HIV/AIDS

Question 1

HIV and AIDS

Answer 1

• HIV = retrovirus
• AIDS = CD4+ count <200 in a patient with HIV

Question 2

AIDS defining diseases

Answer 2

AIDS = CD4+ count < 200 in a patient with HIV
- candidiasis (Candida albicans fungus) of esophagus
- Cryptococcus (Cryptococcus neoformans fungus), extrapulmonary, no ring enhancing lesions
- Cytomegalovirus (beta Herpes)
- Kaposi’s sarcoma (HHV-8)
- Mycobacterium avium complex (MAC, mycobacteria)
- Pneumocystis jirovecii (fungus), crushed ping pong balls, glass in lungs
- progressive multifocal leukoencephalopathy (JC virus, polyomavirus), brain lesions (non-ring enhancing)
- toxoplasmosis of brain (Toxoplasma gondii parasite), multiple ring enhancing lesions

Question 3

HIV testing

Answer 3

HIV screening test:
- HIV-1 antigen/antibody immunoassay
- negative result = negative for HIV-1 & HIV-2 antibodies and p24 antigen
- negative test at day 45 after exposure excludes HIV infection from that exposure
- eclipse phase: undetectable viral load for ~10 days following infection
- false positives due to: pregnancy, autoimmune disorders, recent viral infection/vaccination

current recommendations:
- opt out screening for patients aged 13-64
- high risk persons should be screened annually

Question 4

HIV genome/structural proteins

Answer 4

pol: polymerase
- protease
- reverse transcriptase
- integrase
- target of most HIV drugs

gag: Pr55
- matrix protein: p17
- capsid protein: p24
- nucleocapsids

env: gp160 envelope protein
- cleaved in endoplasmic reticulum to gp120 and pg41
- gp120 attaches to host CD4+ T-cells
- gp41 assists in fusion and entry

Question 5

HIV pathogenesis

Answer 5

• founder HIV enters through mucosal surface and binds to CD4+ cells (helper T-cells, macrophages in tissues, dendritic cells in mucosa)
• infection concentrated in lymphoid tissues ==> explosive growth and high load ==> hematogenous spread
• clinical latency stage: virus mainly replicates within lymph nodes
• asymptomatic/early HIV infection is characterized by a gradually declining CD4+ T-cell count
• symptoms with chronic infection appear when CD4 count gets closer to 200 cells/mm3 ==> Acquired immunodeficiency syndrome (AIDS) after ~10 years

Question 6

HIV tropism

Answer 6

CD4+ and co-receptor are both needed:
- early in infection: bind to CD4 and CCR5 co-receptors on macrophages and dendritic cells; M-tropic virus
- late in infection: bind to CD4 and CXCR4 co-receptors on T-cells; T-tropic virus

Question 7

HIV therapy

Answer 7

Typically treat with 2 NRTIs + 1 other drug (usually a protease inhibitor)
- NRTI: competitively inhibits nucleotide binding to reverse transcriptase and terminates production of dsDNA
- NNRTI: binds to reverse transcriptase and denatures it
- PI: blocks new HIV from being cut into smaller proteins and reassembly
- integrase inhibitor: inhibits HIV integrase and prevents HIV genome integration into host CD4 cell

Question 8

NRTIs

Answer 8

NRTI = nucleoside reverse transcriptase inhibitor
- reverse transcriptase from “pol” gene
- Abacavir: hypersensitivity reaction if HLA-B*5701 positive
- Tenofovir (nucleotide): nephrotoxicity
- Zidovudine (AZT): causes myelosuppression

Question 9

NNRTIs

Answer 9

NNRTI = non-nucleoside reverse transcriptase inhibitor
- reverse transcriptase from “pol” gene
- Efavirenz: causes vivid dreams and CNS symptoms
- Doravarine
- Rilpivirine

Question 10

Protease inhibitors (PIs)

Answer 10

PIs: end in “-navir” (“navir (never) tease a protease)
- protease from “pol” gene
- Atazanavir, Lopinavir, Darunavir
- Ritonavir: can inhibit cyt P450 system and increase various other drug concentrations
- another side effect is lipodystrophy: lipohypertrophy (fat accumulation) or lipoatrophy (loss of fat)
- PIs will increase drug absorption and delay metabolism of other drugs; used in combination w other anti-HIV drugs

Question 11

Integrase inhibitors

Answer 11

integrase inhibitors: end in “-tegravir”
- from “pol” gene
- Raltegravir, Elvitegravir, Dolutegravir, Bictegravir
- side effects: increased creatine kinase (myopathy), weight gain

Question 12

Fusion/Entry inhibitors

Answer 12

Fusion/entry inhibitors:
- Enfuvirtide (T-20)
- Maraviroc

Enfuvirtide:
- binds to gp41, preventing viral fusion/entry
- side effect: skin reaction (sterile skin abscess formation in ~80% at site)

Maraviroc:
- unique MOA: binds to CCR5 and inhibits interaction with gp120
- “Maraviroc inhibits docking”
- side effects: hepatotoxicity

Question 13

HIV drugs mechanism of resistance

Answer 13

many mutations in HIV:
- RT replication errors (RNA => DNA), since there is no proofreading mechanism
- 1 mutation generated for each new genome of ~10,000 nucleotides
- risk of resistance increases with each missed dose

Question 13

HIV lab monitoring

Answer 13

HIV viral load (VL):
- goal to get < 20 copies/mL (undetectable)
- should see at least 1 log decrease during the 4-6 weeks between baseline and follow-up visit
- lack of decrease in VL is most likely due to poor compliance/adherence with medications

CD4 count:
- responds less quickly than VL
- large variation in response
- generally, pt should gain 100 to 150 CD4 cells during first year