HIV/AIDS

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 sarcoma. The patients were noted to have a severe reduction of 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 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 the saliva and urine, and some can provide results within 20 minutes of testing.

How is HIV spread (transmitted)?

HIV is present 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 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. 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 antibodies to HIV 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 contains large amounts of HIV. 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 the blood or genital secretions of 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 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 2 to 6 weeks of an exposure, the majority of infected persons will have a positive HIV antibody test, with virtually all being positive by 6 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. 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 persons 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 persons will become symptom-free (asymptomatic) after this phase of primary infection. During the asymptomatic phase, infected individuals will know whether or not they are infected only if a test for HIV is done. Therefore, anyone who might possibly have been exposed to HIV should seek testing even if they are not experiencing 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 (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. 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 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 individuals not infected with HIV, the CD4 count in the blood is normally above 500 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. Patients who have this CD4 count (fewer than 200 cells per mm3) are referred to as being immunosuppressed. A declining number of CD4 cells means 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. 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 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. 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 the viral suppression may 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 8 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 have suggested that resistance testing be considered in individuals who have never been on therapy, particularly in the first months or even years of infection, to determine if they might have acquired HIV that is resistant to drugs. In fact, the most recent DHHS guidelines (May 4, 2006) formally recommend such testing be performed in all individuals starting therapy for the first time.

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 6 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 non-pregnant 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. 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. 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. Updated guidelines for managing HIV-infected women are updated on a regular basis and can be found at www.hivatis.org.

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 are repeatedly found to have no 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 an individual advancing to the stage of symptomatic disease against the risks associated with therapy. 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 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, for example, by not taking the medications at the correct time. In addition, 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 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 (EpivirTM, 3TC), emtricitabine (EmtrivaTM, FTC) and the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (ViramuneTM, NVP), delavirdine (RescriptorTM, DLV), and efavirenz (SustivaTM, 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 be ineffective. In contrast, HIV becomes resistant to certain other drugs, such as zidovudine (RetrovirTM, AZT), stavudine (ZeritTM, 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 (NorvirTM, RTV) to prevent 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 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 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 predictors of clinical progression, such as the number of CD4 cells and the viral load. Thus, several studies have demonstrated an increased risk of disease advancement in individuals with a CD4 cell count of less than 200 to 350 cells per mm3. 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. In fact, it is likely that there will never be a proper study to answer this question. Therefore, the decision as to when to start treatment continues to be individualized, balancing the known benefits of therapy versus the risks, such as toxicity and the potential development of drug resistance. One can envision that as treatments become easier to take, better tolerated, and increasingly effective, that 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 the DHHS and the IAS.- They recommend treating all patients who have symptoms and those who have CD4 cell counts of less than 200, and, perhaps, 350 cells per mm3 or in those with higher viral loads. Of late, there has been a trend towards focusing more on CD4 cell counts than viral loads in making the decision as to when therapy should be started in asymptomatic individuals. The DHHS guidelines have suggested that therapy be considered even in those with higher CD4 cell counts if viral load is greater than 100,000 copies per mL, or, at least, that CD4 cell counts be followed more closely in this group. The IAS-USA guidelines have tended to use a viral load cutoff for considering therapy in asymptomatic individuals with CD4 cells greater than 100,000 copies per mL. However, it should be kept in mind that the risk of developing short- and long-term toxicity from treatment, and the problem with getting patients to adhere to treatment, are major limitations of therapy that need to be considered before treatment is initiated in order to optimize the chances of success and to avoid the development of drug resistance. 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 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. The patients also need to realize that therapy is a long-term commitment and requires an extraordinary level of adherence to the regimen of 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 and the Henry J. Kaiser Foundation and the IAS-USA Panels. The DHHS guidelines are only one of several developed to provide recommendations for the treatment of HIV disease (www.hivatis.org). The most recent IAS-USA Guidelines were published in the Journal of the American Medical Association (JAMA) in the summer of 2004.

Antiviral treatment options have primarily included combinations of 2 nucleoside analogue reverse transcriptase inhibitors (NRTI), often referred to as "nucs," and 1 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. Alternative preferred regimens include NRTIs with NNRTIs, often called "non-nucs." These NNRTI-containing combinations generally are easier to take than PI-containing combinations and tend to have different side-effects. Although there has been a great deal of interest in the possibility of using an all NRTI regimen, usually as 3 drugs from this class in combination, studies show that, at best, they are less potent than other treatment options. In addition, there are some triple NRTI combinations that have been shown not to be effective and that should be avoided, such as the nucleotide analogue RTI tenofovir (VireadTM, TDF) with 3TC and abacavir (ZiagenTM, ABC) and TDF, didanosine (VidexTM, ddI) and ABC. Results using combinations of 4 NRTIs are limited at this 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 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 persons' own cells, allowing the cell to produce 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 (HIVIDTM, ddC), 3TC, FTC, ABC or TDF. 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 either ZDV or TDF be used with 3TC or FTC. Alternative regimens that include ABC with 3TC (or FTC) and ddI with 3TC (or FTC) have been shown to be quite effective in some studies. Because of drug interactions and toxicities it is generally recommended that 3TC not be used with FTC or d4T with either ZDV or ddI. In addition, recent data has suggested that there may be reduced efficacy and possibly increased toxicity when TDF and ddI are used together. In fact, in the most recent DHHS guidelines it is explicitly stated that this NRTI combination should not be used with EFV in light of the surprisingly poor virologic response.

Usual dosing schedule and meal restrictions for NRTIs

ZDV, zidovudine; d4T, stavudine; ddI, didanosine; ddC, zalcitabine; 3TC, lamivudine; ABC, abacavir; TDF, tenofovir; FTC, emtricitabine.
Available fixed-dose combination pills and dosing include:

• ZDV/3TC (300 mg/150mg) as CombivirTM one twice per day
• ZDV/3TC/ABC (300mg/150mg/300mg) as TrizivirTM one twice per day
• ABC/3TC (600mg/300mg) as EpzicomTM one per day
• TDF/FTC (300mg/200mg) as TruvadaTM 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, and EFV. The majority of experience using NRTIs in combination with an NNRTI is with either ZDV, d4T, TDF or ddI combined with 3TC as the NRTI backbone. These combinations are all considered reasonable starting regimens. It should also be noted that there is substantial data suggesting that combinations made up of 2 NRTIs with NVP is also a viable option.

Usual dosing schedule and meal restrictions for NNRTIs

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 InviraseTM (INV), with the recent discontinuation of the development of the soft gel capsule FortovaseTM (FTV).
• Ritonavir, (NorvirTM, RTV)
• Indinavir (CrixivanTM, IDV)
• Nelfinavir (ViraceptTM, NFV)
• Amprenavir (AgeneraseTM, APV), recently discontinued and replaced by Fos-amprenavir
• Fos-amprenavir (LexivaTM, FPV)
• Lopinavir/ritonavir (KaletraTM, LPV/r), recently modified to a new tablet formulation from the previous soft gel capsule
• Atazanavir (ReyatazTM, ATV)
• Tipranavir (AptivusTM, TPV)

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

Saquinavir was originally formulated as a hard gel capsule called InviraseTM and was taken as 3 capsules three times/day. It was then reformulated as a soft gel capsule called FortovaseTM that had better intestinal absorption and prescribed as 6 capsules three times per day. Currently saquinavir is typically given with boosting by ritonavir. When SQV is combined with RTV, InviraseTM may be better tolerated with sustained high levels of SQV in the blood that are associated with good viral suppression. Consequently, this drug is now routinely given as InviraseTM.

Combinations of PIs, along with the 2 NRTIs, have been used in clinical practice with increasing frequency. Most PI combinations have used low dose RTV, which is a potent inhibitor of the clearance of other drugs used for treating HIV. This means that RTV slows the elimination of other drugs from the body. The idea of using RTV 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, as well as increase levels of the therapeutic agent. The only PI that is not substantially affected by RTV is NFV.

LPV/r comes coformulated as KaletraTM 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 for this to be a therapeutic agent. In contrast, ATV can be given without RTV at a dose of two 200 mg capsules once-daily or two 150 mg capsules 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 those naïve individuals, it can be given as two 700 mg tablets twice-daily or two 700 mg tablet with 200 mg RTV once-daily. In treatment with experienced subjects or when used with NNRTIs it should be given as one 700 mg tablet with 100 mg RTV twice daily. Typical dosing for initial therapy for the PIs with RTV include:

• once daily SQV with RTV (1600 mg/200 mg)
• once daily FPV with RTV (1400 mg/200 mg)
• twice daily FPV with RTV (700 mg/100 mg)
• daily ATV with RTV (300 mg/100 mg)
• twice daily TPV with RTV (500 mg/200 mg)

Fusion Inhibitors

Fusion inhibitors include a new class of drugs that block an early step in the viral life cycle. Enfuvirtide attaches to the envelope surrounding the HIV and prevents it from entering the CD4 cells. This prevents the infection of CD4 cells by HIV. Enfuvirtide (FuzeonTM, T-20) is the first approved drug in this class. It is given as a twice daily, 90 mg, subcutaneous injection. It is used primarily in individuals who have developed resistance to other classes of drugs in order to create a new potent combination treatment and rarely in treatment naïve individuals. Nevertheless, like all other antiretrovirals, it remains 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.
Drugs in Development

There are many drugs currently in development that may simplify therapy and provide important options for those that have developed extensive drug resistance. Drugs that show promise in early clinical trials are often made available by the manufacturers, 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 promising new drugs are made available as part of "compassionate-use" or "expanded-access" programs. One such drug is a PI called darunavir (TMC114) which is given at two 300 mg tablets with 100 mg RTV twice daily. Preliminary data shows that this may reduce viral loads even in those with substantial amounts of drug resistant virus in their blood. Another promising drug in development in an existing class is a new NNRTI call etravirine (TMC 125) which has been shown to be active against virus resistant to currently licensed NNRTIs. Other promising drugs in development include those that target the HIV co-receptors CXCR4 and CCR5 and the enzyme, integrase. Studies to define the safety and efficacy of several drugs in these classes are now in clinical trials.

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 2-6 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.

The newest drugs in this class are TDF and FTC. 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 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 a HIV treatment 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 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. NVP also can cause liver inflammation and in some patients 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 persons 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.

PIs

There are currently eight 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 with the exception being ATV. Other unique toxicities associated with various PIs are kidney stones with IDV, 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.

Monitoring antiviral therapy

Stated briefly, the goals of antiviral therapy are to enhance immunity and delay or prevent clinical advancement to symptomatic disease without inducing important 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 copies per mL, 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 fluctuate spontaneously and changes 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 treatment with careful observation. Patients who have taken numerous antiviral drugs previously would be expected to have a less than 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 his or her medications.

Viral load increasing while on HIV therapy

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 this case, the reason for failing to follow treatment must be established. If the poor adherence is a result of drug side effects, 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, these issues need to be addressed and managed. If necessary, the antiviral medications can be withheld until the issue has been resolved.

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 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. It is suffice 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 expertise in antiviral therapy. Generally, the specialist will change the regimen to one that is likely to be active and then closely follow the virologic response. There is now an abundance of data showing that the use of drug resistance tests can improve the response to a second regimen. Testing can be used to determine if an individuals HIV has become resistant to one or more of the drugs that are being taken. Drug resistance testing is expensive and at times can be difficult to interpret. Therefore, it is best used by those with expertise in this area. Drug resistance testing is currently recommended for all subjects experiencing increases in viral load while on therapy as well as in the setting of pregnancy. Guidelines also are increasingly recommending that such testing be performed in those recently infected who have never been on antiviral therapy because of the increasing frequency with which people are being infected with HIV virus that already is resistant to drugs.

Missing doses or stopping antiviral therapy

It is strongly advised that individuals on an antiviral regimen should 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 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. Nevertheless, stopping 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.