Introduction
HIV, or human immunodeficiency virus, is a type of virus that infects human immune cells. Over time, immune cells are lost, which weakens the immune system and allows patients to be infected by other viruses and develop several types of tumors.
Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV).
History:


Epidemiology
AIDS pandemic:
HIV is the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M—the principal cause of the AIDS pandemic.




Prevalence:

Transmission:
HIV transmission requires contact with a body fluid that contains either infectious virus (virions) or HIV-infected cells or a combination of both. Predominantly through blood, semen, vaginal and rectal fluids, and breast milk, rarely via tears, urine, and saliva. No case of HIV transmission has been traced to the coughing or sneezing of an infected person or to a mosquito bite.
- Unprotected sexual contact (M/C but least efficient)
- Parenteral exposure (e.g. blood transfusion, needle sharing) (2nd M/C)
- Vertical (mother to child) transmission (MTCT):
- In utero transmission
- Perinatal transmission (M/C vertical transmission)
- Via breastfeeding (least common)
Risk of transmission:
- Blood Transfusion (highest risk)
- Other routes: Needle sharing (drug abuse) > receptive anal intercourse > needle-stick injury > vaginal & oral sexual intercourse
- Male to Female Transmission > Female to Male transmission
- Risk of vertical transmission:
- High maternal viremia (M/imp)
- Preterm delivery (< 34 weeks)
- Vitamin A deficiency
- Prolonged rupture of membranes (> 4 hours)
- Low birth weight (LBW)
- Low maternal CD4 count
- Incidence of transmission: Sexual Transmission (Heterosexual in India) > Mother to child > least common modes are blood transfusion & needle-stick injury.
Viral entry:
HIV-1 infection is usually initiated with a single virion infecting a single target cell at the site of entry.
- Mucosal surfaces (M/C portal of entry)

Microbiology
Taxonomy:
- Retrovirus
- Genus: Lentivirus
- Thermolabile
- Subtypes:
- HIV-1 (M/C, worldwide prevalence)
- Groups/lineages: M (Major) (M/C), N (non-M, non-O), O (outlier) and P (Putative)
- M group has 9 subtypes/clades: A, B, C, D, F, G, H, J, & K
- HIV Serotype 1 – Group M – Subtype C (M/C form worldwide): Heterosexual transmission
- Subtype B: Blood and homosexual contact
- Groups/lineages: M (Major) (M/C), N (non-M, non-O), O (outlier) and P (Putative)
- HIV-2 (less pathogenic, Western Africa prevalence)
- HIV-1 (M/C, worldwide prevalence)
Viral structure:
Spherical virion containing an electron-dense, cone-shaped core surrounded by a lipid envelope derived from the host cell membrane.
- Viral core:
- Constituents:
- Major capsid protein p24
- Nucleocapsid protein p7/p9
- 2 copies of viral genomic RNA
- 3 viral enzymes: Protease, reverse transcriptase, and integrase
- Surrounded by a matrix protein called p17, which lies underneath the virion envelope
- Constituents:
- Viral envelope:
- Studded by 2 viral glycoproteins, gp120 and gp41, which are critical for HIV infection of cells.

- 3 structural genes:
- gag: Core forming proteins (incl. p24)
- pol: Reverse Transcriptase, Integrase & Protease
- env: Envelope proteins gp120 (spike protein binds CD4 & chemokine receptors) & gp41 (mediates fusion)
- 7 non-structural genes :
- tat: Transcriptional activator gene
- nef: negative factor gene
- rev: Regulator of virus gene
- vif: Viral infectivity factor gene
- vpu: (only in HIV-1) and vpx (only in HIV-2)
- vpr: Stimulates only the promoter region of the virus
- LTR: Long terminal repeat sequences
HIV life cycle:
- Genome sequence: RNA–ssDNA–dsDNA–RNA
- Viral budding causes loss of plasma membrane integrity: Direct mechanism involved in the CD4+ T Cell dysfunction and depletion

Entry into T-cell:
gp120 – CD4 binding → conformational change → gp120-CD4 bind to CCR5 (chemokine receptor) → gp41 membrane penetration → membrane fusion
- CCR5 Delta 32 mutation: Causes lack of surface expression of the CCR5 co-receptor resulting in blockade of HIV entry and resistance to HIV infection.
- Homozygous alleles: Complete resistance
- Heterozygous alleles: Partial resistance
- DC-SIGN: Cell surface lectin receptor to which the HIV virus has affinity to bind.
- Expression on Dendritic cells (antigen presenting cells): Enhances infectivity of HIV.

Pathophysiology

Immune system evasion/neutralization:
- Hypervariability in the primary sequence of the envelope
- Extensive glycosylation of the envelope
- Conformational masking of neutralizing epitopes
Clinical features
WHO clinical staging:

Primary HIV infection (4-10 weeks after exposure):
Characterized by wide virus dissemination and seeding of lymphoid organs (e.g., Gut-associated Lymphoid Tissue), culminating in the destruction of CD4+ cells. The virus is transmissible during this early infection period.
Acute phase is often, but not always accompanied by “flu-like” symptoms including fever, sore throat, lymphadenopathy, and rash.
- Fever
- Joint pain
- Skin rash
- Sore throat
- Swollen lymph nodes
Chronic “latent” infection (can last for decades):
Chronic infection, or “clinical latency” (1-20 years after infection) is characterized by a constant or slowly increasing level of viremia (1-1×105 copies/mL), also called the “set point”, and steady, near normal (around 1,000 cells/mL) or gradually falling levels of CD4+ T cells. Usually no symptoms are shown during that phase making infected people unaware of their status but they are infective.
- Fever
- Fatigue
- Diarrhoea
- Weight loss
- Oral thrush
- Shingles
- Persistent generalized lymphadenopathy
Clinical progression:
- Typical progressors (80–90%):
- Median survival time: 10 years.
- Rapid Progressors (5–10%): Develop AIDS within 1-3 years
- Long-term Non-progressors:
- Not on ART but don’t develop clinical progression and have stable CD4 cell counts and low levels of detectable viremia (<10,000 copies/mL)
- Elite controllers (small minority):
- Subset of long-term non-progressors whose viral load is undetectable as measured by standard assays (<50 copies/mL) and maintain high CD4 cell counts for prolonged periods.
HIV-infection in children:
- Failure to thrive (universal finding)
- Infections:
- Pneumocystic carinii pneumonia: M/C AIDS defining illness in children
- Oral candidiasis: M/C fungal infectoin
- Recurrent and chronic bacterial infections (esp. Streptococcus pneumoniae)
- GI manifestations: Chronic/recurrent diarrhoea with malabsorption
- Hematological manifestations: Anaemia
- Renal manifestations: Nephrotic syndrome
- Neoplasia: Non-Hodgkin’s lymphoma (NHL), primary CNS lymphoma, leiomyosarcomas
Acquired immune deficiency syndrome (AIDS)
CD4 count < 200 or an AIDS-defining illness is the criteria for a diagnosis of AIDS.
- Median incubation period (from HIV infection until development of AIDS): 10 years
AIDS-defining infections:
- Fungal infections:
- Candidiasis (M/C fungal infection)
- Pneumocystis jiroveci pneumonia (15-30%)
- Coccidioidomycosis (disseminated or extrapulmonary)
- Cryptococcosis (extrapulmonary, M/C cause of meningitis)
- Protozoal and helminthic Infections:
- Histoplasmosis (disseminated or extrapulmonary)
- Isosporiasis (chronic intestinal)
- Cryptosporidiosis (chronic intestinal)
- Toxoplasmosis (CNS or pneumonia)
- Bacterial infections:
- Mycobacterium avium complex disease (disseminated or extrapulmonary):
- Infection with Mycobacterium kansasii or other species
- Mycobacterium tuberculosis infection (at any site, pulmonary or extrapulmonary) (M/C opportunistic infection)
- Recurrent salmonella septicemia
- Mycobacterium avium complex disease (disseminated or extrapulmonary):
- Viral infections:
- Cytomegalovirus (CMV) (pulmonary, intestinal, retinitis, or CNS infections)
- HIV-related encephalopathy
- Herpes simplex virus (localized or disseminated infection)
- Varicella-zoster virus (localized or disseminated infection)
- Progressive multifocal leukoencephalopathy: John Cunningham virus (JC virus)

- Pneumonia
- Coronary heart disease (M/C CVS manifestation)
- HIV-associated cardiomyopathy: Associated with congestive heart failure (CHF)
- HIV-1-associated nephropathy (HIVAN): Form of Focal segmental glomerulosclerosis (FSGS)
- Persistent diarrhoea: Cryptosporidium, Isospora belli, or microsporidia.
- AIDS-dementia complex (M/C neurological manifestation)
- Inflammatory myopathy (M/C skeletal muscle disorder)

AIDS-defining malignancies:
- Kaposi sarcoma (M/C cancer in AIDS) (human herpesvirus 8 (HHV8) infection)
- Non-Hodgkin’s lymphoma (5%): Burkitt, immunoblastic, or primary lymphoma
- M/C site: CNS: Primary central nervous system lymphoma (histologically DLBCL)
- Invasive cervical cancer

Complications

Diagnosis
Blood investigations:
- Viral load: Blood > semen > vaginal fluid > breastmilk & saliva >> minimal to absent: tears, sweat & urine
- TLC: Leucopenia < 2000/mm3
- Absolute CD4+T cell count < 200/mm3
- Reversed CD4: CD8 cell ratio
- Thrombocytopenia
- ↑ IgG & IgA
- Diminished CMI
Serology:
- First-generation test: IgG antibody
- Second-generation test: IgG antibody
- Third-generation test: IgM & IgG antibody
- Fourth-generation test: IgM & IgG antibody and p24 antigen (allows detection before seroconversion)
ELISA (M/C screening test) or Western blot (M/specific; M/C confirmatory test):
Detects specific antibodies against multiple proteins of all 3 major HIV genes – gag, pol, and env.
- Antibody detection sequence: Envelope gp41 > gag protein (p24 and p55) > envelope gp120 > gag protein p17 > pol gene products (p31 and p66)
- Positive Western blot: Antibodies for 2 of 3 HIV proteins: p24, gp41, and gp120/160
- In case of indeterminate results:
- Repeat testing (in 4–6 weeks) or p24 antigen capture assay, HIV-1 RNA assay, or HIV-1 DNA PCR and specific serologic testing for HIV-2.
p24 antigen assay and PCR: Can detect HIV during window period
- Window period or seronegative infective stage: Period b/w infection & detection of antibodies against HIV
- Highly infectious stage
Cartridge-based nucleic acid amplification test (CBNAAT):
- Detection of TB DNA (sputum microscopy has poor sensitivity for detecting TB in HIV infected people due to fewer organisms in sputum)

Management
Antiretroviral therapy (ART):
Recommended for all individuals with HIV, regardless of CD4 T lymphocyte cell count or clinical stage. ART should be initiated in all pregnant and breastfeeding women living with HIV regardless of WHO clinical stage and at any CD4 cell count and continued lifelong. Exclusive breastfeeding as the infant feeding choice in the first 6 months, irrespective of the fact that mother is on ART early or infant is provided with ARV prophylaxis for 6 weeks.

- Reverse transcriptase inhibitors: Bind and inhibit reverse transcriptase enzyme to intercept the multiplication of HIV.
- Types of inhibitors:
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Nucleoside reverse transcriptase inhibitors (NRTI)
- Types of inhibitors:
- Protease inhibitor: Block functioning of protease enzymes in acutely and chronically HIV-infected CD4 cells resulting in the liberation of immature and noninfectious viral particles.
- Fusion inhibitors: Inhibit the fusion of HIV particles with the CD4 cells and block entry into cell.
- Chemokine receptor antagonist: Blocks chemokine receptor 5 (CCR5) antagonist receptor present on CD4 cells. In the absence of vacant CCR5 receptors, HIV fails to gain entry and infect the cell.
- Integrase strand transfer inhibitors: Prevent integration of viral DNA into host genome of CD4 cells by an integrase enzyme preventing replication.

Agent | Common adverse effects |
---|---|
Nucleoside reverse transcriptase inhibitors (NRTI) | |
Abacavir (Ziagen) |
Hypersensitivity reaction |
Didanosine (Videx EC) |
Pancreatitis, peripheral neuropathy |
Emtricitabine (Emtriva) |
Headache, nausea, vomiting, |
Lamivudine (Epivir) |
Headache, nausea, vomiting |
Stavudine (Zerit) |
Pancreatitis, peripheral neuropathy |
Zidovudine (Retrovir) |
Anaemia |
Lamivudine/abacavir (Epzicom) |
See individual agents |
Zidovudine/lamivudine (Combivir) |
See individual agents |
Zidovudine/lamivudine/abacavir (Trizivir) |
See individual agents |
Nucleotide reverse transcriptase inhibitor | |
Tenofovir DF (Viread) |
Bloating, renal dysfunction |
Nonnucleoside reverse transcriptase inhibitors (NNRTI) | |
Delavirdine (Rescriptor) |
Rash |
Efavirenz (Sustiva) |
Dizziness, impaired concentration, vivid dreams |
Etravirine (Intelence) |
Diarrhoea, rash |
Nevirapine (Viramune) |
Rash |
Protease inhibitors: Fat redistribution & metabolic syndrome | |
Atazanavir/r (Reyataz) |
Hyperbilirubinemia |
Darunavir/r (Prezista) |
Diarrhoea, nausea, vomiting, rash |
Fosamprenavir/r (Lexiva) |
Nausea, vomiting, rash |
Indinavir/r (Crixivan) |
Nephrolithiasis |
Lopinavir/r (Kaletra) |
Gastrointestinal upset, nausea, vomiting |
Nelfinavir (Viracept) |
Diarrhoea |
Ritonavir (Norvir) |
Gastrointestinal upset, nausea, vomiting |
Saquinavir/r, hard gel (Invirase) |
Nausea, vomiting |
Tipranavir/r (Aptivus) |
Diarrhoea, nausea, vomiting, rash |
Other | |
Coreceptor antagonist: maraviroc (Selzentry) |
Nausea, vomiting, rash |
Fusion inhibitor: enfuvirtide (Fuzeon) |
Injection site reactions |
Integrase inhibitor: raltegravir (Isentress) |
Headache, nausea, vomiting |
Multiple-class inhibitors: efavirenz/emtricitabine/tenofovir (Atripla); emtricitabine/tenofovir (Truvada) |
See individual agents |
Post-exposure prophylaxis:
- Tenofovir & Lamivudine for 28 days
Prevention of vertical transmission:
- Zidovudine ± lamivudine (during 2nd trimester to the last few weeks of pregnancy or even only during labor and delivery, and to the infant for a week or less, significantly reduced transmission to the infant)
- Prevent neonatal HIV: Single-dose Nevirapine (to mother during labor) and to the baby (within 72 hours after birth)
- Breastfeeding

Prophylaxis regimens:
- Pneumocystis jiroveci pneumonia: < 200 cells/mm3 (200 × 109/L)
- Trimethoprim/sulfamethoxazole (TMP/SMX) OD
- Alternative: Dapsone 100 mg OD (screen for G6PD deficiency)
- Toxoplasmosis: < 100 cells per mm3 (100 × 109/L)
- Trimethoprim/sulfamethoxazole (TMP/SMX) OD
- Mycobacterium avium complex disease: < 50 cells per mm3 (50 × 109 per L)
- Azithromycin 1,200 mg orally per week
- Cryptococcus neoformans: <100/μL
- Oral Fluconazole
- Cerebral toxoplasmosis: <100/μL
- Trimethoprim/sulfamethoxazole (TMP/SMX)
UNAIDS 90-90-90 program:
The Joint United Nations Programme on HIV and AIDS (UNAIDS) is the main advocate for accelerated, comprehensive and coordinated global action on the HIV/AIDS pandemic.

Summary:

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