HIV and AIDS

Etiology

HIV belongs to the Retroviridae family in the Lentivirus genus. The virus mainly targets CD4+ T-lymphocyte helper cells, leading to an extreme form of immune subversion with a continuous loss of these cells. This weakens the immune system and causes many 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 ribonucleic acid (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 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 down. In particular, significant gains have been made in preventing and treating 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 (in those between 15 and 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 regions have 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 have hindered the HIV response. 

HIV infection, diagnosis, treatment, and viral suppression rates vary across and within countries and regions. Globally, women 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 from 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 US 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 deoxyribonucleic acid (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 reaching 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 transfer RNA 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 the other 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 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.[4]

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 results from several studies, the error rate of HIV-1 group M reverse transcriptase (subtype B) is 100 to 1000 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 due to the HIV-specific immune response from the cytotoxic CD8+ T cells.[4] After this decline, the HIV replication settles at a 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.[5]

Histopathology

Lymphadenopathy exhibiting distinctive morphological changes is evident in HIV patients. In untreated cases, pronounced follicular hyperplasia emerges initially, marked by enlarged, irregularly shaped follicles that occupy a substantial portion of the lymph node's cross-sectional area. 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 present when small lymphocytes infiltrate the follicle. Sinusoidal monocytoid B-cell hyperplasia is also present.[6] Mixed follicular hyperplasia is the intermediate stage between florid and follicular involution. Here, the interfollicular area is relatively large compared to florid follicular hyperplasia, and the follicles and interfollicular area are more cellular than those in follicular involution.[6]

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.[6] 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 present with subcapsular and sinusoidal fibrosis.[6]

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.[7]

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.[7] 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. Gatheingr an immunization history to determine which vaccines could offer future protection against vaccine-preventable illnesses is crucial. For instance, Streptococcus pneumoniae, associated with adverse outcomes in HIV-positive individuals, and hepatitis B, linked to a heightened risk of hepatocellular carcinoma progression in those with HIV, underscore the importance of such proactive measures.[8][9]

Social history is an integral part of any medical evaluation. In the context of HIV and AIDS, this history provides insights into the patient’s perceptions of and ability to adhere to treatment, potential barriers to ongoing connection to healthcare services, and identifying needed supports, and should include, among others, the individual’s living situation, income, insurance, family or other support, 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 [10]. 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.[11] 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.[11]

• 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.[11] Lasting an average 18 days, the resolution of symptoms coincides with the setting of a viral replication set-point around 30 days after the initial viremia.[12] Without treatment, higher viral load and increased severity and duration of conversion illness are early predictors of a poorer prognosis.[13]  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.[14] Acute aseptic meningoencephalitis has also been reported as a clinical presentation of acute HIV-1 infection.[4]

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.[6][15] Patients with chronic HIV infection without AIDS can develop oropharyngeal candidiasis,[16] recurrent vulvovaginal candidiasis,[17] oral hairy leukoplakia,[18] disseminated cutaneous herpes simplex virus,[19] and cervical dysplasia or cervical carcinoma in situ.[20] 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.[21]

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:

• Candidiasis of the digestive tract (other than thrush)
• Candidiasis of the pulmonary tract
• Invasive cervical cancer
• Extrapulmonary or disseminated coccidioidomycosis, histoplasmosis, or cryptococcosis, including cryptococcal meningitis
• Chronic intestinal cryptosporidiosis or isosporiasis
• Cytomegalovirus retinitis
• Kaposi sarcoma
• HIV encephalitis and HIV-associated neurocognitive disorder
• Tuberculosis
• Primary lymphoma of the brain
• Non-Hogdkin lymphoma
• Burkitt lymphoma
• Mycobacterial infections
• Pneumocystis jirovecii pneumonia
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia
• HIV-associated wasting syndrome [10]

These AIDS-defining illnesses tend to occur most frequently with low CD4 counts <200 cells/mm³, which correlates with untreated advanced HIV disease as the total lymphocyte count depletes over time.[22][23]

(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. The following tests are used to detect viral proteins:

• 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 immunoglobulin (Ig) IgM and IgG antibodies around days 20 and 30, respectively, after infection [10]

In clinical settings, combination antigen/antibody (Ag/Ab) tests are recommended to identify patients with HIV.[11]. These tests 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 Ag/Ab test result is negative and early HIV infection is suspected, an HIV-1 NAAT to detect HIV RNA should be performed.[10] Specimens indeterminate on the initial Ag/Ab 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.[10][12] 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.[11] 

Once the diagnosis of HIV is established, a baseline laboratory evaluation facilitates the staging of HIV progression, selection of ART, and identification of comorbidities.[11][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. Viral load should be monitored at entry into care, initiation of therapy, and periodically afterward. 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 ART should 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, given that these do not delineate active disease versus previous exposure. Testing for serum cryptococcal antigen should be considered in patients with a CD4 count of 100 cells/mm³ or less. 

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 begin after the diagnosis is confirmed and an initial assessment is completed for all persons with HIV, regardless of their immune status (CD4 count) or clinical stage, unless a severe opportunistic infection is present.[11][NIH. HIV Guidelines. 2023][WHO. Global HIV Strategies. 2022] Management of HIV must include identifying specific support required by the 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 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.[10] INSTI-based regimens achieve faster viral suppression than PI- or NNRTI-containing regimens.[13] 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.[14] 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.[13] 

Comorbid conditions affect HIV ART selection due to contraindications or co-benefits of treatment, including the following:

• 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.[13][NIH. HIV Guidelines. 2023]

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.[13] 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.[15]

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.[13] 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.[13]

Therapy Considerations for Patients With HIV-2 Infections

Current recommendations for treating 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 managing HIV-2 should include 2 NRTIs plus a second-generation INSTI or a ritonavir-boosted PI. [16][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 to treat 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.[17] In vitro studies report strong efficacy for INSTIs against HIV-2. Clinical data regarding mutations and efficacy of the most commonly used INSTI (eg, dolutegravir) is limited, especially in those previously exposed to other INSTIs.[18] Further research is needed to understand resistance patterns for antiretrovirals in patients with HIV-2 infections.

Opportunistic Infections

In addition to rapid ART initiation, 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's CD4 count is 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.[10] Patients with a CD4 count of less than 50 cells/mm³ without 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.[11]

In patients with a severe opportunistic infection, rapid initiation of ART can result in immune reconstitution inflammatory syndrome.[11] To decrease the risk, the opportunistic infection should be treated before initiating ART. Initiate ART within 2 weeks of initiating treatment for most acute opportunistic infections, except acute cryptococcal meningitis.[15] 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.[13]

Monitoring Following Initiation of Treatment 

Once treatment is initiated, the patient’s HIV viral load should be evaluated in 2 to 4 weeks and no later than 8 weeks. The viral load can be rechecked every 4 to 8 weeks after that to ensure 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.[13] Genotype resistance testing should also be obtained if virologic suppression is not achieved.[13]  Once viral suppression is established, the viral load should be monitored every 3 to 4 months.[7] 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

When prescribing antiretrovirals, a wide variety of potential drug-drug interactions, toxicities, and other adverse effects must be considered. Consultation with a pharmacologist is recommended.[NIH. HIV Guidelines. 2023] Some 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 (CYP) P450 enzyme drug interactions.
• Efavirenz can also cause dyslipidemia, rash, and QTc interval prolongations. This therapy has the potential for short- and long-term psychiatric complications, suicidality, catatonia, and late-onset ataxia and encephalopathy.
• Rilpivirine also causes QTc interval prolongation. This medicine is less commonly associated with depression, suicidality, and rash than efavirenz. 

Integrase Strand Transfer Inhibitors

• All of these types of inhibitors 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. This medicine 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, raltegravir 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. This therapy strongly inhibits CYP3A4, resulting in significant potential for drug-drug interactions. Cobicistat 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, assist in monitoring the HIV burden at a population level, plan for prevention and care, and evaluate interventions.[13] The CDC published the current definitions of HIV surveillance cases in 2014. The definitions of surveillance cases are not intended for clinical decision-making.[13] HIV testing confirms the diagnosis and determines acute infection (stage 0), and CD4 count determines 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 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

This stage is 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 test

Stages 1 to 3

These stages are determined based on the CD4 count for all people 6 and older (separate criteria exist for infants younger than 1 year and children 1 to 5 years): 

• Stage 1: 500 or more cells/μL
• Stage 2: 200 to 499 cells/μL
• Stage 3: less than 200 cells/μL

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

• In 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

• In this stage, 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

• In 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 more than 1 month.

Stage 4 or AIDS

• In this stage, 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.[14][15][35][43][44] 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][16]

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.[14] 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.[14]

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).[15] 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.[16] Other factors correlating with poor immunologic recovery include older age, lower nadir CD4 count, and extended ART initiation to viral suppression time.[15]

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.[17] Clients should be offered treatment. For PWID, ongoing socioeconomic and adherence support should be offered, mainly 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 for patients with HIV focuses on minimizing cardiovascular risks for these patients. Multiple different factors contribute to increased cardiovascular risk for patients with HIV, including:

• The prevalence of dyslipidemia among patients with HIV, with and without ART, is high.
• Glucose intolerance or diabetes frequently occurs 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.[18]

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.[7]