According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), an estimated 38.4 million individuals worldwide were living with HIV/AIDS in 2021, more than one-half of whom are women [5]. Eastern and southern Africa account for 94% of new HIV infections [5]. It is important to note that despite increases in certain geographic areas and demographic groups, overall, the rate of new infections is declining. This is due, in part, to lower prices for antiviral medications and implementation of prevention programs [5].

As of 2020, the CDC reports several trends in the HIV/AIDS epidemic [10]:

Once the virus enters the cell, it may replicate, induce cell fusion and propagation of infection, or lead to cell death [13]. The defining characteristic of HIV disease is the immune deficiency state caused by ongoing viral replication and cell-to-cell transmission within lymphoid tissue. With chronicity of infection there is a progressive depletion of CD4 (helper-inducer) lymphocytes, the very T lymphocyte cohort whose function it is to direct other cells in the immune system, and to orchestrate the inactivation of virus antigen. The result is a depressed T lymphocyte functional capacity, characterized by depletion of helper T cells (T4), impaired killer T cell activity, and increased suppressor T cells (T8). In persons with intact lymphocyte immune systems, the normal number of CD4 T cells ranges from 600–1,200 cells/mcL, depending on the stage and duration of infection.

The clinical manifestations of HIV disease are determined by the stage of primary infection and the chronicity and degree of the resultant cellular immunodeficiency state. Acute, primary HIV infection may be asymptomatic, but most often it is manifest by a subacute viral syndrome of malaise and fatigue, fever, sore throat, rash, myalgia, headache, and lymphadenopathy—clinical features similar in many respects to that seen with Epstein-Barr virus mononucleosis, cytomegalovirus (CMV), and certain types of herpes simplex infections [13]. A variety of atypical symptoms and signs may be seen, including aseptic meningitis syndrome, genital ulcers, and ulcerations involving the gingiva, palate, or buccal mucosa. The acute illness usually resolves in less than 14 days but may follow a protracted course over many weeks [13].

Without satisfactory antiretroviral therapy, the usual patient with HIV/AIDS experiences a slow, inexorable wasting illness punctuated by periods of feverishness and diarrhea, becoming increasingly anorectic, malnourished, and lethargic. Late clinical signs include muscle wasting and weakness, anemia and thrombocytopenia, lymphadenopathy, pulmonary infiltrates, and neurologic abnormalities (such as dementia, peripheral neuropathy, and tremors). The median survival of patients with advanced HIV/AIDS (CD4 count <50 cells/mcL) is approximately 12 to 18 months. Patients succumb to complications of uncontrolled infection, malignancy, or critical organ failure (such as uremia or adrenal insufficiency).

On the basis of newly reported cases, the transmission categories are [10]:

Posing the highest risk of infection is unprotected anal receptive intercourse, followed by unprotected vaginal intercourse and unprotected insertive anal intercourse (particularly for uncircumcised men) [29,30]. Risk is reduced through the use of latex condoms. For the wearer, latex condoms provide a mechanical barrier limiting penile exposure to infectious cervical, vaginal, vulvar, or rectal secretions or lesions. Likewise, the partner is protected from infectious pre-ejaculate, semen, and penile lesions. Oil-based lubricants may make latex condoms ineffective and should not be used; water-soluble lubricants are considered safe. Natural membrane condoms (made from lamb cecum) contain small pores and do not block HIV passage. It is estimated that latex condom use reduces the risk of HIV transmission by approximately 70% to 80% [31,32,33]. Although abstinence from sexual contact is the sole way to absolutely prevent transmission, sexual activity in a mutually monogamous relationship in which neither partner is HIV-infected and no other risk factors are present is considered safe [4]. However, men who identify publicly as heterosexual and generally have committed relationships with women, but who also engage in sexual activity with other men, may be a transmission bridge to heterosexual women [34]. To better understand the actual extent of this behavior and its impact on HIV transmission, more research is necessary.

More than 3,100 new HIV infections occurred in 2020 among IDUs [10]. Transmission of HIV among injecting drug users occurs primarily through contamination of injection paraphernalia with infected blood. The risk of sustaining HIV infection from a needle stick with infected blood is approximately 1 in 300 [39]. Behavior such as needle sharing, "booting" the injection with blood, and performing frequent injections increases the risk. Crack cocaine use (by injection or smoking) is associated with a higher prevalence of HIV infection. This may in part be attributed to the exchange of cocaine for sex. Sharing of equipment is common due to legal and financial restrictions and cultural norms, and some studies have linked higher levels of psychologic distress (e.g., anxiety and depressive symptoms) with an increased risk for needle sharing [40]. Secondary transmission occurs to children and sexual partners. Preventative strategies include medication-assisted drug treatment, onsite medical care in a drug treatment program, recruitment of "street" outreach workers for intensive drug and sex risk-reduction educational campaigns, teaching addicts to sterilize their equipment between use, the free provision or exchange of sterile injection equipment (as allowed by law), distribution of condoms and bleach to clean drug use equipment, or a combination of these interventions.

It is recommended that PEP be started as soon as possible after the potential exposure and continue for four weeks [55]. The PHS no longer recommends that the severity of exposure be used to determine the number of drugs offered in an HIV PEP regimen [56]. A regimen containing three (or more) antiretroviral drugs is recommended routinely for all occupational exposures to HIV. The regimen should be administered as soon as possible but within 72 hours of exposure and should be continued for 28 days [57]. The suggested regimen is tenofovir/emtricitabine, plus dolutegravir or bictegravir. PEP should be initiated even if awaiting results of HIV testing on the individual [56,57]. In the setting of pregnancy or breastfeeding, expert consultation is advised [57].

As discussed, HIV infection is a protracted illness that passes through several stages and, if untreated, carries an 80% mortality rate at 10 years. Within 15 to 30 days after acquisition of HIV infection, the majority of patients (50% to 90% in reported series) develop an acute retroviral syndrome similar to infectious mononucleosis [13]. Symptoms include fever, sore throat, malaise, rash, diarrhea, lymphadenopathy, mucocutaneous ulcerations and weight loss averaging 10 pounds. A variety of neurologic syndromes including encephalitis may occur. The illness is self-limited, with an average duration of two to three weeks. Laboratory abnormalities include lymphopenia, atypical lymphocytosis, thrombocytopenia, and a decreased CD4 cell count. During this early phase of clinical illness, HIV antibody tests are often negative and the diagnosis rests on the demonstration of HIV P24 antigen or, preferably, quantitative plasma HIV RNA. Concentrations of HIV RNA in the blood (viral load) are high during the acute syndrome.

Chronic, asymptomatic HIV infection with ongoing low-level viral activity may last for many years before eventual progression to AIDS. Symptomatic illness can be expected to supervene as the CD4 count declines to a level less than 200 cells/mcL, as this correlates with severe immunodeficiency. The CDC defines late-stage HIV infection as AIDS on the basis of two criteria: CD4 count less than 200 cells/mcL or a characteristic AIDS-defining illness such as PJP, central nervous system (CNS) toxoplasmosis, or other opportunistic infections or tumors (Kaposi sarcoma). A variety of clinical syndromes may supervene at this juncture including dementia, peripheral neuropathy, wasting syndrome, and chronic diarrhea. In the United States, common AIDS-defining opportunistic diseases include: PJP, Kaposi sarcoma, candidiasis, cryptococcosis, cryptosporidiosis, CMV, atypical mycobacteriosis, systemic herpes, toxoplasmosis, and tuberculosis [59].

Development of mature infectious virus depends upon enzymatic cleavage of HIV transcribed polyprotein by HIV protease. In binding to the active site of the HIV protease, PIs interrupt the formation of mature infectious particles and reduce viral replication by as much as 99%. Resistance to PIs develops rapidly when these agents are used alone. However, in combination with nucleoside analogs the effect can last for years, often resulting in a reduction of viral load to undetectable levels. Available agents include: ritonavir (Norvir, RTV); saquinavir (Invirase, Fortovase, SQV); atazanavir (Reyataz, ATZ); tipranavir (Aptivus, TPV); darunavir (Prezista; DRV); and fosamprenavir (Lexiva, FPV) [62].

For treatment-naïve patients, initial recommended therapy generally consists of two NRTIs in combination with a third active antiretroviral drug from one of three drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (cobicistat or ritonavir) [61]. These regimens result in maximum reduction of viral load for the longest period of time. When used as initial therapy, these regimens will achieve the goal of no detectable virus in the majority of patients after four to six months [61].

As of 2023, AIDS was no longer among the top 10 causes of death for African American women in the United States [81]. Nevertheless, women of color have been disproportionately affected by HIV/AIDS. In 2019, African American women accounted for 54% of new HIV diagnoses among women in the United States [80]. Although HIV diagnoses among African American women decreased 31% between 2019 and 2018, the incidence rates remain much higher for Black and Hispanic women than for White women [78]. In 2020, the highest number of HIV cases reported were in women 25 to 34 years of age, followed by women 35 to 44 years of age, women 45 to 54 years of age, and women 55 years of age and older. The lowest number of cases were reported in females 13 to 24 years of age [82].

Gender-specific manifestations of HIV disease include irregular menstruation, recurrent vulvovaginal candidiasis, human papillomavirus (HPV)-related cervical dysplasia (abnormal, precancerous cell growth), and cervical cancer [87]. HIV-infected women have a higher prevalence of HPV infection, a higher risk of progression from infection to disease, and an increased risk of invasive cervical cancer and other HPV-related cancers than non-infected women [87]. Research indicates that cART does not significantly decrease the incidence of HPV-related cancers. As such, the American College of Obstetricians and Gynecologists recommends that women younger than 30 years of age with HIV should have cervical cytology screening once every three years rather than annually if they have had three consecutive normal annual results. Women with HIV who are 30 years of age and older can undergo either testing with cytology alone or co-testing with cytology and HPV testing. Women with three consecutive normal annual cytology tests can then be screened annually as can those with one normal co-test [88].

Children receiving cART should be monitored for side effects, adherence, efficacy and toxicity. The U.S. Department of Health and Human Services recommends evaluating all pediatric patients within one to two weeks to monitor compliance, side effects, and response to treatment. Subsequently, a visit should be scheduled every three to four months [95]. Strategies to improve adherence should focus on selecting an appropriate regimen, educating the family/caregiver, and consistent follow-up.

Approximately 17% of newly diagnosed cases of HIV in 2018 occurred in individuals 50 years of age or older; 12.5% of all persons living with HIV/AIDS are 50 years of age and older [96]. Until recently, there had been little attention given to this group. HIV/AIDS has traditionally been thought to be a disease of the young; therefore, in the past, prevention and education campaigns had not been targeted toward older adults. However, evidence points to the increasing number of infected older people and a need for change in prevention and education campaigns. Some older persons may have less knowledge about HIV and risk reduction strategies. Due to divorce or being widowed and the availability of medications to treat erectile dysfunction, increasing numbers of older people are becoming sexually active with multiple partners [96]. For postmenopausal women, contraception is no longer a concern, and they are less likely to use a condom. Furthermore, vaginal drying and thinning associated with aging can result in small tears or cuts during sexual activity, which also raises the risk for infection with HIV/AIDS [96]. Studies indicate that at-risk individuals in this age group are significantly less likely than younger at-risk adults to use condoms during sex [97]. In addition, healthcare professionals are less likely to discuss sexual activity or take a sexual history if the patient is older than 50 years of age [97]. The combination of these factors increases the risk for unprotected sex with new or multiple partners in this age group, thereby increasing their risk for AIDS. This increase should be considered when evaluating older patients.

In 2021, the CDC and the U.S. Department of Health and Human Services released updated clinical practice guidelines for pre-exposure prophylaxis for the prevention of HIV infection [102]. In 2022, the International Antiviral Society published recommendations for the treatment and prevention of HIV infection in adults [57]. These guidelines outline indications for prophylaxis as one prevention option for HIV transmission. The most important first step in determining if an individual is a candidate for pre-exposure prophylaxis is a thorough history, including sexual and injection drug activities. All candidates will be adults without an acute or established HIV diagnosis. Pre-exposure prophylaxis should be offered to all sexually active adults and adolescents at substantial risk of acquiring HIV [57,102]. PrEP is indicated for high-risk MSM, meaning those who have had any male sex partners in the past six months, are not in a monogamous partnership with a recently tested, HIV-negative man, and have one of the following [102]:

Prophylaxis is also recommended for high-risk heterosexual adults who have had sex with an opposite sex partner(s) in the past six months, are not in a monogamous partnership with a recently tested, HIV-negative partner, and one of the following [102]:

IDUs are also considered candidates for pre-exposure prophylaxis if they meet certain criteria. The guideline states that persons who have injected drugs not prescribed by a clinician in past six months may be candidates for prophylaxis if they also are positive for one of the following factors [102]:

Many adolescents engage in behaviors that put them at risk for HIV infection. According to the CDC, 37.4% of high school students reported being sexually active [108]. Approximately 54.3% of currently sexually active high school students had not used a condom at last sexual intercourse; 1.2% had ever injected an illegal drug [108]. Only 71% of U.S. high school districts have adopted a policy specifying that human sexuality is taught, and the content of these discussions may not provide adequate information on the subject. Furthermore, the American Academy of Pediatrics determined that school-based education and intervention programs do not provide the necessary opportunities of confidential discussions or targeted counseling [109]. Healthcare professionals have a unique opportunity to intervene in this population to provide accurate and complete information on HIV transmission and risk reduction.