1959	African man dies of a mysterious viral illness, now recognized as the ancestor of HIV.
1981	CDC reports “gay-related immune deficiency” (GRID) as the cause of outbreaks of deaths of gay men in California and New York. Cases soon appear among heterosexuals, intravenous drug users, and recipients of blood transfusions
1983	Montagnier and Gallo isolate retrovirus later named HIV. CDC warns about possible problems with the blood supply.
1985	HIV test is patented by Gallo’s laboratory. Rock Hudson dies; Ryan White refused admission to school.
1987	Advent of zidovudine (AZT or ZDV) as first treatment for HIV infection.
1992	Combination therapy with zalcitabine (ddC) approved.
1993	Definition of AIDS revised by CDC. Concorde trials from Britain show that patients develop AIDS despite treatment with ZDV.
1996	Advent of protease inhibitors and “triple therapy” regimens. Viral reservoirs persist while viral loads remain undetectable.
1997	ACTG 076 shows AZT in pregnancy and during delivery reduces vertical transmission from 25% to 3%. CDC reports drop in annual AIDS deaths.
1998	First human trials of a vaccine begin. Generic HIV medications become available in Europe.
2001	First-entry inhibitor, enfuvirtide (Fuzeon), is developed.
2004	First generic antiretroviral approved by FDA.
Combination drugs Truvada (emtricitabine and tenofovir) and Epzicom (abacavir and lamivudine) and new protease inhibitors Reyataz and Lexiva become available.
2005	As side effects of chronic HAART identified, experts recommend delay of HAART initiation.
2006	Current scientific opinion holds origin of HIV in the meat and bites of African monkeys.
2009	HIV genome is decoded.

Epidemiology

Key Points

• Of the 33 million persons living with HIV infection worldwide, 1 million live in the United States.

• Incidence of HIV infection in the United States has increased by 15%, whereas mortality has declined by 17% (2004–2007).

• Minorities and women are disproportionately affected by HIV infection.

About 33 million people worldwide are living with HIV/AIDS in 2007. Of these, 2.7 million have been newly infected, and 2 million people have died of HIV/AIDS. Developing countries account for more than 95% of these infections (UN AIDS, 2007). Since 1981, an estimated 1.7 million people have been infected; more than 1 million people in the United States are currently living with HIV/AIDS; and 565,927 have died of AIDS. The number of deaths has declined by 17% between 2003 and 2007. From 2004 to 2007, there has been an increase of 15% in the incidence of HIV/AIDS cases in the United States. This increase occurred mainly in persons age 40 to 44, who accounted for 15% of all HIV/AIDS cases, likely caused by both changes in reporting systems and increased HIV testing.

A disproportionate number of minorities and women are affected by HIV. Although the U.S. population is 13% black, blacks constituted 45% of newly diagnosed cases in 2006, with a rate of infection of 83.7 per 100,000. Of these, 60% are women. Blacks living with HIV/AIDS constitute about 60% of the adult HIV-positive population in 2007, with a rate of 76.7 per 100,000. Similarly, Hispanics, although constituting 12% of the population, reflect 17% of those persons newly infected with HIV in 2006 and 20% of those living with HIV/AIDS in 2007, with rates of 29.3 and 20 per 100,000, respectively. Year-end prevalence rates in 2007 were 185.1 per 100,000 population, with a range between 2.2 in Samoa and 1750 per 100,000 in the District of Columbia.

Acquired immunodeficiency syndrome was diagnosed within 12 months of diagnosis of HIV infection for a larger percentage of Hispanics and male intravenous drug users (IVDUs) and men with high-risk heterosexual contact. Survival after AIDS diagnosis has increased in those who were diagnosed between 1998 and 2000, among men who have sex with men (MSM), and those who have acquired HIV perinatally. More whites survive 48 months after a diagnosis of AIDS than minorities. Survival has declined in IVDUs and with each year of age at diagnosis after age 35 (HIV/AIDS Surveillance Report, 2007).

Modes of Transmission and Relative Risk

Key Points

• Human immunodeficiency virus is transmitted through mucous membranes during anal, vaginal, and oral intercourse.

• Transmission of HIV also occurs through sharing injection equipment and needles. Vertical transmission occurs from mother to child.

• Blood, semen, vaginal fluid, breast milk, cerebrospinal fluid, amniotic fluid, and serosanguineous fluid can transmit HIV; saliva, tears, and sweat do not.

• The virus cannot survive outside the host, and 90% to 99% of infective HIV on dry surfaces is eliminated within hours. Insect bites and casual contact carry no risk.

As epidemic and scientific approaches to HIV infection evolved, the focus shifted from “risk groups” to “risky behaviors.” This distinction is important, because risk groups can give a false sense of security by implying that certain groups of individuals are less vulnerable to infection. Risky behaviors is a more useful term, falling along a spectrum of “no risk” (e.g., complete sexual abstinence), “very low risk” (e.g., 100% use of latex condoms), to “very high risk” (e.g., unprotected receptive anal intercourse with ejaculation), with other behaviors in midspectrum. The physician serves as a source of accurate information to be provided in simple, nonjudgmental terms because ultimately the patient will decide the acceptable degree of risk.

The three main modes of transmission of HIV are as follows:

1. Through the mucous membranes during anal, vaginal, or oral sexual intercourse with an HIV-infected person.Average risk of transmission in heterosexual exposure is 1 in 1000 and increases with commercial sex workers to about 5 to 10 in 100. Co-infection with other sexually transmitted diseases (STDs), rough sex, and higher viral load increase risk, whereas condom use and male circumcision reduce risk. Uncircumcised men run risk similar to a woman, and circumcised men may transmit the virus to female partners four times as efficiently as uncircumcised men. Postmenopausal women are more susceptible because of thinning of the vaginal mucosa. Risk of infection per act has been suggested from cohort studies, so physicians should avoid discussing risks in numeric terms.

2. Through the veins while sharing needles or injection paraphernalia with an HIV-infected person.

3. Vertically from an HIV-infected mother to an infant during pregnancy, delivery, or through breastfeeding. High viral load, prolonged time after rupture of membranes, and chorioamnionitis increase risk of transmission, and peripartum prophylactic antiretroviral therapy decreases risk. Overall risk of transmission by breastfeeding is about 15% to 25% in 18- to 24-month-old infants.

Occupational exposure occurs by needle stick injuries (risk, 3:1000), infected blood or fluid splashing into the mouth or nose, or exposure to infected blood through a cut or an open wound. Mucous membrane exposure carries a risk of infection of about 9 in 10,000. Transmission of HIV through infected blood is extremely rare after routine screening of the blood supply was initiated in 1985. With risk of transmission as low as 2 per million, 16 annual infections are accounted for by infectious donations. Neither insect bites nor casual contact carry any risk.

Human immunodeficiency virus can be transmitted by blood, semen, vaginal fluid, breast milk, and serosanguineous body fluids. Contact with cerebrospinal fluid (CSF), amniotic fluid, and synovial fluid can be a risk factor for HIV transmission. Importantly, although HIV can be present in small quantities in saliva, sweat and tears, contact with these fluids does not transmit HIV. The virus cannot survive outside the host, and the amount of infective virus dried on surfaces is reduced by 90%-99% in a few hours.

Pathophysiology

Key Points

• Human immunodeficiency virus belongs to the viral group of Retroviridae, named for its capacity to synthesize DNA using RNA as a template. The subgroup is Lentivirinae, characterized by a long incubation period.

• HIV-1 is found globally, whereas HIV-2 is found mainly in western Africa, although cases of HIV-2 are being seen more frequently in the United States.

• HIV-1 is further subdivided into group M, O, and N, with group M (subdivided into 10 clades) causing most infections worldwide.

• Billions of virions are turned over daily in the virus, leading to frequent mutations and genetic variations.

Human immunodeficiency virus belongs to the group of viruses called retroviruses, so named because of their capacity to synthesize deoxyribonucleic acid (DNA) using ribonucleic acid (RNA) as a template, facilitated by the enzyme reverse transcriptase. Within the retrovirus class, HIV belongs to the lentivirus subgroup; lentiviruses are characterized by a long incubation period, allowing the infected person to spread the infection because they may remain unaware of their own HIV status (Chiu et al., 1985).

Of the two genetically distinct viral types of HIV, type 1 (HIV-1) is associated with global disease, whereas type 2 (HIV-2) is found mainly in western Africa, although cases of HIV-2 have started to appear in the United States. HIV-1 variants are further divided into group M (main), group O (outlier), and group N (non-M/non-O). As suggested by the name, group M causes most of the infections worldwide and is further subdivided into 10 subtypes, or clades (A-K). Clade C is the most common worldwide, and clade B is most frequently seen in North America and Europe. More than 20 sub-subtypes and circulating recombinant forms (CRFs) are seen in group M alone. AE is a recombinant subtype transmitted most effectively by heterosexual contact and most prevalent in Southeast Asia (Buonaguro et al., 2007). As billions of virions are turned over in the virus on a daily basis, mutations and genetic variations are quite common, a fact that becomes relevant when treatment is considered.

Life Cycle of HIV and Relevance to Treatment

Key Points

• Infection with HIV proceeds in a series of steps, the first step being virion binding to the host cell and releasing the viral RNA. Fusion inhibitors can interrupt this step.

• In step 2, HIV uses reverse transcriptase to convert viral RNA to DNA. RT inhibitors can prevent this step.

• The HIV DNA is then incorporated into the host genome to form the provirus, facilitated by integrase. The virus may remain latent until the CD4+ cell is immune activated, making viral proteins. Integrase Inhibitors interfere with this step.

• Transcription of DNA to RNA occurs in the nucleus. During translation, mRNA takes over the protein-making mechanism to form viral proteins as well as viral RNA. The products are then divided into functional units using viral protease. Protease inhibitors interrupt this step.

• The final step consists of assembly, budding, and pinching off of the viral proteins, RNA, and enzymes inside the host membrane to form the complete virion.

Human immunodeficiency virus gains access to CD4+ cells in stages (Berger et al., 1999; Smith and Daniel, 2006; Zheng et al., 2005). CD4+ cells are the main mediators of cellular immune response, helping T lymphocytes and B lymphocytes to perform their functions. The 800 to 1200 cells/mm³ of blood in healthy people are usually decimated by HIV. Minor infections, such as herpes simplex virus, thrush, and vaginal candidiasis may occur as the CD4+ count falls below 500, when 50% of the immune reserve is depleted. With a worsening disease process and decreasing CD4+ count (<200), risk of life-threatening opportunistic infections and cancer increases. Research has focused on medications that can interrupt the life cycle and slow the infection of cells.

Classification and Staging of HIV/AIDS

Key Points

• The CDC classification uses CD4+ counts and specific HIV-related conditions to stage HIV illness. WHO guidelines use clinical observations.

• The CDC lists AIDS categories as A3, B3, C1, C2, and C3, with 23 AIDS-defining conditions. WHO includes primary HIV infection and four clinical stages.

The two classification systems currently in use to monitor the severity of HIV illness and assist with its management have been developed by the CDC (Table 17-1) and the World Health Organization (WHO) (Box 17-2). The CDC classification, last modified in 1993, uses CD4+ counts and specific HIV-related conditions, whereas the WHO classification, developed in 1990 and revised in 2007, is guided by clinical observations and can be used in settings where access to CD4+ tests is unavailable.

Table 17-1 CDC Classification System of HIV/AIDS