When was HIV discovered, and how is it diagnosed?

In 1981, homosexual men with symptoms of a disease that now are considered typical of the acquired immunodeficiency syndrome (AIDS) were first described in Los Angeles and New York. The men had an unusual type of lung infection (pneumonia) called Pneumocystis carinii (now known as Pneumocystis jiroveci) pneumonia (PCP) and rare skin tumors called Kaposi's sarcomas. The patients were noted to have a severe reduction in a type of cell in the blood that is an important part of the immune system, called CD4 cells. These cells, often referred to as CD4 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 the human immunodeficiency virus (HIV) and belonging to the group of viruses called retroviruses. In 1985, a blood test became available that measures antibodies to HIV that are 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 blood and saliva, some providing results within 20 minutes of testing.

How is HIV spread (transmitted)?

HIV is present to variable degrees in the blood and genital secretions of virtually all individuals infected with HIV, 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 mucus 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, sharing needles, and by transmission from infected mothers to their newborns during pregnancy, labor (the delivery process), or breastfeeding. (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 six months to turn positive after infection occurs, both partners would need to test negative six 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. For 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 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 both antibodies to HIV and the actual virus before transfusion, 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 HIV. Still, theoretical risks are associated with the sharing of toothbrushes and shaving razors because they can cause bleeding, and blood can contain large amounts of HIV. Consequently, these items should not be shared with infected people. 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 the blood or genital secretions of an HIV-infected person? What are symptoms of primary HIV infection?

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%-5% for each exposure. The risk is probably 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 even one sexual event. Thus, people must always be diligent in protecting themselves from potential infection.

Within two to six weeks of an exposure, the majority of infected people will have a positive HIV antibody test, with virtually all being positive by six months. The test used most commonly for diagnosing infection with HIV is referred to as an ELISA. If the ELISA finds the HIV antibody, the presence of the antibody is confirmed by a test called a Western blot. There are now several rapid antibody tests that can be performed on blood or saliva and provide preliminary results within 20 minutes. These tests are fairly accurate but also need be confirmed with a Western blot. It is currently recognized that approximately 20% of HIV-infected individuals in the United States are not aware that they are infected, largely as a result of not having been tested. In September 2007, the Centers for Disease Control and Prevention recommended that HIV antibody testing be performed as part of routine care for individuals presenting to medical attention for any reason. The hope is that this strategy will reduce the number of infected individuals who are not aware of their status in order to both get them into medical care earlier and to counsel them as to how they can prevent spread to others. This strategy can be markedly enhanced with the rapid testing which can provide preliminary results before the patient leaves the medical facility.

During this period of time shortly after infection, more than 50% of those infected will experience a "flu-like" or "infectious mono-like" illness for up to several weeks. This illness is considered the stage of primary HIV infection. The most common symptoms of primary HIV infection are

* fever,


* aching muscles and joints,


* sore throat, and


* swollen glands (lymph nodes) in the neck.

It is not known, however, why only some HIV-infected people develop these symptoms. It also is unknown whether or not having the symptoms is related in any way to the future course of HIV disease. Regardless, infected people will become symptom-free (asymptomatic) after this phase of primary infection. During the first weeks of infection when a patient may have symptoms of primary HIV infection, antibody testing, if performed, may still be negative. If there is suspicion of early infection based upon the types of symptoms present and a potential recent exposure, consideration should be given to having a test performed that specifically looks for the virus circulating in the blood, such as a viral load test. Once the patient enters the asymptomatic phase, infected individuals will know whether or not they are infected if a test for HIV antibodies is done. Therefore, anyone who might possibly have been exposed to HIV should seek testing even if they are not experiencing symptoms.

During all stages of infection, literally billions of HIV particles (copies) are produced every day and circulate in the blood. This production of virus is associated with a decline (at an inconsistent rate) in the number of CD4 cells in the blood over the ensuing years. Although the precise mechanism by which HIV infection results in CD4 cell decline is not known; it probably results from a direct effect of the virus on the cell as well as the body's attempt to clear these infected cells from the system. In addition to virus in the blood, there is also virus throughout the body, especially in the lymph nodes, brain, and genital secretions. The time from HIV infection to the development of AIDS varies. Rarely, some individuals develop complications of HIV that define AIDS within one year, while others remain completely asymptomatic after as many as 20 years from the time of infection. However, the time for progression from initial infection to AIDS is usually approximately eight to10 years. The reason why people experience clinical progression of HIV at different rates remains an area of active research.
What laboratory tests are used to monitor HIV-infected people?

Two blood tests are routinely 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, which determines the so-called viral load, directly measures the amount of virus in the blood.

In individuals not infected with HIV, the CD4 count in the blood is normally above 400 cells per cubic milliliter (mm3) of blood. HIV-infected people generally do not become at risk for complications until their CD4 cells are fewer than 200 cells per mm3. At this level of CD4 cells, the immune system does not function adequately and is considered suppressed. A declining number of CD4 cells means that 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 actually measures the amount of virus in the blood and may partially predict whether or not the CD4 cells will decline in the coming months. In other words, those people with high viral loads are more likely to experience a decline in CD4 cells and progression of disease than those with lower viral loads. In addition, the viral load is a vital tool for monitoring the effectiveness of new therapies and determining when drugs are and are not working. Thus, the viral load will decrease within weeks of initiating an effective antiviral regimen. If a combination of drugs is very potent, the number of HIV copies in the blood will decrease by as much as 100-fold, such as from 100,000 to 1,000 copies per ml of blood in the first two weeks and gradually decrease even further during the ensuing 12-24 weeks. The ultimate goal is to get viral loads to below the limits of detection by standard assays, usually less than 50 or 75 copies per ml of blood. When viral loads are reduced to these low levels, it is believed that as long as the patient consistently takes their medications the viral suppression will persist for many years.

Drug resistance testing also has become a key tool in the management of HIV-infected individuals. Details of these tests will be discussed later. Clearly, resistance testing is now routinely used in individuals experiencing poor responses to HIV therapy or treatment failure. In general, a poor response to initial treatment would include individuals who fail to experience a decline in viral load of approximately 100-fold in the first weeks, have a viral load of greater than 500 copies per ml by week 12, or have levels greater than 50 or 75 copies per ml by week 24. Treatment failure would generally be defined as an increase in viral load after an initial decline in a person who is believed to be consistently taking his or her medications. More recent guidelines from the U.S. Department of Health and Human Services (DHHS) (http://www.hivatis.org) and International AIDS Society-USA (IAS-USA) have suggested that resistance testing be performed in individuals who have never been on therapy to determine if they might have acquired HIV that is resistant to drugs.

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 years and are repeatedly found to have no virus in their blood experience a prompt rebound in the number of viral particles when therapy is discontinued. Consequently, the decision to start therapy must balance the risk versus the benefits of treatment. The risks of therapy include the short- and long-term side effects of the drugs, described in subsequent sections, as well as the possibility that the virus will become resistant to the therapy which can limit options for future treatment.

A major reason that resistance develops is the patient's failure to correctly follow the prescribed treatment, for example, by not taking the medications at the correct time. If virus 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 lamivudine (Epivir, 3TC), emtricitabine (Emtriva, FTC), and the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (Viramune, NVP), delavirdine (Rescriptor, DLV), and efavirenz (Sustiva, EFV). Thus, if these drugs are used as part of a combination of drugs that does not suppress the viral load to undetectable levels, resistance will develop rapidly and the treatment will lose its effectiveness. In contrast, HIV becomes resistant to certain other drugs, such as zidovudine (Retrovir, AZT), stavudine (Zerit, D4T), and protease inhibitors (PIs), over months. In fact, for some PIs whose effects are enhanced by giving them in combination with the PI, ritonavir (Norvir, RTV) to delay their clearance by the body, resistance appears to be markedly delayed. These drugs are discussed in more detail in subsequent sections, but it is important to note that when resistance develops to one drug, it often results in resistance to other related drugs, so called cross-resistance. Nevertheless, HIV-infected individuals must realize that antiviral therapy can be and typically is 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.

Factors to consider before starting antiviral therapy

One of the most controversial areas in 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 progression to AIDS, and treating individuals with AIDS postpones death. Consequently, most experts have long agreed 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 predictors of clinical progression, such as the number of CD4 cells. One can envision that as treatments become easier to take, better tolerated, and increasingly effective, therapy will begin to be started earlier in the course of infection.

When to start antiviral therapy

Guidelines for starting antiviral therapy have been proposed by panels of experts from several groups including the DHHS and IAS-USA. They recommend treating all patients who have symptoms and those who have CD4 cell counts of less than 350 cells per mm3. Recent data supporting even earlier initiation of therapy includes analyses of groups of patients followed over time. Although the data is imperfect, a recent study showed that those who started treatment with CD4 cells greater than 500 cells per mm3 actually were less likely to die than those who did not start treatment until their CD4 cells declined to less than 500 cells/mm3. In addition, there is increasing evidence that ongoing viral replication, even in the setting of high CD4 cells may be associated with damage to the brain, kidneys, heart, and possibly even liver. Along with these studies arguing for earlier treatment, there is growing evidence that currently used treatments are usually very well tolerated and effective in suppressing viral load. Guidelines will continue to change with time, but for now, the emphasis should be on discussing all of the potential benefits and risks of therapy and deciding when is best for each individual. Regardless, all agree that HIV is generally a slowly progressive disease, and therapy rarely needs to be started abruptly. Therefore, there usually is time for each patient to carefully consider options prior to starting treatment.

Before starting treatment, patients must be aware of the short- and long-term side effects of the drugs, including the fact that some long-term complications may not be known. Patients also need to realize that therapy is a long-term commitment and requires consistent adherence to the drugs. 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.

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 DHHS, the IAS-USA panel, and others. The DHHS guidelines are available at http://www.hivatis.org. The most recent IAS-USA guidelines were published in the Journal of the American Medical Association (JAMA) in the summer of 2008.

Antiviral treatment options have primarily included combinations of two nucleoside analogue reverse transcriptase inhibitors (NRTI), often referred to as "nucs," and one PI, typically with a low dose of RTV, a PI used at low doses to increase the level of the principle PI being used, so called "boosting." Alternative, preferred options include the use of two NRTIs with a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI), the latter often called "non-nucs." These NNRTI-containing combinations generally are easier to take than PI-containing combinations and tend to have different side effects. Recently, NRTIs were combined with the integrase inhibitor raltegravir (Isentress, RAL) with very good viral suppression and tolerability. This novel combination has now been approved by the Food and Drug Administration as another treatment option for those initiating therapy for the first time.

Nucleoside and nucleotide analogue reverse transcriptase inhibitors

NRTIs block an enzyme of the HIV called reverse transcriptase that allows HIV to infect human cells, particularly CD4 T cells or lymphocytes. Reverse transcriptase converts HIV genetic material, which is RNA, into human genetic material, which is DNA. The human-like DNA of HIV then becomes part of the infected person's own cells, allowing the cell to produce RNA copies of the HIV that can then go on to attack other not yet infected cells. Thus, blocking reverse transcriptase prevents HIV from taking over (infecting) human cells.

In general, most antiviral regimens for HIV disease contain a backbone of at least two NRTIs. The NRTIs include ZDV, d4T, ddI, zalcitabine (HIVID, ddC), 3TC, FTC, abacavir (Ziagen, ABC) or TDF. The NRTIs FTC and 3TC are highly related compounds and, although data is somewhat limited, most experts agree that they probably can be used interchangeably. That said, many combinations of NRTIs can be used together, with current guidelines generally recommending the fixed-dose combination of TDF with FTC with alternatives being the fixed-dose combinations of ABC/3TC or ZDV/3TC. Other options would include ddI plus 3TC or FTC. ABC has been associated with severe allergic reaction in approximately 5% of patients. Recent studies have shown that a blood test can be performed to determine who is at risk for this reaction so that the drug can be avoided in these individuals and be used in others with greater confidence that there will not be such a reaction.

Usual dosing schedule and meal restrictions for NRTIs

ZDV
d4T
ddl
ddC
3TC
ABC
TDF
FTC

Dose in each pill (mg)
300 30 or 40 100 or 400 0.75 150 or 300 300 300 200
Schedule
1 twice/day 1 twice/day
2 (100) twice/day or
1 (400) once/day
1 thrice/day 1 (150) twice/day or 1(300) once/day 1 twice/day or 2 once/day 1 once/day 1 once/day
Meal restrictions None None
30 minutes before or 60 minutes after a meal None None None None None

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

The following are available fixed-dose combination pills of NRTIs:

* ZDV/3TC (300 mg/150 mg) as Combivir; one twice per day


* ZDV/3TC/ABC (300 mg/150 mg/300 mg) as Trizivir; one twice per day


* ABC/3TC (600 mg/300 mg) as Epzicom; one per day


* TDF/FTC (300 mg/200 mg) as Truvada; one per day

These are standard doses for average-sized adults, and dosing may vary depending upon the weight of a patient. When TDF is taken with ddI, the standard ddI dose should be reduced to 250 mg per day and can be taken with food.

Nonnucleoside analogue reverse transcriptase inhibitors

Like NRTIs, NNRTIs block the reverse transcriptase enzyme preventing uninfected cells from becoming infected.

NNRTIs include NVP, DLV, EFV and the recently approved etravirine (Intelence, ETR). ETR was developed specifically to be an option for patients that have developed resistance to the earlier drugs in the class. NVP, DLV, and EFV are typically used with two NRTIs, and ETR is primarily being used as part of regimens for those with a history of different types of treatment to which they have developed resistance.

Usual dosing schedule and meal restrictions for NNRTIs



NVP
DLV
EFV
ETR

Dose in
each pill (mg)
200 200 600 100
Schedule
1 twice/day
(start with 1 once/day
for first 14 days)
2 thrice/day 1 once/day 2 twice/day



Meal restrictions

None

None

Avoid high-fat meals

After meals

NVP, nevirapine; DLV, delavirdine; EFV, efavirenz; ETR, etravirine.

For people without a history of drug resistance, there is a very effective fixed-dose combination pill that includes TDF with FTC and EFV as a single pill that can be taken once per day.

Protease inhibitors

PIs block the action of an HIV enzyme called protease that allows HIV to produce infectious copies of itself within HIV-infected human cells. Thus, blocking protease prevents HIV in already-infected cells from producing HIV that can infect other, not yet infected cells.

PIs include

* saquinavir (SQV) which comes as the hard gel capsule Invirase (INV),


* ritonavir (Norvir, RTV),


* indinavir (Crixivan, IDV),


* nelfinavir (Viracept, NFV),


* fosamprenavir (Lexiva, FPV),


* lopinavir/ritonavir (Kaletra, LPV/r)


* atazanavir (Reyataz, ATV),


* tipranavir (Aptivus, TPV), and


* darunavir (Prezista, DRV).

Each of these drugs has been shown to effectively reduce the viral load when used in combination with other active drugs.

Usual dosing schedule and meal restrictions for PIs


SQV+ IDV NFV FPV LPV/r ATV TPV DRV
Dose in each pill (mg) 500 400 625 700 200/50 200 or 300 250 400 or 600
Schedule 21 twice/day 2 every 8 hours
2 twice/day 2 twice/day or with RTV2 2 twice/day or 4 once/day 2 (200) or 1 (300) with RTV3 once/day 24 twice/day 8005 once/day or 600 twice/day
Meal restrictions With large meals
1 hour before or 2 hours after meals, or with low-fat meals
With meals None With meals With meals With meals With meals

SQV, saquinavir; IDV, indinavir; NFV, nelfinavir; FPV, fosamprenavir; LPV/r, lopinavir plus ritonavir; ATV, atazanavir; TPV, tipranavir; DRV, darunavir.

1Administered with RTV at a dose of 100 mg twice/day.
2FPV can be given without RTV in patients without resistance to PIs or at a dose of 1,400 mg once daily with either 100 mg or 200 mg of RTV once daily. In treatment-experienced patients, FPV is given at a dose of 700 mg twice daily with RTV 100 mg twice daily.
3ATV can be given alone at a dose of 400 mg once daily or at a dose of 300 mg once daily with RTV 100 mg once/daily.
4TPV is always given at a dose of 500 mg twice/daily with RTV 200 mg twice daily.
5DRV can be given to those with a history of drug resistance at a dose of 600 mg twice daily with 100 mg RTV twice daily. For those without resistance, it can be given at a dose of 800 mg (two 400 mg tablets) with 100 mg RTV once daily.

Although RTV is approved for treatment of HIV-infected patients at a dose of 600 mg twice daily, it is virtually never used at this dose because of severe side effects. Because of this, it is not included in the above table. However, PIs are frequently dosed with low doses of RTV. RTV delays the clearance of the other drugs from the system, making them easier to take and more effective. The dose of RTV varies depending upon which drugs it is being taken with and how it is being administered. The only PI that is not substantially affected by RTV is NFV.

LPV/r comes coformulated as Kaletra while all other RTV-containing regimens require taking RTV along with the other PI. In the case of TPV, RTV must be given as 200 mg with each dose of TPV twice per day. In contrast, ATV can be given without RTV at a dose of two 200 mg capsules once daily or 300 mg with 100 mg RTV once daily. The latter should always be used in PI-experienced subjects and when used in combination with TDF or NNRTIs which can reduce the drug levels of ATV. Similarly, FPV is also used differently in PI-naïve and experienced individuals. In treatment-naïve individuals, it can be given as two 700 mg tablets twice daily or two 700 mg tablets (1,400 mg total) with either 100 or 200 mg RTV, all once daily. In treatment-experienced patients, or when used with NNRTIs, it should be given as one 700 mg tablet with 100 mg RTV, both twice daily. The most recently approved of the PIs is DRV which was initially used exclusively in treatment-experienced patients with drug-resistant virus. In this setting, it is given as 600 mg with 100 mg RTV, both given twice daily. More recently, DRV was approved for those who have never been treated before given at a dose of two 400 mg tablets (800 mg total) once daily with 100 mg of RTV once daily.

Fusion inhibitors

A fusion inhibitor blocks an early step in the viral life cycle. Enfuvirtide (Fuzeon, T-20) attaches to the envelope surrounding the virus and prevents it from entering the CD4 cells. This prevents the infection of CD4 cells by HIV. T-20 is the first approved drug in this class. It is given as a twice daily subcutaneous injection (90 mg). It is used primarily in individuals who have developed resistance to other classes of drugs in order to create a new potent combination. Like all other antivirals, it is most useful in those taking other active drugs at the same time in order to optimize the chance of getting viral loads to undetectable levels and to prevent the development of drug resistance.

CCR5 antagonist

The first available drug in this class is called maraviroc (Selzentry, MVC), which was recently approved for use in combination therapy in treatment-experienced patients with drug-resistant virus who do not have detectable CXCR4-using virus as determined by a tropism assay. This is a unique drug in a new class that blocks viral entry by interacting with the CCR5 molecule on the surface of the CD4 cell. It is known that HIV first binds to the CD4 molecule on the surface of CD4 cells and then connects with the CCR5 or CXCR4 molecule. Only after this second step is the virus able to enter the cell. The CCR5 antagonist prevents viruses that use CCR5 from getting into the cell. What is unique about this drug compared to others is that 20%-50% of patients have viruses that are able to use the CXCR4 receptor. In these cases, CCR5 antagonists do not appear to be active at suppressing virus. Therefore, in order to know if the drug will work for a given patient, a new test needs to be performed, the so called "tropism" assay. This test will tell the provider and patient whether there is virus that uses CXCR4, in which case the patient would not be a candidate for MVC, or if they only have viruses that use CCR5, in which case MVC should be an active drug. Without tropism results, it is impossible to know whether MVC will be an active drug for a given patient.

MVC is dosed at either 300 mg or 150 mg twice daily, depending upon what other drugs it is given with. If the patient is taking any RTV, then they would usually receive the 150 mg dose. If RTV is not being used as part of the regimen, they would generally receive the 300 mg dose and sometimes even higher if it is being used with drugs like ETR. HIV providers are aware that whenever using any anti-HIV medications attention must be given to possible drug interactions.

Integrase inhibitor

The first available drug in this class is RAL and represents a new drug in a new class that appears to be very potent at suppressing HIV in all patients who have never been on this drug or other integrase inhibitors in development. It was initially approved for treatment-experienced patients with drug-resistant virus. It is also now approved for those starting therapy for the first time. The approved dose of RAL is 400 mg twice daily.

Drugs in development

There are many drugs currently in development that may simplify therapy and provide important options for those who have developed extensive drug resistance. Drugs that show promise in early clinical trials are often made available by the manufacturer with approval of the Food and Drug Administration (FDA), to certain individuals. In particular, these drugs are used in individuals no longer responding or able to tolerate currently available agents. The most promising new drugs at this time are those in existing classes, such as a new integrase inhibitor, CCR5 antagonist, and NNRTI.

Side effects of HIV therapy

There are many potential side effects associated with antiviral therapies. The most common ones for each class of drug are summarized in readily available product information. Some specific toxicities are summarized by class below.

NRTIs

Most NRTIs can cause mild nausea and loose stools. In general, these symptoms resolve with time.

ZDV has been associated with decreased production of blood cells by the bone marrow, most often causing anemia, and occasionally hyperpigmentation (most often of the nails).

D4T can damage nerves and cause peripheral neuropathy, a neurological condition with numbness and/or tingling of the feet and hands, and inflammation of the pancreas (pancreatitis) that causes nausea, vomiting, and mid upper abdominal pain.

DDI also causes pancreatitis and, to a lesser extent, peripheral neuropathy. Peripheral neuropathy can become permanent and painful, and pancreatitis can be life-threatening if therapy is not discontinued. The drug ddC also is associated with peripheral neuropathy as well as oral ulcers.

ABC can cause a hypersensitivity reaction during the first two to six weeks of therapy in approximately 5% of individuals. The hypersensitivity reaction most often causes fever and other symptoms, such as muscle aches, nausea, diarrhea, rash, or cough. The symptoms generally get worse with each dose of ABC and, if suspected, therapy must be discontinued and never restarted for fear of developing a life-threatening reaction. There is now a simple blood test that can be performed to determine whether a patient is at risk for developing the hypersensitivity reaction. If the test is positive, the patient should never receive this medication.

TDF is generally well tolerated although there may be rare kidney damage.

FTC is also well tolerated except for the occasional development of hyperpigmentation, most often on the palms and soles. This hyperpigmentation occurs more frequently in people of color.

Although all NRTIs can be associated with lactic acidosis (a serious condition in which lactic acid accumulates in the blood), it may occur more often with some drugs, such as d4T. Although this complication of treatment is rare, it can be severe and life-threatening. Early symptoms of lactic acidosis are nausea, fatigue, and sometimes, shortness of breath. Lactic acidosis needs to be watched for and, if suspected, requires that therapy be discontinued until symptoms and laboratory test abnormalities resolve.

There has been a great deal of attention given to the more recently identified problem of "lipodystrophy." Individuals suffering from this syndrome can be categorized as having lipohypertrophy (fat accumulation) syndromes, such as the "buffalo hump" on the back of the neck, breast enlargement, or increased abdominal girth. Others primarily suffer from lipoatrophy with fat loss under the skin with complaints of prominent veins on the arms and legs, sunken cheeks, and decreased gluteal (buttock) size. These syndromes appear to be related to multiple factors including, but not limited to, drug therapy. The NRTIs appear to be most closely linked to lipoatrophy, in particular D4T and to a lesser extent ZDV. In fact, some studies have suggested slow accumulation of fat in those who modify the NRTI component of their regimen. Some NRTIs also have been linked to elevation in lipid (fat) levels in the blood. While switching therapy is always a consideration in those experiencing potential drug-related toxicity, this should only be done under the careful supervision of an experienced HIV provider.

NNRTIs

The most common side effect associated with NNRTIs is a rash, typically occurring during the first weeks of therapy. This is most common in individuals treated with NVP. In this case, the overall risk of rash is reduced if therapy is started as a single, 200 mg NVP pill once per day during the first two weeks before increasing to the full dose of 200 mg twice per day. If the rash is mild, therapy usually can be continued if antihistamines are given, and if the rash resolves, treatment with the NNRTI can be continued. If the rash is severe, associated with liver inflammation or blisters, changes in the mouth or around the eyes, or with high fevers, therapy with the NNRTI usually needs to be discontinued. Decisions regarding continuing or stopping treatment need to be made with the primary-care provider. In some patients, NVP can cause a severe allergic reaction characterized by fever, rash, and severe liver inflammation. Recent data suggests that the groups at the greatest risk for the severe reaction are those with stronger immune systems, such as HIV-uninfected people given this treatment after an exposure to HIV, women with CD4+ T cells >250 cells per mm3 and men with CD4+ T cells >400 cells per mm3. There is also likely to be increased risk in pregnant women and individuals with other underlying liver diseases. Consequently, NVP probably should not be used in any of these groups, or if used, used with caution. In addition, whenever NVP is started, liver tests that are markers for liver inflammation should be monitored at regular intervals during the first several months of treatment.

Side effects associated with EFV are mostly dizziness, confusion, fatigue, and vivid dreams. These tend to be most prominent during the first weeks of therapy and then often decrease in severity. It is generally recommended that EFV be taken at bedtime so that the patient is asleep during the time dizziness and confusion may be most severe. It is also noteworthy that there may be an increased risk of depression associated with the use of this drug, and it should be used with caution in those with poorly managed depression. Rash and liver inflammation can occur with both EFV and DLV, and these drugs may also be linked to abnormalities of lipids in the blood.

The most common side effect reported with the most recently approved NNRTI, ETR, is rash and it was generally mild and rarely required that medications needed to be stopped.

PIs

There are currently nine approved PIs that all have distinct toxicities. The most common side effects associated with these drugs are nausea and diarrhea, which occur more often with some PIs than others. For example, diarrhea is more common with NFV than other PIs but can occur with any and all drugs in this class. Many of the drugs in this class also increase blood lipid levels, some more than others with ATV and possibly DRV appearing to have less effect on lipids than other drugs in the class. Other unique toxicities associated with various PIs are kidney stones with IDV and ATV and increased blood bilirubin levels with IDV and ATV. Some of these drugs also have been associated with elevations in blood sugar levels and bleeding in hemophiliacs. Finally, little is known regarding the role these drugs may play in the development of lipodystrophy.

Fusion inhibitors

The only drug in this class is T-20, which is administered as a twice daily subcutaneous injection. The most common side effect is redness and pain at the site of injection. Rarely, infection can occur at the injection site. There also are reports of generalized allergic reactions.

CCR5 antagonist

Although there were some early concerns of liver inflammation for drugs in this class, MVC appeared to be well tolerated in clinical trials without any specific toxicities attributable to the drug. However, it is a new drug in a new class and the first to actually target the cell. For these reasons, longer follow-up from clinical trials and those followed in the clinic will be very important for assessing the overall safety of the drug.

Integrase inhibitor

RAL has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems that need to be watched for when starting this or any new medications. As with all new medications, more data will come from extended follow-up of patients in the clinic and in clinical trials.

Monitoring antiviral therapy

The goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing important side effects or selecting for drug resistant virus. Currently, the best marker of a drug's activity is a decrease in the viral load.

Ideally, prior to initiating treatment, the viral load and the CD4 cell count should be checked and the viral load test then repeated after approximately four weeks of treatment. If the patient is beginning a regimen that includes two to three drugs for which the patient's virus does not appear to be resistant, it is expected that the amount of virus should decrease by at least 100-fold during this interval. The ultimate goal is for the viral load to decrease to undetectable levels which should occur by approximately 24 weeks. Those that are not having an appropriate response to therapy need to be questioned to make sure that they are taking their medications correctly, and if not, why. If the viral load is not going to undetectable levels and the patient is taking the medications correctly, then it is likely that there is a resistant virus to some of the medications. Drug-resistance testing then should be performed and the patient managed as described in the next section

Viral load increasing while on HIV therapy

If the patient does suppress their virus to undetectable levels on antiviral therapy but then develops detectable virus, several things should be considered. First, it must be established that the patient is taking the medications correctly. If they are missing doses, then every effort must be made to understand why this is happening and correct the situation, if possible. If the poor adherence is a result of drug side effects, efforts should be directed toward managing the side effects or changing to a better-tolerated regimen. If poor adherence is occurring because of the medication schedule of dosing, new strategies should be discussed such as placing medications in a pillbox, associating the dosing with certain daily activities such as tooth brushing or possibly changing the regimen. Finally, if the reason for poor adherence is depression, substance abuse, or another personal issue, these issues need to be addressed and managed.

It is important to remember that sometimes, for reasons not entirely understood, the viral load can briefly increase. Unexpected increases, therefore, necessitate repeated testing of the viral load before any clinical decisions are made. If, however, the viral load is continually detected despite proper adherence to the prescribed therapy, serious consideration must be given to the possibility that the virus has become resistant to one or more of the medications being given. There is now an abundance of data showing that the use of drug resistance tests can improve the response to a follow-up regimen. Testing can be used to determine if an individual's HIV has become resistant to one or more of the drugs that are being taken. There are currently two main types of resistance tests available in the clinic: one that is called a genotype and the other a phenotype assay. The former looks for mutations in the virus and the latter the actual amount of drug it takes to block infection by the patient's virus. The genotype test is very helpful in those being screened for the presence of resistant virus prior to initiating treatment and those experiencing viral rebound on one of their first treatment regimens. The phenotype test is particularly useful in those who are highly treatment-experienced and have substantial amounts of drug resistance. The information derived from these tests, along with a tropism test will ultimately tell the provider which of the many approved drugs are likely to be fully active against the specific patient's virus. Using this information, the goal is to include at least two and ideally three fully active drugs in the next regimen in order to optimize the chances of suppressing the viral load to undetectable levels.

Missing doses or stopping antiviral therapy

It is strongly advised that individuals on an antiviral regimen not miss any doses of their medications. Unfortunately, life is such that doses often are missed. Reasons for missing doses range from just forgetting to take the medication, leaving town without the medication, or because of 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 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 should work with their HIV provider to restart therapy as soon as is feasible. Stopping antivirals is associated with some risks of developing drug resistance, and those who wish to stop therapy for any one of a number of reasons should discuss this with their health-care provider in advance to establish the best strategy for safely accomplishing this.

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

There are theoretical reasons why patients identified with HIV around the time they are first infected (primary, acute infection) may benefit from the immediate initiation of potent antiviral therapy. Preliminary evidence 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 to work against HIV. Thus, patients may gain improved control of their infection while on therapy and perhaps even after therapy is stopped. 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 is that patients with primary infection should be referred to clinical studies where the potential role of therapy can be discussed and further explored. If emotional or social situations make adherence to such treatment questionable, however, the patients are clearly better off delaying therapy.

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 first major advance in this area came with studies giving ZDV after the first trimester of pregnancy, then intravenously during the delivery process, and then after delivery to the newborn for six weeks. This treatment showed a reduction in the risk of transmission 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 side 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 nonpregnant women with HIV. Exceptions would be during the first trimester, where therapy remains controversial, and avoiding certain drugs that may cause greater concern for fetal toxicity, such as EFV.

All HIV-infected pregnant women should be managed by an obstetrician with experience in dealing with HIV-infected women. Maximal obstetric precautions to minimize transmission of the HIV virus, such as avoiding scalp monitors and minimizing labor after rupture of the uterine membranes, should be observed. 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 where the risk of transmission may be increased. Breastfeeding should be avoided if alternative nutrition for the infant is available since HIV transmission can occur by this route.
What about treating non-HIV-infected 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 uninfected people who are inadvertently exposed by the early administration of antiviral therapy. Because the risk of infection after most isolated exposures is relatively small and the number of patients needed for study would be great, formal studies are difficult to perform. 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 needle stick from an infected person take antiviral medication for four weeks in order to reduce the risk of infection. Guidelines now recommend similar preventive treatment for people with sexual exposures to HIV. Those individuals considering this type of preventative treatment, however, must be aware that post-exposure treatment cannot be relied upon to prevent HIV infection. Moreover, such treatment is not always available at the time most needed and is probably best restricted to unusual and unexpected exposures, such as a broken condom during intercourse. Although regimens with two or three drugs generally are recommended for those exposed in the health-care setting, the best therapy for sexual exposure still is unknown and ideally should be initiated within hours of exposure and certainly within the first several days. Updated guidelines are published and available at http://www.hivatis.org.

What can be done for people who have severe immunosuppression?

Although one goal of antiviral therapy is to prevent the development of immune suppression, some individuals are already immunosuppressed when they first seek medical care. In addition, others may progress to that stage as a result of resistance to antiviral drugs. Nevertheless, every effort must be made to optimize antiviral therapy in 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 http://www.hivatis.org.

In summary, patients with a CD4 cell count of less than 200 should receive preventative treatment against Pneumocystis jiroveci with trimethoprim/sulfamethoxazole (Bactrim, Septra), given once daily or three times weekly. If they are intolerant to that drug, patients can be treated with an alternative drug such as dapsone or atovaquone (Mepron). Those patients with a CD4 cell count of less than 100 cells per mm3 who also have evidence of past infection with Toxoplasma gondii, which is usually determined by the presence of toxoplasma antibodies in the blood, should receive trimethoprim/sulfamethoxazole. Toxoplasmosis is an opportunistic parasitic disease that affects the brain and liver. If a person is using dapsone to prevent Pneumocystis jiroveci, pyrimethamine and leucovorin can be added once a week to dapsone to prevent toxoplasmosis. Finally, patients with a CD4 cell count of less than 50 cells per mm3 should receive preventive treatment for Mycobacterium avium complex (MAC) infection with weekly azithromycin (Zithromax), or as an alternative, twice daily clarithromycin (Biaxin) or rifabutin (Mycobutin). MAC is an opportunistic bacterium that causes infection throughout the body.
What is in the future for HIV-infected individuals and for those at risk to contract HIV?

Trends continue toward simplifying drug regimens to improve adherence and decrease side effects. In addition, the availability of multiple new drugs in new classes have made it possible to suppress viral load to undetectable levels even in the most treatment-experienced patients. With such great success in treatment, it has been disappointing that there has been much less progress in research related to prevention and establishing a cure. Research is attempting to find ways to enhance the body's natural defenses against HIV in order to control viral growth on and off therapy. Similarly, innovative studies are under way to purge or eliminate the HIV from the body. Although all of this research is exciting, it has been met with little success and for at least the near future, patients will need to remain on antiviral therapy.

The good news is that the development of antiviral therapy has led to marked declines in AIDS-related deaths in many parts of the world. The majority of infected individuals, however, do not have access to the expensive antiviral medications. Accordingly, the best hope for limiting the current epidemic of HIV 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 through 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, and often is 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 eight to 10 years.
3. The stage of symptomatic infection, in which the body's immune (or defense) system has been suppressed and 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 combination be well tolerated so that it can be followed consistently without missing doses.