HIV Infection and AIDS

Epidemiology

Worldwide

• At the end of 2018, there were approximately 37 million infected people.
• Sub-Saharan Africa: 
  • The most affected area in the world
  • Approximately > 10% of adults aged 15–49 years are affected.
  • Accounts for > 50% of total global human immunodeficiency virus (HIV) infections

United States

• Approximately 38,700 new cases diagnosed each year
• Approximately 1.1 million individuals currently living with HIV
• HIV infection highest among Hispanics and African Americans (likely due to socioeconomic factors)
• Gay and bisexual males account for most newly diagnosed cases.
• Children usually acquire infection from their mother in utero or via subsequent breastfeeding.

Etiology and Transmission

HIV

• Genus, Lentivirus; family, Retroviridae
• Structure:
  • Virion envelope contains 2 membrane glycoproteins:
    • Gp41 (transmembrane)
    • Gp120 (surface/docking protein)
  • Matrix protein p17: surrounds the virus core
  • Virus core: 
    • Capsid protein p24
    • 2 single-stranded, enveloped positive-sense ribonucleic acid (RNA) coated with nucleocapsid protein
    • Enzymes (reverse transcriptase, integrase, protease)
• Subtypes of HIV:
  • HIV-1:
    • Most common species worldwide
    • Similar to the simian immunodeficiency virus in chimpanzees
    • 4 distinct subgroups (M, N, O, and P)
    • Subgroup M: 90% of HIV/AIDS (acquired immunodeficiency syndrome) worldwide
  • HIV-2:
    • Lower infectivity, less virulent, largely confined to West Africa 
    • Similar to simian immunodeficiency virus from sooty mangabey monkeys
    • 8 known subgroups (A to H)
• Transmission through bodily fluids (i.e., blood, semen, vaginal secretions, and breast milk)

Modes of HIV transmission

Sexual:

• Unprotected sex: 
  • Responsible for 80% of infections
  • Unprotected receptive anal intercourse (URAI) in men and women > unprotected receptive vaginal intercourse
• In anal intercourse, infection occurs:
  • With direct inoculation into the blood in the presence of traumatic tears
  • With easy access to target cells beneath the fragile rectal mucosal membrane
• In the United States, risk noted:
  • In men who have sex with men (highest)
  • Heterosexual individuals
• In Africa, reported infections are predominantly via heterosexual transmission (limited data on homosexual transmission rates).

Parenteral:

• Intravenous (IV) drug use and sharing needles 
• Accidental needle punctures in medical professionals

Vertical:

• Mother to child during pregnancy, delivery, or breastfeeding
• Most cases occur during delivery.
• Risk factors for vertical transmission:
  • No antiretroviral therapy or prophylaxis
  • Elevated maternal viral load
  • Rupture of membranes > 4 hours

Factors affecting transmission

• Viral load: 
  • Quantity of HIV is the primary factor determining transmission.
  • Transmission unlikely if with suppressed viral load (defined as having a viral load of < 400 HIV RNA copies/mL)
• Type of sexual contact: 
  • Receptive anal sex is the most high risk.
  • Circumcision reduces the risk of transmission.
• Mucosal damage: Inflammation, tears, sexually transmitted infection, and irritation of the genital mucous membranes increase transmission risk.
• Recent HIV infection: elevated risk of transmission due to high viral load

Pathophysiology

HIV replication cycle

• Target cells: CD4+ T cells, macrophages, and dendritic cells
• HIV cell entry: 
  • The virion first enters via a break in a mucous membrane. 
  • The virion then crosses the mucosal barrier and seeks target cells.
• HIV replication:
  1. Membrane fusion and binding of receptors (entry): the virion (carrying viral RNA, reverse transcriptase, integrase, and other proteins) initiates entry into the host cell. 
     • Virion binds the CD4 receptor and a chemokine receptor (CCR5 on macrophages, CXCR4 on T cells). 
       • Macrophage-tropic viruses: R5 strains
       • T cell-tropic viruses: X4 strains
     • Binding of gp120 with CD4 and the chemokine receptors leads to a conformational change, exposing the fusion domain at gp41.
     • This process pulls the viral and cellular membranes together, fusing them. 
  2. The capsid protein shell (surrounding the viral RNA and proteins) is uncoated as the virion traverses the cytoplasm.
  3. Reverse transcription: Reverse transcriptase-mediated synthesis of proviral deoxyribonucleic acid (DNA) (from the viral RNA) occurs.
  4. Integration: Viral DNA is transported across the nucleus and integrated into the host DNA, facilitated by integrase. 
  5. Replication: Viral DNA is transcribed, and multiple copies of new HIV RNA form and are transported to the cytoplasm. 
     • New HIV RNA becomes the genome of a new virus. 
     • Other copies of the RNA are used to make new HIV proteins.
  6. Assembly: New viral RNA + proteins + enzymes move to the cell surface and form a noninfectious particle.
  7. Budding and maturation: 
     • Particle (viral RNA + proteins) eventually buds out of the host cell with the immature HIV.
     • Viral protein protease then cleaves newly synthesized polyproteins, producing a mature HIV.

Natural history

Acute phase (infection, dissemination, retroviral syndrome):

• HIV infects and destroys CD4+ T cells, macrophages, and dendritic cells in mucosal tissues.
• Dissemination and replication in lymph nodes occur, then proceed to other lymphoid compartments (more CD4+ target cells) → viremia. 
• Further spread to the plasma and other organs follows. 
• Antiviral immune response leads to seroconversion (about 3–7 weeks).
• CD8+ cytolytic T lymphocytes (CTLs) are activated, and this immune response produces a partial control of viral replication.
• Acute retroviral syndrome:
  • Clinical presentation of self-limited acute viral illness
  • Associated with millions of copies of HIV RNA/mL of plasma
  • High likelihood of transmission during this period

Chronic phase/clinical latency:

• Low-level replication of virus in lymphoid tissues and slow progressive T cell depletion
• Sustained replication generates mutation, contributing to viral escape from the control of CD8+ CTLs.
• Virus may evolve and undergo coreceptor switch (instead of 1 coreceptor, virus can rely on either CCR5 or CXCR4).

AIDS:

• Ongoing activation of T cells results in extensive death of CD4+ T cells.
• Profound immunodeficiency leads to opportunistic infections (usual cause of death).

Clinical Presentation

Categories of HIV infection

The Centers for Disease Control and Prevention (CDC) classification notes that CD4+ T lymphocyte count is: 

• A reliable indicator of disease progression
• A guide to the clinical and therapeutic management of HIV infection

Clinical course and symptoms

Acute retroviral syndrome (acute phase):

• 3–6 weeks after infection
• Infectious mononucleosis-like presentation:
  • Fever, fatigue, myalgias (most common)
  • Retro-orbital headache (may have aseptic meningitis), joint pain, and rash
  • Sore throat and painful mouth sores (aphthous ulcers)
  • Hepatosplenomegaly
  • Swollen lymph nodes (mainly cervical, axillary, and occipital)
  • Nausea, vomiting, diarrhea, and weight loss

Chronic infection (clinical latency):

• Few or no clinical manifestations of infection
• Minor opportunistic infections:
  • Thrush
  • Vaginal candidiasis
  • Herpes zoster
  • Tuberculosis

AIDS:

• Without treatment, progression to AIDS takes place after a chronic phase of 7–10 years.
• AIDS-defining diseases and malignancies
• Opportunistic infections
• Wasting syndrome 
• Encephalopathy associated with HIV

AIDS

• Defined as:
  •  CD4+ T cell count of < 200 cells/μL or a CD4+ T cell percentage of total lymphocytes of < 14%
  • And/or at least 1 AIDS-defining condition (opportunistic infection(s) or illnesses associated with immunosuppression)
• AIDS-defining conditions:
  • Fungal and parasitic infections:
    • Candidiasis 
    • Cryptococcal meningitis
    • Cryptosporidium or Cystoisospora (enteritis/diarrhea)
    • Coccidioidomycosis
    • Pneumocystis jirovecii pneumonia
    • Cerebral toxoplasmosis 
    • Histoplasmosis
  • Bacterial infections:
    • Mycobacterium avium-intracellulare
    • M. tuberculosis
    • Salmonella septicemia
    • Nocardia
  • Viral infections:
    • Herpes zoster
    • Cytomegalovirus (CMV) infections
    • Herpes simplex virus (HSV) encephalitis
    • Progressive multifocal leukoencephalopathy 
  • Malignancies:
    • Lymphoma (Burkitt’s, immunoblastic)
    • Kaposi’s sarcoma
    • Invasive cervical and anal carcinomas
  • Miscellaneous:
    • Wasting syndrome attributed to HIV
    • HIV-associated encephalopathy

Selected infections and conditions

• P. jiroveci pneumonia: 
  • Risk factors:
    • CD4 count < 200/µL
    • Thrush
    • Previous Pneumocystis pneumonia
    • Weight loss
  • Symptoms include dyspnea, fever, and a non-productive cough.
  • Physical exam findings:
    • Tachypnea
    • Tachycardia
    • Crackles and rhonchi; normal auscultation in 50% of cases
  • Chest X-ray shows bilateral interstitial infiltrates.
  • Diagnosis: special silver staining of respiratory secretions showing classic cysts
  • Treatment:
    • Trimethoprim-sulfamethoxazole
    • Alternative: clindamycin + primaquine
    • Moderate or severe hypoxemia: tapering doses of prednisone added
• Cryptococcal meningitis: 
  • Greatest risk if CD4 count < 100/µL
  • Symptoms include headache, fever, altered mental status, and neurologic deficits.
  • Exam shows meningismus in < 40% of patients.
  • Diagnosis:
    • Lumbar puncture including measurement of opening pressure
    • Cerebrospinal fluid (CSF): ↓ white blood cell count, ↑ protein, ↓ or normal glucose 
    • CSF India ink staining (encapsulated yeast organisms), culture
    • CSF cryptococcal antigen testing
    • Serum cryptococcal antigen testing
  • Treatment:
    • Amphotericin B and flucytosine for 2 weeks
    • Then oral fluconazole for 8 weeks or until the patient is culture negative
• Toxoplasma encephalitis: 
  • Greatest risk if CD4 count < 100/uL
  • Symptoms include headache, confusion, fever, seizures, and lethargy.
  • Exam shows ataxia, focal neurologic, and sensory deficits.
  • Diagnosis: 
    • Brain imaging: multiple ring-enhancing lesions
    • + Toxoplasma gondii IgG antibody
    • Typical clinical syndrome
  • Treatment: pyrimethamine, sulfadiazine, and folinic acid for 6 weeks
• Disseminated M. avium complex (MAC) infection: 
  • Greatest risk if CD4 count < 50/µL
  • Symptoms include fever, weight loss, night sweats, abdominal pain, and diarrhea.
  • Exam shows lymphadenopathy and hepatosplenomegaly.
  • Laboratory studies: severe anemia (due to bone marrow involvement), ↑ alkaline phosphatase, ↑ lactate dehydrogenase
  • Diagnosis: blood cultures
  • Treatment:
    • Macrolide + ethambutol 
    • +/- Rifabutin (if with ↑ mycobacterial burden)
• Nervous system conditions of AIDS:
  • 90% of patients exhibit neurologic involvement on autopsy.
  • Some findings:
    • Vacuolar myelopathy: microscopically resembles subacute combined degeneration (vitamin B₁₂ deficiency)
    • AIDS-associated peripheral neuropathies (most common: distal sensory polyneuropathy)
    • HIV meningoencephalitis: dementia, ataxia, bowel and bladder incontinence
    • AIDS dementia complex or HIV encephalopathy

Diagnosis

Diagnostic approach

• Pre-test counseling:
  • Discuss the indication for HIV testing.
  • Risk assessment (patient risk behaviors)
  • Implications of positive test results
  • Discuss confidentiality and follow-up.
• Indications for testing:
  • Screening: Test all adolescents and adults at increased risk for HIV infection, and all pregnant women.
  • Any patients with features of acute or chronic HIV infection
• Laboratory testing:
  • 4th-generation enzyme immunoassay (EIA) for HIV-1 and -2
    • Detects antibodies (generally appear 3–12 weeks following infection) and p24 antigen of HIV
    • Negative result: no need for further testing
    • Positive result: Test HIV-1 and -2 antibody differentiation immunoassay.
    • Indeterminate result: Test with FDA-approved HIV-1 nucleic acid test. 
  • Other tests for HIV:  
    • Western blot: separation of viral proteins by molecular weight on polyacrylamide gel (2 bands present = positive)
    • Reverse transcriptase-polymerase chain reaction (RT-PCR) testing: virus quantification or HIV RNA for monitoring

Additional tests and monitoring

• HIV-related:
  • CD4+ T cell count (assess immune function)
  • Viral RNA load (assess viremia)
  • HIV resistance testing or genotyping (rate of HIV resistance to current therapy: 4%–10%)
  • HLA-B*5701:
    • Obtain before starting patients on an abacavir (ABC)-containing regimen 
    • If positive, patient should not get ABC due to hypersensitivity reaction
• HBV and HCV serology (viral hepatitis status affects choice of therapy) 
• Other sexually transmitted diseases
• Other tests needed for monitoring and determination of co-morbidities:
  • Basic metabolic panel
  • Liver function tests (some of the antiretrovirals cause alterations in liver function)
  • Complete blood count (CBC) with differential count
  • Fasting lipid profile (some antiretrovirals cause lipid problems)
  • Fasting glucose or hemoglobin A1c (antiretrovirals cause issues with glucose tolerance)
  • Urinalysis (due to the prevalence of HIV nephropathy)
  • Pregnancy test (treatment needed in pregnant women)
• Monitoring:
  • Viral RNA load (indicator of antiretroviral therapy response):
    • ↓ Viral loads indicate effective treatment
    • A prognostic marker in long-term treatment
  • CD4+ T cell count: increases with antiretroviral therapy (ART)

Management

Antiretroviral drugs

• Reverse transcriptase inhibitors interfere with the translation of viral RNA into DNA:
  • Nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine, emtricitabine, tenofovir)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, doravirine, etravirine)
• Protease inhibitors (PIs):
  • Block the cleavage of protein precursors necessary for the production of infectious viral particles 
  • Examples: atazanavir, darunavir, lopinavir
• Integrase strand transfer inhibitors 
  • Prevent the insertion of the viral genome into the host DNA 
  • Examples: dolutegravir, elvitegravir
• Entry inhibitors: 
  • CCR5 antagonist: 
    • Inhibits the attachment of the virus to the CD4 cell by blocking binding of gp120 
    • Maraviroc
  • Fusion inhibitor: 
    • Interferes with fusion of the cell membranes of HIV and the CD4 cell 
    • Enfuvirtide
  • Attachment inhibitor: 
    • Binds gp120, preventing viral attachment 
    • Fostemsavir
• Post-attachment inhibitor: 
  • Blocks CD4 molecule, thus inhibiting virion entry
  • Ibalizumab

Treatment approach

• Initiate antiretroviral therapy (ART) promptly!
• Goals:
  • Suppress plasma HIV RNA.
  • Improve immunologic function.
  • Reduce HIV-associated complications and prolong survival.
  • Prevent HIV transmission.
• Avoiding resistance: Triple-drug therapy given HIV resistance develops quickly to 1- or 2-drug regimens.
• Combination ART for treatment-naive patients (Department of Health and Human Services Panel, 2019):
  • Bictegravir + tenofovir alafenamide + emtricitabine 
  • Dolutegravir + tenofovir alafenamide/disoproxil fumarate + emtricitabine or lamivudine
  • Raltegravir + tenofovir alafenamide/disoproxil fumarate + emtricitabine or lamivudine 
  • Dolutegravir + abacavir + lamivudine: only for individuals who are HLA-B*5701 negative and without chronic HBV 
  • Dolutegravir + lamivudine, except for:
    • Individuals with HIV RNA > 500,000 copies/mL
    • Individuals with HBV co-infection
    • Individuals needing to initiate ART before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available
• Once initiated, treatment is indefinite.

Immune reconstitution inflammatory syndrome (IRIS)

• Worsening of preexisting or untreated opportunistic infections when combination antiretroviral therapy (cART) is initiated
  • Paradoxical IRIS: worsening of known or pre-existing condition
  • Unmasking IRIS: symptoms associated with previously undiagnosed condition
• Frequently seen in tuberculosis
• Onset: 1 week to a few months of cART initiation
• Pathogenesis: inflammatory response similar to type IV hypersensitivity reaction
• Treatment:
  • Treat opportunistic infection.
  • May delay antiretroviral therapy (e.g., cryptococcal and tuberculous meningitis)
  • Glucocorticoids as needed with a subsequent taper

Prevention and Prophylaxis

General prevention

• Safe-sex practices (use of condoms)
• Treatment of sexually transmitted diseases 
• Male circumcision
• Use of sterile instruments 
• Proper personal protective equipment for medical professionals
• Opioid substitution therapy (↓ illicit drug and injection use)
• Adequate pre- and perinatal care (to reduce transmission to infants)
• Pre- and post-exposure prophylaxis 
• Adequate ART for infected individuals

Prophylaxis

• Post-exposure prophylaxis: 
  • Within 72 hours of exposure after contact with mucous membranes or parenteral contact with HIV-infected materials
  • Taken for 28 days
  • Combination of 3 antiretroviral drugs 
  • Options:
    • Raltegravir + tenofovir-emtricitabine 
    • Dolutegravir + tenofovir-emtricitabine
• Pre-exposure prophylaxis (PrEP):
  • Reduce the risk in uninfected high-risk individuals: 
    • Sexual partners of HIV-infected patients
    • Men/transgender women who have sex with men
    • Men (who do not use condoms) in high-prevalence areas
  • Combination of emtricitabine and tenofovir
• Perinatal prophylaxis: 
  • Highest risk of HIV transmission is during delivery.
  • Goal is to block transmission (from mother to baby): 
    • Treat HIV-positive patients immediately and do not wait for genotyping.
    • Regimen can be changed later.
  • Zidovudine or 3-drug regimen (depending on maternal viral load/risk of transmission) given to infant as prophylaxis

HIV in Special Populations

Pregnancy

• Testing:
  • HIV testing as part of prenatal care
  • Repeat test in 3rd trimester in patients at high risk for HIV infection
  • Repeat test in patients with sexually transmitted disease
• Transmission: 
  • During pregnancy
  • Delivery (highest risk)
  • Breastfeeding
• Risk depends on maternal viral load.
• Maternal management:
  • Reducing transmission: 
    • cART throughout pregnancy
    • Breastfeeding should be avoided in the United States (alternative infant nutrition easily available) but not in developing nations.
  • Delivery method for mothers who did not receive ART (high risk of transmission): cesarean delivery, if possible (based on obstetric indications)
  • Delivery methods for mothers on ART:
    • Maternal viral load > 1,000 copies/mL (high risk of transmission): cesarean delivery at 38 weeks (before labor and rupture of membranes)
    • Maternal viral load ≤ 1,000 copies/mL but > 50 copies/mL: vaginal delivery possible (decide by obstetric indications)
    • Maternal viral load < 50 copies/mL: vaginal delivery possible (decide by obstetric indications)
  • Postpartum: Treatment should by continued by the mother.

Newborns

• HIV diagnostic testing for all infants with perinatal HIV exposure:
  • Use PCR (HIV RNA or HIV DNA nucleic acid tests):
    • Not HIV antibody immunoassay
    • False positives in antibody tests in children < 18 months of age (circulating maternal antibodies still present)
  • Timing:
    • 14–21 days
    • 1–2 months
    • 4–6 months
• Low risk of perinatal HIV transmission:
  • Considered in:
    • Mothers on ART during pregnancy with compliance
    • Confirmed HIV RNA level of < 50 copies/mL (viral suppression) near delivery
  • Neonatal medication: zidovudine for 4 weeks
• High risk of perinatal HIV transmission:
  • Considered in:
    • Mothers without antepartum/intrapartum ART or only intrapartum ART
    • Mothers without viral suppression
    • Mothers with acute HIV during pregnancy or breastfeeding
  • Intrapartum: IV zidovudine in HIV RNA >1000 copies/mL
  • Birth to 6 weeks (presumptive HIV therapy for neonate): 
    • Zidovudine + lamivudine + nevirapine 
    • Zidovudine + lamivudine + raltegravir
• Presumed newborn exposure:
  • Considered in:
    • Mothers who have at least 1 positive HIV test at delivery or postpartum
    • Mothers whose newborns have a positive HIV antibody test
  • Same medications as presumptive HIV therapy for neonate
• Newborn with HIV (confirmed HIV virologic test): Use 3-drug ART (using appropriate doses).

Children

• Transmission: 
  • Vertical transmission (most common route of transmission) 
  • Others: blood transfusion, sexual abuse, injection drug use
  • Increased risk of HIV infection among those having unprotected sex, and teenage boys who have intercourse with partners of same sex
• Presentation:
  • Children:
    • Infant rapid progressors: develop severe signs of AIDS early in life that contribute to death (by age 2–4 years)
    • Unique features: short stature, developmental delay, aspiration and swallowing problems, recurrent ear infections, and delayed puberty
  • Adolescents: often asymptomatic until CD4 count falls
  • Other findings:
    • Opportunistic infections
    • Organ system disease (e.g., nephropathy, encephalopathy, hepatitis)
    • Malignancy (e.g., non-Hodgkin’s lymphoma)
• Diagnosis: 
  • < 18 months: PCR (HIV RNA or HIV DNA nucleic acid tests), not HIV antibody immunoassay
  • > 18 months: HIV antibody immunoassay
• Management:
  • Combination antiretroviral therapy (3-drug regimen)
  • Treat opportunistic infections
• Prevention:
  • Routine “opt out” testing (HIV test is included in standard preventive tests and patient is given opportunity to decline)
  • Treat pregnant women to reduce viral load (↓ transmission).
  • Infant prophylaxis
  • In United States: no breastfeeding 
  • Routine screening offered at least by the age of 16 in high-prevalence areas

• Immunologic categories:
  • Stages of HIV in children are dependent on age and CD4 T cell count.
  • If a stage 3 opportunistic infection is detected, the patient has AIDS regardless of level of CD4 T cell count.

Elderly

• In 2018, > 50% of HIV-infected Americans were > 50 years of age.
• Challenges:
  • Age-related liver/kidney dysfunction may increase side effects of ART or drug toxicity.
  • Higher risk of drug-to-drug interactions
  • Age and HIV increase the risk of cardiovascular disease, bone loss, and cancer.

Differential Diagnosis

• Infectious mononucleosis (IM): a contagious viral infection caused by the Epstein-Barr virus. Transmission is via the spread of infected saliva. Clinical manifestations include fever, tonsillar pharyngitis, and lymphadenopathy. The infection can be similar to acute retroviral syndrome. Diagnosis is clinical and confirmed through heterophile antibody testing. 
• Toxoplasmosis: a disease caused by T. gondii, a parasite that lives in the feline gut (definite host). Transmission is by consumption of raw meat or food contaminated by cat feces. Presentation depends on the host’s immunity. Immunocompetent patients usually have no or mild viral symptoms. Immunocompromised patients develop cerebral or ocular toxoplasmosis.
• Cryptococcosis: a fungal infection that most often affects immunocompromised patients (e.g., AIDS, malignancy, transplant recipients, chronic corticosteroid use). Patients present with headaches and abnormal mental status. Cryptococcal capsular antigen in CSF and culture establish the diagnosis.
• Hodgkin’s lymphoma: a malignancy of B lymphocytes within the lymph nodes. Presentation of the disease is with palpable nontender lymphadenopathy, mostly in the neck, supraclavicular area, and axilla. Constitutional “B symptoms” (fever, night sweats, and weight loss) are also noted. The pathognomic histological finding is a Reed-Sternberg cell (giant B cells with eosinophilic inclusions).