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October 1997

  1. Oral Transmission of Drug Resistant Thrush
  2. Drug-Resistant TB: Are You at Risk?
  3. Better Treatment for Cryptococcal Meningitis
  4. Standard Syphilis Treatment Effective in People with HIV
  5. Should You Be on Preventive Therapy Against TB?
  6. Help for Those with KS
  7. Should You Be Vaccinated Against Hepatitis A?
  8. More on Thalidomide
  9. Be Berry Careful
  10. Combivir® Approved

Oral Transmission of Drug Resistant Thrush

Deep kissing may transmit a hard-to-treat form of candidiasis

French researchers recently issued a warning to people with HIV: Drug-resistant thrush can be spread through oral contact -- that is, through kissing. Thrush, which your healthcare provider may call by its scientific name, candidiasis, is a common opportunistic infection in people with advanced HIV disease. This fungal infection usually occurs in the mouth or the throat, but it can also occur in the vagina. When thrush develops in the mouth and throat, it appears as white or red patches on the skin. If not treated promptly with an antifungal agent, candidiasis can make swallowing difficult and can cause nausea, changes in the way food tastes, and loss of appetite. When thrush occurs in the vagina it is commonly called a "yeast infection." Its symptoms are itching, burning, and a thick yellowish discharge.

Candidiasis, wherever it occurs, responds readily to drug therapy. Indeed, it responds so well to fluconazole (Diflucan®) that this drug has become the agent of choice to treat outbreaks of thrush and to prevent recurrent infections. Because thrush is so common in people with HIV disease, and because fluconazole is so widely used to treat this condition, some patients eventually develop thrush that is unresponsive to this drug (see "The Problem of Fluconazole-Resistant Thrush," Vol. 1, No. 3).

As a rule, this resistance develops only after patients have been on fluconazole treatment for extended periods of time, and in any case the number of people who develop hard-to-treat thrush is small: no more than 5% to 7% of all people with HIV. The number of people who pass the drug-resistant form of thrush to others is doubtless much smaller, but it appears that rare cases of transmission do occur.

Scientists at the Pasteur Institute who studied the oral flora of ten HIV-positive couples discovered the same strains of candida in each couple -- strongly suggesting that transmission had taken place between the partners. More conclusive proof that the drug-resistant form of thrush can be transmitted orally came when the French researchers took samples from the three people in the study who had never had an outbreak of thrush and had never been treated with fluconazole. All three of these individuals were found to have candida strains that were resistant to fluconazole -- but, significantly, none had disease.

What this means for you:

It should come as no surprise to us that candida strains with resistance to fluconazole can be transmitted from one HIV-positive individual to another, since we know that resistance to AZT and other antiretroviral agents can be transmitted in this way. Taken together, these findings are a powerful argument for the practice of safe sex, even between two HIV-positive partners. Unsafe sexual acts may provide some transient pleasure, but they may also provide a conduit for the transmission of drug-resistant forms of various viruses -- and the acquisition of these hard-to-treat viral strains can compound the problems of living with HIV.

Although the French investigators who issued this alert made no effort to establish the route of transmission, kissing may not be the only culprit. In theory, anyway, an HIV-positive woman with a fluconazole-resistant yeast infection could transmit a drug-resistant strain of candida to a partner during vaginal-oral sexual activity. This alert applies only to oral-oral and vaginal-oral contact between HIV-positive individuals; HIV-negative partners are at no risk of infection, and there is no need to stop kissing family and friends (see "A Kiss Is Just a Kiss," in this issue).

People with drug-resistant thrush know who they are. Most of them are being treated with an alternative to the standard dose of fluconazole. If they are not on high-dose fluconazole (800 mg per day) they are likely to be taking itraconazole (Sporanox®), ketoconazole (Nizoral®), flucyosine, or intravenous amphotericin-B. Patients who know they have thrush that is resistant to fluconazole should share this information with their sexual partners. And no one should be overly alarmed by this report, because carrying a resistant strain of candida is not the same thing as having drug-resistant thrush.

People living with HIV must behave responsibly with each and every one of their sexual partners, each and every time they have sex -- even when a partner does not insist on safety. This code of personal responsibility includes telling your partner if you have thrush that is resistant to standard drug therapy. It is possible for people with HIV to have sexual relations that are stimulating and gratifying, emotionally saturated and erotically charged, but for those with fluconazole-resistant thrush, deep kissing may be unwise. Pleasurable as the act is for both partners, it can leave both of them carrying a drug-resistant strain of candida. Fortunately, oral contact with parts of the body other than the mouth and vagina also brings pleasure, and it carries no risk of transmission.

William G. Powderly, M.D.
Washington University School of Medicine
St. Louis, MO

Drug-Resistant TB: Are You at Risk?

C.D.C. data can help identify vulnerable groups

Because their immune systems are compromised, people with HIV often fail to mount a measurable response to the only currently available clinical test that measures latent TB infection, the so-called tuberculin skin test, even when they are in fact infected with tuberculosis. As a result, healthcare providers are unable to identify a significant proportion of those who are infected with both HIV and TB.

This has become a matter of great concern since the emergence of strains of tuberculosis that are resistant to one or more of the drugs that are used to treat this increasingly prevalent opportunistic infection. Multidrug-resistant tuberculosis -- MDR-TB -- is hard to treat, rapidly progressive, and often fatal in people with HIV disease, so early identification of individuals infected with drug-resistant strains -- and aggressive treatment of their infections -- is essential (see "Guidelines for the Treatment of TB in People with HIV").

Since 1993 the C.D.C. has been collecting drug-susceptibility data on patients diagnosed with tuberculosis. Over the past four years the agency has been able to obtain susceptibility results for 89% of all patients with culture-positive TB, 92% of foreign-born patients, and 89% of patients infected with both TB and HIV.

First the good news: 97% of patients from whom drug- susceptibility results were obtained turned out to be infected with bacteria that were susceptible to at least two of the three first-line anti-TB agents (i.e., isoniazid, rifampin, and ethambutol). Now the bad news: Resistance to first-line drugs was significantly higher among HIV-positive individuals than among those uninfected with the virus. Infection rates were also higher among the foreign-born and among residents of New York City -- confirming that place of birth and place of residence are risk factors for having drug-resistant TB.

The C.D.C. notes that persons born in Mexico, Vietnam, China, Haiti, India, South Korea, and the Philippines -- all countries where tuberculosis is endemic -- accounted for 66% of the cases of drug-resistant TB seen in foreign-born individuals. HIV-infected individuals from these countries should be especially vigilant for symptoms that suggest active tuberculosis. These symptoms include: fever, night sweats, cough, shortness of breath, weight loss, and chills. If you were born in one of these countries (or one of its neighbors) and you develop one or more of these symptoms, see your doctor immediately.

New York City accounted for a staggering percentage of all cases of drug-resistant TB reported to the C.D.C.: fully 31% of all HIV-positive MDR-TB patients came from Manhattan or one of its boroughs. Accordingly, the C.D.C. warns that HIV-infected patients from New York City should consider themselves at extremely high risk for drug-resistant TB. This caution also applies to residents of New York State and the District of Columbia, because the incidence of MDR-TB is more than twice as high in these three areas than it is elsewhere in the nation.

What this means for you:

The emergence of multidrug-resistant strains of tuberculosis has vastly complicated the clinical management of TB in HIV-infected individuals. Disease progression is often rapid in such persons, and because they are highly infectious, these individuals can transmit TB to uninfected partners, care providers, and healthcare professionals. Indeed, TB is the only AIDS-related opportunistic infection that can be readily spread to uninfected individuals. Everyone who comes into close contact with TB patients needs to bear this in mind. People who look after patients with TB, especially MDR-TB, should have tuberculin skin tests on a regular basis. And people with advanced HIV disease should avoid contact with TB patients altogether whenever possible.

The key to successful treatment of TB is directly-observed therapy. DOT, the acronym given to this rigorous approach to eradicating TB, calls for the administration of all doses of anti-TB medications under the direct supervision of a care provider or health-department official. In New York City the MDR-TB case load has fallen by 44% since DOT programs were instituted by the Department of Health. In the District of Columbia, by contrast, cutbacks in funds allocated to DOT programs led to a 36% rise in the number of TB cases recorded in 1996.

Robert M. Jasmer, M.D.
UCSF School of Medicine
San Francisco General Hospital

Better Treatment for Cryptococcal Meningitis

IV amphotericin-B, followed with either Diflucan® and Sporanox®, eradicates this OI in up to 72% of treated patients

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and the AIDS Clinical Trials Group (ACTG) are shedding light on how best to treat cryptococcal meningitis in people with HIV. These groups studied more than 300 HIV-positive people during their first bouts with cryptococcal meningitis and compared two treatment regimens in two phases.

For the first two weeks of treatment, participants were given either amphotericin-B alone or amphotericin-B plus flucytosine. (Intravenous amphotericin-B is standard first-line therapy for cryptococcal meningitis.) This first phase of treatment was followed with eight weeks of therapy with either fluconazole (Diflucan®) or itraconazole (Sporanox®). After the first phase of treatment, 51% of those receiving amphotericin-B alone had negative cerebrospinal-fluid cultures, while 60% of those receiving both amphotericin-B and flucytosine had negative cultures.

At the end of the follow-up phase of the trial, 60% of the participants who were treated with itraconazole had negative cerebrospinal cultures, compared with 72% of those on fluconazole. The addition of flucytosine to IV amphotericin-B during the initial phase of treatment was judged to be beneficial. During follow-up treatment, fluconazole was somewhat preferable to itraconazole, but researchers noted that itraconazole is an effective option for patients who have developed resistance to fluconazole.

Standard Syphilis Treatment Effective in People with HIV

More aggressive therapy offers no added benefit

Unprotected sexual activity not only exposes people with HIV to reinfection with drug-resistant forms of that virus, it also exposes these individuals to other sexually-transmitted diseases, notably syphilis. Penicillin is the standard treatment for syphilis, but some have suggested that stronger treatment is advisable for people with HIV, who may be at greater risk of developing neurosyphilis -- a form of the disease that invades the central nervous system and the brain. Untreated, this form of syphilis can eventually lead to motor disturbances, blindness, and insanity. Researchers at the Centers for Disease Control and Prevention therefore compared two syphilis treatment regimens. A four-year study of 541 people with syphilis t, including 101 who had HIV, has shown that more aggressive therpay offers no added benefit.

Participants in the trial were given either penecillin alone or penecillin plus amoxicilin and probenicid to combat syphilis. As a whole, the participants who were HIV-positive responded less promtly to therapy than their HIV-negative counterparts. But whethewr the study participants had HIV or not, responses were comparable to either regimen. Given the equivalent efficacy of these two regimens -- one standard, one enhanced -- the C.D.C. says that its exiasting guidelines for syphilis treatment are suitable for most people, including those with HIV.

Should You Be on Preventive Therapy Against TB?

Not unless there is a strong chance that you are infected, the data show

The AIDS pandemic has spurred a resurgence in tuberculosis rates around the globe, and TB is the leading cause of death among HIV-infected individuals worldwide. Because people with HIV are at heightened risk of developing TB, experts have long debated the wisdom of anti-TB preventive therapy in HIV-positive individuals. Would it work, or would it simply promote the development of drug-resistant strains of TB? Would it prove cost-effective, or would it only consume resources better used elsewhere?

The results of a recent, five-year study of more than 500 people with HIV at high risk for TB suggest that preventive therapy is not necessary for those who have not been exposed to tuberculosis. Researchers at the Terry Beirn Community Programs for Clinical Research on AIDS conducted this study in HIV-positive individuals who showed no reaction to the standard skin test for TB but who had at least two risk factors for TB (such as country of origin or place of residence).

After 33 months of follow-up, three of the 260 participants who received the preventive therapy, and six of the 257 participants who got the placebo, developed TB. The researchers deemed the difference in rates to be insignificant, and they recorded no difference between the two groups in AIDS progression, mortality, or other adverse reactions.

What this means for you:

People with advanced HIV disease are already taking pills as prophylaxis against pneumocystis pneumonia, and depending on their medical history they may also be receiving prophylaxis against recurrent CMV infection, toxoplasmosis, and/or MAC. For them, the news that they do not have to add one or more anti-TB agents to their prophylactic regimen is doubtless good news.

This does not mean that HIV-positive people with a negative tuberculin skin test are necessarily at low risk for TB. It merely means that taking an anti-TB drug prophylactically does not substantially reduce that risk. We know that many people with HIV fail to respond to the skin test even though they have been exposed to tuberculosis, so a negative skin test is no guarantee that you are not harboring latent TB.

All HIV-infected individuals who come from countries with high rates of TB or who live in cities with high rates of TB should consult their care providers and have periodic tuberculin skin tests. These individuals may indeed be candidates for TB prophylaxis. As a general rule, however, it seems wisest, for now, to restrict the use of TB prophylaxis to individuals who are known to have recently come into close contact with someone who has active tuberculosis.

Robert M. Jasmer, M.D.
UCSF School of Medicine
San Francisco General Hospital

Help for Those with KS

New therapies shrink lesions, reduce pain and other symptoms

The past few months have brought encouraging news about several treatments for Kaposi's sarcoma (KS), both approved and experimental. First, the F.D.A. approved Bristol-Myers Squibb's anti-cancer drug Taxol® for use against KS. Clinical studies have demonstrated that Taxol, while it does not cure KS, shrinks the lesions associated with this skin cancer and reduces the pain caused by the lesions. Researchers report that Taxol has proven effective in reducing lesion size in some people with KS who have failed to respond to other therapies.

Next, doctors from the University of California at San Francisco reported that five patients with KS experienced improvement when they began taking the protease inhibitor ritonavir (Norvir®). In all five cases ritonavir was added to whatever combination of antiviral drugs the patients were already taking. It is impossible to say, at this point, if the response that was seen in this handful of patients was a specific to ritonavir or was yet another demonstration of the potency of the protease inhibitors as a class. It remains to be seen if ritonavir alone will prove to be a useful weapon against KS.

Finally, Allergan Ligand Retinoid Therapeutics reported promising results for its experimental KS therapy, panretin topical gel, and applied for F.D.A. approval. Allergan Ligand is also testing an oral version of panretin.

Should You Be Vaccinated Against Hepatitis A?

A recent study says the answer is yes, and the process won't harm your immune system

Because any infection can prove to be more challenging and damaging to people with compromised immune systems, people with HIV are encouraged to do what they can to avoid all infections, even the flu. Many standard vaccinations -- including the one for flu -- are recommended for HIV-infected individuals, but there have been lingering questions about the safety of certain vaccinations for this group. On the one hand, there was a feeling that vaccination against some infections was superfluous, because the risk of infection was so slight. A corollary concern was that certain vaccines, by triggering a strong immune response (as vaccines are supposed to do), might actually increase HIV activity in the process. Therefore, the possible merits of each immunization have been weighed against the perceived risks.

A new Australian study suggests that the hepatitis A vaccine is safe for people with HIV. In this study 90 men with HIV received the required two doses of the vaccine, either one month apart or six months apart, while controls in each group were given placebo. After a year, researchers found no difference in CD4 counts, progression to AIDS, or mortality between those who had been vaccinated and those who had not. The Australian team noted that fully 88% of those who were vaccinated were successfully immunized against hepatitis A, with no difference in efficacy between those who had the vaccinations one month apart and those who had them six months apart. The team consequently recommends that all people with HIV who are at risk for hepatitis A -- which can be spread through unprotected sexual contact as well as through contaminated food and water -- should be vaccinated against this common and potentially deadly viral infection.

More on Thalidomide

Effective against mouth ulcers, this once-banned drug may also combat AIDS-related wasting

Thalidomide, introduced in Europe in the 1950s, was originally prescribed as a sedative. It was withdrawn from the market in 1962 when it was found to cause phocomilia, a birth defect characterized by shortened or missing limbs in the offspring of women who took the drug while they were pregnant. The product was never approved for use in this country.

In the last issue of AIDS Care we reported that thalidomide has been warily dusted off and is showing promise as a treatment for mouth and throat ulcers in people with HIV. Research from Rockefeller University indicates that the drug's potential uses in people with HIV disease are more varied: thalidomide appears to combat AIDS-related wasting, and it may even stimulate the immune system.

In the Rockefeller study, 13 people with HIV were given thalidomide for 14 days. Participants experienced significant weight gains. On average, body weight rose almost 4% by the end of the second week of treatment. The participants in this short, small pilot study also had higher total lymphocyte and CD8 cell counts after two weeks of therapy. It remains to be seen if longer courses of thalidomide will lead to greater gains, and if those improvements will endure when treatment ends.

Be Berry Careful

Taking simple precautions can reduce your chances of getting hepatitis or cyclospora from contaminated produce

Last spring an outbreak of hepatitis A, which was linked to a shipment of berries from South America, raised concerns about the safety of imported produce. According to the C.D.C., these concerns are well-founded -- and they are not limited to hepatitis. In the first half of 1997, for example, more than 1,300 cases of cyclospora infection were reported to the C.D.C. Many of those cases could be traced to contaminated raspberries from Guatemala, where the disease is common.

Cyclospora is a nearly invisible, food- and water-borne parasite, rarely seen in the United States before last year, that can cause debilitating diarrhea, severe cramps, chills, fever, nausea, and weight loss. Americans, who have had little or no exposure to this exotic microbe, tend to have more severe symptoms than citizens of Guatemala and other Third World countries where cyclospora is endemic.

With the U.S. importing more and more produce from developing countries over the past decade, the problem of contaminated food is increasing in scope -- and it is likely to grow worse, not better, as this country buys more and more of its fresh produce overseas. (At present, the U.S. imports only 1% of its sweet corn and 2% of its lemons, but 31% of the grapes we eat are grown abroad, as is 40% of the asparagus and 97% of the mangos.) As Dr. Dan Colley, the director of the C.D.C.'s division of parasitic diseases, observes: "We eat out of everybody else's garden now."

As with other food- and water-borne infections, the danger of serious illness is much greater for the elderly, for children, and for people with weakened immune systems. The C.D.C. reports that 22 people were hospitalized last summer for severe dehydration due to cyclospora infection.

The problem has left cautious people with HIV looking at produce suspiciously. To avoid cyclospora infection, the C.D.C. recommends that you treat produce here as carefully as you would treat it on a foreign trip. All raw fruits and vegetables should be washed thoroughly, and you may want to avoid produce from developing countries. If your CD4 count is below 100, you might want to take the additional precaution of avoiding salads and other raw vegetables and fruits at salad bars, restaurants, and other places where the produce may not have been well washed.

Combivir® Approved
The F.D.A. has just approved the first two-in-one pill for antiretroviral therapy. As its name suggests, Combivir® combines two widely prescribed antiretroviral agents, AZT and 3TC, in a single tablet. These two drugs are routinely prescribed together because the addition of 3TC to an AZT-containing regimen results in the reversal of high-level resistance to AZT and leads to more durable suppression of viral load. The particular advantage of Combivir, which is now on pharmacy shelves, is that it allows patients to take fewer pills -- two tablets a day, instead of the eight pills per day that patients assigned AZT and 3TC must take. This simplified dosing will make it easier for people with HIV who are taking these two drugs to remain compliant with their daily pill-taking schedule.

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This article was provided by San Francisco General Hospital. It is a part of the publication AIDS Care.