1. The initial stage of infection (primary infection), which occurs within weeks of acquiring the virus, often is characterized by the 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 – In AIDS, the immune system collapses and the body falls prey to secondary, opportunistic infections and cancers that typically kill the person).

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.

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.

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.

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 for at least 6 months on treatment, they are no longer able to sexually transmit HIV to an uninfected partner.

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 6 months of therapy, there is no longer any risk of sexually transmitting HIV to their partners, leading to the phrase that undetectable equals untransmittable (although in most studies undetectable is defined as viral loads of < 200-400 copies/mL).

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.

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 the 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), rilpivirine (Edurant, RPV), and doravirine (Pifeltro, DOR) 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 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 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.