Categories
Internal Medicine

HIV/AIDS

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).

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:

CupKHPvWYAAGxUa
Deeks, S. G., Overbaugh, J., Phillips, A., & Buchbinder, S. (2015). HIV infection. Nature Reviews Disease Primers, 1(1), 15035. https://doi.org/10.1038/nrdp.2015.35
cshperspectmed-hiv-006841_f1
Origins of human AIDS viruses. Old World monkeys are naturally infected with more than 40 different lentiviruses, termed simian immunodeficiency viruses (SIVs) with a suffix to denote their primate species of origin (e.g., SIVsmm from sooty mangabeys). Several of these SIVs have crossed the species barrier to great apes and humans, generating new pathogens (see text for details). Known examples of cross-species transmissions, as well as the resulting viruses, are highlighted in red. | Sharp, P. M., & Hahn, B. H. (2011). Origins of HIV and the AIDS pandemic. Cold Spring Harbor perspectives in medicine, 1(1), a006841. doi:10.1101/cshperspect.a006841

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:

mic-03-451-g01
Worldwide distribution of estimated HIV-1 infections in 2014, trends in the incidence of new infections from 2000 to 2014, and HIV-1 subtypes | Numbers and percentages based on UNAIDS fact sheet 2015.

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)
cshperspectmed-hiv-006965_f3
Model of cervicovaginal infection by HIV-1: Preferential R5 HIV-1 transmission is illustrated along with potential roles for Langerhans cells, dendritic cells, and tissue macrophages. Most HIV-1 transmitted/founder viruses replicate efficiently in CD4+ T cells but not in monocyte-derived macrophages (Salazar-Gonzalez et al. 2009; Li et al. 2010), raising questions about the role of macrophages in HIV-1 transmission. Virus-host cell interactions in the initial days of infection have been elucidated primarily in the SIV-Indian rhesus macaque infection model (Haase 2010) and in human tissue explants (Hladik and McElrath 2008) | Pope M, Haase AT 2003. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat Med 9: 847–852

Microbiology

Taxonomy:

  • Retrovirus
  • Genus: Lentivirus
  • Thermolabile
  • Subtypes:
    1. HIV-1 (M/C, worldwide prevalence)
      • Groups/lineages: M (Major) (M/C), (non-M, non-O), (outlier) and (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
    2. HIV-2 (less pathogenic, Western Africa 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
  • Viral envelope:
    • Studded by 2 viral glycoproteins, gp120 and gp41, which are critical for HIV infection of cells.
tmh-0043-0203-g03
Schematic view of the HIV particle, corresponding electron micrograph (right) and immunoblot bands (left). | Gp = Glycoprotein; p = protein; SU = surface protein; TM = transmembrane protein; gp120 (precursor of SU and TM); RT = reverse transcriptase; IN = integrase; CA = capsid protein; MA = matrix protein; PR = protease; NC = nucleic acid binding protein; LI = link protein. MHCs (major histocompatibility complexes) are HLA antigens | German Advisory Committee Blood (Arbeitskreis Blut), Subgroup ‘Assessment of Pathogens Transmissible by Blood’ (2016). Human Immunodeficiency Virus (HIV). Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie, 43(3), 203–222. doi:10.1159/000445852
  • 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
mic-03-451-g04
Different steps of the viral life cycle: The infection cycle begins with the attachment of the envelope (Env) glycoprotein spikes with the CD4 receptor and the membrane-spanning coreceptor (step 1), leading to fusion of the viral and cellular membranes and entry of the viral particle into the cell (step 2). Partial uncoating (step 3) facilitates reverse transcription (step 4), which in turn yields the pre-integration complex (PIC). Following import into the cell nucleus (step 5), PIC-associated integrase orchestrates the formation of the integrated provirus (step 6). Proviral transcription (step 7) yields viral messenger RNAs (mRNAs) of different sizes. Following export (step 8), mRNAs serve as templates for protein production (step 9), and genome-length RNA is incorporated into viral particles with protein components (step 10). Viral-particle budding (step 11) and release (step 12) is accompanied or soon followed by protease-mediated maturation (step 13) to create an infectious viral particle. | Becerra, J. C., Bildstein, L. S., & Gach, J. S. (2016). Recent Insights into the HIV/AIDS Pandemic. Microbial Cell (Graz, Austria), 3(9), 451–475. https://doi.org/10.15698/mic2016.09.529

Entry into T-cell:

gp120 – CD4 binding → conformational change → gp120-CD4 bind to CCR5 (chemokine receptor) → gp41 membrane penetrationmembrane 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.
mic-03-451-g06
Working model of HIV-1 entry: HIV entry is initiated by attachment of gp120 to CD4, which induces a conformational change in gp120. Following engagement of coreceptor, gp120 undergoes further conformational changes that allow for the insertion of the gp41 fusion peptide into the host membrane. The formation of the six-helix bundle brings the host and viral membranes into close proximity and creates a fusion pore, allowing entry of the HIV capsid into the host cell. | Didigu CA, Doms RW. Novel approaches to inhibit HIV entry. Viruses. 2012;4(2):309–324. doi: 10.3390/v4020309.

Pathophysiology

41572_2015_article_bfnrdp201535_fig1_html
HIV infection and AIDS | Deeks, S. G., Overbaugh, J., Phillips, A., & Buchbinder, S. (2015). HIV infection. Nature Reviews Disease Primers, 1(1), 15035. https://doi.org/10.1038/nrdp.2015.35

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:

who-hiv-staging-1-3
WHO clinical staging of HIV/AIDS

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
  • 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)
869a3a46e3434d03b970bbb582ae0d4dx733x668
  • 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)
afp20170801p161-fb
Computed tomography image of Staphylococcus aureus necrotizing pneumonia in a patient with human immunodeficiency virus infection. The arrow indicates extensive left upper lobe consolidation with rim-enhancing cavitary lesions and air-fluid levels, and multiple septations. | Chu C, Pollock LC, Selwyn PA. HIV-Associated Complications: A Systems-Based Approach. Am Fam Physician. 2017;96(3):161–169.

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
nihms-1037079-f0005
Clinical manifestations of KS: Different manifestations of Kaposi sarcoma (KS) include (part a) macular lesions on the back and nodules on the arm; (part b) extensive KS plaques on the legs with tumour-associated oedema; (part c) exophytic KS lesions on the foot; (part d) extensive gingival KS nodules; and (part e) flat, violaceous lesions on the hard palate. The image in part c is of a patient with classic KS; all other images are of patients with AIDS-related KS. | Cesarman, E., Damania, B., Krown, S. E., Martin, J., Bower, M., & Whitby, D. (2019). Kaposi sarcoma. Nature Reviews. Disease Primers, 5(1), 9. https://doi.org/10.1038/s41572-019-0060-9

Complications

afp20110215p395-t1
Chu, C., & Selwyn, P. A. (2011). Complications of HIV infection: a systems-based approach. American family physician, 83(4), 395–406.

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)
nihms15115f4
The course of HIV-1 infection defined by the level of viral replication: Plasma viraemia (top), and dynamic changes of the CD4+ T-lymphocyte compartments (bottom). Primary infection characterised by high plasma viraemia (red line, top), low CD4 cells (green line, bottom), and absence of HIV-1 specific antibodies (orange line, bottom). Viraemia drops as cytotoxic CD8+ T-lymphocytes (CTL) develop (blue line, bottom) and an individual viral-load set point is reached during chronic infection. Viral set points dir er greatly among individuals (eg, red dotted line, top) and predict disease progression. Viral diversity increases through out the disease (closed circles, top). The risk of transmission is highest in the first weeks when viraemia peaks (closed circles, top). | GALT=gut-associated lymphoid tissues. | Simon, V., Ho, D. D., & Abdool Karim, Q. (2006). HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet (London, England), 368(9534), 489–504. https://doi.org/10.1016/S0140-6736(06)69157-5

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.
mic-03-451-g05
The course of untreated HIV infection and changes after antiretroviral therapy: In untreated HIV infection the blood CD4 T cell count progressively declines over the course of infection (A). After initiation of antiretroviral therapy the HIV RNA copy numbers significantly decrease below detection limit followed by recovery of CD4 T cells, which can vary notably between individuals (B). | Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet. 2014;384(9939):258–271. doi: 10.1016/S0140-6736(14)60164-1.
  • Reverse transcriptase inhibitorsBind 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)
  • Protease inhibitorBlock 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.
nrdp201535-f4
The HIV life cycle | Deeks, S. G., Overbaugh, J., Phillips, A., & Buchbinder, S. (2015). HIV infection. Nature Reviews Disease Primers, 1(1), 15035. https://doi.org/10.1038/nrdp.2015.35
AgentCommon adverse effects

Nucleoside reverse transcriptase inhibitors (NRTI)

Abacavir (Ziagen)

Hypersensitivity reaction

Didanosine (Videx EC)

Pancreatitis, peripheral neuropathy

Emtricitabine (Emtriva)

Headache, nausea, vomiting, pregnancy

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:

41572_2015_article_bfnrdp201560_figa_html
Deeks, S. G., Overbaugh, J., Phillips, A., & Buchbinder, S. (2015). HIV infection. Nature Reviews Disease Primers, 1(1), 15035. https://doi.org/10.1038/nrdp.2015.35

One reply on “HIV/AIDS”

Leave a Reply