X, Ghosh S, Taylor, ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, Saag MS, Shaw GM. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995;373:117-122.
  3. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996;271:1582-1586.
  4. Mansky LM,Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995;69:5087-5094.
  5. Moore JP, Ho DD. HIV-1 neutralization: the consequences of viral adaptation to growth on transformed T cells. AIDS 1995;9 (supl A): S117-S136
  6. Coffin JM. HIV replication dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483-488.

May '96

Children's use of protease drugs

Q. We have an adopted child who was HIV infected at birth. Our understanding is that protease inhibitors are the way to go in combination with nucleoside analogs. The problem is that she has been on AZT for eight years, having been the first baby in the nation to start therapy at eight weeks old. We are finding that this disqualifies her from almost all other studies, particularly those using protease inhibitors. Her doctor says protease inhibitors haven't been "proven" in children, but can give me no examples of drugs that worked in adults but not in children. She has been essentially asymptomatic until now, but she has experienced some liver problems of late and we are more worried about her.

A. Regarding pediatrics, there are no data yet on dosing in children for any of the protease inhibitors. However, Abbott is working with the NIH on this and dosing recommendations will follow shortly. The issue is the immature liver. As these drugs are exclusively metabolized by it, one has to determine what doses will be both effective and safe for children.

When these data are available, this child should be switched to a new nucleoside combination (d4T and 3TC) and start ritonavir (it comes in a liquid which makes it easier to give to children). I am concerned about the "liver problems." The parents should aggressively consult their doctors and find out the nature of the liver problems. I hope it will not preclude the use of protease inhibitors.

Martin Markowitz, MD, is a staff investigator at the Aaron Diamond AIDS Research Center and assistant professor of medicine at New York University School of Medicine.

Healing and HIV

Q. Is there any correlation know between a fracture which heals very poorly and HIV infection?

A. There is very little published experience on wound healing and HIV infection. Early in the epidemic there were anecdotal reports and a clinical impression that wound healing was delayed in patients with HIV infection, especially those with AIDS, which led to suggestions in the surgical literature that more conservative approaches be taken to patients with AIDS who develop problems where surgery might be indicated. However, with increasing experience it appears that this initial impression is erroneous, particularly for HIV-positive patients with higher CD4+ counts who seem to have no greater risk of delayed healing or wound infections than HIV-negative patients.

It may be a little different for patients with more advanced disease as there are at least two situations where some literature does suggest some delay in wound healing-oral surgery (eg, tooth extraction) and anorectal surgery. Both are situations where infection can easily follow surgery and the increased risk of infection may be the primary problem. Even for these situations, however, the literature is conflicting and there are some papers suggesting no increased risk.

I am not aware on any published experience in the orthopedic literature specifically addressing fractures. From a clinical perspective, if there is delayed healing of a fracture, I would be most worried about infection. If the patient in question had more advanced HIV infection, then the possibility of an unusual or opportunistic pathogen should also be considered, and biopsies should be performed to determine if infection is indeed causing non-union.

William Powderly, MD, FRCPI, is Associate Professor of Medicine and Co-Director of the Division of Infectious Diseases at Washington University School of Medicine, St. Louis, Missouri.

Antacids and drug absorption

Q. Given Pepto Bismol's GI "coating" action, is there any danger of its use decreasing the absorption of antiretroviral drugs? I'm concerned about the protease inhibitors, especially saquinavir. What about other antacids, simethicone, etc?

A. Saquinavir, ritonavir and nelfinavir are all taken with food. Therefore, one should not need to coadminister these medications with Pepto Bismol or any of the liquid antacids. These agents are relatively short-acting; therefore one should not be concerned about taking these drugs between dosing intervals. Indinavir is taken on an empty stomach, therefore, the dose should not be taken with Pepto Bismol or other over-the-counter antacids. Remember, both Prevacid and Prilosec, both antiulcer drugs should not be coadministered with ritonavir. In addition, it is a good idea to avoid these two drugs if one is taking indinavir or nelfinavir as well. Cimeti-dine may increase ritonavir levels due to metabolic inhibition, and an alternative is best used if one is on ritonavir. The bottom line is, if the protease inhibitors are taken as directed, one will get optimal results. One may take Pepto Bismol, liquid antacids, or simethicone between dosing intervals.
-Martin Markowitz, MD.

When to start antivirals after seroconversion?

Q.After experiencing flu-like and cold-like symptoms for two months, I had an HIV test and tested positive. I had tested negative two years before. At the time I got my results my T cells were 699. One month later my viral load was 120,000. I think I may have been infected within the last four or five months. I would think that if this is so, my T cells should be higher and my viral load lower. Can these numbers reflect an initial flareup related to seroconversion? I thought acute symptoms only lasted a couple of weeks. The numbers seem to indicate that I should start antiviral therapy, but I'm hesitant to do that if the numbers are only due to seroconversion and might look better soon.

A. Following exposure to HIV, approximately 80 percent of individuals will experience a "primary viral syndrome," which occurs two to eight weeks after exposure, reflects infection with HIV as the immune system responds in an attempt to contain the virus, and may produce flu-like symptoms, such as fatigue, malaise, fever, cold symptoms, myalgias, arthralgias etc. The syndrome can last from days to months with lingering symptoms, such as fatigue, cough, and rhinitis. Thereafter, the HIV antibody tests, ELISA and Western Blot, turn positive (seroconversion) in 80 percent of individuals within 89 days, but can take as long as six months to become reactive to confirm infection by HIV.

In the first six to 12 months after becoming infected with HIV, the CD4+ helper lymphocytes (T4 cells) will decline. Depending on the laboratory used, normal values in HIV negative individuals are as follows: CD4+ percent, 31 percent or greater; CD4+ count, 364-1500. It is not unusual to see these values drop significantly during this first year (AIDS-related infections have rarely been documented to occur during this time), but, in most individuals, these immune cells rise to normal levels again, although to levels below those prior to seroconversion. A CD4+ count of 699 is normal. Many physicians prefer to more accurately follow the CD4+ percent, since the variation is much smaller than that of CD4+ cells, that is, CD4+ lymphocyte numbers can vary 50 percent above or below the average depending upon the number of white blood cells (WBC) and lymphocyte percentage which can be affected by the time of day blood is drawn, infections, stress, exercise, medications, sunburn, time between blood collection and analysis, and other factors.

Medication prophylaxes against AIDS-related infections are usually unnecessary with a CD4+ percent above 15-20 percent. And CD4+ numbers will naturally decline in the first several years of HIV infection as the WBC count declines and the immune system mounts its unique responses against the chronic viral infection.

Immediately after infection with HIV, the viral load, as measured by the HIV RNA PCR test (number of copies of HIV RNA/ml), will rise rapidly, as will the HIV p24 antigen, another marker used to monitor HIV replication. After six to 12 months, these values should drop markedly and may become undetectable. Recent studies have shown that a viral load should ideally be maintained below 10,000 copies HIV RNA/ml to minimize immunosuppression and risk for development of AIDS-related infections. The values presented here do not "indicate that antiviral therapy should be started." Many researchers do believe that individuals may benefit by initiating antiviral therapy as early as possible, such as immediately after seroconversion. Studies, however, have not proven this approach to be clinically beneficial.

Because it is well-documented that HIV can develop resistance to all of the currently available anti-HIV therapies, especially when used as monotherapy, most clinicians base their decision to begin antiviral therapies upon serial determinations of the viral load (for example, if it rises consistently above 10,000-50,000 copies) and CD4+ lymphocyte analyses (eg, if the CD4+ percent and CD4+ count are confirmed to be declining), as well as the development of clinical symptoms (such as shingles, thrush, or leukoplakia).

Gary Blick, MD, is the medical director of Blick Medical Associates, Greenwich, Connecticut.
Our e-mail address: iapac@aol.com

April '96

Brown teeth?

Q. A friend of mine told me that he was using Peridex mouthwash for his thrush, which worked well. I asked my doctor for a prescription, but when I gargled, my teeth started turning brown. My friend never has this problem. The thrush is gone, but what can I do about the stains on my teeth?

A. Chlorhexidine gluconate 0.12 percent is approved in the United States as an antibacterial oral rinse. This mouthrinse is sold under the trade names of Peridex, by Procter & Gamble, and Perigard, by Colgate. Chlorhexidine gluconate 0.12 percent is a prescription medication used as a mouthrinse (swish and spit out) for 30 seconds, 0.5 oz or one tablespoon twice daily. Several studies have evaluated the efficacy of this oral rinse as prophylaxis and treatment for thrush (oral candidiasis). Studies in patients undergoing bone marrow transplants showed that rinses with chlorhexidine gluconate 0.12 percent prior to and during induction of immune suppression reduced the subsequent incidence of oral candidiasis. Chlorhexidine gluconate 0.12 percent oral rinses may also be useful to treat existing oral candidiasis in patients with HIV disease and slight immune suppression. When the immune system gets severely depressed this topical rinse is not very effective. However, it may be instituted as maintenance therapy for patients that have successfully been treated with approved antifungal medications. As such, the mouthrinse is instituted on a regular daily schedule. There have been some side effects associated with this oral rinse. Foremost, in individuals with a tendency of getting staining on their teeth, from tobacco use, coffee, tea, etc, this oral rinse may produce profound staining. This may not occur in individuals without usual problems of staining. The staining can easily be removed with a professional cleaning. Some changes in taste sensation have also been reported. This problem can be alleviated by rinsing the mouth with water after using the chlorhexidine mouthrinse.

Lastly, both Peridex and Perigard contain 11-12 percent alcohol. This may pose a problem for individuals who cannot tolerate or have a history of abusing alcohol.

Michael Glick, DMD, is associate professor and director of the Infectious Disease Program, Department of Oral Medicine, at the University of Pennsylvania School of Dental Medicine.

Laser treatment for KS lesions

Q. Does anyone know about the use of lasers for KS skin lesions? I recently saw a news piece about using lasers for the removal of birth marks. It worked by decreasing the size of capillaries. Any information would be appreciated.

A. Treatment of cutaneous lesions of Kaposi's sarcoma is important primarily for cosmesis but occasionally is indicated because there may be interference with vision or other functions. Commonly used topical therapies include intralesional injections of vinblastine, liquid nitrogen cryosurgery, and local radiation.

Several lasers specific for vascular lesions have been developed over recent years. Doctors have asked whether these would be useful for treatment of Kaposi's sarcoma.

In a few pilot studies that have been conducted informally, these lasers have not been found to be highly successful in treatment of these lesions. The main reason for this is that even though the lesions are of vascular differentiation, they are not comprised of normal blood vessels containing erythrocytes. There are numerous erythrocytes in lesions which causes the reddish to purple color but most of them are outside vascular spaces. Furthermore, there are abundant spindle cells which do not preferentially absorb the laser light. Thus, at this point, laser therapy is not considered to be an effective form of therapy for cutaneous Kaposi's sarcoma and is not as useful as liquid nitrogen cryotherapy or intralesional chemotherapy.

Clay J. Cockerell, MD, is associate professor of dermatology and pathology and director of dermatopathology, University of Texas Southwestern Medical Center, Dallas.

March '96

Protease info

Q. I've been reading a lot of stories on the Abbott protease inhibitor. I have two questions. First, does the Abbott drug also help treat opportunistic infections? Don't most people die from opportunistic infections? Second, I'm trying to compare he Abbott protease inhibitor with the Merck protease inhibitor. And what is the relationship between a drop in viral load and survival?

A. First, [Abbott's] ritonavir is an antiviral. It directly treats HIV-1 infection. It does not treat opportunistic infections. However, the immunologic benefit of control of ongoing viral replication is improved survival of immune cells which translates into immunologic benefit. Therefore, a direct benefit of treating the virus is an improved immune system, which translates into fewer opportunistic infections. Remember, these infections are called opportunistic because they need a weakened host to do their damage.

As to the second question, there have been no head-on comparisons between the Merck compound, indinavir, and ritonavir. In different trials and different patient populations it would appear that the virologic benefit and immunologic benefit of the drugs are comparable. Viral load is a measure of the number of infected T cells in an HIV-infected individual. Persons with a high viral load are producing many infected cells which are turning over quickly. Reduction in this level improves the immune condition of the host. Therefore, for people with far advanced HIV disease who are at high risk of death, a reduction in viral load can improve survival by providing immune benefits. In earlier stage subjects, sustained reductions of viral load will likely prove beneficial.

Martin Markowitz, MD, is a Staff Investigator at the Aaron Diamond AIDS Research Center and Assistant Professor of Medicine at New York University School of Medicine.

Vitamin C?

Q. I was wondering if someone could summarize the current scientific opinions on the effect of vitamin C on the immune system. For the last three weeks or so I have been taking large doses (2000+ mg/day) of C to combat a cold. And now I find I have shingles. Shingles is a remanifestation of chickenpox; the doctor said it is normally brought on when you are rundown or tired, ie, your immune system isn't running very well. The trouble is, I've been sitting round doing nothing for about the past two months (university holidays), and didn't really party to excess. I remember reading a post in a drugs newsgroup from the creator of this group, which said that when he stopped taking antioxidants, his T-cell count rose... so I'm wondering if in fact vitamin C is responsible for the decline in my immune system's ability to fight the chickenpox/shingles virus. Comments? -Russell

A. Observations on sailors with limited access to fresh vegetables and fruits and development of scurvy established the essential nature of vitamin C for humans. Extensive studies in animals, particularly in guinea pigs, have documented that vitamin C (ascorbic acid) is important for maintenance of optimum immunity. This is specially true for phagocytic function; for example, those with low levels of vitamin C have reduced mobility and bacterial killing capacity of neutrophils and macrophages. This vitamin is also important for cell-mediated immunity, but its role in antibody production is questionable.

Additional vitamin C has been suggested for those who smoke; their blood levels of ascorbate are lower than nonsmokers', and reduced intake correlates with poor lung function. Another group with greater needs for vitamin C is the elderly, many of whom have inadequate intake of fresh vegetables and fruits and consequently decreased blood levels of vitamin C. Ensuring an adequate intake of vitamin C reduces the risk of senile cataracts in old age.

To answer the specific problem posed by Russell, whereas modest amounts of vitamin C are essential and perhaps beneficial, megadoses may be associated with some side effects, including increased gastric acidity, urinary irritation, and kidney stones. Consumption of more than 2 grams of vitamin C per day has been associated with slightly reduced immune responses, including phagocyte movement and function. In the light of these observations, it is possible that the complication of shingles may have resulted from dosing with large amounts of vitamin C. Of course, one cannot prove a cause and effect relationship in this instance. We do know that megadoses of other nutrients such as zinc, iron, and vitamin A can impair selected immune responses, thereby raising the potential for infection. These observations and Russell's case history emphasize the maxim that in the field of diet and nutrition, balance and moderation are the keys to optimum health.

R.K. Chandra, MD, is Professor of Pediatric Medicine and Biochemistry at the Memorial University of Newfoundland, Canada and Director of Immunology at the Dr. Charles A. Janeway Child Health Centre.

Feb. 96

What's cachexia?

Q. Can someone provide a good clinical definition of cachexia? Webster's Collegiate describes it as a general physical wasting and malnutrition "usually" associated with chronic disease. Is there a specific "physiological" mechanism associated with HIV infection and/or immune suppression to which cachexia is attributed? If not, how is it distinguished from weight loss or malnutrition caused by other factors (such as appetite suppression or diarrhea due to drug side effects, poverty, etc.)?

A. Cachexia is derived from the Greek words kakos (bad) and hexis (body habitus). "Consumption" was a colloquialism that described cachexia, most notably in fatal cases of tuberculosis. In present usage, it refers to anyone who is uncomfortably skinny. In fact, cachexia is quite different from starvation, in that the metabolic adaptations to reduce protein losses, typical of starvation, do not occur.

The definition is correct in that it usually is associated with chronic disease. The key word is chronic. Cachexia is characterized by rapid depletion of the body's protein, particularly in skeletal muscle, with less rapid loss of fat. The immune response has high requirements for protein and calories. in addition, the inflammatory process, the so-called acute phase response, produces very large quantities of protein to help clear and replace dead material. The essential amino acids to support this response come from the skeletal muscles, since the body has no storage repository for protein. When the injury is acute or self-limited, the changes reverse, and skeletal muscle protein is depleted. When the injurious process is either repetitive or chronic, the degree of skeletal muscle depletion becomes severe, and may even become life-threatening. Classic descriptions note sallow skin, rough mucous membrane, generalized muscle atrophy, dependent edema, anemia, etc.

Donald Kotler, MD, is Associate Professor of Medicine at Columbia University College of Physicians and Surgeons and Director of GI Immunology at St. Luke's-Roosevelt Hospital in New York City.

Special benefit in healthy gums?

Q. What would be the advantages, aside from the obvious ones, for people with HIV/AIDS to keep their gums in a very healthy state? Would it reduce the probability of AIDS developing or minimize the disease if the gums are kept healthy? The obvious benefits are, fewer visits would be required for cleaning the teeth and gums. There would be no bleeding to deal with, lessening the chance of transmitting HIV.

A. This is a very interesting query with several responses: First and foremost, this is a quality-of-life issue. It is of utmost importance for individuals with chronic illnesses to feel good about their health, which is not necessarily directly related to their disease. This has never been more true than with regards to oral health. Most patients feel physically better after a dental hygiene cleaning and polish of their teeth. As HIV replication is partially dependent on immune stimulation, any elimination of possible sources of infection, such as that seen in periodontal disease, is ultimately beneficial. Thus, reduction of oral bacterial load will potentially reduce immune stimulation. Normal bacterial pathogens associated with the periodontium can stimulate growth of different lesions found on the gums. For instance, gingival Kaposi's sarcoma lesions have been shown to partially regress after scaling and rootplaning, ie, removal of bacterial pathogens of underlying tissues. Recent studies have indicated presence of subgingival Candida infection. It has even been speculated that subgingival Candida is a potential reservoir for oral candidiasis. Obviously, if this is true, clean gums will reduce the incidence of such an occurrence.

Lastly, periodontal disease may manifest differently in immune suppressed individuals. Common clinical manifestations found in healthy individuals can have a severe course and even have to be treated differently. These complications can be minimized if immunosuppressed persons regularly cleanse their gums.

Regarding the possible increased chance of transmitting HIV by individuals with active bleeding secondary to periodontal disease, this has never been documented. On the contrary, studies have shown that even in patients with gingival bleeding, a very low level of infectious virus can be found in saliva. This is most probably due to anti-HIV proteins found in saliva.

Michael Glick, DMD, is Associate Professor and Director of the Infectious Disease Program, Department of Oral Medicine at the University of Pennsylvania School of Dental Medicine.

Ritonavir interactions

Q. Is there anyone who can explain why the Abbott protease inhibitor, ritonavir (Norvir), has so many drug interaction restrictions? Patients cannot take rifabutin, ketoconazole or fluconazole (Mycobutin, Nizoral, or Diflucan, respectively). Why are the other protease inhibitors (such as Roche's saquinavir or Merck's indinavir) not restricted?

A. Ritonavir binds to and completely inhibits a specific liver enzyme which is required to metabolize a long list of drugs. In the presence of ritonavir the levels of the forbidden drugs become very high, thus increasing the likelihood of drug toxicity. Therefore a sedative such as Versed in the "usual" dose could result in respiratory depression or death if ritonavir is given simultaneously. Similarly, rifabutin, known to cause hepatitis, may do so in the presence of ritonavir.

The concern over antihistamines stems from the reported interaction between these drugs (Seldane, Hismanal) and the macrolide antibiotics (erythromycin) which similarly decrease the metabolism of the antihistamines. Life-threatening cardiac arrythmia and death have been reported in persons treated with erythromycin and Seldane. Thus the need to avoid certain drugs when using ritonavir. These drug interactions are theoretical. No fatalities or life threatening toxicities associated with ritonavir exposure have been attributable to these interactions. However, the warning should not be taken lightly, and individuals should be aware of the potential risks. Although the other protease inhibitors may compete for metabolism with similar drugs, and some potentiation may exist, the degree of binding and subsequent inhibition of the specific liver enzyme with ritonavir is greatest and the potential for significant drug interactions is greatest. Finally, although at present this seems to be a disadvantage of ritonavir, this quality may allow for a favorable interaction between it and other protease inhibitors. It is critical to state that concomitant use of ritonavir with other protease inhibitors is strongly discouraged until dosing issues are determined.

Martin Markowitz, MD, is a Staff Investigator at the Aaron Diamond AIDS Research Center and Assistant Professor of Medicine at New York University School of Medicine.

Aspergillus aspects

Q. My doctor tells me that a cavity has developed in my chest, from which they took samples and found evidence of a mold or fungal agent called Aspergillus. I can't find any information on Aspergillus. Does anyone know of any sources of info?

A. Aspergillus represents a family of molds that are ubiquitous in the environment, but rarely cause infection in persons with normal host defenses. Aspergillosis is increasingly recognized as a late complication of advanced HIV disease, although it is still an unusual infection. Most cases described occur at very low CD4+ counts, usually in the context of other risk factors for Aspergillus infection such as neutropenia, steroid use, alcoholism, marijuana use, prolonged antibacterial therapy or malignancy. Most patients initially present with pulmonary disease. Although cough and fever may be presenting symptoms, infection is usually first diagnosed by chest X-ray. The usual radiographic patterns are of progressive cavitatory pneumonitis or diffuse infiltrates. Obstructive bronchial lesions and necrotizing tracheitis have also been described. Aspergillus may spread to other organs or start in the brain and sinuses usually causing focal central nervous system signs, or mental status changes. Disseminated aspergillosis is usually fatal (especially if the brain is involved), although patients with more focal disease may respond to therapy. The usual treatment is amphotericin B (at doses of at least 1.0 mg/kg/day) which has to be given intravenously. The major problem with amphotericin B at this dosage is nephrotoxicity (which may be a particular issue if patients also require therapy with foscarnet or pentamidine). Recently the FDA approved a liposomal formulation of amphotericin B for patients with aspergillosis who fail or develop toxicity with regular amphotericin B. The liposomal drug is clearly less toxic but is also very costly, (the cost of a daily dosage is about $400). Itraconazole, 400 mg daily, may be also useful for patients intolerant of amphotericin B and for long-term suppression. It has the advantage of being given by mouth. In trials, itraconazole was least effective in aspergillosis in patients with AIDS, which may be partially explained by problems with absorption. If itraconazole is used, drug levels must be checked to verify that the drug is being absorbed.

William Powderly, MD, FRCPI, is Associate Professor of Medicine and Co-Director of the Division of Infectious Diseases at Washington University School of Medicine, St. Louis, Missouri.




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