Continuing Education Activity

Clinical prevention of HIV infection and AIDS is the cornerstone of controlling the global HIV pandemic that has now killed more than 40.4 million people globally, including 1.5 million children. While a cure remains out of reach, HIV infection is now seen as a chronic illness due to the effectiveness of antiretroviral therapy. Combined with significant advancements in prevention, the goal of halting the global HIV pandemic is now feasible. 

This activity comprehensively reviews HIV transmission, pathophysiology, clinical presentations, evaluation, up-to-date treatment, reporting, and program implementation considerations for specific population groups. Clinicians can expect to increase their knowledge, skills, and competence in HIV care, improving patient outcomes, reducing transmissions, and contributing to global efforts against the disease. 

The role of the interprofessional team is highlighted throughout the CME, emphasizing collaboration among clinical, public health, and other interdisciplinary team members. This approach acknowledges the complexity of clinical HIV management, considering socio-economic factors, the need for patient-centered care and continuous quality improvement, and the importance of social and regulatory environments to achieve optimal patient and population outcomes. By providing up-to-date information on HIV management and fostering collaboration among healthcare professionals, this CME aims to empower clinicians to navigate the evolving challenges posed by HIV, ultimately contributing to better patient care and global outcomes.

Objectives:

• Determine the stage of HIV infection and related comorbidities to ensure accurate and timely diagnosis and appropriate treatment planning for individual patients.

• Implement current guidelines and evidence-based practices in the treatment of HIV to optimize patient outcomes, including the initiation and management of antiretroviral therapy, prophylaxis for opportunistic infections, and prevention and management of adverse effects.

• Communicate HIV-related information effectively to patients, ensuring a clear understanding of the diagnosis, treatment options, and the importance of adherence while demonstrating cultural sensitivity and maintaining confidentiality.

• Collaborate with interprofessional team members, including nurses, pharmacists, social workers, nutritionists, public health professionals, community health workers, peer support workers, researchers, and others, to ensure continuity of care and improve individual and population outcomes for HIV prevention and treatment.

Introduction

First isolated and identified in 1983, the human immunodeficiency virus (HIV) has claimed approximately 40.4 million lives worldwide as of 2022. This number is staggering, and unchecked would lead to a global health crisis. However, the research, development, and widespread availability of highly active antiretroviral therapies (ARTs) have helped contain the HIV pandemic. Likewise, advances in the treatment of HIV and opportunistic infections have rendered the disease a manageable chronic illness. People living with HIV can live long and healthy lives, with chronic disease prevention a health priority in this population.

With adequate resources and will, advances in prevention, treatment, and implementation science make the United Nations General Assembly's 95-95-95 goals attainable. By 2025, these aim for 95% of people living with HIV to have a diagnosis, 95% with a diagnosis to be taking ART, and 95% of those taking ART to have a suppressed viral load.[WHO. Global Health Sector HIV Strategies. 2022] Globally, HIV infection and mortality rates show a steady decrease. However, some countries report an uptrend in the rate of infections, mostly where political or other turmoil is occurring or where HIV is highly stigmatized.[UNAIDS. Global Report. 2023] With improvements in treatment, the number of people living with HIV is also increasing, with approximately 37.7 million people living with HIV in 2020 and 39 million people in 2022, two-thirds of whom live in Africa.[1] 

HIV still comes with high costs to the patient and the healthcare system. Infection with HIV increases the risk of chronic disease, particularly cardiac and neurological diseases. Despite the effectiveness of ART in delaying disease progress, treatment does not cure HIV, comes with adverse effects, and requires consistent, prolonged connection to the healthcare system. Barriers to universal treatment exist, including public- and self-stigma, lack of adequate access to care, inappropriate care, and costs.

Utilizing current local clinical guidelines for managing HIV improves patient outcomes and prevents HIV transmission. Implementation recommendations within clinical guidelines promote quality programming for prompt diagnosis, treatment, and connection to care for everyone living with or at risk of acquiring HIV. Increasing the involvement of community-led organizations in HIV testing and treatment and integrating HIV services with those for other related health issues extend the reach of HIV services, improve linkage to care, and contribute to improved overall health. Supportive social and policy environments regarding, for example, access to services, screening, and reporting test results, and discrimination can safeguard patients and the community at large.

Focusing primarily on HIV-1, this clinical reference is designed to review the pathophysiology, clinical manifestations, and recommended treatment options for patients with HIV to help primary clinical providers obtain concise and up-to-date guidance for the management of HIV. The optimal social and policy environments to support the HIV response, as recommended by the World Health Organization (WHO), the Joint UN Programme for HIV/AIDS (UNAIDS), the United States Centers for Disease Control (CDC), and state legislatures, with Florida legislation provided as an example, are discussed.

See StatPearls' companion topic, "HIV-2 Infection," for further information on HIV-2 infection.

Etiology

HIV belongs to the Retroviridae family in the Lentivirus genus. It was first isolated and identified in 1983.[1] The virus mainly targets CD4+ T-lymphocyte helper (CD4) cells, leading to an extreme form of immune subversion with a continuous loss of these cells. This weakens the immune system and causes a myriad of clinical manifestations of this disease. Untreated HIV infection eventually progresses to acquired immunodeficiency syndrome (AIDS). At this stage, the immune system cannot prevent infections, resulting in the individual's death due to opportunistic infections.[1] 

Two main types of HIV exist: HIV type 1 (HIV-1) and HIV type 2 (HIV-2). Although HIV-1 and HIV-2 genomes are structurally similar, they have significant divergence at the amino acid level. The 2 viruses result from 2 different zoonotic transmissions of simian immunodeficiency viruses and, as a result, have substantial differences in their severity, transmissibility, and prognosis. Note that HIV-1 and HIV-2 are only 60% identical at the amino acid level and have a mere 48% identity at the nucleotide level.[2]

HIV-1 and HIV-2 particles comprise a lipid membrane surrounding a protein capsid. The capsid, in turn, holds a nucleoprotein complex or core consisting of 2 identical copies of viral genomic RNA along with nucleocapsid, integrase, and reverse transcriptase proteins. The capsid protein organizes into a lattice structure, giving the capsid a characteristic conical shape.[3]

HIV is transmitted via various body fluids (ie, blood, amniotic fluid, breast milk, semen, pre-ejaculate, rectal fluids, and vaginal fluids). HIV can be transmitted via sexual contact, during pregnancy and delivery, and via fomites, such as reusable medical equipment or injection drug equipment.[WHO. Consolidated HIV Guidelines. 2021]

See StatPearls' companion topic, "HIV Prevention," for further information on HIV transmission.

Epidemiology

HIV remains a significant public health issue worldwide. The HIV-1 virus causes most HIV infections, with HIV-2 infections accounting for only 1 to 2 million of total HIV infections. The prevalence of HIV-2 exceeds 1% of infections only in West Africa, although infections occur less commonly on all continents, particularly those with colonial or other ties to the area. According to the WHO HIV factsheet, 39 million people were living with HIV at the end of 2022, with the majority (25.6 million) living in Sub-Saharan Africa.[WHO. HIV Data and Statistics. 2023] In 2022, 1.3 million new cases of HIV were reported worldwide, with 630,000 deaths related to HIV in the same year.

While some countries report an increase in new infections, the overall global trend in HIV incidence is downward. In particular, significant gains have been made in the prevention and treatment of HIV infection in eastern and southern Africa, where the virus is most prevalent. From 2010 to 2022, there were 57% fewer new infections and 58% fewer AIDS-related deaths in the region.[UNAIDS. Global Report. 2023]

Progress is slower in other areas, mainly where marked inequities and low prioritization of the HIV response exist. A study of global trends in HIV among adolescents and young adults showed a decrease in HIV incidence from 34.5 per 100,000 population in 1990 to 22.7 per 100,000 population in 2019.[4] However, between 2010 and 2022 in Asia and the Pacific, a quarter of new infections affected people aged 15 to 24 and their partners, with some countries reporting nearly half of all new infections in this population. In total, new HIV infections have decreased by only 14% in the region.[UNAIDS. Global Report. 2023]

Most concerningly, HIV incidence is increasing in some regions. The WHO Middle East and North African region has seen a 61% increase in the incidence of HIV between 2010 and 2022, the largest in the world.[UNAIDS. Global Report. 2023] Due to the low prevalence of HIV in this region, the number of people infected (about 16,000 people in 2022) is small relative to the 160,000 people estimated to be infected in Eastern Europe and Central Asia in 2022. New HIV infections in this region increased by 49% between 2010 and 2022. Challenging legal environments, human rights violations, and military conflicts hinder the HIV response. 

HIV infection, diagnosis, treatment, and viral suppression rates vary across and within countries and regions. Globally, females accounted for 65.8% of new HIV cases in 2019.[4] However, diagnosis, treatment, and viral suppression rates are lower among adolescent and adult men. For example, a phylogenetic study in Uganda estimated that men are 1.5 to 1 times less likely to be virally suppressed than women. Interventions that increase viral suppression rates among men to the same level as those in women would close the gender disparity in incident HIV infections.  

UNAIDS and WHO identify 5 key populations who are disproportionately affected by HIV and warrant specific care and support to reduce global transmissions: men who have sex with men (MSM), sex workers, people in prisons and other closed settings, people who inject drugs (PWID), and transgender and gender-diverse people.[5][UNAIDS. Global Report. 2023]

The vast majority of new HIV infections worldwide occur due to sexual contact. Most of these infections are transmitted via heterosexual contact due to the high number of infections in Africa, where this mode of transmission is dominant.[6] Most new HIV diagnoses in most other regions of the world occur in MSM.[WHO. HIV Data and Statistics. 2023] In the United States (US), in 2021, 70% of all new infections were in MSM, while only 22% occurred via heterosexual contact.[CDC. Basic Statistics. 2023] 

Injection drug use is another significant risk factor for HIV infection. According to a meta-analysis from 2008, approximately 3.0 million PWID are living with HIV worldwide.[7] According to the CDC HIV Factsheet, 1 in 10 new HIV infections in the United States can be attributed to injection drug use either alone or in MSM who report injection drug use. A systematic review evaluating the effectiveness of needle and syringe exchange programs reported that adequate needle and syringe exchange programs were effective in reducing the sharing and reuse of needles and syringes and HIV transmission among PWID.[8]

See StatPearls' companion topic, "HIV Prevention," for more details on the epidemiology of HIV, including the populations most impacted by HIV.

Pathophysiology

The Retroviridae family is unique among viruses, with the RNA viral genome reverse-transcribed into DNA before being integrated into the host DNA, resulting in lifelong infection. The pathophysiologic process is best known for HIV-1, with more recent research contributing to the understanding of differences in HIV-2 and HTLV viral replication and biology. 

As the primary host cellular receptor for HIV-1 and HIV-2 is the CD4 molecule, T cells and macrophages that express the CD4 molecule are the primary viral targets.[2] Envelope glycoprotein on the surface of the viral particle helps facilitate viral entry into the host cell. Chemokine coreceptors 5 (CCR5) and 4 (CXCR4) on the host cell surface trigger a conformational change in the envelop protein, which results in the fusion of the viral and host cellular membranes. Once membrane fusion occurs, the viral capsid is released into the host cell.[2]

The HIV-1 viral capsid remains intact or nearly intact until it reaches the nuclear pore complexes on the nuclear envelope of the host cell. Previously thought to occur in the cytoplasm, reverse transcription is now believed to occur during or shortly after the capsid is imported into the nucleus; the nuclear capsid is essential in the efficiency of reverse transcription. The precise location and mechanism of reverse transcription and the role of the capsid in this have not been fully elucidated.[2] Some molecular studies suggest uncoating and reverse transcription begins in the nucleus. In contrast, others suggest a partial uncoating of the viral capsid at the nuclear pore complexes, with early stages of viral DNA production occurring near the nuclear envelope of the host cell.[2] 

The viral reverse transcriptase enzyme initiates reverse transcription using host tRNAs as primers, which bind at the 5' ends of the 2 identical RNA strands and progress in a 5' to 3' direction. Negative-sense single-stranded DNA is initially produced, with doubling of the strand beginning part way along the viral genome. Elongation continues to the end of the genome, after which each strand's synthesis is completed using one another as a template.[2] The viral integrase protein then somewhat randomly integrates the dsDNA into the host DNA. 

The process of viral formation is beyond the scope of this review. Once viral particles are formed, they can then go on to infect other host cells to propagate the infection. Within 2 days of the initial mucosal exposure, HIV can be detected in the regional lymph node tissue. From here, the virus only requires an additional 3 days to be detectable in the plasma.[9]

Genomic diversification is an important aspect of the pathogenesis of HIV infection, leading to changes in the severity of the disease and its response to ART. One of the primary driving factors for HIV-1 mutagenesis is the error rate of the reverse transcriptase encoded by the virus. According to some studies, the error rate of HIV-1 group M reverse transcriptase (subtype B) is 100 to 1,000 times higher than that of the cellular DNA polymerases. These errors are incorporated into the viral genome and contribute to viral diversification.[2] Other intrinsic and extrinsic factors, such as recombination errors, host restriction factors, and depletion of host deoxynucleoside triphosphates, can lead to viral mutagenesis and diversification, leading to ART failure.[2]

In the initial phase of the infection, viral replication is rampant, with an exponential increase in the plasma HIV RNA level due to the large population of susceptible CD4+ T cells without any host immune response. Subsequently, a significant decline from the peak viremia level occurs. This is due to the HIV-specific immune response from the cytotoxic CD8+ T cells.[9] After this decline, the HIV replication settles at a set point where ongoing replication and infection continue, but the initial intense immune response with its associated symptoms resolves.

The exact mechanisms involving the failure of humoral immunity are not fully understood. T cells within B cell follicles, particularly the follicular T helper cells and follicular T regulatory cells, are thought to be involved in poor humoral immunity and HIV persistence in patients treated with ART. In addition, follicular CD8+ cytotoxic T cells are relatively less abundant than their extrafollicular counterparts in people with HIV, likewise thought to contribute to disrupted immunogenesis.[10]

Histopathology

Lymphadenopathy with characteristic morphologic changes is seen in patients with HIV. Without treatment, florid follicular hyperplasia is seen in the initial stages. This is characterized by large, irregularly shaped follicles that span the majority of the cross-sectional area in the lymph node. The mantle cell zones are absent or dramatically decreased. Centroblasts are the dominant cell types; the germinal centers have a "starry-sky" appearance. Follicle lysis or fragmentation is seen when small lymphocytes infiltrate the follicle. Sinusoidal monocytoid B-cell hyperplasia is also present.[11]

Mixed follicular hyperplasia is the intermediate stage between florid follicular hyperplasia and follicular involution. Here, the interfollicular area is relatively large compared to that in florid follicular hyperplasia, and the follicles and interfollicular area are more cellular than those in follicular involution.[11]

In follicular involution, small, atrophic, and hypocellular follicles are seen. The germinal centers contain hyalinized follicular dendritic cell meshworks with few germinal center B cells. Hyalinized blood vessels are seen penetrating the follicles. Due to the scarcity of lymphocytes, the interfollicular area is expanded with a washed-out appearance. Histiocytes and polytypic plasma cells are abundantly present.[11]

Eventually, the lymph nodes enter the lymphocyte depletion stage, characterized by the loss of germinal centers and the near absence of lymphocytes. These lymph nodes contain medullary cords and sinusoids. The interfollicular area primarily consists of histiocytes, plasma cells, and a few immunoblasts. Focal hyaline deposits may be seen with subcapsular and sinusoidal fibrosis.[11]

History and Physical

A thorough medical history and physical exam, including a review of systems, are indicated for patients with confirmed or suspected HIV infections. Attention should be paid to signs and symptoms that help rule out other conditions in the differential diagnosis or that signal opportunistic infections or other HIV-associated sequelae. These aid in the staging of HIV infection and ensure any concurrent conditions are addressed.[12]

In addition to characterizing symptoms, the history should seek risk factors for HIV transmission in a nonjudgmental manner. This includes sexual contact and behavior, drug use, and receipt of blood transfusions. The sexual history should elucidate information regarding the number of partners, sexual practices, frequency and type of barrier protection used, and previous history of sexually transmitted infections (STIs). The HIV status of current and past partners should additionally be obtained.[12] Drug use history should include the type and frequency of substances used, means of administration, and source and sharing of equipment. A mental health history identifies depression, other mental illnesses, or substance use that may result in barriers to care or contribute to the development of chronic diseases.

Social history is an integral part of any medical evaluation. In the context of HIV and AIDS, it provides insights into the client's perceptions of and ability to adhere to treatment, potential barriers to ongoing connection to healthcare services, and to identify needed supports. This should include, among others, the client's living situation, income, insurance, family or other supports, experiences of stigma, coping strategies, and exposure to sexual or other violence.

The US National Institutes of Health (NIH) describes 3 broad stages of HIV infection that develop over time: acute HIV infection, chronic or asymptomatic HIV infection, and AIDS.[NIH. Stages of HIV Fact Sheet. 2021] The CDC maintains a staging system based on CD4 and AIDS-defining illnesses intended for surveillance purposes [13]. The WHO has a staging system based on clinical presentation that can be used for clinical or surveillance purposes in areas with limited or no availability of CD4 testing.[WHO. HIV Case Definitions. 2007]

Acute HIV Infection

While 90% of persons with acute HIV infection have at least 1 symptom in the first 4 weeks after primary HIV infection, these are usually mild, nonspecific, self-limited, and never brought to clinical attention.[14] Some patients present to care with more severe symptoms, known as acute retroviral syndrome or seroconversion illness. These symptoms are listed below in order of decreasing frequency.[14]

• Fever
• Fatigue
• Muscle pain
• Skin rash
• Headache
• Sore throat
• Swollen lymph nodes
• Joint pain
• Night sweats
• Diarrhea

Symptom onset occurs acutely around 2 to 4 weeks (range 4 days to 8 weeks) after viral infection, just before peak viremia.[14] Lasting on average 18 days, the resolution of symptoms coincides with the setting of a viral replication set-point around 30 days after the initial viremia.[15] Without treatment, higher viral load and increased severity and duration of conversion illness are early predictors of a poorer prognosis.[16] 

Mucocutaneous ulceration is a characteristic feature of acute HIV characterized by shallow, sharply demarcated ulcers that have a white base surrounded by a thin area of erythema. Depending on the mode of transmission, ulcers may be located on the oral, anal, penile, or esophageal mucosa.[17] Acute aseptic meningoencephalitis has also been reported as a clinical presentation of acute HIV-1 infection.[9]

Chronic HIV Infection

After HIV acquisition and subsequent setting of the viral set point, patients enter the chronic phase of the infection. Most patients with chronic HIV infection remain asymptomatic before developing AIDS. However, nonspecific fatigue may be present, and persistent generalized lymphadenopathy is usual. Generalized lymphadenopathy is characterized by at least 2 noncontiguous sites other than inguinal nodes exhibiting enlarged lymph nodes for more than 3 to 6 months, not explained by other lymphoproliferative or infectious causes.[18][11]

Patients with chronic HIV infection without AIDS can develop oropharyngeal candidiasis,[19] recurrent vulvovaginal candidiasis,[20] oral hairy leukoplakia,[21] disseminated cutaneous herpes simplex virus,[22] and cervical dysplasia or cervical carcinoma in situ.[23] Cutaneous manifestations such as seborrheic dermatitis, bacillary angiomatosis, varicella-zoster virus reactivations, and molluscum contagiosum infections are common and tend to be severe in patients with HIV.[24]

AIDS

Eventually, HIV progresses to advanced disease, particularly if un- or inadequately treated. AIDS can be diagnosed when specific AIDS-defining conditions are noted, regardless of the CD4 count. These AIDS-defining conditions, as outlined by the CDC, include:[13]

• Candidiasis of the digestive tract (other than thrush)
• Candidiasis of the pulmonary tract
• Invasive cervical cancer
• Extrapulmonary or disseminated coccidioidomycosis, histoplasmosis, or cryptococcosis
• Chronic intestinal cryptosporidiosis or isosporiasis
• Cytomegalovirus retinitis
• Kaposi sarcoma
• HIV encephalitis
• Primary lymphoma of the brain
• Burkitt lymphoma
• Mycobacterial infections
• Pneumocystis jirovecii pneumonia
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia
• HIV-associated Wasting Syndrome

(Refer to the Staging section below for further information on WHO and CDC staging systems).

Evaluation

Testing is required to confirm a diagnosis of HIV. Antibody tests, antigen-antibody tests, and nucleic acid amplification tests (NAATs) are available for screening or confirmation of HIV infection in symptomatic illness. No currently available testing technology can detect HIV infection during the initial aviremic phase of the infection, known as the window or eclipse period.[25]

• NAAT - detects HIV RNA in the blood around 6 to 8 days after infection.
• Antigen tests - detect viral proteins such as p24 antigen as early as days 13 to 20 after infection.
• Antigen-antibody tests - detect viral proteins as with other antigen tests, plus anti-HIV IgM and IgG antibodies around days 20 and 30, respectively, after infection. 

In clinical settings, combination Ag/Ab tests are recommended to identify patients with HIV.[26]. These are available in most commercial laboratories and hospitals in developed nations and are increasingly available worldwide. Ideally, the Ag/Ab test should be fourth-generation, which can detect HIV-1 and HIV-2 antibodies and the HIV-1 p24 antigen. A supplemental antibody immunoassay that differentiates between HIV-1 and -2 is required if the initial positive test cannot make this distinction. All initial positive test results are followed by a second, different HIV test, preferably one that is laboratory-based, to confirm a diagnosis of HIV. The false positive rate of third- and fourth-generation tests is very low. 

If the combination assay result is negative, no further testing is indicated unless HIV exposure was too recent for detectable p24 antigen levels to have developed. If the initial antigen-antibody test result is negative and early HIV infection is suspected, an HIV-1 NAAT to detect HIV RNA should be performed.[25] Specimens indeterminate on the initial antigen-antibody test or nonreactive or indeterminate with the HIV-1–specific and HIV-2–specific antibody assay are also followed up with an HIV-1 NAAT. 

An acute HIV infection is diagnosed in the context of a positive NAAT test result in the setting of:

• A recent negative screening immunoassay result.
• A positive antigen-antibody immunoassay result, with a negative antibody-only immunoassay result.
• A nonreactive or indeterminate HIV-1–specific and HIV-2–specific antibody assay result following a positive screening assay result. 

A negative HIV-1 NAAT result in the last settings indicates a false-positive HIV-1 test result.[25][27] When clinical suspicion for HIV is high and initial test results are negative, testing should be repeated in 1 to 3 weeks. 

Home-based, point-of-care, or rapid tests are essential to increase testing frequency or extend testing into populations that may otherwise not get tested. As with other HIV tests, positive results from point-of-care testing should be followed with standard laboratory, instrument-based immunoassays to confirm the diagnosis.[26] 

Once the diagnosis of HIV is established, a baseline laboratory evaluation facilitates the staging of HIV progression, selection of ART, and identification of comorbidities.[26][NIH. Guidelines for HIV. 2023][WHO. Consolidated HIV Guidelines. 2021]

• Quantitative CD4+ T-lymphocyte cell count
• Quantitative plasma HIV-1 RNA (viral load)
• Complete blood count, glucose, blood urea nitrogen, creatinine, liver enzymes, bilirubin, urinalysis, serum lipids, and serology for Hepatitis A, B, and C
• HLAb*5701 test (if abacavir is being considered) 
• Genotypic drug-resistance assessment focusing on genes for reverse transcriptase and protease in treatment-naive people, with the addition of integrase strand transfer inhibitor (INSTI) for those who have previously taken ARTs
• Other tests, as indicated from the history and physical exam, such as testing for STIs, opportunistic infections, or cancer

Viral load is the most important indicator of initial and sustained response to ART. As some treatment regimes are ineffective in patients with high baseline viral loads, viral load also aids in ART selection. It should be monitored at entry into care, initiation of therapy, and periodically after that.

CD4 is the best indicator of immune function, disease progression, and survival and determines the need to start prophylaxis for opportunistic infections. Blood must be drawn for CD4 testing before ART starts, but starting ART need not be delayed pending results. If CD4 is unavailable, the WHO staging system should be used. Monitoring of other CD subsets is not recommended due to costs and lack of clinical utility. (Refer to the Staging section below for more information on the WHO staging system). 

Routine testing for herpes simplex IgG, cytomegalovirus IgG, and toxoplasma IgG is not recommended. Testing for serum cryptococcal antigen should be considered in patients with a CD4 count of 100 cells/mm³ or below. 

See StatPearls' companion topic, "HIV Testing," for further information on HIV testing. 

Treatment / Management

The goal of HIV-1 therapy with antiretroviral medications is to achieve sustained virologic suppression. According to current WHO and CDC guidelines, ART should ideally be started at the time the diagnosis is confirmed and an initial assessment completed for all persons with HIV, regardless of their immune status (CD4 count) or clinical stage, unless a severe opportunistic infection is present.[26][NIH. HIV Guidelines. 2023][WHO. Global HIV Strategies. 2022] Management of HIV must include identifying specific supports required by the individual patient to maintain medication adherence, particularly for those who are marginalized by their socioeconomic circumstances. The choice of treatment must consider client preferences. 

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), and protease inhibitors (PIs) are used in treatment-naive patients. NRTIs inhibit viral replication by binding the viral reverse transcriptase, effectively terminating DNA prolongation in both HIV-1 and HIV-2 infections. NNRTIs likewise block DNA prolongation by binding the viral reverse transcriptase at a separate site but are only active against HIV-1 infections. INSTIs inhibit the transcribed viral DNA from integrating into the host genome. PIs block the last step in the viral maturation process, rendering assembled viral particles immature and noninfectious. The most common drugs within each class used in the initial treatment of HIV infection are listed below.[NIH. HIV Guidelines. 2023]

• Nucleoside/nucleotide reverse transcriptase inhibitors
  • Abacavir (contraindicated for patients who are HLA-B*5701 positive)
  • Emtricitabine
  • Lamivudine
  • Tenofovir (tenofovir alafenamide or tenofovir disoproxil fumarate) 
  • Zidovudine
• Non-nucleoside reverse transcriptase inhibitors
  • Efavirenz
  • Rilpivirine
  • Doravirine
  • Etravirine
  • Nevirapine
• Integrase strand transfer inhibitors
  • Raltegravir
  • Elvitegravir with pharmacologic boosting agent cobicistat
  • Dolutegravir 
  • Bictegravir
  • Cabotegravir
• Protease inhibitors 
  • Atazanavir 
  • Darunavir
  • Fosamprenavir
  • Ritonavir boosted lopinavir
  • Nelfinavir
  • Tipranavir

Other drug classes, such as CCR5 antagonists, fusion inhibitors, attachment inhibitors, capsid inhibitors, and post-attachment inhibitors, are reserved for patients with multidrug-resistant HIV infections.

Recommended Therapy for Treatment-Naive Patients

Current guidelines recommend that INSTI-based therapy with dual NRTI-backbone be started before receipt of further laboratory testing results for most persons with HIV.[NIH. HIV Guidelines. 2023] Tenofovir plus lamivudine or emtricitabine are the preferred NRTIs, and bictegravir and dolutegravir are the preferred INSTIs due to their effectiveness, side-effect profiles and lower propensity to develop resistance.[25] INSTI-based regimens achieve faster viral suppression than PI- or NNRTI-containing regimens.[28] The addition of other agents, even in the setting of advanced HIV on presentation, does not improve clinical outcomes at the onset of treatment and is therefore not recommended.[29] Abacavir is no longer recommended as initial therapy due to its association with cardiovascular disease, the risk of hypersensitivity, and the need for HLA B*5701 testing.[28] 

Comorbid conditions affect HIV ART selection due to contraindications or co-benefits of treatment, including the following:[28][NIH. HIV Guidelines. 2023]

• Hepatitis B virus (HBV) coinfection - Tenofovir-containing ART regimens are preferred as tenofovir suppresses HBV replication. ART regimens that use lamivudine or emtricitabine without tenofovir should be avoided as they can result in the rapid emergence of resistant HBV.
• Renal dysfunction - Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction and should be avoided in patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m². Tenofovir alafenamide (TAF) can be used unless the patient has severely reduced renal function (eGFR <30 ml/min/1.73 m²) and is not on dialysis, in which case no tenofovir formulation should be given. The preferred regimen is dolutegravir plus lamivudine, adjusted for renal function. Atazanavir should also be avoided in patients with reduced kidney function.
• Osteoporosis - TAF is associated with less bone loss and is preferred over TDF-containing regimens.
• Pregnancy - Bictegravir, doravirine, cabotegravir, dolutegravir/lamivudine combination, and dolutegravir/rilpivirine combination should not be initiated during pregnancy as there is limited data to support their safety. Cobicistat-containing regimens should not be used during pregnancy due to inadequate drug levels.

Once laboratory test results are available, the initial regime may be adjusted. If the patient’s HIV RNA level is less than 500 000 copies/mL, and no evidence of HBV coinfection or lamivudine resistance exists, switching to a 2-drug regimen using dolutegravir and lamivudine combination can be considered.[28] A dual NRTI coformulation plus an antiretroviral from another class is used for those unable to take an INSTI-based regimen. For example, the PI darunavir is boosted with cobicistat, ritonavir, or an NNRTI, either efavirenz or rilpivirine.[30]

Recommended Therapy for Patients on Preexposure Prophylaxis

Patients who are on preexposure prophylaxis (PrEP) with TAF or TDF with emtricitabine who subsequently acquire HIV require resistance testing before initiating therapy. They can be initiated on INSTI-containing regimens outlined above while genotype/resistance testing is pending.[28] Patients who acquire HIV after receiving cabotegravir for PrEP require INSTI genotyping before beginning therapy with an INSTI-based regimen. While the results are pending, a boosted PI regimen containing darunavir and a tenofovir-based dual NRTI coformulation should be used.[28]

Therapy Considerations for Patients With HIV-2 Infections

Current recommendations for the treatment of HIV-2 are primarily based on single-arm or observational studies, as most research and treatment efforts have focused on HIV-1. The initial regimen for the management of HIV-2 should include 2 NRTIs plus a second-generation INSTI or a ritonavir-boosted PI. [31][NIH. HIV Guidelines. 2023] TDF and emtricitabine are the preferred NRTIs. Dolutegravir is recommended as the preferred INSTI. Darunavir and lopinavir are more active against HIV-2 than other PIs and are the preferred agents. Two-drug regimens that are used in the treatment of HIV-1 and any regimen containing NNRTIs are ineffective against HIV-2 and should not be used in these infections. 

Drug resistance assays for HIV-2 are limited to research laboratories, complicating the management of these infections. Current data suggests that HIV-2 is susceptible to NRTIs; however, HIV-2 is more likely to develop resistance than HIV-1. Patients with HIV-2 mutations may exhibit complex patterns of PI cross-resistance, making sequential PI regimens ineffective for patients with this infection.[32] In vitro studies report strong efficacy for INSTIs against HIV-2. Clinical data regarding mutations and efficacy of the most commonly used INSTI (dolutegravir) is limited, especially in those previously exposed to other INSTIs.[33] Further research is needed to understand resistance patterns for antiretrovirals in patients with HIV-2 infections.

Opportunistic Infections

In addition to rapid initiation of ART, prophylaxis for opportunistic infections should be started based on the level of immunosuppression.

• Pneumocystis jirovecii (previous P carinii) - Prophylaxis is indicated for patients with thrush on presentation or a CD4 count of less than 200 cells/mm³.
• Cryptococcus neoformans and Cryptococcus gatti - Patients with a CD4 count of less than 100 cells/mm³ and a positive serum cryptococcal antigen result require prophylaxis.
• Histoplasma capsulatum - Prophylaxis is recommended in areas where histoplasmosis is endemic and the patient has a CD4 count of less than 150 cells/mm³.
• Mycobacterium avium complex (MAC) infection - If patients with HIV are rapidly initiated on ART, prophylaxis for MAC is not required.[25] Patients with a CD4 count of less than 50 cells/mm³ who are not on ART should receive prophylaxis.
• Toxoplasma gondii - Patients with CD4 counts less than 100 cells/mm³ who have positive test results for toxoplasma antibodies require chemoprophylaxis.[26]

In patients with a serious opportunistic infection, rapid initiation of ART can result in immune reconstitution inflammatory syndrome.[26] To decrease the risk, initiate treatment of the opportunistic infection before initiating ART. ART should be started within 2 weeks of initiation of treatment for most acute opportunistic infections, except acute cryptococcal meningitis.[30] Patients with cryptococcal meningitis may be initiated on HIV therapy within 2 to 4 weeks of antifungal therapy. HIV treatment should be initiated within 2 weeks of tuberculosis treatment in patients who have active tuberculosis, especially if they have severe immunosuppression (CD4 count <50 cells/mm³); however, if there is evidence of tuberculous meningitis, ART should be given with high-dose corticosteroid treatment.[28]

Monitoring Following Initiation of Treatment 

Once treatment is initiated, the patient’s HIV viral load should be checked in 2 to 4 weeks and no later than 8 weeks. It can be rechecked every 4 to 8 weeks after that to ensure that it continues to decline. Virologic suppression to undetectable levels (defined as an HIV RNA level of <200 copies/mL) may take up to 24 weeks of continuous therapy. If the HIV RNA level has not declined by 2 log₁₀ copies/mL within 12 weeks and adherence is confirmed, evaluation for resistance with genotype testing for the patient’s regimen is recommended.[28] Genotype resistance testing should also be obtained if virologic suppression is not achieved.[28] 

Once viral suppression is established, the viral load should be monitored every 3 to 4 months.[12] An HIV RNA level that remains persistently below this lower limit of detection demonstrates sustained virologic suppression, the primary goal of HIV therapy. 

See StatPearls’ companion topic, “HIV Antiretroviral Therapy,” for further information on the adverse effects, contraindications, monitoring, and toxicity of ART. See StatPearls’ companion topic, “HIV-2 Infection,” for further information on the treatment of HIV-2 Infection.

Differential Diagnosis

HIV infection should be considered in any patient with recurrent serious infections. Other conditions that may have similar effects on the patient's immune system include:

• Severe malnutrition
• Severe combined immune deficiency syndrome
• Chemotherapy-induced immunosuppression

The differential diagnosis in patients who present with acute HIV infection includes:

• Mononucleosis
• Toxoplasmosis
• Viral hepatitis
• Systemic lupus erythematosus

Toxicity and Adverse Effect Management

A wide variety of potential drug-drug interactions, toxicities, and other adverse effects must be considered when prescribing antiretrovirals. Consultation with a pharmacologist is recommended.[NIH. HIV Guidelines. 2023] Some of the more common reactions are provided below. 

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Abacavir is contraindicated for patients who are positive for the HLA-B*5701 allele due to the risk of hypersensitivity reactions. Pretesting is required before prescribing any regimen containing abacavir. Some studies have also demonstrated increased cardiovascular risk with abacavir.
• TAF is associated with higher lipid levels and weight gain.
• TDF is associated with renal toxicity, proximal tubulopathy, and acute or chronic renal insufficiency, particularly when combined with boosters. Tubulopathy can cause osteomalacia. TDF can also cause decreased bone density.   
• Didanosine and stavudine are no longer used due to severe adverse reactions and toxicity.

Non-Nucleoside Reverse Transcriptase Inhibitors

• Doravirine, efavirenz, and rilpivirine have the potential for cytochrome P450 (CYP) enzyme drug interactions.
• Efavirenz can also cause dyslipidemia, rash, and QTc interval prolongations. It has the potential for short- and long-term psychiatric complications, suicidality, catatonia, and late-onset ataxia and encephalopathy.
• Rilpivirine also causes QTc interval prolongation. It is less commonly associated with depression, suicidality, and rash than efavirenz. 

Integrase Strand Transfer Inhibitors

• All can cause weight gain.
• Several inhibit creatinine excretion without affecting glomerular filtration, including bictegravir, dolutegravir, and cobicistat.
• Bictegravir has the potential for drug-drug interactions as it is a substrate for the enzymes CYP3A4 and UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1).
• Dolutegravir exposure during conception may be associated with neural tube defects. Clinicians should discuss this possibility when prescribing medications to people of childbearing potential.
• Raltegravir can increase creatinine kinase and cause myopathy and rhabdomyolysis. It has been reported to cause severe hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis. As a UGT1A1 substrate, it has the potential for drug-drug interactions. Rarely, it has been associated with depression and suicidal ideation in those with preexisting psychiatric conditions. 
• Cobicistat is an INSTI used exclusively as a pharmacokinetic enhancer of certain PIs and INSTIs. It strongly inhibits CYP3A4, resulting in significant potential for drug-drug interactions. It must be discontinued in severe hepatic impairment. Like other INSTIs, it can cause increases in creatinine excretion without impacting glomerular filtration.

Protease Inhibitors

• PIs other than atazanavir are associated with an increased risk of cardiovascular events.
• Atazanavir and darunavir are both CYP3A4 inhibitors and substrates with the potential for many drug interactions. Both are co-formulated with cobicistat or ritonavir. 
• Atazanavir coformulations can cause indirect hyperbilirubinemia, nephrolithiasis, cholelithiasis, nephrotoxicity, and gastrointestinal adverse effects. 
• Darunavir coformulations can cause skin rash, gastrointestinal adverse effects, and hepatotoxicity, particularly in those with preexisting liver disease.  

Staging

Staging systems can be used for clinical or surveillance purposes to assess the rate of progression to more advanced stages. This assists in monitoring the HIV burden at a population level, planning for prevention and care, and evaluating interventions.[13]

In the United States, the current HIV surveillance case definitions are those published by the CDC in 2014. The surveillance case definitions are not intended for clinical decision-making.[13] HIV testing is used to confirm the diagnosis and determine acute infection (stage 0), and CD4 count is used to determine stages 1 to 3. All surveillance cases are assumed to be HIV-1 unless laboratory evidence indicates HIV-2. The criteria for stage 0 supersede and are independent of the criteria used for other stages.

• Confirmed HIV case
  • For all adults, adolescents, and children aged 18 months and older:
    • A second, different HIV test confirms a positive result from an initial HIV antibody or antibody-antigen test.
    • Clinical criteria can be used where HIV test results have not been recorded, but other presumptive evidence exists, such as receipt of therapy for HIV or an AIDS-defining illness.  
• Stage 0
  • Defined by a positive test result within 180 days of:
    • A negative or indeterminate test result;
    • A negative initial immunoassay result followed by a positive NAAT test result done to confirm acute infection;
    • A positive NAAT test result following a positive antigen or antigen-antibody test result but unconfirmed by a second one.  
• Stages 1 to 3
  • Determined based on the CD4 count for all people 6 years or older: 
    • Stage 1 - 500 or more cells/μl
    • Stage 2 - 200 to 499 cells/μl
    • Stage 3 - less than 200 cells/μl
  • Separate criteria exist for infants aged less than 1 year and children aged 1 to 5. 

Globally, case definitions for HIV vary by country based on the testing technologies most appropriate for use in the local context. The WHO recommends test-based confirmation in adults and children 18 months or older to require a positive result from a rapid or laboratory-based HIV antibody, antigen, or virological test, confirmed by a second positive test result relying on different antigens or different test operating characteristics.[WHO. HIV Case Definitions. 2007] Advanced HIV is confirmed by the diagnosis of a condition associated with advanced disease or a CD4 count of less than 200 cells/mm³ in an adult or child living with HIV.[WHO. Consolidated HIV Guidelines. 2021]

The WHO's clinical staging for HIV can be used for clinical and surveillance purposes in resource-limited areas where CD4 testing may not be available.[WHO. HIV Case Definition. 2007] Advanced disease is defined as Stage 3 or 4.

• Stage 0 or Primary HIV Infection
  • Patients have 1 or more symptoms that are associated with an acute HIV infection or a constellation of symptoms consistent with acute retroviral syndrome.
• Stage 1
  • Patients are asymptomatic or have persistent generalized lymphadenopathy, defined as enlarged lymph nodes (>1 cm) in 2 or more non-contiguous sites (excluding inguinal nodes) that are not better explained by any other cause.
• Stage 2
  • Patients have unexplained weight loss (moderate degree, <10% of body weight), recurrent respiratory tract infections, herpes zoster exacerbations (mild to moderate severity), angular cheilitis, recurrent oral ulcerations, papular pruritic eruptions, seborrhoeic dermatitis, or fungal fingernail infections.
• Stage 3
  • Patients have severe weight loss (>10% of body weight), unexplained chronic diarrhea, persistent fever, oral candidiasis, oral hairy leukoplakia, pulmonary tuberculosis, severe invasive bacterial infections (such as pneumonia, empyema, osteomyelitis, meningitis, and bacteremia), acute necrotizing ulcerative stomatitis, gingivitis or periodontitis, or unexplained anemia, neutropenia, or thrombocytopenia for >1 month.
• Stage 4 or AIDS
  • Patients develop HIV wasting syndrome, pneumocystis pneumonia, chronic herpes simplex infection, esophageal candidiasis, extrapulmonary tuberculosis, Kaposi sarcoma, toxoplasmosis, HIV encephalopathy, extrapulmonary cryptococcosis infections, disseminated non-tuberculous mycobacterial infections, progressive multifocal leukoencephalopathy, pulmonary candidiasis, cryptosporidiosis, isosporiasis, cytomegalovirus retinitis (or in an organ other than liver, spleen or lymph nodes), disseminated mycoses (such as histoplasmosis, coccidiomycosis, penicilliosis), recurrent salmonella septicemia, lymphoma (cerebral or B cell non-Hodgkin), invasive cervical carcinoma, or visceral leishmaniasis.

The WHO defines HIV wasting syndrome as the presence of unexplained weight loss that is greater than 10% of the body weight, with the presence of either unexplained chronic diarrhea or unexplained fever for 1 month or more. WHO clinical stage 4 and the CDC criteria for AIDS are almost identical.[13][WHO. HIV Case Definition. 2007]

A wide variety of studies in resource-limited settings have evaluated the utility of the WHO staging system for predicting immunological status as defined by CD4 count. These have found highly variable sensitivity and specificity across various CD4 cut-off levels, questioning its utility for clinical decision-making.[35][43][44][34][35] This underscores the importance of expanding the availability of CD4 and viral load testing and the WHO and CDC recommendations to offer treatment to all those who are HIV positive.[WHO. Global HIV Strategies. 2022][NIH. HIV Guidelines. 2023][36]

Prognosis

Without therapy, HIV infections are invariably fatal. Effective ART with sustained virologic suppression dramatically improves the clinical outcomes for persons living with HIV. A meta-analysis from 2017 estimates a life expectancy in high-income countries of 43.3 years after starting ART at the age of 20 years and 32.2 years if ART starts at 35 years of age.[37] Life expectancy in low to middle-income countries is 28.3 and 25.6 years if ART starts at ages 20 and 35, respectively. In all income regions, life expectancy after starting ART has improved, likely reflecting improvements in therapy and management such as improved ART regimens, earlier initiation of ART, and better socioeconomic and adherence support.[37]

Viral suppression is the key determinant of prognosis. Patients who achieve virologic suppression for at least 3 years without full immunologic recovery (CD4 count <200 cells/mm³) have 2.6 times greater all-cause mortality than those who achieve immunologic recovery (CD4 >200 cells/mm³).[38] Treatment at diagnosis is associated with improved outcomes and better immune system recovery. Delaying ART until the patient's CD4 count is less than 200 cells/mm³ decreases the likelihood of the CD4 count normalizing, even after multiple years of otherwise effective antiretroviral therapy. This increases the patient's risk of AIDS and non-AIDS-related morbidity and mortality.[39] Other factors correlating with poor immunologic recovery include older age, lower nadir CD4 count, and extended ART initiation to viral suppression time.[38]

Hepatitis C infection, Hepatitis B infection, and active injection drug use are identified as important factors contributing to higher morbidity and mortality among patients with HIV-1 infections.[40] Clients should be offered treatment. For PWID, ongoing socioeconomic and adherence support should be offered, particularly if addiction treatment is not currently indicated or available.

Complications

Complications Related to HIV Infection

The advent of ART has dramatically decreased the incidence of opportunistic infections and HIV-associated malignancies. However, progression to AIDS remains a significant complication of HIV infection. Screening and monitoring are warranted for AIDS-defining illnesses as appropriate to the patient's clinical status. In addition, screening and monitoring for specific HIV- and ART-related complications is required. 

• HIV-associated neurocognitive disorders and psychiatric complications, with the use of efavirenz and, less frequently, rilpivirine and other INSTIs.
• HIV-associated distal symmetric polyneuropathy.
• HIV-associated lipodystrophy.
• Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors.

Detailed pathophysiology, evaluation, and treatment of AIDS-defining illnesses and other HIV- and ART-related conditions are beyond the scope of this review. See StatPearls' companion articles on "AIDS," "HIV Neurocognitive Disorders," and "HIV-Associated Lipodystrophy" for further information on these topics.  

ART-Related Complications

The advent of ART has also raised the risk of cardiovascular disease morbidity and mortality. Persons living with HIV now experience age-related comorbidities such as cardiovascular disease much more frequently than in the past, and much of the long-term care of patients with HIV focuses on minimizing cardiovascular risks for these patients. Multiple different factors contribute to increased cardiovascular risk for patients with HIV.

• The prevalence of dyslipidemia among patients with HIV, with and without ART, is high.
• Glucose intolerance or diabetes occurs frequently in patients receiving ART. This may be due to specific ART agents, such as earlier-generation protease inhibitors.
• Multiple ART regimens are associated with weight gain.

Weight gain is essentially ubiquitous in patients on ART and is one of the most important contributors to cardiovascular risk for patients with HIV. The exact mechanisms involved are unknown. Some ART agents contribute more to weight gain than others. INSTIs are associated with more weight gain compared to PIs or NNRTIs, and TAF is associated with more weight gain than TDF, abacavir, or zidovudine.[41]

Current guidelines recommend the initiation of lifestyle modification counseling from the onset of ART to mitigate weight gain and metabolic complications. Routine screening for glucose intolerance/diabetes and hyperlipidemia is recommended throughout care.[12] 

Deterrence and Patient Education

Ongoing education, support, and counseling from the interdisciplinary care team are essential for clients living with HIV. Patients can also be referred to organizations such as the CDC or NIH, which have various resources available to support patients, including those for specific populations.[CDC. HIV Basics. 2022][NIH. Fact-sheets. 2023] 

HIV Treatment

Patients should be aware of the need for regular labwork and follow-up with a healthcare provider to ensure optimal HIV control and prevent potential complications. Patients should be encouraged to keep all medical appointments and to speak freely and openly with their healthcare providers to ensure adverse effects, potential barriers to treatment, and other health concerns can be addressed promptly and effectively. 

Patients undergoing HIV treatment require intense education and ongoing counseling to promote medication adherence. This includes the importance of starting ART as soon as possible after diagnosis and the need to take the medications consistently for life. Medication adherence is essential to achieve HIV viral load suppression. Viral load increases within weeks of stopping HIV medications, increasing the risk of developing resistant organisms, complications from HIV infections, and transmission. Helping patients understand the challenges often faced with medication adherence can encourage them to seek support with any barriers they may encounter. Patients should be offered home nurse visits, blister packs, or automated reminders as needed to support adherence. (Refer to the Enhancing Healthcare Team Outcomes section for more on the role of the interdisciplinary care team in supporting client adherence to therapy).

Patients should be aware of signs and symptoms that might indicate toxicity from ART and the recommended actions should these occur. Minor adverse effects, such as nausea upon initiation of therapy, can be managed with over-the-counter medications. At the same time, signs and symptoms of liver or kidney injury should lead patients to seek immediate medical care. Patients should be aware of the potential for drug-drug interactions and the importance of the pharmacist in managing their medications. They should be encouraged to keep a record of their medications with them at all times should medical care be required.

People with HIV are at elevated risk of cardiac and metabolic complications, may face complications that affect their nutrition, and may need to avoid certain foods due to immunocompromise. Lifestyle modifications to encourage healthy eating, regular exercise, and the management of other risk factors, such as smoking, should be recommended and supported throughout the person's life. (Refer to the Toxicity and Adverse Effect Management section for further information on toxicity and adverse effect management). 

Prevention of HIV Transmission

Clients with HIV are often highly motivated to prevent transmission to others, particularly when they have a partner who is not infected with HIV. Recent data from the United States reveals that every 10% increase in viral suppression on a population level is associated with a 4% decline in the incidence of HIV in the subsequent year.[42] Ongoing clinical education and emphasis on "undetectable equals untransmittable" is an essential part of treatment for individuals with HIV, for their health and that of their partner or partners. People of child-bearing age may be concerned about transmission of HIV infection during pregnancy and should be made aware of the options for treatment and the benefits of planning ahead.     

People who do not have an undetectable viral load because they are early in treatment or unable to achieve one for any reason have other ways to protect others. The person can correctly and consistently use condoms, choose sexual activities with lower or no risk, encourage their partners to take PrEP, and avoid sharing needles, syringes, and other drug injection equipment. 

People may be required to disclose their HIV or other communicable disease status, for example, to healthcare providers in jurisdictions with these requirements or to healthcare regulatory authorities if they provide healthcare services.

Stigma, Discrimination, and Mental Health

Being diagnosed with a chronic illness can be a significant source of stress for anyone due to the need to adhere carefully to treatment and regularly undergo testing and follow-up with healthcare providers. The diagnosis can challenge one's sense of well-being or complicate existing mental health or other conditions. Individuals may feel sadness, hopelessness, or anger.

In addition to the challenges facing anyone with a new diagnosis of a serious chronic illness, persons with HIV face additional challenges due to stigma and discrimination, including self-stigma.[CDC. HIV Basics. 2021] This occurs when persons with HIV internalize the negative opinions of others, such as believing only certain kinds of people acquire HIV or that they deserve to get it because of their behaviors. The need to tell sexual or injection partners about an HIV infection before sex or drug use can be uncomfortable for people or can provoke anxiety if punitive laws exist for the failure to disclose. Persons with HIV may have fears associated with protecting others, which limit their interactions with other people and lead to isolation.  

A referral to a psychologist, social worker, specialized nurse, public health, other interdisciplinary team member, or support group can assist patients in coping with these issues. Likewise, encouraging patients to share their HIV status with certain friends and family can lead to practical and emotional benefits for them.  

See StatPearls' companion topics, "Antiretroviral Therapy" and "HIV Prevention," for further information on toxicity and management of adverse effects of antiretroviral therapy and HIV prevention. 

Pearls and Other Issues

Clinicians must be aware of any rules and regulations regarding HIV screening, testing, reporting, and management of HIV that may exist in the jurisdiction in which they are practicing. These rules and regulations vary widely in their approach. In some jurisdictions, rules and regulations may sit within public health acts and follow a progressive enforcement framework; in others, they may sit within criminal law and carry significant penalties. (Refer to “Social and Legal Environments” in the Enhancing Healthcare Team Outcomes section for more information on policy recommendations).

Relevant State Laws

Most states have defined guidelines in their administrative codes in the United States. For example, Florida Administrative Code Rule 64B8-13.005 states that every physician licensee must complete one (1) hour of Category I American Medical Association Continuing Medical Education that covers HIV and AIDS every 2 years. This includes information regarding Florida State Law for HIV testing and test result reporting provided in statutes 381.004 and 384.25 mandating the following:

• Before HIV testing, the patient must be notified orally or in writing that the test is planned. The patient must be given the right to refuse testing, which is documented in the medical record.
• If the patient or their legal guardian signs a medical consent form for medical care in a healthcare setting (eg, clinic, emergency setting, or hospital), a separate consent form for an HIV test during the period in which the general consent is in effect is NOT required.
• In a nonhealthcare setting, such as community outreach programs, informed consent with the option to decline testing and information regarding sites that provide anonymous testing in the community must be obtained.
• In the event of a positive test result, the patient must be provided with appropriate care and medical support services, information on the importance of notifying partners who may have been exposed, and ways to prevent transmission. 
• In the event of a negative test result, every effort should be made to notify the patient of the result, and information regarding ways to prevent the acquisition of HIV should be provided.
• In a healthcare setting, if the patient is discharged before the results are available, informing the county health department to notify the test subject fulfills the responsibility, even in the event of a positive test result.
• Preliminary (unconfirmed) tests that yield positive results can be revealed only when decisions about medical management cannot await confirmation, including the need to provide recommendations to the person tested. Results can be revealed only to specific people:
  • The person tested and clinicians directly responsible for the medical care and decision-making for the tested individual.
  • The person tested and clinicians responsible for the care and decision-making of a newborn who may be affected by these results.
  • Healthcare personnel subject to a significant exposure from the person whose results were positive.
  • Individuals tested using rapid testing technologies in accordance with manufacturers’ instructions approved by the Food and Drug Administration. 
• Unconfirmed test results must not be characterized as an HIV diagnosis to the patient. The rationale for releasing unconfirmed results must be documented in the chart. Confirmatory testing must be obtained, and the results must be communicated to the individual tested.
• Positive HIV test results, after confirmatory testing, may only be released to the tested individual or their designated legally authorized representative.
• Results must be reported to the State Health Department in accordance with rules for reporting and controlling disease. Results may also be shared with health providers who use semen or body parts from an infected individual, health facility committees for purposes of program monitoring and evaluation, and authorized researchers and epidemiologists, as proscribed under appropriate statutes and procedures.
• The patient must provide written authorization for the release of such testing to any other individual or third-party payor for HIV test results to be released. A general consent for releasing medical records is insufficient in this scenario. A specific authorization for the release of HIV test results must be provided.
• If HIV testing is conducted due to exposure of medical personnel, the occurrence shall be documented and recorded only in the personnel record of the medical personnel. In addition, the cost of the initial HIV test shall be borne by the medical personnel or their employer.
• If the source of the exposure is not available or will not voluntarily present for testing, the medical personnel or the employer may seek a court order for HIV testing from the source individual. The test results should be released to the source and the person who experienced the exposure.
• Clinicians, laboratories, and healthcare facilities that make a diagnosis of or treat a person with HIV/AIDS must report the result as outlined above no later than 2 weeks following the diagnosis or treatment.
• Violation of these rules is subject to penalties, fines, and disciplinary actions.

Impact of Legislation on HIV Testing

Laws and regulations concerning HIV and AIDS are developed considering a variety of parameters that impact patients’ willingness to test for HIV. For example, to provide patients with privacy, confidentiality, and dignity, the Florida legislature considered the need for informed consent and privacy in designing its laws regarding HIV and other sexually transmitted diseases, including laws for reporting.

• Informed Consent
  • Includes an explanation to the patient regarding confidentiality, mandatory reporting, and the opportunity for anonymous testing.
  • Maintains that in a healthcare setting, a patient must be notified of a planned HIV test, and they have the right to refuse the test.
  • Allows a legal guardian to provide informed consent if a person is incompetent, incapacitated, or a legal minor.
• Confidentiality
  • Ensures information regarding a person’s HIV status is kept confidential, except when:
    • The patient gives consent.
    • The data is provided for statistical purposes and excludes identifying information.
    • The clinician or facility must disclose the result for mandatory reporting to medical personnel, state agencies, or mandated court jurisdiction.
    • The information needs to be disclosed during a medical emergency; only relevant information for the patient’s care can be disclosed.
  • Defines consequences if confidentiality is violated.
    • The person commits a misdemeanor of the first degree, which is punishable by a fine of up to $1,000 and up to 1 year in prison.
    • A person who spreads information about an individual with HIV or another sexually transmitted disease for monetary gain or with malicious intent commits a felony in the third degree, which is punishable by a fine of up to $5,000 or imprisonment of up to 5 years.
• Reporting
  • Ensures results are promptly and confidentially reported to the Florida Department of Health to allow for contact follow-up and other public health activities, such as surveillance. A positive test result or other diagnosis of HIV or AIDS must be reported within 2 weeks using the system developed by the CDC or an equivalent system to ensure confidentiality.
  • The Department of Health may fine anyone who fails to report HIV or AIDS up to $500 for each offense, and a regulatory agency will be informed of the violation.

 [See Florida State Statutes, Title XXIX Public Health, Chapter 381 Public Health: General Provisions]

Enhancing Healthcare Team Outcomes

Almost 21 million lives have been saved with antiretroviral therapy worldwide.[UNAIDS. Global Report. 2023] However, millions of people around the globe are missed or inadequately served by current prevention and treatment services. Key indicators of the quality of HIV care for optimal patient and population health outcomes include the linkage of HIV-positive individuals to care, receipt of treatment by those who are linked to care, and attainment of viral suppression amongst those who are treated. 

For example, in the United States in 2021, 80% of people diagnosed with HIV were linked to care within 30 days of diagnosis, defined as at least 1 viral load or CD4 test within that time. However, of all people with an HIV diagnosis in 2021, only 54% were retained in care (defined as ≥2 viral load or CD4 tests ≥3 months apart in 2021), and only 66% were virally suppressed (defined as an HIV RNA level of <200 copies/mL).

Within countries, variability in key quality care indicators exists across populations. While the disparities are greatest in low- and middle-income countries, significant inequities continue to exist in HIV prevalence and incidence across population groups, even in countries with well-developed HIV responses. For example, compared with the general population in the United States, HIV disproportionately affects PWID, those who live in the US South, and those who are Black, African American, Hispanic, Latino, transgender, or MSM.[28] Across the European Economic Area, migrants accounted for 44% of new HIV diagnoses in 2019.[28]

A successful HIV response depends on multiple factors, including utilizing a team-based and patient-centered care approach, a focus on prevention in the community and healthcare settings, robust monitoring and surveillance systems, continuous program quality improvement, and supportive social and legal environments. 

An integrated interprofessional team of physicians, nurses, pharmacists, social workers, public health officials, and community partners is essential to improve clinical outcomes for patients with HIV, improve population health, and ultimately change the course of the global HIV pandemic.

Patient-Centered, Team-Based Care

Putting patients at the center allows the maximum benefit from HIV care and prevention services, leading to improved clinical and public health outcomes.[WHO. People-Centred Health Services. 2016][WHO. Men and HIV Interventions. 2023]. As HIV is an epidemic that disproportionately affects marginalized populations, programming that places the individual at the center of care ensures equality of access to testing and care, minimizes stigma, and overcomes socioeconomic barriers that limit access to care. For example, patients who have HIV or are at risk for HIV acquisition and have underlying socioeconomic disadvantages or substance use disorders are at high risk for medical nonadherence. 

Physicians, nurse practitioners, and physician assistants all provide primary care to patients with HIV. Clinician use of current HIV guidelines, genotype resistance testing, and measures to support adherence to therapy ensures patients receive adequate medical treatment throughout their lives. Systematic monitoring for complications minimizes the risk and consequences of the disease and ART.

Nurses play an essential role in achieving care and public health goals by supporting patients in understanding, for example, the risk of transmission, complications, and the need for medication adherence. Home-visiting nurses can help patients stay linked with medical care and obtain laboratory testing in patients with limited transportation resources. According to a study from sub-Saharan Africa, immediate ART at the time of home-based positive test results increased clinical follow-up and ongoing linkage to care.[25] Nurses and nutritionists can monitor weight and promote adequate nutrition and hydration to promote overall health, minimize cardiovascular risks, and minimize the risk of HIV wasting syndrome.

Pharmacists augment the patient's understanding of their treatment by discussing potential adverse effects of therapy, ways to minimize drug interactions, and ensuring patients know when to seek help should any treatment complications occur. Measures such as blister-packed medications can ease the burden of setting up pills, minimize the risk of incorrect dosing, and improve medication adherence.

Public health nurses and physicians are important in connecting and following up with contacts to prevent further transmission. They have a primary role in preventing HIV in the community, including identifying and responding rapidly to HIV outbreaks in the community. They also support the patient care team in unusual instances where patients are persistently unwilling or unable to follow recommendations to prevent transmission. (Refer to "Community HIV Prevention" below for further information on this topic). 

Community health, peer support, and social workers are vital in promoting patient well-being and improving linkage to care. Social workers can allocate resources for transportation and childcare support, provide assistance with mental health services, or make referrals to finance medications where this is a barrier. Community health and peer support workers, for example, assist in the development of stigma-free services or increase the availability of home-based services. 

See the Statpearls' companion article "HIV Antiretroviral Therapy" for further information on interprofessional team roles in maintaining HIV therapy. 

Community HIV Prevention

Primordial, primary, and secondary prevention are all important in the context of improving outcomes for HIV infection. The percentage of new transmissions and the number of HIV-positive people who are aware of their HIV status are key quality indicators for prevention efforts. Worldwide, 86% of the 39 million people estimated to be living with HIV knew their status in 2022.[UNAIDS. Global Report. 2023] In the United States, 87% of the estimated 1.2 million people living with HIV knew their status in 2021.[CDC. US HIV Statistics. 2023] 

Primordial prevention includes addressing the determinants of health that lead to increased risks for acquiring HIV, including poverty, discrimination, stigma, or other mechanisms that marginalize certain groups of people. Beneficial social and policy environments are essential in primordial prevention and along the prevention and care spectrum. (Refer to "Social and Policy Environments" below for more information on measures to improve social determinants of health for HIV prevention). 

Primary prevention targets those who have risk factors. This includes public awareness and education regarding safe sexual practices and ways to reduce the risk of HIV transmission among PWID. The promotion of safer sexual practices, treatment of opioid use disorder, and widespread access to clean syringe services and other harm reduction approaches are effective prevention strategies that should be implemented across the globe.[28] Voluntary medical circumcision for heterosexual males is another effective prevention approach in southern and eastern areas of Africa where HIV is highly prevalent. PrEP is a highly effective strategy for those at high risk, for example, due to having a sexual partner who is HIV positive, having multiple sexual partners without using condoms consistently, or the use of injection drugs. 

Developing cost-effective recommendations and education to screen for HIV is a critical component of HIV prevention. For example, the US Preventive Services Task Force (USPSTF) recommends clinicians in the United States screen all pregnant individuals as well as routine and voluntary HIV screening among all persons aged 15 to 65 years, with particular emphasis on individuals at high risk of infection.[43] Maternal HIV screening has resulted in a significant decline in mother-to-child HIV transmission, preventing nearly 22,000 perinatal infections between 1994 and 2010.[44] 

Treatment as prevention recognizes the fact that HIV is not sexually transmitted if the viral load is undetectable (defined as <200 copies of HIV-1 RNA/mL of plasma).[45][46][45] Otherwise known as undetectable=utransmittable or U=U, evidence is increasing of its effectiveness for those who share drug injection equipment. Emphasis on U=U can be a strong motivator for patient adherence to medication. However, even with undetectable viral loads, HIV transmission still occurs perinatally and via breast milk.

See the Statpearls' companion articles on "Prevention of HIV" for further information on PrEP, PEP, and recommendations for screening for HIV, amongst others. 

HIV Prevention in Healthcare Settings

In the healthcare context, the use of rigorous infection prevention and control procedures has led to widespread decreases in occupationally and iatrogenically transmitted HIV. The elimination in many countries of the reuse of needles, syringes, and other medical equipment that can transmit HIV has been a global success story. 

The widespread implementation of standard precautions, previously called universal precautions, is another key preventive strategy. Initially developed to prevent HIV transmission, standard precautions are utilized to avoid the transmission of all infectious agents. The first line of defense to break the chain of transmission of infectious agents in healthcare settings is the application of standard precautions to all patients, irrespective of their known or suspected infection status. The type of infection control practice necessary is based on the level of anticipated contact with the patient and assumes that any patient's blood or body fluids may contain an infectious agent.

Hand hygiene is the single most important measure to prevent transmission of disease. Hand hygiene includes washing hands with soap and water for at least 40 to 60 seconds when visibly soiled, after restroom use, or potential exposure to spore-forming organisms. Alcohol-based hand rubs can otherwise be utilized. Hand-washing is conducted between patients, immediately after gloves are removed, and before and after any direct patient contact or contact with invasive devices, blood or body fluids, secretions, mucous membranes, or nonintact skin, even if gloves are worn.

Gloves are used when touching blood, body fluids, secretions, mucous membranes, or nonintact skin. A mask, goggles, eye visor, face shield, or gown are used when blood, body fluids, secretions, or excretions may be splashed. Needles and sharps should be discarded immediately in appropriate puncture-resistant containers.

Occupational post-exposure prophylaxis (PEP) is an essential component of prevention in healthcare settings, as eliminating inadvertent exposures to potentially infectious body fluids is difficult to achieve. PEP involves the provision of a minimum of 3 antiretroviral drugs for 28 days for all occupational exposures to HIV, starting as soon as possible after the exposure and within 72 hours.[47] Counseling, HIV testing at baseline and follow-up, and monitoring for toxicity are also provided. Utilization of the PEP consultation service for clinicians is recommended in all cases. A live hotline in the United States is available from 9 am to 2 am Eastern time at 1-888-448-4911.[27]

See the Statpearls' companion article on "Universal Precautions"  for further information on standard precautions. 

Monitoring, Surveillance, and Continuous Quality Improvement

Collecting and using reliable, granular, and timely data is essential to improve team performance and population health. Using data means identifying at-risk clients, setting targets, and developing strategies to reach those targets. UNAIDS first proposed a set of global 90-90-90 HIV prevention targets for HIV in 2014, which were committed to by countries of the UN General Assembly. Although these goals were not reached, many countries made significant progress. Setting 95-95-95 goals for 2025, the goals were updated in 2020 and adopted by the UN General Assembly in 2021.  

• 95% of all individuals with HIV will know their status
• 95% of all those who have HIV will receive antiretroviral therapy 
• 95% of all people on ART will achieve viral suppression

The projected impact of this will be fewer than 370,000 people acquiring HIV and fewer than 250,000 people dying from HIV worldwide in 2025.

The WHO and country and state disease control and prevention centers, such as the US CDC, are primary data sources for monitoring HIV trends and progress toward goals. Behavioral and clinical characteristics of adults diagnosed with HIV infection are followed in the United States by the Medical Monitoring Project. Instituted in 2005, it is a cross-sectional, nationally representative, complex sample survey.[CDC. HIV Surveillance Report 2021 Cycle. 2023] The CDC's AtlasPlus allows practitioners to explore national HIV, hepatitis, STI, and tuberculosis data relevant to their population.[CDC. NCCHHSTP AtlasPlus. 2023] All data from 2020 and 2021 must be interpreted in the context of decreased case surveillance and access to HIV services during the COVID-19 pandemic.[CDC. HIV Basic Statistics. 2023]

In collaboration with local or state public health authorities, clinicians can improve clinical care and contribute to population health improvements by fully completing reporting forms where required, participating in initiatives to streamline and improve surveillance, and engaging in continuous program quality improvement within their practice setting utilizing public health and program-specific data.

Social and Policy Environments

Local legislative bodies, other policy-making organizations, and institutions can improve patient-centered care and population health outcomes for HIV by basing legislative and policy frameworks that influence the effectiveness of HIV and AIDS programming on recommendations developed by organizations such as the UNAIDS, WHO, and the NIH.[UNAIDS. Global Report. 2023][WHO. Global HIV Strategies. 2022]

The WHO recommends specific HIV policies that promote optimal HIV testing and care and tracks country progression towards these. These recommendations include the use of PrEP, dual HIV and syphilis rapid diagnostic tests, self-testing, optimal first- and second-line treatments, routine viral load testing, and same-day ART initiation, amongst other measures, in national policies and guidelines.[WHO. Global HIV Strategies. 2022] UNAIDS, WHO, and national HIV strategies outline key social, legal, and policy factors that lead to better patient and population health outcomes for HIV prevention and care.[UNAIDS. Global Report. 2023][WHO. Global HIV Strategies. 2022]

Political commitment and adequate resources are fundamental building blocks for an adequate HIV response.[UNAIDS. Global Report. 2023] The setting of targets can be an important component in garnering political commitment. The US National HIV/AIDS Strategy [US Gov. National HIV/AIDS Strategy. 2023] and the Ending the HIV Epidemic in the United States initiative aim to reduce new HIV transmissions in the United States by 90% by 2030, prioritizing the reduction of HIV-related health disparities and health inequities and improving well-being for people who live with HIV.[CDC. Ending the HIV epidemic. 2023]

A renewed global commitment to funding is necessary. The gap between actual and required funding is widening in low- and middle-income countries, mainly due to a decrease in the proportion of funding provided by high-income nations.[UNAIDS. Global Report. 2023] Fully funded resilient, integrated, and accessible public and community health systems lead to increased uptake of both HIV and other health services. Social and structural inequalities to HIV-related services, resources, and tools can be addressed through universal health care, shared service delivery models, and measures to improve access to medicines and other health technologies for those experiencing marginalization, including uninsured or underinsured individuals in the United States.

The removal, or at a minimum, the nonenforcement of harmful laws must be a priority. These continue to limit access to health care for people living with HIV and increase the risk of acquiring HIV for those already vulnerable. For example, laws criminalizing HIV exposure, non-disclosure, and transmission discourage people from getting tested, increasing transmission and creating a barrier to early treatment. Likewise, the criminalization of particular groups of people undermines an effective HIV response by discouraging sex workers, MSM, and those who are transgender or inject drugs from using prevention and treatment programs due to fear of arrest and prosecution. A 2015 study estimated that 33% to 46% of all new HIV infections over a decade could be avoided by decriminalizing sex work worldwide.[UNAIDS. Global Report. 2023]

Many countries have amended laws to remove barriers to the HIV response, including decriminalizing vertical HIV transmission in Belize in 2023, sex work in Belgium in 2022, and same-sex sexual relations in several others in 2022 and 2023. However, there have been concerning setbacks in many countries, including Indonesia 

Strengthening laws, policies, and systems that realize and protect human rights is also necessary. For example, the promotion of gender equity and safe work environments leads to lower vulnerability for women and girls. Modeling studies from Canada and Kenya show that the elimination of violence by police, clients, and strangers could avert 17% to 20% of new HIV infections among female sex workers and their clients in a decade.[UNAIDS. Global Report. 2023]    

Strengthened policies and laws augment the education and community action necessary to address the stigma and discrimination that impact the health and well-being of people living with HIV. One in 3 of the countries reporting to UNAIDS on HIV policies report that 10% of MSM and more than 50% of sex workers, PWID, and transgender individuals avoid healthcare due to fears of stigma, discrimination, or confidentiality.  

Rooted in outdated fears of HIV from the 1980s, stigma and discrimination must be addressed through open discussion about HIV using non-stigmatizing language both within and outside of health care.[CDC. HIV Basics. 2022] Discrimination can manifest in healthcare settings as the refusal of service to people with HIV, the use of stigmatizing language, or the absence of appropriate services, resources, or tools.