Human Immunodeficiency Virus (HIV)

• The human immunodeficiency virus (HIV) is a type of virus called a retrovirus, which can infect humans when it comes in contact with tissues 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, 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 without treatment.
  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. These mutations enable 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 are those that effectively suppress viral replication in the blood and also are well tolerated and simple to take so that people can take the medications consistently without missing doses.

The history of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) dates back to 1981, when gay men with symptoms and signs of a disease that now are considered typical of 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 (CD4 cells) that is an important part of the immune system. These cells, often referred to as T cells, help the body fight infections. Shortly thereafter, this disease was recognized throughout the United States, Western Europe, and Africa. In 1983, researchers in the United States and France described the virus that causes AIDS, now known as HIV, belonging to the group of viruses called retroviruses. While HIV infection is required to develop AIDS, the actual definition of AIDS is the development of a low CD4 cell count (<200 cells/mm³) or any one of a long list of complications of HIV infection ranging from a variety of so-called "opportunistic infections," cancers, neurologic symptoms, and wasting syndromes.

In 1985, a blood test became available that measures antibodies to HIV that are the body's immune response to the HIV. The test that for decades had been most commonly used for diagnosing infection with HIV was referred to as an ELISA. If the ELISA found HIV antibodies, the results needed to be confirmed, typically by a test called a Western blot. Recently, tests have become available to look for these same antibodies in saliva, some providing results within one to 20 minutes of testing. As a result, the FDA has approved home HIV antibody testing that is self-administered using saliva. Antibodies to HIV typically develop within several weeks of infection. During this interval, patients have virus in their body but will test negative by the standard antibody test, the so-called "window period." In this setting, the diagnosis can be made if a test is used that actually detects the presence of virus in the blood rather than the antibodies, such as tests for HIV RNA or p24 antigen. Several tests are now approved that measure both HIV antibodies and p24 antigen, shrinking the duration of the window period from infection to diagnosis in which the infection is difficult to detect. In fact, federal guidelines currently recommend that HIV screening tests be performed with these assays and, if they are positive, that a confirmatory antibody test be performed that will determine if the patient has HIV-1, the most common form of HIV circulating around the world, or HIV-2, a related virus that occurs most frequently in Western Africa. If the confirmatory antibody test is negative, then there remains the possibility that the original test detected viral p24 antigen and not antibodies, and therefore infection still is likely. Therefore, the recommendations are that if the confirmatory antibody test is negative a test for HIV RNA test for the presence of virus, should be performed. If the antibody is negative and the viral test is positive, the patient is diagnosed with acute or primary HIV infection and will develop a positive antibody test over the ensuing weeks.

Although the tests for detecting HIV infection continue to improve, they still require that people volunteer for testing. It is estimated that approximately 15% of those infected with HIV in the United States are unaware of their infection because they have never been tested. In order to decrease the number that are unaware of their HIV infection status, in 2006, the Centers for Disease Control and Prevention recommended that all people between 13 and 64 years of age be provided HIV testing whenever they encounter the health care system for any reason. In addition, resources are available to facilitate people finding local HIV testing centers (https://gettested.cdc.gov/).

HIV is present to variable degrees in the blood and genital secretions of virtually all untreated 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, 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 mother-to-child transmission 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 weeks to turn positive after infection occurs, both partners would need to test negative for at least 12 and up to 24 weeks 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. Recent data has convincingly demonstrated that once a person has virologic suppression in blood after least six months of treatment, their likelihood of transmitting HIV to an uninfected partner, even without condoms, is virtually zero if they continue treatment.

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.

Risk factors for acquiring HIV infection include increased amounts of virus in fluids and/or breaks in the skin or mucous membranes which also contain these fluids. The former primarily relates to the viral load in the infected person's blood and genital fluids. In fact, when the former is high, the latter usually is also quite elevated. This is in part why those on effective antiretroviral therapy are less likely to transmit the virus to their partners. In fact, recent data has demonstrated that if a person's plasma viral load is consistently undetectable for at least six months of therapy, the risk of transmitting HIV to their partner is essentially zero, leading to the phrase that undetectable equals untransmittable. With regard to disruption of mucous membranes and local trauma, this is often associated with the presence of other sexually transmitted diseases (for example, herpes and syphilis) or traumatic sexual activities. Another risk factor for HIV acquisition by a man is the presence of foreskin. This has most convincingly been demonstrated in high-risk heterosexual men in developing countries where the risk declines after adult male circumcision.

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, in the absence of antiretroviral therapy, the time for progression from initial infection to AIDS is approximately eight to 10 years. The reason why people experience clinical progression of HIV at different rates remains an area of active research.

Within weeks of infection, many people will develop the varied symptoms of primary or acute infection, which typically has been described as a mononucleosis- or influenza-like illness but can range from minimal fever, aches, and pains to very severe symptoms. 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-positive people develop these symptoms. It also is also not completely known 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 may still be negative (the so-called window period). 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 or the use of an assay that identifies HIV p24 antigen, for example, the new fourth-generation antibody/antigen combination test. Identifying and diagnosing individuals with primary infection is important to assure early access into care and to counsel them regarding the risk of transmitting to others. The latter is particularly important since patients with primary HIV infection have very high levels of virus throughout their body and are likely to be highly infectious. There is no definitive data showing that initiation of antiretroviral therapy during this early stage of infection results in clinical benefits. Nevertheless, it is generally thought that the benefits of reducing the size of the HIV in the body, preserving select immune responses, and reducing transmissibility favors early treatment. 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.

Shortly after primary infection, most HIV-positive individuals enter a period of many years where they have no symptoms at all. During this time, CD4 cells may gradually decline, and with this decline in the immune system, patients may develop the mild HIV symptoms and signs such as vaginal or oral candidiasis thrush (a fungal infection), fungal infections of the nails, a white brush-like border on the sides of tongue called hairy leukoplakia, chronic rashes, diarrhea, fatigue, and weight loss. Any of these symptoms should prompt HIV testing if it is not being done for other reasons. With a further decline in function of the immune system, patients are at increasing risk of developing more severe complications of HIV, including more serious infections (opportunistic infections), malignancies, severe weight loss, and decline in mental function. From a practical perspective, most physicians think about patients with HIV diseases as having no symptoms, mild symptoms, or being severely symptomatic. In addition, many would characterize a patient's level of immunosuppression by the degree and type of symptoms they have as well as the CD4 cell count. The Centers for Disease Control and Prevention have defined the presence of a long list of specific diseases or the presence of less than 200 CD4 cells per mm³ as meeting a somewhat arbitrary definition of AIDS. It is important to note that with effective antiretroviral therapy many of the signs and symptoms of HIV as well as severity of immunosuppression can be completely reversed, restoring even the most symptomatic patients to a state of excellent health.

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 receptive anal intercourse without a condom when the partner is not on antiretroviral therapy. In this case, the risk of infection may be as high as 3%-5% for each exposure. The risk is probably less for receptive 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.

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.

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 mm³ of blood. People generally do not become at risk for HIV-specific 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 severely 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 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 hundredfold, 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 20 to 50 copies per mL of blood. When viral loads are reduced to these low levels, it is believed that the viral suppression will persist for many years as long as the patient consistently takes their medications.

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 hundredfold in the first weeks, have a viral load of greater than 500 copies per mL by week 12, or have levels greater than 50 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. Since drug-resistant virus can be transmitted, guidelines from the U.S. Department of Health and Human Services (DHHS) (https://aidsinfo.nih.gov/) and International Antiviral 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.

First of all, there is no evidence that people infected with HIV can be cured by the currently available therapies, although research related to curing people of infection will be discussed later. In general, those who are treated for years and are repeatedly found to have no virus in their blood by standard viral load assays will 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. The risks of both of these problems are quite small with the treatment options currently available.

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 the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (Epivir, 3TC) and emtricitabine (Emtriva, FTC), the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (Viramune, NVP), delavirdine (Rescriptor, DLV), efavirenz (Sustiva, EFV), and rilpivirine (Edurant, RPV), as well as the integrase strand transfer inhibitors (InSTIs) such as raltegravir (Isentress, RAL) and elvitegravir (Vitekta, EVG). Thus, if these drugs are used as part of a combination of agents that do 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 other drugs, such as the boosted protease inhibitors (PIs), over months. Resistance also seems to be relatively uncommon with some of the newer InSTIs, such as dolutegravir (tivicay, DTG) and bictegravir (BIC), which is only available as a combination pill (Biktarvy) with tenofovir alafenamide (TAF) and emtricitabine (FTC). 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.

What factors should be considered before starting antiviral therapy?

Until very recently, one of the biggest questions related to the management of HIV disease was the optimal time to start antiviral treatment. For some time, there had been very strong data demonstrating that therapy is appropriate for those with CD4 cells numbering less than 350 cells/mm³ in the blood. There have also long been strong recommendations to treat patients with select conditions regardless of their CD4 cell count, such as during pregnancy in order to prevent transmission of HIV to the baby or those who have HIV-associated renal disease or chronic hepatitis B infection where the antiviral treatment for HIV also treats the hepatitis virus. There are now several very large studies that have shifted all guidelines around the world to recommending treatment of all HIV-infected individuals at the time of diagnosis no matter what the CD4 cell count. Regardless, prior to initiating antiviral therapy, everything possible should be done to ensure that the patient is committed to the treatment, able to adhere to the regimen, and will follow up with his or her health care professional to assess whether medications are tolerated and working.

In the United States, 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 https://aidsinfo.nih.gov/. The most recent IAS-USA guidelines were published in the Journal of the American Medical Association (JAMA) in the summer of 2018.

Antiviral treatment options have primarily included combinations of two NRTIs, often referred to as "nucs," and a third drug, typically being a boosted PI, a NNRTI, often called "non-nucs," and InSTIs such as RAL, EVG, DTG, or BIC. Many of these drugs are available in fixed-dose combinations as well as increasing numbers of drugs as single-tablet regimens.

Guidelines for starting antiviral therapy have been proposed by panels of experts from several groups, including the DHHS (https://aidsinfo.nih.gov/) and IAS-USA. There are similar guidelines for treatment throughout Europe and by the World Health Organization for treatment in resource-limited countries. Until recently a recommendation supporting the start of therapy in those with CD4 cells greater than 500 cells was based upon evidence that ongoing viral replication, even in the setting of high CD4 cell counts, may be associated with damage to the brain, kidneys, heart, and possibly even liver. Along with this rationale, it was clear that newer regimens were easy to take, including a growing number of one-pill-per-day options, with minimal side effects. Another compelling argument that can be made for early therapy is the ability to reduce the risk of transmission to uninfected partners. A study called HPTN 052 demonstrated that amongst couples where one person is HIV-infected and the other is not, those who were on antiretroviral therapy were 96% less likely to transmit HIV to their uninfected partner than those not on treatment. Finally, a large study was recently reported that demonstrated unequivocally that starting therapy even with a CD4 cell count of greater than 500 cells/mm³ was associated with less risk of disease progression than waiting until CD4 cells were less than 350 cells/mm³. This study was called the START study and demonstrated a major reduction in disease progression with early therapy with virtually no increased risk for side effects. Based upon START, HPTN 052 and other accumulated data, currently all major guidelines around the world, including those of the World Health Organization recommend that antiretroviral therapy be initiated in all HIV-infected patients at the time of diagnosis. It is worth noting that these recommendations for universal treatment of HIV-infected patients will be limited by resources available for antiviral treatment in resource-limited countries.

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.

NRTIs block an enzyme of the human immunodeficiency virus called reverse transcriptase that allows HIV to infect human cells, particularly CD4 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 zidovudine (Retrovir, ZDV), stavudine (Zerit, d4T), didanosine (Videx, ddI), zalcitabine (HIVID, ddC), lamivudine (Epivir, 3TC), emtricitabine (Emtriva, FTC), abacavir (Ziagen, ABC), tenofovir disoproxil fumarate (Viread, TDF), and tenofovir alafenamide (Descovy, TAF). The latter drug is a new formulation of tenofovir that is now part of multiple fixed-dose combinations. This form of tenofovir has been shown to be equally effective as TDF but with less renal and bone toxicity. 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 (Truvada), or TAF with FTC (Descovy), both of which are also available as part of single tablet regimens. An alternative regimen uses the fixed-dose combination of ABC/3TC (Epzicom) alone or combined as a single tablet regimen with DTG (Triumeq). ABC has been associated with severe allergic reactions in approximately 5% of patients. Recent studies have shown that a blood test (HLA-B*5701) 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. In fact, when available, it is now the standard of care to perform this test prior to initiation of ABC. The main side effects associated with TDF are reduced kidney function and bone density.

What are the usual dosing schedule and meal restrictions for NRTIs?

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
• TAF/FTC (25 mg/200 mg) as Descovy; one per day

These are standard doses for average-sized adults, and dosing may vary depending upon the weight of a patient. Certain combinations of drugs in this class should generally be avoided, including d4T with ZDV or ddI, 3TC with FTC, and TDF with ddI.

The new formulation of tenofovir (TAF) is available as combination pills only, including EVG/COBI/FTC/TAF (Genvoya, 150/150/200/10 mg), FTC/TAF (Descovy, 200/25 mg), TAF/FTC/RPV (Complera, 25/200/25 mg), BIC/FTC/TAF (25/200/25 mg), and darunavir (DRV)/Cobicistat (COBI)/FTC/TAF (800/150/200/10 mg). The new formulation of tenofovir results in lower plasma levels and higher intracellular concentrations of the active drug. Data demonstrate that compared to TDF-containing regimens this form is equally effective with less adverse effects on bone mineral density and possibly on the kidneys.

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

NNRTIs include nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). ETR was developed specifically to be an option for patients who have developed resistance to the earlier drugs in the class. NVP, DLV, EFV, RPV, and DOR 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.

For people without a history of drug resistance, there are now three effective fixed-dose combination pills that include TDF, plus FTC with either EFV (Sustiva) or RPV (Complera), or plus 3TC with DOR, all of which are available as a single pill that can be taken once per day. There is also a formulation of TAF plus FTC with RPV (Odefsey). The combination with RPV (Complera) was shown to be very effective and well tolerated but not as good at suppressing the viral load as the combination with EFV (Atripla), particularly amongst those who started therapy with higher viral loads and lower CD4 cell counts (for example, >100,000 copies/mL and <200 cells/mm³, respectively). It is currently recommended only for those that have viral load levels of <100,000 copies/mL and CD4 cell counts greater than 200 cells/mm³.

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 (Invirase and Fortovase, 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), and
• tipranavir (Aptivus, TPV),
• darunavir (Prezista, DRV).

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

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 800 mg once daily with 100 mg of 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. Another recently approved boosting agent is COBI which has no anti-HIV activity but can be given with once daily ATV or DRV as an alternative to RTV for pharmacologic boosting. There are also fixed-dose combinations of each, for example, ATV 300 mg combined with COBI 150 mg (Evotaz) and DRV 800 mg combined with COBI 150 mg (Prezcobix). A single-tablet formulation is now also available with DRV/COBI/FTC/TAF (800/150/200/10 mg) once daily.

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.

The only available drug in this class is called maraviroc (Selzentry, MVC), which is now approved for use in combination therapy in treatment-experienced and naïve patients 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 assays. 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 typically 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.

The first available drug in this class was RAL, which is very potent at suppressing HIV in all patients who have never been on this drug or others in the class. 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 with a newer formulation that can be given to those starting therapy for the first time or stably suppressed on RAL twice daily that can be given as two 600 mg tablets once daily. As noted above, a second drug in this class, EVG, is approved for use as first-line therapy as part of the fixed-dose combination pill of TDF/FTC/COBI/EVG and more recently TAF/FTC/COBI/EVG as a stand-alone drug for use in treatment-experienced patients combining it with a ritonavir-boosted PI. This drug is well tolerated and given as one pill per day, but unlike RAL it does need to be taken with food and it has interactions with other drugs since it must be used with RTV or COBI, so it must be used with caution in those on multiple medications. Another InSTI, DTG is currently recommended for those starting therapy for the first time with either TDF/FTC or ABC/3TC and is available as a fixed-dose combination of ABC/3TC/DTG that can be given as a single pill per day. This drug has a limited number of drug-drug interactions and is generally well tolerated with resistance rarely emerging in those experience virologic failure. It is also frequently active in those who have developed InSTI resistance to RAL and EVG, although it often needs to be given in this setting at a dose of 50 mg twice daily. The most recently approved InSTI is called bictegravir (BIC) that has few drug-drug interactions, is potent, well-tolerated, and can be given with or without food. It is only available as a single-tablet regimen as BIC/FTC/TAF. Thus far, data suggests that selection of drug resistance in those starting therapy with this regimen is extremely rare.

Two large studies recently demonstrated that in those with viral loads less than 500,000 copies/mL a regimen of DTG plus 3TC was as effective in suppressing viral after one year as the traditional regimen of DTG with two NRTIs. This regimen will likely soon be available as a single-tablet regimen for initial therapy in those without chronic hepatitis B, no underlying drug resistance, and viral loads less than 500,000 copies/mL.

There are now 10 approved combination pills that allow for a full regimen to be taken as a single pill once per day, so called single tablet regimens. This includes the following NRTI plus third drug combinations:

• TDF/FTC/EFV (300/200/600 mg) as Atripla
• TDF/FTC/RPV (300/200/25 mg) as Complera
• TAF/FTC/RPV (25/200/25 mg) as Odefsey
• TDF/FTC/EVG/COBI (300/200/150/150 mg) as Stribild
• TAF/FTC/EVG/COBI (25/200/150/150 mg) as Genvoya
• ABC/3TC/DTG (600/300/50 mg) as Triumeq
• BIC/FTC/TAF (50/200/10) as Biktarvy
• DRV/COBI/FTC/TAF (800/150/200/10) as Symtuza
• DOR/3TC/TDF (100/300/300) as Delstrigo
• DTG/RPV (50/25) as Juluca, which is only approved for those stably suppressed on an alternative regimen with no history of drug resistance

A monoclonal antibody called ibalizumab (Trogarzo) binds the CD4 molecule (a receptor for HIV on cells), which prevents viral entry into the cell. Medical professionals administer the drug as an intravenous infusion of 2,000 mg once, then two weeks later at 2,000 mg again, followed by 800 mg every two weeks. It is appropriate for heavily treatment-experienced patients with multidrug resistant virus who need new therapeutic options in order to achieve an undetectable viral load.

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 to certain individuals with approval of the FDA. In particular, these drugs are used in individuals who are no longer responding or able to tolerate currently available agents. The next drugs likely to be approved for use will be long-acting injectable formulation of RPV in development along with a long-acting new InSTI called cabotegravir (CAB). An early stage study showed that the combination of short-acting RPV and CAB was able to maintain virologic suppression in those with a suppressed viral load. A follow-up study showed maintenance of suppression with the long-acting regimen given intramuscularly once monthly and every other month. There are three large studies under way to definitively address safety and efficacy of this regimen given either monthly or every other month.

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 (HLA-B*5701) 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. There is also conflicting data stating that abacavir may or may not be associated with increased risk of cardiovascular events.

TDF is generally well tolerated although there may be rare kidney damage and may have a greater impact on reducing bone density than other agents. Both of these problems appear to be attenuated with the new formulation of tenofovir called TAF.

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 professional. 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. Side effects appear to be uncommon with RPV with some uncertainty as to whether it is associated with various neurologic symptoms.

All of the NNRTIs are associated with important drug-drug interactions so they must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

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 DRV appearing to have less effect on lipids than other drugs in the class. Other unique toxicities associated with various PIs are kidney stones, kidney damage, and increases in blood bilirubin levels and potentially jaundice 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. There is also some data suggesting that LPV/RTV and DRV may be associated with an increased risk of cardiovascular events.

Most PIs are associated with important drug-drug interactions so they must be used with caution in patients on other medications. There are numerous resources available to patients on these medications to make sure that they do not adversely interact with other HIV or non HIV-related drugs.

Fusion inhibitors

The only drug in this class is T-20, which is administered as a twice-daily subcutaneous injection. The most common side effects are 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. There are important drug-drug interactions with MVC, so it too must be used with caution in patients on other medications.

Integrase strand transfer inhibitors

RAL has not been strongly linked to any specific side effect in clinical trials. However, there have been some cases of muscle problems and of increasing depression that needs to be watched for when starting this or any new medications. EVG appears to be well tolerated when used as the fixed-dose combination of Stribild or Genvoya, with the anticipated effect on measures of kidney function and bone mineral density with Stribild and COBI component of the regimen being associated with drug-drug interactions. DTG has been associated with mild headache, insomnia, and nausea in some patients and like COBI is associated with mild early decrease in measures of renal function that actually do not reflect true kidney damage.

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 a hundredfold during this interval. The ultimate goal is for the viral load to decrease to undetectable levels which should occur by approximately 12-24 weeks. There are some individuals that despite taking all of their medications correctly will suppress their viral load to less than 200 copies/mL but not consistently undetectable levels. It is not completely known how to optimally manage this situation but many experts would continue to monitor on current therapy as long as viral load remains below 200 copies/mL. Those who 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. Once the patient's viral load is suppressed, they can often have viral load and CD4 cell counts performed less frequently (for example, every three to four months and in select cases every six months or possibly even less).

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, especially if viral load is greater than 200 copies/mL. 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, especially to the protease class. 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 at times preferably three fully active drugs in the next regimen in order to optimize the chances of suppressing the viral load to undetectable levels. It is often useful to seek expert consultation in managing those with multidrug resistant virus.

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 professional in advance to establish the best strategy for safely accomplishing this.

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, although research will certainly continue in the coming years in this area. In addition, recent data demonstrated that a subset of those starting ART within the first weeks of infection were able to stop therapy after many years and maintain good viral control off treatment. While this response does not occur in the majority of similarly treated patients, the observations are intriguing and an area of ongoing research. Regardless, at least for now it is premature to think that early treatment may result in a cure, although other benefits may still exist, including avoiding the substantial damage to the immune system that occurs during the first weeks of infection. In addition, these individuals have very high levels of virus in their blood and genital secretions, and early treatment might reduce their risk of transmitting HIV to others. There also is evidence that those who develop such symptoms during the early days of infection may be at greater risk of disease progression than those who become infected with minimal or no symptoms. Due to the absence of definitive data, guidelines vary, but since it is now recommended that all patients initiate therapy at the time of diagnosis it is generally recommended that patients with primary infection be offered early therapy.

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%. There is strong data that women who have viral suppression during pregnancy have a very low risk of transmitting HIV to their baby, perhaps even less than 1%. 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. The choice of medications in this situation should be determined after consultation with an expert in treating HIV-infected pregnant women.

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. When breastfeeding is done, it should be in conjunction with antiretroviral therapy for the mother if at all possible. Updated guidelines for managing HIV-infected women are updated on a regular basis and can be found at https://aidsinfo.nih.gov/.

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 https://aidsinfo.nih.gov/.

In summary, patients with a CD4 cell count of less than 200 cells/mm³ 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/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/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. Many of these drugs can be stopped if initial antiviral therapy results in good viral suppression and sustained increases in CD4 cells.

Trends continue toward simplifying drug regimens to improve adherence and decrease side effects. In addition, the availability of multiple new drugs in new classes has made it possible to suppress viral load to undetectable levels even in many of the most treatment-experienced patients. Moreover, many are virologically suppressed taking a single well-tolerated pill per day. As noted in the section on new therapies in development, another major advance could emerge with the availability of every one to two month injections of long-acting therapies. With great success in treatment, the field has increasingly considered strategies that may someday allow patients to control viral replication without the use of antiretrovirals. This could be in the form of a true cure with complete eradication of HIV from the body or a functional cure where the virus persists but is unable to replicated, a situation analogous to what happens when patients are on effective antiretroviral therapy. Research is in the very earliest stages with regard to development of strategies for viral eradication. Studies to control viral replication in the absence of antiretroviral therapy are actively being pursued, although thus far with limited success. One strategy has been to use immune-based therapies to boost the natural immune response to HIV and allow for complete or partial control. Another area of research is to purge infected cells, so-called "latent reservoir," with various agents to facilitate eradication from the body. While research in these areas is under way, it has met with limited success.

The report of the so-called "Berlin patient" has stimulated a great deal of interest in cure research. This HIV-infected man had leukemia, which was treated with a bone marrow transplant. His health care providers were able to identify a tissue-matched donor who happened to be one of the rare individuals who carried a genetic defect resulting in the lack of CCR5 on the surface of their cells. CCR5 is required for certain types of HIV to enter the cells, and these unique individuals are relatively resistant to infection. After the bone marrow transplant, the patient was able to stop antiretroviral therapy and for years has not had detectable HIV in his body. It is worth noting that this individual experienced far more than the engraftment of unique bone marrow. He underwent intensive chemotherapy and radiation treatment to destroy most immune cells in the body, as well as graft-versus-host disease, which could also further destroy residual HIV-infected cells. Together these events could have markedly reduced the reservoir of virus that persists in the body of all infected individuals, which could have facilitated the purported "cure" or set the stage for the ultimate success associated with the engraftment of the unique bone marrow. There was recently excitement about two individuals who underwent so-called "stem cell transplants" but without the unique donor that was used by the Berlin patient. While virus remained at very low levels in these individuals while on therapy, at three and eight months after treatment interruption, HIV came storming back. Consequently, the experience with the Berlin patient has not yet been replicated and, even if it is, will not be an option for most people. First, bone marrow transplants are associated with very high risk of illness and death, and second, very few patients who need a bone marrow transplant for any reason are likely to find a tissue-matched donor who carries this rare genetic mutation. However, research is pursuing the potential role each part of this individual's treatment may have had on the successful control of HIV off therapy, as well as working on ways to genetically engineer an individual's own blood CD4 cells or stem cells to not have the CCR5 molecule. While this research is in the very early stages of development, it certainly provides hope for the future of research related to HIV eradication and/or cure.

Early advances in preventing HIV transmission resulted from educational programs describing how transmission occurs and providing barrier protection for those exposed to genital secretions and new needles or bleach to those exposed to blood by sharing needles. Despite these efforts, new infection in both the developed and developing worlds has continued at high rates.

Historically, the greatest success in preventing viral transmission has resulted from the development of preventative vaccines. Unfortunately, decades of research to develop an HIV vaccine has led to little hope for success. In 2007, a major setback in this area occurred when the STEP study investigating a promising vaccine candidate was prematurely stopped due to the lack of evidence that it produced any protection from HIV infection. In contrast, a glimmer of hope did emerge with the report in 2009 of the results of the RV 144 Thai HIV vaccine trial, which demonstrated borderline effectiveness in the more than 16,000 recipients. While this vaccine demonstrated only limited evidence of protection, research is under way to further explore what can be learned for future vaccine development from this modest success.

In light of the limited ability of counseling and testing to curb the spread of the HIV pandemic, many researchers have moved toward other biologic strategies for preventing HIV that do not rely solely on people changing their behavior. It is in this area where there has been some success. During the last 10 years, there were several large studies showing that male circumcision along with behavioral counseling reduced the risk of heterosexual men acquiring HIV infection. This provides a novel prevention strategy for at-risk, HIV-uninfected heterosexual men. Another major advance on the prevention front came from the HPTN 052 study in which HIV-infected individuals with CD4 cells between 350 cells/mm³ and 550 cells/mm³ who had uninfected partners were randomly assigned to initiate antiviral therapy or wait until their CD4 cells declined to less than 250 cells/mm³ or they developed symptoms consistent with disease progression. All enrolled individuals were aggressively counseled about continued safe sex practices, provided condoms, and were monitored for sexual activities. The study ultimately showed that those treated early were more than 96% less likely to transmit to their partner than those who had antiviral treatment deferred. Subsequent cohort studies have shown that those who are virologically suppressed on antiretroviral therapy for at least six months have essentially no risk of transmitting to uninfected partners, even when not using condoms.

As opposed to treating infected people to protect their uninfected partners, another approach is to provide antiviral treatment to uninfected individuals, so-called pre-exposure prophylaxis (PrEP). The first success in this research arena came from the CAPRISA 004 study, which showed that vaginal administration before and after intercourse of a gel containing the antiretroviral agent tenofovir reduced the risk of transmission of both HIV and herpes simplex virus to heterosexual women. Other studies are under way to confirm the results of this study as well as to determine whether the results are any different if the agent is administered daily rather than simply around the time of intercourse. One such study was not be able to show that once-daily tenofovir vaginal gel demonstrated protection from infection compared to placebo gel. The reasons for this finding are not completely known, but it does appear that adherence with the therapy was very poor.

In 2010, the iPrEx study reported the results of the first large study testing the effectiveness of PrEP using orally administered therapy, as opposed to topical agents as in the vaginal PrEP studies. In this study, HIV-uninfected men who had sex with men who took TDF/FTC once daily along with a comprehensive program to promote safe-sex practices and early treatment of sexually transmitted diseases experienced a markedly reduced risk of acquiring HIV compared with those receiving similar prevention practice without TDF/FTC. There are several other studies that have shown that once daily TDF or TDF/FTC have been effective for PrEP in heterosexual men, women, and intravenous drug users. Nevertheless, there are other studies of high-risk HIV-uninfected women that have shown no benefit, with convincing data in both studies demonstrating extremely low levels of treatment adherence with study medications. Based upon the data available, the United States FDA has approved TDF/FTC for use in high-risk HIV-uninfected individuals. When this therapy is utilized, it is clear that people need to be extensively counseled regarding the importance of continued use of condoms as well as diligent screening for HIV infection, acquisition of sexually transmitted diseases, as well as treatment adherence. Treated individuals also need to be made aware of potential side effects of treatment, including gastrointestinal symptoms, kidney damage, and decreases in bone mineral density.

Several novel strategies are being pursued to overcome the difficulty in getting people to adhere to PrEP. This includes studies to see whether treatment can be given less than daily, for example, around risk-taking activities. Other options include long-acting formulations, such as a vaginal ring impregnated with antiviral agents or long-acting intramuscular injections of CAB, described above under new treatments that could be administered every few months.

A final prevention strategy of last resort is the use of antiretrovirals as post-exposure prophylaxis, so-called "PEP," to prevent infection after a potential exposure to HIV-containing blood or genital secretions. Animal studies and some human experience suggest that PEP may be effective in preventing HIV transmission, and it is based upon these limited data that current recommendations have been developed for health care workers and people in the community exposed to potentially infectious material. Current guidelines suggest that those experiencing a needle stick or who are sexually exposed to genital secretions of an HIV-infected person should take antiretrovirals for four weeks. 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 it is most needed and is probably best restricted to unusual and unexpected exposures, such as a broken condom during intercourse. If PEP is to be initiated, it should occur within hours of exposure and certainly within the first several days. Updated guidelines are published and available at https://aidsinfo.nih.gov/.