General Considerations

When AIDS was first recognized in the United States in 1981, cases were identified by finding severe opportunistic infections, such as Pneumocystis pneumonia, cytomegalovirus retinitis, and Kaposi sarcoma, that indicated profound defects in cellular immunity in the absence of other causes of immunodeficiency. When the HIV virus was identified as the cause of the syndrome, it became obvious that severe opportunistic infections and unusual neoplasms were at one end of a spectrum of disease, while healthy seropositive individuals were at the other end.

The earliest stage of HIV infection is acute infection. Acute retroviral syndrome, while not universal, is characterized by an illness with systemic symptoms including fever, rash, pharyngitis, swollen lymph nodes, and less commonly aseptic meningitis. Diagnosis is made in a patient who was previously known to be living without HIV or of unknown HIV status in whom these characteristic symptoms develop following an exposure to HIV. Diagnosis of acute HIV is made by finding a positive HIV viral load in the setting of characteristic symptoms, with or without a positive HIV antigen/antibody test in cases which the patient is still in the window period (prior to seroconversion to a positive HIV antibody status). If acute infection is suspected but the HIV viral load test is negative, the test should be repeated in 1-2 weeks. In patients with acute infection, antibodies subsequently will develop with time, although taking pre-exposure prophylaxis can delay their development. Patients with acute or newly diagnosed infection should receive prompt antiretroviral treatment (see Treatment section, below).

Not all people with HIV have a diagnosis of acute illness. Patients may convert from being HIV antigen/antibody-negative to positive without developing symptoms or having come to medical attention. Once the acute infection stage has passed, patients generally enter an asymptomatic phase; in the years before effective antiviral therapy, it was found that this asymptomatic stage could last for years, although during this stage the immune system was being harmed and systemic inflammation occurred.

The classification "AIDS" defines the late stage of HIV infection.

The CDC AIDS case definition (Table 33-1. CDC AIDS Case Definition for Surveillance of Adults and Adolescents) includes opportunistic infections and malignancies that rarely occur in the absence of severe immunodeficiency (eg, Pneumocystis pneumonia, CNS lymphoma, cytomegalovirus retinitis). It also classifies persons as having AIDS if they have a positive HIV antibody test and certain infections and malignancies that can occur in immunocompetent hosts but that are more common among people with HIV (eg, pulmonary tuberculosis, invasive cervical cancer). Several nonspecific conditions, including dementia and wasting (documented weight loss)-in the presence of a positive HIV test-are also classified as AIDS. The definition includes criteria for both definitive and presumptive diagnoses of certain infections and malignancies. Finally, persons with a positive HIV test whose CD4 lymphocyte count drops below 200 cells/mcL or a CD4 lymphocyte percentage below 14% are considered to have AIDS.

Inclusion of persons with low CD4 counts as AIDS cases reflects the recognition that immunodeficiency is the defining characteristic of AIDS. The choice of a cutoff point at 200 cells/mcL is supported by several cohort studies showing that AIDS will develop within 3 years in over 80% of persons with counts below this level in the absence of antiretroviral therapy (ART). Fortunately, the prognosis of people with HIV/AIDS has dramatically improved due to the development of ART. One consequence is that fewer people with HIV ever develop an infection or malignancy or have a low enough CD4 count to classify them as having AIDS, which means that the CDC definition has become a less useful measure of the impact of HIV/AIDS in the United States. Conversely, persons in whom AIDS had been previously diagnosed based on a serious opportunistic infection, malignancy, or immunodeficiency may now be markedly healthier, with high CD4 counts, due to the use of ART. Therefore, the Social Security Administration, as well as most social service agencies, now focus on functional assessment for determining eligibility for benefits rather than the simple presence or absence of an AIDS-defining illness, as in the past.

Epidemiology

The modes of transmission of HIV are similar to those of hepatitis B, in particular with respect to sexual, parenteral, and vertical transmission. Although certain sexual behaviors (eg, receptive anal intercourse) confer higher risk than other sexual behaviors (eg, insertive vaginal intercourse), it is difficult to quantify per-contact risks. Nonetheless, the best available estimates indicate that the risk of HIV transmission with receptive anal intercourse is 138 per 10,000 exposures, with insertive anal intercourse being 11 per 10,000 exposures. Receptive vaginal intercourse results in HIV transmission in 8 per 10,000 exposures, with insertive vaginal intercourse being 4 per 10,000 exposures, and a negligible risk with insertive or receptive oral intercourse.

All per-contact risk estimates assume that the source is a person with HIV. If the HIV status of the source is unknown, the risk of transmission is the risk of transmission multiplied by the probability that the source has HIV infection. This probability varies by sexual behavior, age, and geographic area. A number of cofactors are known to increase the risk of HIV transmission during a given encounter, including the presence of ulcerative or inflammatory sexually transmitted diseases, trauma, active menses, and the absence of male circumcision.

The risk of acquiring HIV infection from a needlestick with blood infected with HIV is estimated to be 23 per 10,000 exposures. Factors known to increase the risk of transmission include depth of penetration, hollow bore needles, visible blood on the needle, and advanced stage of disease in the source. The risk of HIV transmission from a mucosal splash with infected blood is unknown but is assumed to be significantly lower.

The risk of acquiring HIV infection from injection drug use with sharing of needles from a person with HIV is estimated at 63 per 10,000 exposures. Use of clean needles markedly decreases the chance of HIV transmission but does not eliminate it if other drug paraphernalia are shared (eg, cookers).

When blood transfusion from a donor with HIV occurs, the risk of transmission is 93%. Fortunately, since 1985, blood donor screening for HIV has been universally practiced in the United States. Also, persons who have recently engaged in behaviors that might result in HIV acquisition (eg, sex with a person at risk for HIV, injection drug use) are not allowed to donate. This essentially eliminates donations from persons who have acquired HIV but have not yet developed a positive antigen/antibody test (ie, persons in the "window" period). HIV antigen and viral load testing have been added to the screening of blood to further lower the chance of HIV transmission. With these precautions, the chance of HIV transmission with receipt of blood transfusion in the United States is about 1:2,000,000.

Between 13% and 40% of children born to a mother with HIV contract HIV infection when the mother has not received treatment or when the child has not received perinatal HIV prophylaxis. The risk is higher with vaginal than with cesarean delivery; higher among mothers with high viral loads; and higher among those who breastfeed their children. The combination of prenatal HIV testing and counseling, ART for mothers with HIV during pregnancy and for the infant immediately after birth, scheduled cesarean delivery if the mother has a viral load that is unknown or not virally suppressed at delivery, and avoidance of breastfeeding has reduced the rate of perinatal transmission of HIV to less than 1% in the United States and Europe. Importantly, breastfeeding has important nutritional and immunologic benefits for children, so international guidelines recommend lactating mothers living with HIV on ART breastfeed their infants (http://clinicalinfo.hiv.gov/en/guidelines/perinatal/introduction; http://www.who.int/news-room/questions-and-answers/item/hiv-aids-infant-feeding-and-nutrition).

HIV has not been shown to be transmitted by respiratory droplet spread, by vectors such as mosquitoes, or by casual nonsexual contact. Saliva, sweat, stool, and tears are not considered infectious fluids.

Approximately 1.2 million adults and adolescents in the United States are estimated to be living with HIV. In 2021 36,136 people received an HIV diagnosis in the United States and 6 dependent areas-an 18% increase from 2020, although the destabilizing impact of the COVID-19 pandemic on HIV testing is most likely responsible for underreporting of HIV diagnoses in 2020. As a result, the best guess is that HIV diagnoses have remained essentially flat since 2019. In 2021, men who have sex with men (MSM) were the population most affected by HIV in the United States and accounted for 67-71% of all diagnoses (25,482 when including 1375 MSM who also had injection drug use). People who acquired HIV through heterosexual contact made up 22% (8059) of HIV diagnoses in the United States in 2020, with heterosexual women accounting for 18% of new diagnoses. People who inject recreational drugs (including MSM who use injection drugs) accounted for 11% of new HIV diagnoses in 2021. Among persons with HIV in the United States, the prevalence of infection in Black, Indigenous and People of Color is disproportionally higher than among White people. In 2021, people who self-identify as Black represented 12% of the US population but accounted for 40% of new HIV diagnoses, and people who self-identify as Latino/Latina (who represent 19% of the US population) accounted for 29% of new HIV diagnoses.

In general, the progression of HIV-related illness is similar regardless of gender, although women generally have lower viral loads then men early in infection. There are other important differences. Women are at risk for gynecologic complications of HIV, including recurrent candidal vaginitis, pelvic inflammatory disease, and cervical dysplasia and carcinoma. Violence directed against women, pregnancy, and frequent occurrence of drug use and poverty all complicate the treatment of women with HIV.

Worldwide there are an estimated 39 million people with HIV, with heterosexual spread being the most common mode of transmission for men and women. There were 1.33 million new HIV infections worldwide in 2022, with 650,000 deaths from HIV/AIDS. Since the beginning of the HIV pandemic, 40.4 million people have died. The reason for the greater risk for transmission with heterosexual intercourse in Africa and Asia than in the United States may relate to cofactors such as general health status, the presence of genital ulcers, relative lack of male circumcision, the number of sexual partners, and different HIV serotypes. Worldwide, 75% of adults have access to lifesaving ART and the overall rates of virologic suppression at 1 year after starting ART is estimated at 79% and at 3 years is estimated at 59%. In the United States, rates of virologic suppression vary by type of care. The Ryan White Care HIV program provides a comprehensive system of primary medical care, ART, and essential support services to people with HIV, including a specific focus on supporting community needs. In 2021 in the United States, for every 100 people diagnosed with HIV, about 75% received some HIV care, 54% were retained in care, and 66% were virally suppressed.

Etiology

HIV, like other retroviruses, depends on a unique enzyme, reverse transcriptase (RNA-dependent DNA polymerase), to replicate within host cells. The other major pathogenic human retrovirus, human T-cell lymphotropic/leukemia virus (HTLV)-I, is associated with lymphoma, while HIV is not known to be directly oncogenic. The HIV genomes contain genes for three basic structural proteins and at least five other regulatory proteins; gag codes for group antigen proteins, pol codes for polymerase, and env codes for the external envelope protein. The greatest variability in strains of HIV occurs in the viral envelope. Since antibodies directed against the envelope are generally non-neutralizing, this variability and failure of antibodies to protect against infection presents challenges for vaccine development. The latest HIV vaccine candidate of diverse HIV subtypes in a benign adenoviral vector failed to reduce HIV incidence in a large trial called Mosaico that included 3900 MSM. However, three mRNA HIV vaccine candidates are being tested in humans within the HIV Vaccine Trials Network 302 Study.

In addition to the classic AIDS virus (HIV-1), another major type of HIV called HIV-2 was isolated in West African patients. HIV-2 has the same genetic organization as HIV-1, but there are significant differences in the envelope glycoproteins. Some infected individuals exhibit AIDS-like illnesses, but the rate of progression in individuals living with HIV-2 infection is generally slower than that of HIV-1 infection. HIV-2 remains relatively rare in the United States but has become more common in Western Europe due to immigration from endemic areas. HIV-2 is detected by the HIV differentiation assay used as a confirmatory test following a positive HIV antigen/antibody test.

Pathogenesis

The hallmark of symptomatic HIV infection is immunodeficiency caused by continuing viral replication and infection of immune cells. The virus can infect all cells expressing the CD4 receptor, which HIV uses to attach to the cell. Chemokine co-receptors (CCR5 or CXCR4) are required for virus entry, and individuals with heterozygous CCR5 deletions (ie, "delta 32") are less likely to become infected and, once infected, the disease is more likely to progress slowly. Individuals with homozygous CCR5 deletions are highly resistant to HIV infection; stem cell transplants from these individuals are the only strategy that has worked for HIV cure to date. Once it enters a cell, HIV can replicate and cause cell fusion or death. A latent state is also established, with reverse transcription of the HIV RNA into DNA and subsequent integration of the HIV genome into the cell's genome. The cell principally infected is the CD4 (helper-inducer) lymphocyte, which directs many other cells in the immune network. However, HIV can infect any cell with CD4 receptors, including macrophages, dendritic cells, and monocytes. With increasing duration of infection, the number of CD4 lymphocytes falls and immunodeficiency worsens. Some of the immunologic defects, however, are explained not by quantitative abnormalities of lymphocyte subsets but by qualitative defects in CD4 responsiveness induced by HIV.

Other cells in the immune network that are affected by HIV include B lymphocytes. The defect in B cells is partly due to disordered CD4 lymphocyte function. These direct and indirect effects can lead to generalized hypergammaglobulinemia and can also depress B-cell responses to new antigen challenges (eg, to vaccination, including COVID-19 vaccines). Because of these defects, the immunodeficiency of HIV is mixed. Elements of humoral and cellular immunodeficiency are present, especially in children, which can predispose to bacterial infections along with the unusual viral, fungal and parasitic infections seen with T-cell depletion. Macrophages act as a reservoir for HIV and serve to disseminate it to other organ systems (eg, the CNS).

Apart from the immunologic effects of HIV, the virus can also directly cause a variety of neurologic effects. Neuropathology largely results from the release of cytokines and other neurotoxins by infected macrophages. Perturbations of excitatory neurotransmitters and calcium flux may contribute to neurologic dysfunction. Direct HIV infection of renal tubular cells and GI epithelium may contribute to these organ system manifestations of infection.

Pathophysiology

Clinically, the syndromes caused by HIV infection are usually explicable by one of three known mechanisms: immunodeficiency, autoimmunity, and allergic and hypersensitivity reactions.