Opportunistic Infections: They're Still Here
When I first got involved in HIV/AIDS treatment education and advocacy work about ten years ago, more than 40,000 people were dying of AIDS every year in this country, compared to the 16,000 or so deaths reported annually today. In an attempt to find my own niche among the brilliant minds and eloquent voices of AIDS activism, it was the opportunistic infections -- those insidious and often deadly complications of AIDS -- that captured my attention. I'd watch friends and colleagues gasp for air while fighting PCP, waste away as a result of MAC or cryptosporidiosis, and literally lose their minds to toxoplasmosis, cryptococcal meningitis, AIDS-related dementia, or progressive multifocal leukoencephalopathy (PML). In turn, I heard my calling -- to become an effective OI treatment activist and educator.
Soon after learning everything I could about OIs and beginning work on a number of campaigns to speed the development of life-saving treatments, OI rates plummeted, thanks to the widespread use of combination antiretroviral treatment that began in 1996. But OIs still do occur, and there is growing concern that the increasing number of people failing antiretroviral therapy will soon result in a rise in the number of AIDS-related OIs and deaths. In turn, there will always be a need for effective OI treatment activism, along with comprehensive and up-to-date information that can help all HIV-positive people better understand OIs, including the ways in which they can be prevented and treated.
Because there have been significantly fewer people with HIV experiencing OIs over the past six years, the flow of OI-related treatment research has been reduced to a trickle. However, there have been a number of advances. What follows is an overview of some of the more common OIs -- including those that are still frequently documented in HIV-positive people -- and some of the more important advances that have been made over the past ten years.
A number of bacterial infections continue to be a source of concern for many HIV-positive people, including those who are responding well to antiretroviral drug treatment. One example is syphilis, caused by the bacterium Treponema pallidum, which has made something of a comeback in recent years. In New York City alone, syphilis rates more than doubled from 2001 to 2002, primarily among gay and bisexual men. Because syphilis is an "ulcerative" sexually transmitted disease (STD), meaning that it can cause open sores, it carries with it an increased risk of HIV transmission. Research indicates that syphilis is more likely to run a more rapid and harmful course of disease in people with HIV, including those with relatively healthy immune systems. In turn, modern-day treatment initiatives tend to be a bit more aggressive. HIV-positive patients generally receive three weekly injections of high-dose penicillin for the treatment of primary or secondary syphilis, as opposed to the one-time penicillin injection used to treat HIV-negative patients.
Tuberculosis (TB) remains one of the most common causes of sickness and death among people with HIV. Even though 150,000 people in the United States have been infected with Mycobacterium tuberculosis, the bacterium that causes TB, most (between 90% and 95%) have immune systems that are healthy enough to prevent the bacteria from ever causing active TB. In people with HIV, the immune system may eventually lose control of the bacterium, causing the infection to spread and cause active disease. This process can take many months or years. In other words, Mycobacterium tuberculosis can remain alive in someone's body for many years, but may only become active once the immune system becomes suppressed. TB has been seen in many HIV-positive patients with moderate CD4 cell suppression -- meaning a CD4 cell count between 200 and 400 -- and can actually result in more pronounced symptoms when the CD4 cell count is above 200.
To test for Mycobacterium tuberculosis infection, a skin test called PPD is performed. It is generally recommended that HIV-positive people receive this test on an annual basis, particularly if they are homeless, intravenous drug users, or incarcerated, due to the higher rates in these populations. PPD testing involves pieces of the bacteria that are injected directly into the skin. If someone has been exposed to the bacteria in the past, the immune system will immediately recognize the PPD, resulting in a firm, relatively large bump at the site of the injection. Depending on the size of the PPD bump -- and taking into consideration other factors such as HIV status, age, immigration status, intravenous drug use history, and recent exposure to someone with active TB -- treatment is sometimes deemed necessary. For HIV-positive people who were recently exposed to someone with active TB or develop PPD bumps that are 5 millimeters in diameter or larger -- but do not have symptoms of TB -- a nine-month course of isoniazid should be started.
For HIV-positive patients who are PPD positive and have signs and/or symptoms of disease -- such as an abnormal chest x-ray and difficulty breathing -- TB is suspected but must be confirmed by actually isolating the germ in the laboratory. The recommended treatment for active TB is almost the same for HIV-positive people as it is for HIV-negative people. For the first two months, a combination of four antibiotics is taken. After that, a combination of two drugs must be taken for an additional four months. However, one of the drugs typically used for the entire six months of treatment -- rifampin -- does not mix well with anti-HIV drugs. And because it is generally recommended that HIV-positive patients either start or continue their anti-HIV drugs while being treated for TB, researchers have determined in recent years that another, similar antibiotic -- rifabutin (Mycobutin) -- can be used as a substitute for rifampin. Although the dose of rifabutin may need to be reduced, depending on which anti-HIV drugs are being taken, it can be combined safely with other medications.
Bacterial Pneumonia and Bronchitis
Research has consistently found that bronchitis and bacterial pneumonia are more likely to occur in HIV-positive people, regardless of their CD4 cell counts. In other words, people with HIV -- even if their CD4 cell counts are high -- are more likely to experience bacterial respiratory problems than HIV-negative people. What's more, HIV-positive people with suppressed immune systems are much more likely to see a mild case of bronchitis develop into serious pneumonia, which can be life-threatening if not diagnosed and treated promptly.
For people with HIV, respiratory problems are nothing to cough at. No matter how high the CD4 cells or low the viral load, difficulty breathing -- whether or not a cough is present -- should be brought to the attention of a healthcare provider.
Mycobacterium Avium Complex (MAC)
MAC, which can affect the liver, the spleen, and the bone marrow and cause severe symptoms (fever, weight loss, and diarrhea, to name a few), is typically seen in patients with fewer than 100 CD4 cells. Because antiretroviral treatment has allowed many HIV-positive people to keep their CD4 cells above and beyond this level, MAC rates are at an all-time low. However, MAC has long been a serious threat to HIV-positive people and effective preventive medications -- known as prophylaxis -- remain the best tools to prevent MAC from occurring in people with suppressed immune systems.
The drugs typically prescribed to prevent MAC are azithromycin (Zithromax), which is taken once a week, or clarithromycin (Biaxin), which is taken once a day. These drugs replaced rifabutin (Mycobutin) as the prophylaxis of choice back in the mid-1990s. Clinical trials have demonstrated that they are more effective than rifabutin -- both clarithromycin and azithromycin, if taken correctly, can reduce the risk of MAC by 70% -- and are much less likely to interact with anti-HIV medications. Clarithromycin should not be used with Sustiva (efavirenz), since Sustiva can lower blood levels and, therefore, the effectiveness of clarithromycin.
Once upon a time, it was generally recommended that, once an HIV-positive person started on MAC prophylaxis, it should be continued for life. This is no longer the case for patients who are able to increase their CD4 cell counts to levels above 100 -- and keep them there for at least three months. Similarly, patients who experience MAC have long been told to continue treatment for life to prevent the disease from recurring. We now know that such maintenance therapy -- which is also known as "secondary" prophylaxis -- can be discontinued if CD4 cells can be pushed above 100 for at least six months.
Rates of CMV, a viral infection that can affect the eyes and a number of other organs in the body, remain low in the United States. When CMV does occur, a number of treatments are available, thanks to a tremendous amount of research conducted throughout the 1990s. These include medications administered intravenously (foscarnet [Foscavir], ganciclovir [Cytovene], or cidofovir [Vistide]), by mouth (valganciclovir [Valcyte]), or directly into the eyes (ganciclovir implants [Vitrasert] or fomivirsen injections [Vitravene]). The most important advance in recent years can be found in studies suggesting that CMV maintenance therapy -- usually oral ganciclovir (Cytovene) -- can be stopped in patients who have been treated for the disease and whose CD4 cell counts increase to levels above 100 or 150 for at least six months.
Herpes Simplex Virus (HSV)
Herpes simplex virus 1 (HSV-1) is responsible for oral herpes (cold sores), and herpes simplex virus 2 (HSV-2) is responsible for genital herpes. While antiretroviral treatment has allowed HIV-positive people to avoid more serious herpes outbreaks, there are no guarantees that herpes sores won't recur. Two drugs have been approved for herpes outbreaks over the past decade: valacyclovir (Valtrex), a form of acyclovir (Zovirax) that only needs to be taken once a day (Zovirax needed to be taken three to five times a day), and famciclovir (Famvir). New treatments are also being developed for herpes, including a topical foscarnet cream; a topical gel of the anti-CMV drug cidofovir; and a topical cream with the code name SP-303T, a drug that has been shown to be active against a number of different viruses. Another topical drug being studied for oral and genital herpes is trifluridine, which is already approved for the treatment of herpes infection of the eye.
HPV is spread via sexual activity. Nearly 40 million people in the United States are infected with HPV, which can cause three different types of diseases, mostly in or around the genital area. HPV can cause warts -- small, raised, hard lumps that grow in clumps -- to form in or around the vagina, anus, or the tip of the penis. They are usually called warts when they are found on the skin and condylomas when they're on the genitalia. HPV can also cause dysplasia -- abnormal cells found inside the anus or within the cervix (the neck of the uterus, or womb). Dysplasia is often referred to as a "pre-cancer" form of disease, though not all men or women with dysplasia go on to develop cancer. If cancer does occur, the four most common types are cervical cancer, anal cancer, rectal cancer, and penile cancer. If not diagnosed and treated early, these forms of cancer can be life threatening.
HIV-positive people are more likely to be infected with HPV than HIV-negative people. Because of immune-suppression, HIV-positive people are also more likely to develop genital warts, as well as cervical or anal cancer, as a result of HPV. Researchers don't yet know if anti-HIV drugs will help reduce the number of new cases of genital warts or anal or cervical cancers. In fact, some researchers speculate that, because anti-HIV drugs have been successful in keeping people alive longer, the risk of developing genital warts or cancer might increase.
While a blood test can check for HPV infection, a positive result doesn't really say much. Being infected with HPV does not mean that genital warts will develop, nor does it mean that dysplasia or cancer will occur. Genital warts -- which can often be felt with a finger and are visible to the naked eye -- should be reported to a healthcare provider. The warts should be biopsied (a sample collected in a minor surgical procedure) to determine if they might go on to cause cancer.
To check for dysplasia or cancer, a healthcare provider can perform a Pap smear, in which cells are scraped from the cervix or anus and examined under a microscope. If the cells are found to be abnormal, a second Pap smear should be conducted to confirm these results. Women should have their first cervical Pap smear by age 18 or when they become sexually active, whichever comes first. It is recommended that HIV-positive women have a cervical Pap smear every six months. Men and women who practice anal sex should also have regular anal Pap smears.
An abnormal Pap smear result calls for closer examination. At this point, an anoscope or colposcope -- two magnifying devices -- are used to look for cancerous or pre-cancerous patches, or lesions, inside the anus or cervix. These lesions are often referred to as either anal or cervical intraepithelial neoplasia (AIN or CIN). If lesions are found, a biopsy can be performed to learn more about the abnormal cells.
Depending on the results of the biopsy, AIN and CIN are given a stage number: I, II, or III. The stage of dysplasia depends on the thickness of abnormal cells within the cervical or anal wall. AIN or CIN I is considered to be a mild form of dysplasia and generally does not require therapy (but must be monitored closely), whereas AIN or CIN II or III are considered to be more advanced forms of dysplasia and are more likely to develop into cancer. Advanced forms of AIN or CIN often require therapy to prevent them from developing into cancer.
The only treatments available are those to remove or destroy irregular cells, such as those that make up genital warts or cervical/anal dysplasia or cancer. Treatments aimed at the underlying cause of these problems -- HPV -- are still being studied.
Therapy for genital warts and low-grade dysplasia is not required, but is often recommended to prevent them from progressing. Intermediate and high-grade dysplasia, as well as cervical or anal cancer, almost always require therapy to prevent them from becoming life-threatening problems.
Treating warts, dysplasia, and cancers depends on the location and severity of disease. For example, topical gels and creams -- such as podofilox (Condylox), podophyllum (Podocon-25), trichloroacetic acid, and imiquimod (Aldara) -- are used only for the treatment of genital warts. In general, they have shown to be 30% to 80% effective in reducing wart size, sometimes dramatically. All topical treatments, with the exception of imiquimod, can be used to treat warts inside the anus or vagina. Cervical or anal dysplasia, particularly AIN or CIN II or III, are treated using cryotherapy (liquid nitrogen to freeze warts), laser treatment (using a high-powered light beam to burn and remove abnormal anal and cervical tissues), and surgery. Cervical and anal cancer (carcinoma) are treated like other forms of cancer. Radiation and/or surgery are often necessary to either destroy or remove the cancer and the surrounding tissue. If the cancer spreads, chemotherapy is often used to kill cancer cells in other parts of the body.
Above all, it is very important that HIV-positive people engaging in vaginal or anal sex -- even if condoms are being used regularly -- discuss HPV and Pap smears with their healthcare providers. And if anal and/or cervical condylomas or dysplasia are suspected, follow up and treatment should be handled by an expert: an obstetrician/gynecologist or a proctologist/anal surgeon familiar with the treatment and care of HIV-positive people.
Progressive Multifocal Leukoencephalopathy (PML)
PML is a life-threatening infection of the brain that can occur in people living with HIV. It is caused by a virus -- the JC virus. The "JC" are the initials of the first patient to be diagnosed with PML. More than 70% of all adults in the United States are infected with the JC virus, usually during early childhood. However, the virus only becomes active in people who have compromised immune systems, including those with HIV. It usually occurs in people with very low CD4 cell counts (less than 100), but has been seen in some HIV-positive people with as many as 500 CD4 cells.
PML is almost always progressive and fatal. Its symptoms include mental deterioration, vision loss, speech disturbances, ataxia (inability to coordinate movements), paralysis, and coma. Death usually occurs between one and four months after the first symptoms appear. However, there have been a number of reported cases with survival ranging from several months to years.
Unfortunately, there are still no proven treatments for PML. A number of medications have been studied, none of which have panned out as effective options. Hope is not lost, though -- patients with PML whose CD4 cell counts improve with the use of antiretroviral therapy can sometimes halt the progression or reverse their symptoms of PML -- the best PML news we've heard in a long time.
Systemic Fungal Infections
Fungal infections such as aspergillosis, histoplasmosis, and coccidioidomycosis can occur in anybody, but are more likely to cause serious disease and affect a number of organs in HIV-positive people with suppressed immune systems. These three infections are generally treated using intravenous amphotericin B (Fungizone), which is often combined with oral antifungals. Intravenous amphotericin B can be a toxic drug. Fortunately, liposomal formulations of amphotericin B -- which attach the drug to microscopic spheres of fat -- are a possibility, as they have been shown to be just as effective and somewhat less toxic than standard amphotericin B for the treatment of several types of fungal infections. Liposomal formulations include Abelcet, Amphotec, and AmBisome.
Cryptococcal meningitis is a serious infection of the brain and spinal column that can occur in people living with HIV, particularly those with fewer than 50 CD4 cells. It is important to treat cryptococcal meningitis aggressively. For the first two weeks of treatment, the drug amphotericin B (Fungizone) is given every day through an IV line, along with a second drug taken by mouth: flucytosine (Ancobon). As for the possibility of using liposomal amphotericin B, recent studies conclude that it is equally toxic -- and less effective -- than Fungizone in patients with cryptococcal meningitis. Still, liposomal amphotericin B is sometimes prescribed for patients who become very ill while taking Fungizone or develop kidney problems, a potential side effect of Fungizone. If liposomal amphotericin B is used, experts recommend using the brand AmBisome rather than the brands Abelcet or Amphotec. After two weeks of taking amphotericin B and Ancobon, both drugs are stopped and another drug, fluconazole (Diflucan), is immediately started. This is necessary to help prevent the cryptococcal meningitis from recurring. Fluconazole is taken by mouth, every day, at a dose of 200 mg. At the present time, it is recommended that fluconazole be continued for the rest of a patient's life. It is still not clear how high CD4 cells need to increase using anti-HIV drugs before fluconazole can be safely stopped.
In HIV-positive people, candida infection of the mouth (oral thrush) or the vagina (vaginal yeast infections) can occur at any time, regardless of their CD4 cell counts. However, oral thrush and vaginal yeast infections are more likely to occur, and recur more frequently, the more the immune system becomes damaged. HIV-positive people with damaged immune systems, usually with CD4 cell counts less than 200, are also more likely to develop candidiasis deeper in their bodies, such as in the esophagus or the lungs.
Numerous antifungals are available to treat oral thrush, including medications in the form of lozenges that are sucked or liquids that are swished around the mouth (Mycelex, Mycostatin, and Fungizone). The most common treatments for vaginal yeast infections are medicated creams or suppositories placed into the vagina (Gyne-Lotrimin, Mycelex, Monistat, Terazol, Vagistat, Femstat). If oral thrush and vaginal yeast infections do not go away with the use of these drugs, more potent medications such as ketoconazole (Nizoral), itraconazole (Sporanox), or fluconazole (Diflucan) can be taken. Compared to swish-and-swallow liquids and lozenges and vaginal creams, these drugs are more likely to cause side effects, including stomach upset, diarrhea, nausea, and elevated liver enzymes. There are also several novel medications being developed, including CS-758, which is similar to many of the currently available options, P-113, a peptide that may be less likely to result in drug resistance, and MycoGrab, an antibody-like product that is effective against candida strains resistant to current antifungals.
Cryptosporidiosis and Microsporidiosis
"Crypto" and "micro" are infections that affect the lining of the small intestine and can cause severe diarrhea and prevent vital nutrients -- and medications -- from being absorbed properly (malabsorption). While anybody exposed to these two protozoa can get sick from them, diarrhea and malabsorption is usually limited to a few days in people with healthy immune systems. People with compromised immune systems -- usually those with CD4 cell counts below 150 -- may experience prolonged and severe bouts of diarrhea and malabsorption that can be difficult to treat.
Unfortunately, there are no universally effective treatments for crypto and micro. Many drugs have been studied in clinical trials. Some have been complete failures. Others have been shown to be effective for some people but not for others. The best treatment for these two infections appears to be antiretroviral therapy. By treating HIV effectively, it's possible to increase CD4 cell counts to levels above 150. This has proven to work well for many HIV-positive people with crypto or micro.
Pneumocystis Pneumonia (PCP)
Until recently, PCP was officially called Pneumocystis carinii pneumonia. It is now believed that this form of pneumonia is caused by Pneumocystis jiroveci, not Pneumocystis carinii. Complicating matters further are studies suggesting that P. jiroveci is a fungus, not a protozoan. Call it what you will, it's still a common and life-threatening disease among HIV-positive patients who see their CD4 cells fall below 200.
Bactrim or Septra remain the most effective PCP prophylaxis drugs -- these are both brand names for the combination drug trimethoprim-sulfamethoxazole (TMP/SMX) -- although as many as one-third of all HIV-positive people are allergic to it. Fortunately, it's now possible to undergo a "desensitization" protocol; under the close supervision of a doctor, patients start by taking tiny doses and gradually work their way up to the full dose within a few days or weeks. This has allowed many people allergic to TMP/SMX to take this drug without problems. And there is still the possibility of switching to aerosolized pentamidine (NebuPent), dapsone (Avlosulfon), or atovaquone (Mepron), three drugs that have been around for several years.
Similar to MAC, it was once believed that, if PCP prophylaxis is deemed necessary, it should be continued for life. This is no longer the case for patients whose CD4 cell counts increase to levels above 200 -- and stay there for at least three months -- with the use of antiretroviral treatment. And the same goes for patients who have been treated for PCP and have been instructed to continue taking maintenance therapy -- usually Bactrim or Septra -- for the rest of their lives. We now know that maintenance therapy can also be discontinued if CD4 cells are elevated above 200 for at least three months with the use of antiretroviral therapy.
I'll always remember the words of a fellow advocate and educator: HIV doesn't kill people, opportunistic infections do. These words were very much self-evident ten years ago and they are just as valid today. The good news is that the majority of HIV-positive people living in the United States today are being kept out of harm's way thanks to the availability -- and continual development -- of potent anti-HIV drugs and effective anti-HIV drug combinations. The disturbing news is that OIs are still very much a reality for many HIV-positive people, and there is a growing number of people who are simply out of anti-HIV treatment options and are seeing their CD4 cell counts dwindle to levels at which OIs become possible.
A dismal picture? Perhaps. There is, however, an encouraging bottom line to consider: OI prophylaxis and treatments have advanced to the point that many OIs can either be prevented or successfully treated. Before anti-HIV drug "cocktails" came along, it was the advances in prophylaxis and OI treatment that could be credited for saving and prolonging lives. Understandably, the incredible advances in anti-HIV therapy have stolen much of the OI thunder -- but it's good to know that highly effective OI prevention and treatment options are still very much available to those who need them.
Tim Horn is Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York. He is also the head medical writer for AIDSmeds.com.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.