• When was HIV discovered and how is it diagnosed?
• How is HIV spread (transmitted)?
• What happens after an exposure to an HIV-infected person?
• What laboratory tests are used to monitor HIV-infected people?
• What are the key principles in managing HIV infection?
• What factors should be considered before starting antiviral therapy?
• What is the best initial therapy for HIV?
• What are the side effects of HIV therapy?
• How should a person be monitored while on antiviral therapy?
• What should be done if the patient's viral load starts to increase while on treatment?
• What if a dose of antiviral medication is missed or therapy is stopped?
• Should patients with the "flu"- or "mono"-like illness of primary HIV infection be treated?
• What about treatment for HIV during pregnancy?
• What about treating people who are exposed to the blood or genital secretions of an HIV-infected person?
• What can be done for people who have severe immunosuppression?
• What is in the future for HIV-infected individuals and for those at risk to contract HIV?
• HIV At A Glance

When was HIV discovered and how is it diagnosed?

In 1981, homosexual men with symptoms that now are considered diagnostic of AIDS were first described in Los Angeles and New York. The men had an unusual type of lung infection (pneumonia) called Pneumocystis carinii pneumonia (PCP) and rare skin tumors called Kaposi's sarcoma. The patients were noted to have severe suppression of a specific type of immune blood cells, called CD4 cells. These cells, often referred to as T cells, help the body fight infections. Shortly thereafter, this disease was recognized throughout the United States, Western Europe, and Africa. In 1983, researchers in the United States and France described the virus that causes AIDS, now known as HIV. In 1985, a blood test became available that measures antibodies to HIV, which thereby detects the body's immune response to the HIV. This blood test remains the best method for diagnosing HIV infection. Recently, tests have become available to look for these same antibodies in the saliva and urine.

How is HIV spread (transmitted)?

HIV is present in the blood and genital secretions of virtually all infected individuals, regardless of whether or not they have symptoms. The spread of HIV can occur when these secretions come in contact with tissues such as those lining the vagina, anal area, mouth, or eyes (the mucosal membranes), or with a break in the skin, such as from a cut or puncture by a needle. The most common ways in which HIV is spreading throughout the world include sexual contact, needle sharing, and transmission from infected mothers to their newborns during pregnancy, labor (the delivery process), or breast- feeding. (See the section below on treatment during pregnancy for a discussion on reducing the risk of transmission to the newborn.)

Sexual transmission of HIV has been described from men to men, men to women, women to men, and women to women through vaginal, anal, and oral sex. The best way to avoid sexual transmission is abstinence from sex until it is certain that both partners in a monogamous relationship are not HIV-infected. Because the HIV antibody test can take up to 6 months to turn positive, both partners would need to test negative 6 months after their last potential exposure to HIV. If abstinence is out of the question, the next best method is the use of latex barriers. This involves placing a condom on the penis as soon as an erection is achieved in order to avoid exposure to pre- ejaculatory and ejaculatory fluids that contain infectious HIV. Concerning oral sex, condoms should be used for fellatio (oral contact with the penis) and latex barriers (dental dams) for cunnilingus (oral contact with the vaginal area). A dental dam is any piece of latex that prevents vaginal secretions from coming in direct contact with the mouth. Although such dams occasionally can be purchased, they are most often created by cutting a square piece of latex from a condom.

The spread of HIV by exposure to infected blood usually results from sharing needles, as in those used for illicit drugs. HIV also can be spread by sharing needles for anabolic steroids taken to increase muscle, tattooing, and body piercing. To prevent the spread of HIV, as well as other diseases including hepatitis, needles should never be shared. At the beginning of the HIV epidemic, many individuals acquired HIV infection from blood transfusions or blood products, such as those used for hemophiliacs. Currently, however, because blood is tested for antibodies to HIV before transfusing it, the risk of acquiring HIV from a blood transfusion in the United States is extremely small and is considered insignificant.

There is little evidence that HIV can be transferred by casual exposure, as might occur in a household setting. For example, unless there are open sores or blood in the mouth, kissing is generally considered not to be a risk factor for transmitting HIV. This is because saliva, in contrast to genital secretions, has been shown to contain very little of the virus. Still, theoretical risks are associated with the sharing of toothbrushes and shaving razors because they can cause bleeding. Consequently, these items should not be shared with infected persons. Similarly, without sexual exposure or direct contact with blood, there is little if any risk of HIV contagion in the workplace or classroom.

What happens after an exposure to an HIV- infected person?

The risk of HIV transmission occurring after any potential exposure to bodily fluids is poorly defined. The highest risk sexual activity, however, is thought to be anal intercourse without a condom. In this case, the risk of infection may be as high as 3% to 5% for each exposure. The risk probably is less for vaginal intercourse without a condom and even less for oral sex without a latex barrier. Despite the fact that no single sexual exposure carries a high risk of contagion, HIV infection can occur after any isolated sexual event. Thus, people must always be diligent in protecting themselves from potential infection.

Within 2 to 6 weeks of an exposure, infected persons will usually have a positive HIV antibody test as shown by both the screening test referred to as an ELISA, and the confirmatory test called a Western blot. During this time, more than 50% of those infected will experience a "flu"- or infectious "mono"-like illness for up to several weeks. This illness is considered the stage of primary HIV infection. The most common symptoms in this stage are fever , aching muscles and joints, sore throat , and swollen glands (lymph nodes) in the neck. It is not known, however, why only some infected persons develop these symptoms. It also unknown whether or not having the symptoms has any impact on the future course of the disease. Regardless, infected persons will become symptom-free (asymptomatic) after this phase. During the asymptomatic phase, affected individuals will know whether or not they are infected only if a test for HIV is done. Therefore, anyone who possibly could have been exposed to HIV should seek testing even if they are not experiencing any symptoms. HIV testing can be performed by a physician or at a testing center.

During the asymptomatic stage of infection, literally billions of HIV particles are produced every day. This viral reproduction is associated with a decline (at an inconsistent rate) in the number of CD4 cells over the ensuing years. In addition to the virus being in the blood, it is also present throughout the body, especially in the lymph nodes, brain, and genital secretions. The time from HIV infection to the development of AIDS varies. Some people develop symptoms, signaling the complications of HIV that define AIDS, within 1 year of infection. Others, however, remain completely asymptomatic after as many as 20 years. The average time for progression from initial infection to AIDS is 8 to10 years. The reason why different people advance at various rates is an area of active research.

What laboratory tests are used to monitor HIV- infected people?

Two blood tests are used to monitor HIV-infected people. One of these tests, which counts the number of CD4 cells, assesses the status of the immune system. The other test, the so called viral load, directly measures the amount of virus. In individuals not infected with HIV, the CD4 count in the blood is normally above 500 cells per milliliter. HIV-infected people generally do not become at risk for complications until their CD4 cells are fewer than 200 cells per milliliter. At this level of CD4 cells, the immune system does not function adequately and is considered suppressed. Patients who have this CD4 count are referred to as being immunosuppressed. A declining number of CD4 cells indicates that the HIV disease is advancing. Thus, a low CD4 cell count signals that the person is at risk for one of the many unusual infections (the so-called opportunistic infections) that occur in individuals who are immunosuppressed. In addition, the actual CD4 cell count indicates which specific therapies should be initiated to prevent those infections.

The viral load predicts whether or not the CD4 cells will decline in the coming months. In other words, those persons with high viral loads are more likely to experience a decline in CD4 cells and progression of disease than those with lower viral loads. Therefore, knowing the amount of virus can be used to predict the development of the disease. The viral load also is a vital tool for monitoring the effectiveness of new therapies and determining when drugs stop working. The viral load will decrease within weeks of initiating an effective antiviral regimen. If a combination is very potent, the number of viruses in the blood will decrease by as much as 100-fold, such as from 100,000 to 1,000 copies per milliliter in the first 2 weeks and gradually decrease even further during the ensuing 12 to 24 weeks. Moreover, it has become increasingly clear that the greater the decline of the viral load after beginning therapy, the longer it will remain suppressed.

What are the key principles in managing HIV infection?

First of all, there is no evidence that people infected with HIV can be cured by the currently available therapies. In fact, individuals who are treated for up to three years and repeatedly test for an undetectable level of the virus in their blood experience a prompt rebound increase in the number of viral particles when therapy is discontinued. Consequently, the decision to start therapy must balance the risk of advancement to symptomatic disease against the risks associated with therapy. The risks of therapy include the short and long-term side effects, described in subsequent sections, as well as the possibility that the virus will become resistant to therapy. This resistance then limits the options for future treatment.

A major reason that resistance develops is the patient's failure to correctly follow the prescribed treatment, such as not taking the medications at the correct time. Another factor is that the likelihood of suppressing the virus to undetectable levels is not as good for patients with lower CD4 cell counts and higher viral loads. Finally, if the viral load remains detectable on any given regimen, resistance eventually will develop. Indeed, with certain drugs, resistance may develop in a matter of weeks, such as with 3TC (lamivudine, Epivir) and the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (Viramune TM), delavirdine (Rescriptor TM), and efavirenz (Sustiva TM). Thus, if these drugs are used as part of a combination that does not suppress the viral load to undetectable levels, resistance will develop rapidly and the treatment will be rendered ineffective. In contrast, HIV becomes resistant to certain other drugs, such as zidovudine (AZT), stavudine (D4T), and protease inhibitors, over months. (These drugs all are discussed in more detail in subsequent sections.) In addition, resistance to one drug often results in the same reaction to other related drugs, a so called cross-resistance. Nevertheless, HIV-infected individuals must realize that antiviral therapy can be very effective. This is the case even in those who have a low CD4 cell count and advanced disease, as long as drug resistance has not developed.

What factors should be considered before starting antiviral therapy?

One of the most controversial areas regarding the management of HIV disease is deciding the best time to start antiviral treatment. Clearly, therapy during the mildly symptomatic stage of the disease delays its progression to AIDS, and treating individuals with AIDS postpones death. Consequently, most experts agree that patients who have experienced complications of HIV disease, such as oral thrush (yeast infection in the mouth), chronic unexplained diarrhea , fevers, weight loss, opportunistic infections, or dementia (for example, forgetfulness) should be started on antiviral treatment even if the symptoms are mild. In patients who do not have symptoms, however, there is more uncertainty. Most recommendations for this group are based on the markers of clinical progression, that is, the number of CD4 cells and the viral load. Several studies have demonstrated an increased risk of disease advancement in individuals with a CD4 cell count of less than 350 to 500. Similarly, those with elevated viral loads, regardless of the CD4 cell count, are at increased risk for disease progression. Debate continues, however, regarding the best threshold level at which to set the viral load to trigger the beginning of drug treatment.

Panels of experts from the US Department of Health and Human Services and the International AIDS Society have proposed guidelines for starting antiviral therapy. They recommend treating all patients who have symptoms and those who have CD4 cell counts of less than 350 (and many patients with less than 500) or viral loads greater than approximately 10,000 to 20,000 regardless of the number of CD4 cells. However, it should be kept in mind that the likelihood of short and long-term toxicity is significant with any treatment program, adherence to the regimen is difficult, and viral resistance to the drugs occurs. Other authorities, therefore, have proposed delaying therapy until the viral load is even higher. Regardless, all agree that HIV is a slowly progressive disease and therapy rarely needs to be abruptly started. Therefore, there is usually time for each patient to carefully consider options prior to deciding when to start treatment.

Before starting treatment, patients must be aware of the short and long-term side effects, including the fact that some long-term complications may not be known. The patients also need to realize that therapy is a long-term commitment and requires an extraordinary level of adherence to the regimen. In addition, clinicians and patients should recognize that depression , feelings of isolation, substance abuse, and side effects of the antiviral drugs can all be associated with the failure to follow the treatment program.

What is the best initial therapy for HIV?

Guidelines for using antiviral therapy have been developed and are updated on a regular basis by an expert panel assembled by the Department of Health and Human Services and the Henry J. Kaiser Foundation. Their guidelines are only one of several developed to provide recommendations for the treatment of HIV disease (www.hivatis.org).

Antiviral treatment options have primarily included combinations of 2 nucleoside analogue reverse transcriptase inhibitors (NRTI), often referred to as "nucs," and 1 protease inhibitor (PI). In addition, together with 2 NRTIs, several combinations of 2 PIs have been used instead of a single PI because these regimens are easier to follow and/or have fewer side effects. Recently, there has been increasing experience with regimens that combine NRTIs with NNRTIs, often called "non-nucs." These NNRTI-containing combinations generally are easier to take than PI-containing combinations and the Pls can be reserved for future use. Finally, preliminary data now indicate that combinations of three NRTIs alone may be effective, particularly in patients with lower viral loads (less than 100,000).

In general, most antiviral regimens for HIV disease contain a backbone of at least two NRTIs. The NRTIs include zidovudine (ZDV, AZT, Retrovir TM), stavudine (d4T, Zerit TM), didanosine (ddI, Videx TM), zalcitabine (ddC, HIVID TM), lamivudine (3TC, Epivir TM), and abacavir (ABC, Ziagen TM). A typical regimen will include either ZDV or d4T along with ddI, ddC or 3TC. Although abacavir, the newest of the NRTIs, can be used with any or all of these drugs, the best way to use it is not yet known. In regimens of three NRTIs, where NNRTIs and PIs are not used, the majority of the data is derived from experience with the combination of ZDV, 3TC, and abacavir.

Usual dosing schedule and meal restrictions for NRTIs

ZDV, zidovudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine, 3TC, lamivudine; ABC, abacavir.

*ZDV and 3TC come in a combination pill, Combivir, that can be taken as 1 pill twice per day.

These are standard doses for average sized adults and dosing may vary depending upon weight of the patient.

NNRTIs include nevirapine (Viramune^TM), delavirdine (Rescriptor^TM), and efavirenz (Sustiva^TM). The majority of experience using NRTIs in combination with NNRTIs is with ZDV, 3TC, and efavirenz. This combination is considered a reasonable starting regimen. It should also be noted that there is preliminary data suggesting that combinations made up of 2 NRTIs along with one of the other NNRTIs may also prove to be viable options.

Usual dosing schedule and meal restrictions for NNRTIs.

*Increasing data available with 3 twice/day

Protease inhibitors include saquinavir (Invirase,^TM Fortovase^TM), ritonavir (Norvir^TM), indinavir (Crixivan^TM), nelfinavir (Viracept^TM), and amprenavir (Agenerase^TM). Actually, each of these drugs has been shown to effectively reduce the viral load when used in combination with two NRTIs.

Usual dosing schedule and meal restrictions for PIs

This was originally formulated as Invirase^TM, which was taken as 3 capsules three times/day, and then was reformulated as Fortovase^TM, a soft gel capsule with better intestinal absorption, which is prescribed as 6 capsules three times per day.

*Increasing data is available for dosing at 8 capsules twice per day.

Combinations of PIs, along with the 2 NRTIs, have been used in clinical practice with increasing frequency. Most PI combinations have used ritonavir, which is a potent inhibitor of the clearance of other drugs. This means that ritonavir slows the elimination of other drugs from the body. The idea of the ritonavir in these combinations is to decrease the dose of each drug in the regimen, decrease the frequency of dosing, and at times minimize meal restrictions. The meal restrictions often are needed because certain drugs may not be absorbed effectively by the body if taken with food, while other drugs should be taken with food to avoid upsetting the stomach. Patients, therefore, must carefully coordinate their medications with the timing of meals. The need for this coordination often makes the regimen more difficult to follow.

The best studied combination of PIs has been ritonavir at 400 mg twice per day (instead of the usual 600 mg twice per day) with saquinavir at 400 mg twice per day (instead of the usual 1200 mg of Fortovase^TM three times per day). Also, some experience using ritonavir with indinavir indicates that indinavir can be taken twice daily without consideration for meals. The optimal dose for this combination has not been defined. The most commonly used regimens, however, combine ritonavir 400 mg twice per day with indinavir 400 mg twice per day, or ritonavir 200 mg twice per day with indinavir 800 mg twice per day. Other combinations of PIs also are being studied, such as nelfinavir with saquinavir. In addition, recent studies are attempting to establish whether the clearance-inhibiting properties of ritonavir may allow for once a day dosing of PIs.

Drugs that show promise in early clinical trials are made available by the manufacturers, with approval of the Food and Drug Administration (FDA), to certain individuals. These are patients who are no longer responding to currently available agents or are unable to tolerate them. The promising new drugs are made available as part of "compassionate-use" or "expanded-access" programs. One such drug is a PI called ABT-378, which is taken as a 400 mg dose in combination with a low dose (100 mg) of ritonavir twice daily. To receive more information regarding this program, physicians can call the Abbott ABT-378/r Early Access Program at (919) 998-2619.

Another drug, called Tenofovir, recently has been made available through "expanded-access." This drug is in a new class of agents, referred to as nucleotide analogue reverse transcriptase inhibitors. The nucleotide analogues slow down a similar step in viral reproduction as do the nucleoside analogues. The two classes of drugs, however, are sufficiently different from one another that patients for whom a nucleoside is unsuccessful may still respond to the nucleotide. As with other drugs made available through these programs, the potency of Tenofovir to reduce the viral load and its potential side effects are still being established. To receive more information regarding this program, physicians can call the Compassionate Access Coordinating Center at (800) 276-0231.

What are the side effects of HIV therapy?

There are many potential side effects associated with these antiviral therapies. The most common ones for each class are summarized in the tables below.

Common side effects of NRTIs

ZDV, zidovudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine, 3TC, lamivudine, ABC, abacavir

Common side effects of NNRTIs

Common side effects of PIs:

During the last three years, increased blood fats (specifically the lipids called triglycerides and cholesterol) have been noted to develop in association with some of the antiviral therapies. In addition, a syndrome loosely referred to as lipodystrophy has been described. This syndrome refers to people who have developed loss of subcutaneous fat (fat under the skin), which causes sunken cheeks and prominent veins in their arms and legs. Other physical changes related to this syndrome include deposits of fat in the abdomen, resulting in a protruding belly, or over the back of the neck, producing a so-called buffalo hump. All of these abnormalities in blood and body fat were noted before many of the newer drugs were available. These abnormalities appear to be occurring with increasing frequency, thereby raising a concern that they may be long-term complications of the older current therapies. The actual cause of these abnormalities, whether they occur with some drugs more than with others, and how to manage them are unknown.

How should a person be monitored while on antiviral therapy?

Stated briefly, the goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing significant side effects. Currently, the best marker of a drug's activity is a decrease in the viral load. Sometimes, however, the amount of virus will fluctuate spontaneously. Changes of less than 3-fold, such as from 30,000 to 10,000, may not be clinically meaningful. No treatment decisions should be made, therefore, based on a single measurement of the viral load. Although the CD4 cell count is expected to stabilize or increase as a result of effective therapy, CD4 measurements also can vary spontaneously and should be interpreted cautiously.

Ideally, prior to initiating treatment, the viral load and the CD4 cell count should be checked twice over a 1 to 4 week period. The viral load test should then be repeated after 2 to 4 weeks of treatment to assure that the therapy is working. If the patient has never been treated before, and is beginning a regimen thought to be highly active, the amount of virus should decrease by 10 to 100-fold during this interval. The best response to treatment would be for the viral load to decrease to undetectable levels. Assuming an optimal response to a new regimen, the viral load should decrease gradually to fewer than 500 copies by 8 to 12 weeks and fewer than 50 copies by 16 to 24 weeks. The appropriate strategy for managing patients who are taking the medication as prescribed, but who do not achieve these viral milestones, has not been defined. The options in this situation include adding one or two additional drugs, changing all of the medications, or continuing a careful observation. Patients who have taken a lot of antiviral drugs would be expected to have a less complete response to treatment. The reduction of their viral load, therefore, will likely be more modest. Regardless, a change of less than 3-fold suggests that the medications are not effective or the person is not taking them.

What should be done if the patient's viral load starts to increase while on treatment?

When monitoring a patient's viral load during treatment, it is important to realize that increases in the amount of virus can occur for several reasons. One reason might be that the person is not taking the medications appropriately, in which case an explanation for this failure to follow treatment must be established. If the poor adherence is a result of drug toxicity, efforts should be directed towards managing the side effects or changing to a better-tolerated regimen. If the reason is difficulty with the dosing schedule, new strategies should be discussed. Such strategies might include placing medications in a pillbox, associating the dosing with certain daily activities such as brushing teeth, or possibly changing the regimen. Finally, if the reason for poor adherence is depression, substance abuse, or another personal issue, that problem should be managed. In addition, if necessary, the antiviral medications can be withheld until the problem has been resolved.

Remember that sometimes, for reasons not entirely understood, the viral load can briefly increase. Unexpected increases, therefore, necessitate a repeated testing of the viral load before any clinical decisions are made. If, however, the viral load is continually elevated despite proper adherence to the prescribed therapy, serious consideration must be given to the possibility that the virus has become resistant to one or all of the medications being given. The best strategy for dealing with this situation has not yet been defined. Suffice it to say that this situation is complex and methods for managing the problem are evolving. Accordingly, these patients should be referred to a clinician with an expertise in antiviral therapy. Generally, the specialist will change the regimen to one that is unlikely to cause drug resistance. Recently, an increasing amount of data suggests that newly available tests for drug resistance may help select the next regimen. These tests, however, can cost $400 to $1000 and are often not reimbursed by insurance. Furthermore, the tests can be difficult to interpret without expertise in this area.

What if a dose of antiviral medication is missed or therapy is stopped?

It is strongly advised that people on an antiviral regimen should not miss any doses of their medications. Unfortunately, life is such that doses often are missed. The reasons for missed doses range from patients just forgetting to take their medication, leaving town without their medicines, to a medical emergency, such as the need for urgent surgery. For example, after an appendectomy for acute appendicitis , a patient may not be able to take oral medication for up to several days. When a dose is missed, the patient should contact his or her physician without delay to discuss the course of action. The options in this situation are to take the missed doses immediately or simply resume the drugs with the next scheduled dose.

Although every missed dose increases the chance that the virus will develop resistance to the drugs, a single missed dose should not be cause for alarm. On the contrary, it is an opportunity to learn from the experience and determine why it happened, if it is likely to happen again, and what that can be done to minimize missing future doses. Furthermore, if a patient cannot resume medication for a limited time, such as in a medical emergency, there still is no cause for alarm. In this circumstance, the patient can be assured that as long as all medications are stopped simultaneously and then restarted in the future, the risk of developing drug resistance is small.

Should patients with the "flu"- or "mono"-like illness of primary HIV infection be treated?

Patients who are identified as having HIV around the time they are first infected may benefit from potent antiviral therapy given at that time. The rationale for initiating this early treatment is primarily theoretical. Preliminary evidence, however, suggests that unique aspects of the body's immune response to the virus may be preserved by this strategy. It is thought that treatment during the primary infection may be an opportunity to help the body's natural defense system work against HIV. Thus, patients may gain an improved control of their infection while on therapy, and perhaps even after therapy is stopped. For the present, unfortunately, patients who initiate therapy during the primary infection will need to remain on some form of antiviral treatment indefinitely. Studies are underway to determine if there are circumstances in which therapy can be safely discontinued without resulting in an increase in the viral load.

At one time, the hope was that if therapy was started very early in the course of the infection, HIV could be eradicated. Most evidence today, however, suggests that this is not the case. Consequently, early treatment is not likely to result in a cure, although other benefits may still exist. The current recommendation, therefore, is that these patients should be referred to clinical studies if they are able to commit to follow an effective antiviral regimen. If emotional or social situations make adherence to such treatment questionable, however, the patients are better off delaying therapy. After all, on the average, infected persons can expect to remain healthy for a prolonged period of time. Regardless, patients need to be aware that initiating treatment early puts them at risk for developing short and long-term side effects as well as resistance to the drugs.

What about treatment for HIV during pregnancy?

One of the greatest advances in the management of HIV infection has been in pregnant women. Prior to antiviral therapy, the risk of HIV transmission from an infected mother to her newborn was approximately 25-35%.The antiviral medications are not given to women in the first trimester (that is, the first 3 months of pregnancy) because during that time, drugs are more likely to cause fetal abnormalities. Studies in which ZDV was begun after the first trimester, then given intravenously during the delivery process, and after delivery administered to the newborn for 6 weeks, showed that the risk of transmission was reduced to less than 10%.Although less data are available with more potent drug combinations, clinical experience suggests that the risk of transmission may be reduced to less than 5%.Current recommendations are to advise HIV-infected pregnant women regarding both the unknown effects of antiviral therapy on the fetus and the promising clinical experience with potent therapy in preventing transmission. In the final analysis, however, pregnant women with HIV should be treated essentially the same as non-pregnant women with HIV, except during the first trimester.

All HIV-infected pregnant women should be managed by an obstetrician with experience in this area. Maximal obstetric precautions such as avoiding scalp monitors and minimizing labor after rupture of the uterine membranes can be implemented. In addition, the potential use of an elective Caesarean section (C- section) should be discussed, particularly in those women without good viral control of their HIV infection. A C-section, which eliminates the necessity of a vaginal delivery, may thereby provide as yet undefined, additional benefits. Remember also that breast feeding should be avoided if alternative nutrition for the infant is available. Despite the reduced risk of transmission associated with antiviral therapy, pregnant women with HIV need to be thoroughly counseled regarding all risks, as well as all options, including therapeutic abortions when appropriate.

What about treating people exposed to the blood or genital secretions of an HIV-infected person?

Recently, a great deal of interest has focused on preventing transmission to exposed individuals by early administration of antiviral therapy. Because the risk of contagion after most isolated exposures is relatively small, generally less than 5%, formal studies are difficult to perform in patients. Animal studies and some human experience, however, suggest that post-exposure treatment may be effective. In fact, the current recommendation is that health care workers who experience a needlestick from an infected person take antiviral medication for 4 weeks in order to reduce the risk of contagion.

Extending that recommendation, many physicians have proposed similar preventive treatment for people with sexual exposures to HIV. At least 5 limitations, however, apply to this proposal. First, post- exposure treatment cannot be relied upon to prevent the spread of HIV. Second, such treatment should be restricted, for now, to unusual and unexpected exposures, such as a broken condom during intercourse. Third, although regimens with 2 or 3 drugs generally are recommended for those exposed in the healthcare setting, the best therapy for sexual exposure is unknown. Fourth, therapy probably will be most effective if started within the first 2 hours after an exposure. Fifth, a 4-week supply of a three- drug combination of antiviral drugs costs approximately $1000, which generally is not covered by insurance.

What can be done for people who have severe immunosuppression?

Although one goal of antiviral therapy is to prevent suppression of the immune system, some individuals are already immunosuppressed when they first seek medical care. Others progress to that stage as a result of resistance to antiviral drugs. Nevertheless, every effort must be made to optimize antiviral therapy in all of these patients. In addition, certain specific antibiotics should be initiated, depending on the number of CD4 cells, to prevent the complications (that is, the opportunistic infections) that are associated with HIV immunosuppression. Guidelines for the prevention of opportunistic infections can be found at www.hivatis.org.

In summary, patients with a CD4 cell count of less than 200 should receive preventative treatment against Pneumocystis carinii (the opportunistic bacteria that cause pneumonia) with trimethoprim/sulfamethoxazole (Bactrim^TM, Septra^TM), given once daily or three times weekly. If they are intolerant to that drug, patients can be treated with an alternative agent such as dapsone, pentamidine, or atovoquone (Mepron^TM). Those patients with a CD4 cell count of less than 100 who also have evidence of past infection with toxoplasma, which is typically determined by the presence of toxoplasma antibodies in the blood, should receive trimethoprim/sulfamethoxazole. If they are already on dapsone, then pyramethamine and leukovorin can be added once a week to their regimen.  Toxoplasmosis is an opportunistic parasitic disease that affects the brain and liver. Finally, patients with a CD4 cell count of less than 50 should receive preventive treatment for Mycobacterium avium complex (MAC) infection with weekly azithromycin (Zithromax^TM), or as an alternative, twice daily clarithromycin (Biaxin^TM) or mycobutin (Rifabutin^TM). MAC are opportunistic bacteria that cause infections of the intestine, lungs, and liver.

What is in the future for HIV-infected individuals and for those at risk to contract HIV?

Trends continue towards simplifying drug regimens to improve adherence and decrease side effects. In addition, many new drugs are being developed. These new agents are in the currently available classes of drugs as well as in new classes, such as those that block the virus from entering cells or from incorporating itself into the human genetic material. Both of these actions prevent the virus from duplicating itself, thereby inhibiting an increase in the viral load. Perhaps even more importantly, researchers are attempting to enhance the body's natural defenses against HIV in order to control viral growth. An example of this approach is the use of an HIV vaccine, with or without antiviral therapy. Also, innovative studies are underway to try to purge or eliminate the HIV from the body. The rationale for purging is to allow for the withdrawal of therapy without a rebound increase in the number of viral particles in the blood. For example, drugs have been developed to stimulate HIV-infected CD4 cells, which then would be expected to undergo viral or immune self-destruction. Although all of this research is exciting and, in the long run, promising, the reality is that in the near future, patients will need to remain on antiviral therapy.

The good news is that the development of antiviral therapy has led to a marked decline in AIDS-related deaths in many parts of the world. The majority of infected individuals, however, do not have access to these expensive medications. Accordingly, the best hope for limiting the current epidemic around the world remains an effective vaccine. Unfortunately, despite increasing research in this area, the development of a vaccine continues to lag far behind the progress that has been made in antiviral therapy.

HIV At A Glance

• The human immunodeficiency virus (HIV) is a type of virus called a retrovirus, which infects humans when it comes in contact with tissues such as those that line the vagina, anal area, mouth, or eyes, or a break in the skin.
• HIV infection is generally a slowly progressive disease in which the virus is present throughout the body at all stages of the disease.
• Three stages of HIV infection have been described.

  1) The initial stage of infection (primary infection), which occurs within weeks of acquiring the virus, is often characterized by a "flu"- or "mono"-like illness that generally resolves within weeks.

  2) The stage of chronic asymptomatic infection (meaning a long duration of infection without symptoms) lasts an average of 8 to10 years.

  3) The stage of symptomatic infection, in which the body's immune (or defense) system has declined so that complications have developed, is called the acquired immunodeficiency syndrome (AIDS). The symptoms are caused by the complications of AIDS, which include one or more unusual infections or cancers, severe loss of weight, and intellectual deterioration (called dementia).

• When HIV grows (that is, by reproducing itself), it acquires the ability to change (mutate) its own structure. This mutation enables the virus to become resistant to previously effective drug therapy.
• The goals of drug therapy are to prevent damage to the immune system by the HIV virus and to halt or delay the progress of the infection to symptomatic disease.
• Therapy for HIV includes combinations of drugs that decrease the growth of the virus to such an extent that the treatment prevents or markedly delays the development of viral resistance to the drugs.
• The best combination of drugs for HIV has not yet been defined, but one of the most important factors is that the regimen be well tolerated so that it can be followed consistently without missing doses.

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