Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern that ultimately results in chronic immunodeficiency. HIV can be transmitted sexually, parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common in the young adult population between 20 and 30 years of age. The virus infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells, which are one of the key mechanisms of cellular immune defense. The three major stages of HIV infection are acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS). Detailed classifications of clinical staging have been established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). During the acute infection stage, the virus reproduces rapidly in the body, which can lead to the onset of acute, nonspecific (e.g., flu-like) symptoms, also known as acute retroviral syndrome (ARS), within 2–4 weeks. However, approximately half of all infected individuals remain asymptomatic. Once the acute infection stage subsides, the clinical latency stage begins. As with the acute infection stage, many individuals remain asymptomatic during this period while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia). The last stage, AIDS, is characterized by AIDS-defining conditions, such as Kaposi sarcoma, and/or a CD4 count < 200 cells/mm3.
HIV infection can be reliably detected using antigen/antibody-based tests. In patients with confirmed infection, treatment with a combination of antiretroviral medications (ART) is started as soon as possible. The effectiveness of the treatment is monitored via regular checks of CD4 count and viral load. Patients in the advanced stages of HIV infection may additionally require treatment of and prophylaxis for opportunistic infections. Significant advances in treatment mean that the average life expectancy of HIV patients receiving ART is approaching that of the general population. Partners of HIV-positive people and individuals at high risk of HIV infection can reduce the risk of contracting the infection by taking ART prior to exposure (preexposure prophylaxis) or following exposure (postexposure prophylaxis) to the virus.
- Incidence (in the US)
- US: ∼ 1.2 million
- Global: ∼ 37 million
Epidemiological data refers to the US, unless otherwise specified.
Pathogen (human immunodeficiency virus)
- Family: Retroviridae
- Genus: Lentivirus
- HIV-1: most common species worldwide
- HIV-2: restricted almost completely to West Africa
- Structure: icosahedral with a conical capsid and a spiked envelope
Function of structural proteins
- pol gene codes for a polyprotein which consists of
- gag gene codes for gag protein, which consists of
- env gene codes for gp160 which gets cleaved into envelope glycoproteins
- tat gene (trans-activator of transcription) codes for tat protein which promotes viral transcription
- rev gene: codes for the rev protein, which regulates translocation of unspliced and incompletely spliced mRNAs
Routes of transmission
Sexual: : responsible for ∼ 80% of infections worldwide
- Risk per sexual act
- Risk for men who have sex with men (MSM): 0.5% for receptive partner
- Risk for male-to-female sex
- 0.1% for female partner
- 0.05% for male partner
- Modifying factors
- Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml 
- Circumcision: reduced risk of infection for circumcised men 
- Co-infection: genital inflammation (e.g., as a result of co-infection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission
- Genital mucosal damage: increases risk of transmission
- Risk per sexual act
- Parenteral transmission
- Vertical transmission: from mother to child
Risk of transmission can be lowered significantly if HIV infection is treated consistently and viral load is below the limit of detection.
Natural history of HIV infection
Initial infection and HIV replication cycle
- HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on host cells with its gp120 glycoprotein (binding)
Viral envelope fuses with host cell, capsid enters the cell.
- For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.
- Viral entry into macrophages via CCR5 mainly occurs during the early stages of infection, while entry via CXCR4 occurs in later stages.
- Individuals without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygous CCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).
- A virion's RNA is transcribed into dsDNA by viral reverse transcriptase and then integrated into the host's DNA by viral integrase.
- Viral DNA is replicated and virions are assembled
- Virion repurposes a portion of the cell's membrane as an envelope and leaves the cell (budding) → cell death 
Progression to chronic immunodeficiency
- HIV infects CD4+ lymphocytes, then reproduces and spreads to other CD4+ lymphocytes near the original site of infection → infection of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and dissemination → acute HIV syndrome with high viral load
- After the acute stage, viral load decreases and remains at roughly that level for approximately 8–10 years (clinical latency stage ).
- During the clinical latency phase, the virus mainly replicates inside the lymph nodes.
- Increasing loss of CD4+ lymphocytes impairs immune function and, thereby, facilitates opportunistic infections and development of malignancies (AIDS). These secondary diseases are usually the cause of death in individuals with HIV.
- Increased viral load generally leads to a decreased number of CD4+ lymphocytes and vice versa, but the relation is not linear.
Viral load predicts the rate of disease progression and CD4 count correlates with immune function.
Acute HIV syndrome does not develop in all patients. Absence of symptoms may delay diagnosis.
The role of immune response
- Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection.
HIV evades immune control via:
- Genetic mutation and recombination
- Downregulation of surface molecules in infected cells
- There are no clinical features specific to HIV infection
- In early HIV infection, patients are often asymptomatic.
- Incubation period: usually 2–4 weeks 
- Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak: during AIDS-stage)
Acute HIV infection 
- Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome
Clinical latency and AIDS
- Clinical latency: Infected individuals may still be asymptomatic.
Non-AIDS-defining conditions (common when CD4+ count is below 500 cells/mm3)
- Chronic subfebrile temperatures
- Persistent generalized lymphadenopathy
- Chronic diarrhea (> 1 month)
- Localized opportunistic infections
- Oral hairy leukoplakia: lesions that cannot be scraped off located mainly on the lateral borders of the tongue; triggered by Epstein-Barr virus
- HPV-related: squamous cell carcinoma of the anus (common in men who have sex with men) or cervix
- Skin manifestations (e.g. molluscum contagiosum, warts; , exacerbations of psoriasis, shingles)
- AIDS: See “.”
CDC classification system for HIV 
- CDC categories of HIV are based on CD4 count in combination with current or previously diagnosed HIV-related conditions.
- Any patient belonging in categories A3, B3 or C1-C3 is considered to have AIDS.
| CD4 cell count category |
(normal cell count: 500–1500 cells/mm3)
Clinical category A
Asymptomatic, Acute HIV
Clinical category B
Clinical category C
|(1) ≥ 500 cells/mm3||A1||B1||C1|
|(2) 200–499 cells/mm3||A2||B2||C2|
|(3) < 200 cells/mm3||A3||B3||C3|
PGL= Persistent generalized lymphadenopathy
WHO (World Health Organization) classification 
WHO classifies individuals with confirmed HIV infection according to clinical features and diagnostic findings:
- Primary HIV infection: acute retroviral syndrome or asymptomatic
- Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
- Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections
- Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 37.6°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/mm3) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
- Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma, Pneumocystis pneumonia)
Specific screening and testing strategies depend on local factors including regional prevalence and testing capabilities.
- Assess for HIV screening indications (below).
- If indications are present, perform a screening test appropriate to the patient age group.
- Negative test
- Positive test: Send confirmatory tests.
- If confirmatory test supports positive HIV diagnosis:
- Obtain laboratory studies to assess baseline organ function prior to starting treatment.
- Screen for potential complications.
Overview of tests and methods 
- HIV antigen alone: detects HIV p24 antigen
HIV antibody assays (i.e., third-generation and below): Detect IgM and IgG antibodies.
- Enzyme-linked immunosorbent assays (ELISA)
- HIV-1 and HIV-2 antibody differentiation immunoassay
- Western blot: Detects only IgG antibody to HIV-1
- Laboratory methods
- Combination HIV antibody with HIV antigen test; (i.e., fourth-generation and above): Can detect HIV IgG and IgM antibodies and p24 antigen. 
|Comparison of HIV serological assays |
|First-generation HIV test|
|Second-generation HIV test|
|Third-generation HIV test|
|Fourth-generation HIV test|
|Fifth-generation HIV test |
Virological testing 
- Can detect HIV-1 RNA and/or DNA (depending on the test)
- Laboratory method: nucleic acid testing (NAT)
Screening and diagnosis
|Recommended laboratory-based HIV studies |
|Screening||Adults and children ≥ 18 months|
|Infants < 18 months|| |
|Confirmation||Adults and children > 24 months|
|Infants ≤ 24 months|| |
Indications for HIV testing 
- Routine screening
- All patients with clinical features of acute or chronic HIV infection or opportunistic infections
- All individuals with possible past exposure, especially individuals at high risk of HIV infection (e.g., sex workers, men who have sex with men, individuals who use IV drugs, partners of HIV-positive individuals)
- Annual screening for individuals at high risk of HIV infection
In most US states, HIV testing requires patient consent (opt-out); in the majority of locations, oral consent is sufficient, but check local guidance.
Screening studies 
- Fourth-generation HIV test (combination HIV antibody with HIV antigen) ; 
- Third-generation HIV test (antibody only): frequently used in rapid tests (point-of-care tests)
- Virological tests
- HIV-1 and HIV-2 antibody differentiation immunoassay 
- HIV-1 western blot: The CDC no longer recommends western blot tests for confirmation of HIV infection. 
HIV-1 NAT ; 
- Timing: Can measure the amount of viral RNA in the blood and detect HIV infection earlier than antibody/antigen-based tests (∼ 10 days after transmission).
- Results 
- HIV-1 NAT ; 
Additional evaluation for patients with newly diagnosed HIV 
Assessment of organ function
- Assessment of renal function (BMP, urinalysis)
- Liver chemistries
- Lipid panel
- Fasting glucose or HbA1c
- Baseline ophthalmologic evaluation
- Patients of childbearing age: pregnancy test
Advanced HIV studies
- HIV drug resistance testing: Genotypic assays are preferred over phenotypic assays. 
- CD4+ count: correlates with overall immune function ; 
- Viral RNA load: indicator of ART response
- CD4 cell percentage: used for the assessment of immune function and less variable than CD4+ count 
- CD4:CD8 ratios (no longer routinely recommended): an increase in the ratio following ART initiation suggests improved immune system functioning
Screening for associated complications
- STI screen: syphilis, gonorrhea, chlamydia, and, for women, trichomoniasis
- and screening
- Toxoplasma gondii IgG
- PPD or IGRA via
- Additional tests to consider in select patient groups:
General principles 
- All individuals with HIV infection, regardless of CD4 count, should begin antiretroviral therapy (ART) as soon as possible
- Tailor therapy to the HIV genotype, if needed.
- Establish regular monitoring to assess treatment response.
- Prevention and management of co-infections and complications
- Prevention of onward transmission
Counseling and psychosocial support
- Provide counseling regarding diagnosis and management
- Multidisciplinary management recommended
Adherence to ART can be improved by considering and addressing modifiable factors such as comorbid mental illness or , unstable housing, and barriers to attending regular clinic visits. 
- Start ART as soon as possible to prevent further progression of the disease. 
- Factors to consider when selecting a regimen include: 
Initial ART regimens 
- Preferred ART regimens should consist of one of the following combinations:
|Recommended initial regimens |
|Regimen||Recommended drug combinations||Combination tablet||Indications/contraindications|
|2 NRTIs PLUS 1 INI|| |
|1 NRTI PLUS 1 INI|| |
When available, use combination tablets to reduce pill burden and improve adherence. 
- Patients with renal impairment
Patients with hepatic impairment or hepatitis B co-infection
- In patients with moderate to severe cirrhosis: Avoid abacavir, tenofovir alafenamide, nevirapine, darunavir, atazanavir, and dolutegravir.
- In hepatitis B co-infection
- Antiretrovirals that also have anti-HBV activity should be included in the regimen used to treat HIV. These include:
- Discontinuation of drugs that have anti-HBV activity can lead to reactivation of HBV and cause serious hepatocellular damage.
- ART combinations that should be avoided
Overview of antiretroviral drugs 
Nucleoside reverse transcriptase inhibitors (NRTIs)
- Medications in class
Mechanism of action
- NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3' to 5' phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
- Activation requires intracellular phosphorylation, thus, NRTI efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state. 
- Resistance is caused by mutations in the gene that codes for reverse transcriptase (pol gene) 
General adverse effects 
- Mitochondrial toxicity 
HIV-associated lipodystrophy (Cushing syndrome-like appearance): abnormal distribution of fat ; 
- Loss of subcutaneous fatty tissue (lipoatrophy) in the face, extremities, and buttocks
- Probable accumulation of fat in liver, muscles, abdomen, breasts, neck (double chin), and upper back (enlarged dorsocervical fat pad)
- Metabolic changes: impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL)
Additional medication-specific adverse effects 
- Abacavir hypersensitivity reaction 
- Pancreatitis: didanosine, stavudine
- Cardiovascular disease: abacavir
- Nephrotoxicity : tenofovir
- Osteoporosis: tenofovir
- Bone marrow suppression causing anemia and neutropenia: zidovudine
- Melanonychia: zidovudine
- DNA-depleting mitochondrial myopathy with red “ragged” fiber appearance: zidovudine 
Nonnucleoside reverse-transcriptase inhibitors (NNRTIs)
Medications in class
- Mechanism of action
- General adverse effects 
- Additional medication-specific adverse effects 
HIV protease inhibitors (PIs)
Medications in class
- Mechanism of action: inhibition of viral HIV-1 protease (encoded by pol gene) → inability to cleave viral polyproteins into functional units → generation of impaired viral proteins → production of immature (noninfectious) virions 
General adverse effects 
- GI upset (nausea, vomiting, diarrhea)
- Nephrolithiasis, crystal-induced nephropathy, and hematuria 
- Metabolic abnormalities
- Increased risk of bleeding in patients with hemophilia 
- Changes to hair, e.g., thinning
- Additional medication-specific adverse effects: thrombocytopenia with indinavir (rare) 
Medications in class
- Mechanism of action: inhibition of the viral integrase → blockade of viral DNA integration into the host's DNA → inhibition of viral replication 
General adverse effects 
- Hypersensitivity syndrome in rare cases
- Additional medication-specific adverse effects: : muscle inflammation causing elevated creatinine kinase : raltegravir, dolutegravir 
Entry inhibitors 
- Description: Hetereogenic class of antiretroviral drugs that inhibit binding or fusion of HIV virions with human cells.
- Enfuvirtide (fusion inhibitor)
- Maraviroc (CCR5-antagonist): used in infection with drug-resistant HIV-1 
“Enfuvirtide provides defusion of viral fusion.”
“Maraviroc will block the viral dock.”
Monitoring antiretroviral therapy
The treatment response of patients with HIV who are on ART should be frequently monitored by assessing their CD4+ count and HIV viral load. Any concerns regarding the failure of treatment should be referred to the infectious disease service. 
Monitoring studies 
|Frequency of monitoring studies |
|Frequency of test||Test|
4–8 weeks after initiation of ART
|Every 3–6 months|
|Every 6 months|
|Every 12 months|
Patients should have monitoring studies performed more frequently if clinically indicated or in treatment failure!
Virological failure 
- Definition: the inability to maintain or achieve viral levels of < 200 copies/mL
- Causes: patient-related factors (e.g., poor drug adherence, cost), HIV-related factors (e.g., drug resistance, high pretreatment viral load), ART-related factors (e.g., drug interactions, suboptimal pharmacokinetics)
- Management: Address any identifiable cause of failure and adjust ART regimen if indicated.
Poor CD4 count recovery 
- Definition: CD4+ counts remain persistently low (< 500, although effects are most concerning if CD4 remains < 200) despite adequate suppressive ART. These individuals have increased morbidity and mortality.
- Causes: medication side effects, co-infections such as HIV-2 and HCV, other medical problems such as malignancy
- Management: Identify modifiable causes of CD4 cell lymphopenia. Changing or adding antiretrovirals is not recommended.
Preventative health care
Opportunistic infections 
- Patients with low CD4 counts are at increased risk of opportunistic infections.
- See “HIV-associated conditions” for further information on prevention and management.
- In addition to routine vaccinations, the following vaccines should be prioritized in this population:
- See “Immunizations in individuals with HIV”.
- Early diagnosis and treatment of HIV with ART is the most important step in preventing HIV-associated malignancies.
- Treat co-infections (e.g., HBV and HCV).
- Ensure patients receive vaccinations for oncogenic viruses (e.g., HPV, hepatitis B).
- Encourage behavioral modifications.
- Age-appropriate cancer screening
- Follow modified screening for HPV-associated cancers.
Patients who start ART are at risk of developing complications related to the recovery of their immune system. Complications relating to immunocompromise (especially if CD4 levels are < 200) and/or HIV infection itself may also be seen (see “”).
Immune reconstitution inflammatory syndrome (IRIS) 
- Definition: an inflammatory syndrome that can occur after initiation of ART and consists of either the appearance of a new condition or worsening of a preexisting condition
- Epidemiology: common; occurs in ∼ 15–25% of patients starting ART 
- Etiology: believed to result from the restoration of the immune system and its response to antigenic stimulation. The stimulus may be: 
Risk factors 
- Low CD4 count (especially CD4 < 50), CD4 percentage, and/or lower CD4:CD8 ratio at ART initiation
- High viral load at ART initiation
- Younger age
- Male sex
- Rapid fall of viral RNA on initiation of ART
- Diagnosis of an opportunistic infection prior to starting ART
- A short interval of time between the initiation of ART and treatment of an opportunistic infection
Clinical presentation 
- Develops within 4–8 weeks of initiation of ART
- Presentation varies depending on the underlying illness, however, patients often have clinical deterioration and localized tissue inflammation.
Diagnosis is clinical and based on presence of the following: : 
- Symptoms cannot be explained by the expected clinical course of a known infection, a drug side-effect, or a new infection.
- Symptoms of an infectious or inflammatory (e.g., autoimmune) condition
- Treatment with effective ART (defined by a significant decrease in HIV viral RNA or an increase in CD4 count)
- HIV diagnosis
- Management 
We list the most important complications. The selection is not exhaustive.
Morbidity and mortality among patient subsets
- Untreated, HIV leads to death on average 8–10 years after infection.
- Progression varies among individuals: Some patients may die within a few years while others can remain asymptomatic for decades.
- Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months).
- The average life expectancy of HIV-infected individuals who receive adequate antiretroviral treatment is approaching that of noninfected individuals of the same age. 
- Individuals with HIV infection on adequate antiretroviral therapy are more likely to develop chronic comorbidities (e.g., cardiovascular disease, diabetes, cancer) than healthy individuals. 
- Individual prognosis depends on various factors, including:
Risk reduction 
All patients should be counseled on the following risk reduction measures.
- Barrier contraception
- Avoiding shared IV drug equipment
- Regular HIV and STI screenings (including in all new sexual partners)
HIV preexposure prophylaxis (PrEP) 
- Definition: the use of ART to prevent infection in individuals at high risk of contracting HIV
Indications for HIV PrEP
- Men who have sex with men
- Heterosexual men and women
- Individuals who inject drugs with high-risk needle behavior (e.g., sharing needles or equipment) or with an HIV-positive injection partner
- Timing: prior to the exposure to HIV and continued for a month after the exposure 
HIV postexposure prophylaxis (PEP) 
- Definition: a short course of ART taken by patients after a potential exposure to HIV
- Indications for HIV PEP
- Timing: : Initiate as soon as possible (ideally within 1–2 hours of exposure)
- Drugs: a three-drug regimen is recommended (similar to ART). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor, e.g. : 
- For occupational exposure, follow the procedure for health care personnel exposures (see “Infection Prevention and Control”).
- Counsel patients to use barrier contraception, avoid donation of blood, semen, or tissue, and, if possible, avoid pregnancy and breastfeeding throughout the 6-month follow-up period.
- Ensure patients are educated about the adverse effects of medications and that they have appointments booked for testing (see “Follow-up for exposure to bloodborne viruses”).
Special patient groups
HIV in pregnancy
Antepartum and intrapartum management
- Combined antiretroviral therapy (cART) is recommended throughout pregnancy and delivery.
- The mode of delivery and the use of additional IV zidovudine depend on the maternal viral load during the intrapartum period, both of which must be considered to reduce the risk of transmission of HIV to the infant.
- Zidovudine is also one of the few antiretroviral medications approved for HIV postexposure prophylaxis in neonates.
|Intrapartum management of HIV |
|Maternal viral load near time of delivery||Delivery method||Intrapartum antiretroviral treatment||Infant prophylaxis|
|> 1000 copies/mL OR unknown viral load OR poor adherence to ARV treatment|
|> 50–≤ 1000 copies/mL|| || |
|≤ 50 copies/mL|| || |
- Postpartum management
- Diagnosis in infants: : if < 18 months, diagnosis is confirmed via PCR, not ELISA
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