#98903: HIV/AIDS: Epidemic Update

The global healthcare community first became aware of the illness now known as HIV/AIDS in 1981. In subsequent decades, the HIV pandemic, and associated disease burden of AIDS, emerged as a major public health issue worldwide. The incidence of HIV infection continues to escalate in some developing countries of the world, compared with a notable stabilization in new cases and fatalities in most developed countries.

Two human immunodeficiency viruses, HIV-1 and HIV-2, have been identified and both cause AIDS. Researchers in the United States and England have traced the ancestry of the HIV-1 virus to two strains found in African red-capped mangabeys and greater spot-nosed monkeys. The strains most likely combined in chimpanzees that ate the monkeys, resulting in the chimpanzees developing simian immunodeficiency virus (SIV). Chimpanzees then transmitted the virus to humans, likely around 1908 [1]. Genetic studies suggest that the lower monkeys first became infected with SIV 100,000 years ago [2].

HIV-2 is believed to be endemic in West Africa, though even areas with previously high rates (e.g., Senegal) are seeing HIV-2 being increasingly overtaken by HIV-1 [1]. Several well-documented cases of HIV-2 infection have been reported in Europeans and among West Africans residing abroad. A total of 242 cases meeting the Centers for Disease Control and Prevention's (CDC's) definition of HIV-2 infection were reported between 1988 and 2010 in the United States, the majority of which were associated with immigration from, travel to, or a sexual partner from West Africa [3]. Differences in the global spread are attributed to differences in transmissibility and duration of infectiousness [4].

According to the World Health Organization (WHO), an estimated 37.7 million individuals worldwide were living with HIV by the end of 2020, of whom more than two-thirds (25.4 million) were in the WHO African Region [5]. Northern Africa, the Middle East, and eastern Europe and central Asia (particularly the Russian Federation) have had the fastest growing epidemics—new HIV infections in these regions have approximately doubled in the past 20 years. In 2020, an estimated 680,000 people died from HIV-related causes and 1.5 million people acquired HIV infection [5]. It is important to note that despite increases in certain geographic areas and demographic groups, overall, the rate of new infections was declining prior to the COVID-19 pandemic. Service disruptions during COVID-19 have slowed the pace of public health response to HIV, raising concern that increasing HIV infections and excess HIV-related deaths may erode the progress made in sub-Saharan Africa [5].

Beginning in 2003, the U.S. government has worked to fight the disease in Africa, partially through the implementation of the President's Emergency Plan for AIDS Relief (PEPFAR) [6]. PEPFAR was reauthorized in 2008, with a total of $48 billion in funds over the following five years and expansion to address additional health issues, including malaria, tuberculosis, maternal health, and clean water [7]. This was extended to 2023 with the PEPFAR Extension Act of 2018 [8].

At year-end 2019, an estimated 1.2 million individuals 13 years of age or older were living with HIV/AIDS in the United States [9]. The CDC estimates that approximately 13% of these individuals were unaware of their infection [9]. When reviewing trends in HIV transmission, one should keep in mind that the widespread use of antiretroviral therapy has resulted in fewer deaths and longer survival.

As of 2019, the Centers for Disease Control and Prevention (CDC) report several statistics and trends in the HIV/AIDS epidemic [9]:

HIV, known formerly as human T cell lymphotropic virus (HTLV-III), is a member of the retrovirus group and as such carries a ribonucleic acid (RNA) genome and a reverse transcriptase enzyme (RNA-directed DNA polymerase) that enables the virus to replicate within infected host cells. Susceptibility in humans is determined by the binding affinity of virion envelope proteins for a specific cell surface receptor molecule (CD4+) found on tissue dendritic cells, macrophages, and CD4+ T lymphocytes. The pathogenesis of infection, and the subsequent perpetuation of the disease state, involves a complex set of interactions by which HIV is able to take advantage of cellular pathways while avoiding or neutralizing various components of the immune system [11,12].

The most common mode of HIV infection is sexual transmission across exposed mucosal epithelium. Dendritic cells and macrophages are found beneath the mucosal epithelium of the anogenital and cervicovaginal tracts, as well as within tonsillar and adenoidal tissue. Studies in primates demonstrate that after the virus penetrates the mucosal epithelium, infection is initiated within nearby dendritic cells and macrophages. Infected dendritic cells then fuse with CD4+ T lymphocytes and the infection extends to deeper tissue and, shortly thereafter, to regional lymph nodes [12]. Within days, this proliferation of infected CD4+ T lymphocytes, combined with the migration of infected macrophages, leads to the appearance of viral RNA in the blood stream. This is followed by widespread secondary amplification of infection within the lymphoid tissue of the gastrointestinal tract, spleen, and bone marrow.

Once the virus enters the cell, it may replicate, induce cell fusion and propagation of infection, or lead to cell death [12]. HIV targets the immune system, and the defining characteristic of HIV disease is progressive immunodeficiency caused by ongoing viral replication and cell-to-cell transmission within lymphoid tissue. With chronicity 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). Eventually, impaired immunity renders the individual vulnerable to opportunistic infection and certain malignancies. The common laboratory measure of immune function is the CD4 cell count. 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 [12]. 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 [12].

Early in the chronic phase of HIV infection, when the CD4 lymphocyte population is only modestly depressed and declining slowly, patients are often asymptomatic or may exhibit generalized lymphadenopathy and recurrent oropharyngeal candidiasis (thrush). During this stage, a reservoir of HIV is established throughout the lymphoid tissue system, including the spleen. Gradually, wandering (infected) macrophages disseminate the virus to certain internal organs, notably the brain, kidney, and adrenal glands.

Chronic HIV disease follows a variable course but eventually leads to a variety of clinical manifestations, some of which are directly related to the impact of chronic infection on vital organs. Common syndromes include HIV encephalopathy and dementia, peripheral neuropathy, interstitial nephropathy, a variety of skin eruptions, and signs of adrenal insufficiency.

The late clinical manifestations of HIV disease are most frequently the result of acquired immunodeficiency syndrome (AIDS) that follows progressive depletion of CD4+ T lymphocytes to levels <200 cells/mcL. AIDS-defining illnesses include secondary, opportunistic infections and certain malignancies usually encountered only in clinical settings of severely impaired cellular immunity.

Opportunistic infections are very common in persons with undiagnosed or poorly treated chronic HIV infection and are of two types. The first type is infection newly acquired by exposure to micro-organisms normally nonpathogenic, or of low pathogenicity, for persons with a healthy immune system. Examples are Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, and atypical mycobacteria, all of which are commonly associated with inhalational exposures and transient colonization of the respiratory tract in healthy individuals. The second type is reactivation of latent infection acquired earlier in life, which typically remains dormant throughout life. Examples of this type are CMV, Toxoplasma gondii, Mycobacterium tuberculosis, and Histoplasma capsulatum. The advent of an opportunistic infection may serve as the herald sign of unrecognized, undiagnosed chronic HIV infection/AIDS.

Clinically, these infections tend to present in one of several distinct syndromes, with useful differential diagnosis considerations:

Late clinical manifestations related to HIV-induced malignancy include Kaposi sarcoma of the skin or respiratory tract and lymphoma presenting as lymphadenopathy, splenomegaly, or focal gastrointestinal disease.

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]:

The CDC has published guidelines for medical professionals to integrate HIV prevention into the regular medical care of those living with HIV. The three major components of the recommendation are: screening for HIV transmission risk behaviors and sexually transmitted infections (STIs); providing brief, behavioral risk-reduction interventions in the office setting and referring selected patients for additional prevention interventions and other related services; and facilitating notification and counseling for sex and needle-sharing partners of infected persons [16,17].

Clinical latency, sometimes referred to as the window period, is the time elapsed between acquisition of the virus and the body's immune response sufficient to generate detectable antibody. This latent period is longer for HIV than for most other viral pathogens and is variable among newly infected individuals.

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 [12]. 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.

Following the host immune response, coincident with seroconversion and the rise in CD8 cytotoxic T cells, the viral load decreases steadily, reaching a relatively stable level at about six months. At this juncture, the degree of viral load correlates with the subsequent pace of disease progression. Patients having the highest viral loads, exhibit the most rapid progression to AIDS. As a result of the ongoing, protracted infection of target lymphocytes, the CD4 count gradually declines over time in the absence of treatment, at the average annual rate of about 50 cells/mcL.

Approximately 10% to 20% of persons with newly acquired HIV are asymptomatic during the initial two months following acute infection. While initial routine laboratory studies are relatively normal, serologic and virologic studies are positive and these patients show the same host-virus dynamics, including gradual decline in CD4 count, as that seen in symptomatic patients.

The serologic diagnosis of HIV infection in an asymptomatic patient does not, in and of itself, establish how recently the patient became infected. The stage of infection may be estimated on the basis of careful history and physical examination, and a standard laboratory evaluation that includes complete blood counts, lymphocyte subsets or CD4 count, and viral load. The duration of this asymptomatic stage is variable depending on prevailing CD4 count and viral load and is amenable to treatment with combination antiretroviral therapy (cART).

In the months following acute infection, whether symptomatic or not, many patients have persistent, painless generalized lymphadenopathy (PGL) without other disease manifestations. PGL is defined as palpable lymph node enlargement of 1 cm or greater at two or more extrainguinal sites that persists for more than three months in the absence of a concurrent illness or explanation other than HIV infection. In some cases, lymphadenopathy regresses as HIV disease advances, probably because the architecture of the lymph node is gradually destroyed [4].

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, the most common AIDS-defining opportunistic diseases are: PJP, Kaposi sarcoma, candidiasis, cryptococcosis, cryptosporidiosis, CMV, atypical mycobacteriosis, systemic herpes, toxoplasmosis, and tuberculosis [41].

In the absence of effective therapy, the average survival is approximately 3.5 years after the patient's CD4 count has reached 200 cells/mcL and 1.5 years for the patient who has developed an AIDS-defining diagnosis. The natural history and the prognosis for the patient with chronic HIV infection have been dramatically altered by antiretroviral therapy, especially by the use of cART that followed the introduction of protease inhibitors (PIs) and NNRTIs in 1996.

HIV disease is treated with therapeutic regimens consisting of a combination of three or more antiretroviral drugs. Current cART does not cure HIV infection but does suppress viral replication and allow immune system recovery sufficient to restore a sense of well-being and regain the capacity to avoid opportunistic infections. Since 2016, the WHO has recommended that all people living with HIV be provided lifelong ART, including children, adolescents, adults, and pregnant and breastfeeding women, regardless of clinical status or CD4 cell count [5]. By June 2021, 187 countries had adopted this recommendation, covering 99% of all people living with HIV globally.

cART consists of two or more drugs selected from eight major classes of agents: NRTIs, NNRTIs, PIs, fusion inhibitors (FIs), INSTIs, chemokine (C-C motif) receptor 5 (CCR5) antagonists, gp120 attachment inhibitors, and capsid inhibitors. Initiated in 1995 in the United States, antiretroviral therapy regimens have been effective in dramatically decreasing HIV-related morbidity and mortality and should be considered for all HIV-infected persons who qualify for such therapy. In addition to combination therapy, the sequencing of drugs and the preservation of future treatment options are also important. Two types of combination regimens are recommended as initial therapy: INSTI-based regimens or a PI-based regimen. The goal of these regimens is to effectively reduce HIV-associated morbidity, prolong the duration and quality of survival, restore and preserve immunologic function, and prevent HIV transmission while also avoiding drug resistance [42]. A significant proportion of patients starting cART are infected with drug-resistant strains of HIV, which may lead to suboptimal virologic responses. Therefore, pretreatment genotypic resistance testing should be used to guide selection of the most optimal initial regimen [42].

Initiation of Therapy

The decision to initiate antiretroviral therapy is one that requires careful discussion with the patient, usually in consultation with an infectious disease specialist or other physician well versed in the use of cART. Physicians and patients alike should be aware of the advantages, potential toxicities, and complexity of monitoring therapy. Clinicians should consult PHS, the National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) published guidelines for the use of antiretroviral agents in adults and adolescents living with HIV [42]. A typical initial regimen consists of three HIV medications from two drug classes. At the present time, the most active triple-drug regimen in a previously untreated patient can be expected to reduce the viral load below detectable levels, increase CD4 counts by an average of 100–150 cells/mcL, reduce the risk of HIV-associated complications, and prolong survival. However, the ability to achieve this advantage depends on the patient's willingness to accept a complex medical regimen that requires "many pills," rigorous compliance, frequent follow-up, and moderate risk for drug toxicity. In reaching a decision it is helpful to bear in mind that prognosis is determined by viral load and the CD4 count. Patients having a viral load in excess of 60,000 copies per milliliter have a relatively rapid course and average survival of a little more than four years. In contrast, those with less than 6,000 copies per milliliter have an average survival of more than 10 years. The CD4 count is also a prognostic factor, as counts less than 350 cells/mcL indicate severe damage to immune function and corresponding risk for opportunistic infection.

According to the Panel on Antiretroviral Guidelines for Adults and Adolescents, antiretroviral therapy is recommended for all individuals with HIV, including those with early HIV infection and should be initiated as soon as possible after diagnosis.

(https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf Last Accessed: March 11, 2022)

Strength of Recommendation: AII (Strong recommendation based on well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes)

Antiretroviral therapy should be initiated immediately for all patients infected with HIV in order to reduce the risk of disease progression and limit transmission [42]. There is growing evidence that early initiation of cART is effective in preventing clinical events (e.g., non-AIDS malignancies, infection, AIDS-defining illness) regardless of pre-treatment CD4 count [48,49]. Advances in the development of antiretroviral medications and combination tablets makes adherence to therapy more effective, more convenient, and better tolerated than regimens used in the past. Deferral of therapy may be considered in patients with high CD4 counts (e.g., more than 500 cells/mcL) if adherence will be very difficult or impossible, comorbidities complicate or prohibit antiviral therapy, or a patient is considered a long-term non-progressor [42].

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) [42]. 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 [42].

Absent timely diagnosis and treatment of HIV, opportunistic infections are often the first clinical indication a patient has AIDS. Pneumocystis pneumonia, toxoplasma encephalitis, cytomegalovirus retinitis, cryptococcal meningitis, and disseminated atypical mycobacterial infection are often hallmarks of AIDS. Before effective cART, these complications occurred on average 7 to 10 years after HIV infection, and patients usually survived only 1 to 2 years after the initial manifestation of AIDS [50].

Depending on the CD4 count and other risk factors, asymptomatic patients with HIV may benefit from prescribed prophylaxis against opportunistic infections. Achieving and maintaining durable viral suppression with cART is important in prevention of infection; however, the CDC estimates only about half of diagnosed patients linked to care have durable viral suppression [50]. Poor adherence and unfavorable pharmacokinetics are among causes for suboptimal response to treatment. Recommendations for antimicrobial prophylaxis of opportunistic infections are summarized inTable 1 according to guidelines provided by the CDC, the NIH, and IDSA [50]. Prophylactic therapy for these conditions is strongly recommended because these infections are relatively common in patients with HIV, preventive therapy is simple and cost-effective, and efficacy has been established in clinical studies. In addition, all patients should be vaccinated with pneumococcal vaccine. Hepatitis B vaccination should be considered in patients whose serologic testing indicates susceptibility.

The CDC, the National Institutes of Health, and the IDSA have developed guidelines for the prevention of opportunistic infections among HIV-infected individuals [50]. The guidelines are specific to each opportunistic infection and can be viewed at https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection.

Tuberculosis is the leading cause of morbidity and mortality among people living with HIV worldwide, with 1 million reported cases and 374,000 deaths in 2017 [52]. People coinfected with HIV and latent tuberculosis have a 20 to 30 times greater risk of developing active tuberculosis compared with people not infected with HIV [51]. While cART significantly decreases the risk of conversion from latent to active disease, patients with HIV remain at higher risk of tuberculosis disease than the general population [50]. Among individuals in the United States with tuberculosis, an estimated 8.6% are coinfected with HIV [51].

In addition to the recommended prophylaxis to prevent a first episode of opportunistic tuberculosis, NIH/IDSA guidelines for the treatment of HIV-related active tuberculosis have been published [52]. In general, treatment of suspected tuberculosis for individuals with HIV is the same as treatment for individuals without HIV and should include an initial four-drug combination of isoniazid, rifampin, ethambutol, and pyrazinamide until susceptibility to isoniazid and rifampin has been confirmed [52]. If rapid drug sensitivity testing indicates resistance to rifampin, a multidrug-resistant tuberculosis regimen (including levofloxacin or moxifloxacin and either an aminoglycoside or capreomycin) should be used initially until conventional sensitivity results are available [52]. Guideline recommendations call for directly observed therapy for all patients with HIV-related tuberculosis; prolonged treatment (up to nine months) for patients with a delayed clinical or bacteriologic response to therapy or perhaps with cavitary disease on chest radiograph; and rifabutin-based regimens given at least three times a week for patients with tuberculosis and advanced HIV disease [52]. Special considerations apply to children and pregnant women with HIV-related tuberculosis.

Optimal management of HIV-related tuberculosis is complex, involving decisions around duration of therapy, timing of cART, and support services to assure adherence to observed therapy and regular follow-up care. Healthcare professionals should consult the guidelines to ensure use of the most effective management strategies for patients with tuberculosis and HIV, while concurrently promoting optimal cART for these patients.

Women now make up nearly half of all AIDS cases worldwide and approximately 25% in the United States [53]. The rate of HIV infection in women had been rising rapidly, but the proportion of new HIV diagnoses among women in 2010 (20%) represented a 21% decrease since 2008 [53,56]. From 2016 to 2019, the annual incidence of HIV infection in women remained stable in the United States at 4,5 per 100,000; by comparison, the rate among men was five times higher (21.0) [9]. In the last 30 years, the proportion of AIDS cases in women has tripled, from 8% in 1985 to 24% in 2016 [53,56]. In 1993, when the CDC expanded the case definition of AIDS, there was a 151% increase in the number of AIDS cases in women and a 105% increase in cases in men. More women were found to meet the AIDS case definition when the CD4+ T-lymphocyte count of <200 cells/mcL was added to the criteria. This may be evidence that the previous case definitions based on the clinical characteristics of men did not accurately reflect the clinical manifestations of HIV in women [54].

AIDS is no longer a leading cause of death in women overall in the United States, but it remains the fifth leading cause of death in African American women 35 to 44 years of age [55]. Women of color have been disproportionately affected by HIV/AIDS, with Black women accounting for 64% of new HIV diagnoses among women in the United States while representing only 13% of the female population [53]. Women of color also tend to contract HIV at a younger age than their White counterparts.

The risk for acquisition of HIV and the factors that may affect seroconversion in heterosexual women are areas of research. It is clear that, in the absence of protective measures, women are much more likely to become infected with HIV through heterosexual sex (i.e., vaginal or anal receptive sex) than men. Although latex condoms are effective at preventing transmission of HIV when used correctly and consistently, some women may be afraid of the repercussions of insisting on condom use with their partners [56].

In the United States today, the predominant route of infection with HIV in children is perinatal (from an infected pregnant woman to her fetus or infant) [65]. Thus, the epidemic in children is closely linked to the epidemic in women.

The Panel on Antiretroviral Guidelines for Adults and Adolescents asserts that older persons with HIV are probably at an even greater risk of polypharmacy-related adverse consequences than younger or similarly aged people without HIV, and it is very important to remain vigilant to potential drug-drug interactions given the high prevalence of polypharmacy in this population.

(https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf Last Accessed: March 11, 2022)

Strength of Recommendation: Expert Opinion/Consensus Statement

Approximately 17% of newly diagnosed cases of HIV in 2018 occurred in individuals 50 years of age or older; 51% of all persons living with HIV/AIDS are 50 years of age or older [68]. Until recently, there had been little attention given to this group. HIV/AIDS has traditionally been thought to be the 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 [68]. 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 [68]. Studies indicate that at-risk individuals in this age group are significantly less likely than younger at-risk adults to use condoms during sex [69]. 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 [69]. 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.

Early possible signs of immunosuppression that are frequently overlooked or mistakenly attributed to aging include thrush and skin problems, especially seborrheic dermatitis and herpes zoster. When HIV is not recognized or treated, the most typical opportunistic infections are PJP and recurrent bacterial pneumonia, CMV, and Mycobacterium tuberculosis or Mycobacterium avium complex. PJP can present as bacterial pneumonia, bronchitis, or congestive heart failure. Early HIV symptoms in the elderly, such as fatigue and weight loss, may appear to be a normal part of aging, and AIDS-related dementia is often mistaken for Alzheimer disease.

In 2012, the FDA approved the first medication for the prevention of sexually transmitted HIV infection, the combination drug Truvada (emtricitabine/tenofovir DF) [70]. In 2019, another combination drug—Descovy (emtricitabine/tenofovir alafenamide)—was approved to prevent HIV infection [79]. In 2021, the FDA approved the first injectible agent for the prevention of HIV infection; cabotegravir is given first as two initiation injections administered one month apart, and then every two months thereafter [82]. In conjunction with safer sex practices, these agents have been found to be partially effective as pre-exposure prophylaxis in high-risk patients. The Chemoprophylaxis for HIV Prevention in Men study, also known as iPrEx, studied the effect of once-daily Truvada in 2,499 HIV-seronegative men or transgender women who have sex with men compared to placebo [71]. Researchers found that persons receiving Truvada experienced a 44% reduction in the incidence of HIV after a median of 1.2 years compared to placebo. Pre-exposure prophylaxis was most effective among participants at particularly high risk for HIV (i.e., self-reports of unprotected receptive anal intercourse). Research has indicated that Descovy and cabotegravir are similarly effective [79].

In 2021, the CDC and the U.S. Department of Health and Human Services updated their clinical practice guidelines for pre-exposure prophylaxis for the prevention of HIV infection [72]. This guideline outlines 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 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 [72]:

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 [72]:

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 the past six months may be candidates for prophylaxis if they also are positive for one of the following factors [72]:

Injection cabotegravir given bimonthly and fixed-dose combination tenofovir and emtricitabine (Truvada or Descovy) taken daily are approved for pre-exposure prophylaxis, and they are considered the recommended first-line option [70,72,79,82]. However, because tenofovir alone has been proven effective in trials with IDU and heterosexually active men and women, it is the alternative option for these populations [72]. No other antiretroviral regimens should be used for pre-exposure prophylaxis.

All patients prescribed pre-exposure prophylaxis must have a negative HIV test prior to initiating treatment and every three months thereafter. In addition, patients should be advised regarding possible side effects and the continued necessity for safe sex practices. Eligible patients should also be screened for hepatitis B and have a confirmed creatinine clearance of 60 mL per minute or greater [72].

Both preventive and therapeutic vaccines are being studied for use in the fight against HIV. Preventive vaccines are developed to protect individuals from contracting HIV, while the goal of therapeutic vaccines is to boost immune response to and better control existing HIV infection. Of course, the ultimate goal in vaccine research is a vaccine that will prevent infection; however, despite many trials, no vaccine effective in preventing HIV has been discovered.

Most progress on HIV vaccine development may be monitored through the International AIDS Vaccine Initiative (IAVI). The IAVI has three main objectives: accelerating the development of AIDS vaccines, establishing partnerships to expand the diversity and number of AIDS vaccine candidates, and building support for AIDS vaccine research and development [73].

Because HIV is spread predominantly through sexual transmission, the development of chemical and physical barriers that can be used intravaginally or intrarectally to inactivate HIV and other STI pathogens is critically important for controlling HIV infection.

Researchers are developing and testing new creams or gels (topical microbicides) that could be applied before intercourse to protect individuals against HIV and other sexually transmitted organisms [74]. One of the most promising is 1% vaginal gel formulation of tenofovir, which showed a 54% decrease in the incidence of HIV infection in high adherers in one clinical trial [75]. Another option is a flexible silicone matrix polymer ring containing dapirivine, an NNRTI, which is slowly released over the course of one month [74]. However, there are concerns regarding compliance with recommendations to ensure protection.

New topical microbicide candidates would ideally be non-irritating and inexpensive. In addition, they should be available in both spermicidal and non-spermicidal formulations so women do not have to put themselves at risk for acquiring HIV and other STIs in order to conceive a child.

Many adolescents engage in behaviors that put them at risk for HIV infection. According to the CDC, 39.5% of high school students [76]. Approximately 45.7% of currently sexually active high school students had not used a condom at last sexual intercourse; 1.6% had ever injected an illegal drug [76]. Although 85.3% of adolescents report having received education on HIV prevention in school, 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 [77]. Healthcare professionals have a unique opportunity to intervene in this population to provide accurate and complete information on HIV transmission and risk reduction.