Sunday, August 21, 2011

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.

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.

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.

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.

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) ( 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.

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.