HIV Flashcards
How is HIV monitored?
Viral load and CD4 count
- Viral load predicts the rate of disease progression
- CD4 correlates with immune function
What cells does HIV target?
CD4 cells = T lymphocytes (T helper cells), macrophages, monocytes, dendritic cells
Greatest concentration of cells in gut associated lymphoid tissue (GALT)
In HIV, what proteins are coded by the pol gene?
Polly is a Really Important Person:
- Reverse Transcriptase: converts viral RNA to dsDNA
- Protease: cleavage of gag and gag-pol proteins during maturation of the virus
- Integrase: helps insert the viral genes into the host genome
The gag gene codes for gag protein which consists of:
Matrix protein (p17 protein) Nucleocapsids Capsid proteins (p24 protein)
The components of the env gene in HIV
env gene codes for gp160 which gets cleaved into envelope glycoproteins
- gp120 allows HIV to attach to CD4+ T cells
- gp41 assist in fusion and entry of the virus into the host cell
How does HIV attach to human cells?
HIV uses gp120 and gp41 to first attach to CD4 molecules and then either CCR5 or CXCR4 on the surface of human cells.
gp120 binding to coreceptors change during the course of untreated infection
- During early HIV, gp120 only binds to the CCR5 chemokine receptor.
- Later mutant HIV strains that can also bind to the CXCR4 chemokine receptor.
- HIV strains that can bind to CCR5 or CXCR4 replicate more rapidly and deplete CD4 cells faster.
- Absence of CCR5 on the surface of human cells prevents HIV attachment and infection (homozygous for the pair deletion in the gene for CCR5 coreceptor)
- HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on target cells with its gp120 glycoprotein (binding)
▪ Cells that have CD4 receptors: T lymphocytes (e.g., T helper cells), macrophages, monocytes, dendritic cells. - 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
What gene is associated with slower progression from HIV to AIDs
HLAB*57.01 is associated with slower progress to AIDs
HLAB57.01 essential for HIV viral replication.
HLA-B*5701-positive patients have a strongly increased risk of a delayed hypersensitivity reaction to abacavir
What do broadly neutralising antibodies do in HIV?
They target the gp41-gp120 envelope protein
When should antiretroviral therapy be commenced for HIV?
As soon as possible regardless of CD4 count
Which antiretroviral drugs do not target both HIV-1 and HIV-2
All antiretroviral drugs are able to target both HIV-1 and HIV-2, except for enfuvirtide and NNRTIs
MOA of nucleoside reverse transcriptase inhibitors (NRTI) and examples, SE
NRTI - “vudine’”
Bind to viral reverse transcriptase at deoxynucleotide binding site, blocking DNA synthesis. Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Low barrier to resistance for lamivudine and emtracitabine.
A genetic barrier to resistance can be defined basically as the number of mutations required to confer resistance. For instance, NNRTIs have a low genetic barrier as a single mutation can cause resistance to most agents, whereas PIs have a high genetic barrier as multiple mutations are required.
Examples:
- Zidovudine*: lipodystrophy (abnormal distribution of fat like cushing), metabolic toxicity, GI side effects, bone marrow suppression (anaemia especially zidovudine)
- Lamivudine (none)
- Emtrcitabine (none)
- Abacavir: hypersensitivity test for HLAB5701, CVD risk
- Tenofovir disoproxil fumarate*: nephrotoxicity (proximal tubular dysfunction, ATN), reduced BMD
- Tenofovir alafenamide*: formulated to cause less nephrotoxicity
MOA of nonnucleoside reverse transcriptase inhibitors (NNRTI) and examples, SE
Also bind viral RT but not at deoxynucleoside binding site, alter conformation of enzyme blocking DNA synthesis. Low barrier to resistance. NNRTIs do not require intracellular phosphorylation for activation but are instead direct inhibitors.
Examples:
- Nevirapine*: hypersensitivity reactions including fatal hepatitis (hepatoxicity)
- Efavirenz*: CNS SE In 1st few weeks - sedation/insomnia, vivid dreams, other neuropsych SE, increased LFTs, lipids
- Rilpiverine: can prolong QTC
- Delaveridine: rash (usually treat through), headache
- Etravine: rash (usually treat through), GI SE
- Doravirine
MOA of protease inhibitors and examples + SE
“-navir”
Blocks viral protease preventing maturation of virus during and after budding of virion leading to the production of defective virus. High barrier to resistance when boosted.
SE for all: GI SE (nausea, diarrhoea), metabolic SE - dyslipidaemia, impaired glucose tolerance (inhibit GLUT4), lipodystrophy
Can cause nephrolithiasis, crystal induced nephropathy, haematuria
- Ritonavir: poorly tolerated, only used to “boost” other PI by inhibiting CYP3A4/cytochrome P450
- Lopinavir
- Atazanaivr: elevated bilirubin, rarely renal stones
- Darunavir: rash (usually treat through)
Indanivir: thrombocytopenia
MOA of integrase inhibitors, examples and SE
- “gravir”
Inhibit viral integrase preventing integration of viral DNA into host DNA. Leads to rapid reduction in viral load. Low barrier to resistance for raltegravir but high for dolutegravir. - Raltegravir: increas CK, cases of rahbdo
- Elvitegravir: co-formulation with CYP3A4 inhibitor cobicistat
- Dolutegravir: headache, depression/anxiety, small increase in neural tube defects
- Bictegravir: headache, GI SE, avoid dofetilide
MOA of entry inhibitors, examples, SE
- Hetereogenic class of antiretroviral drugs that inhibit binding or fusion of HIV virions with human cells.
- Enfuvirtide (fusion inhibitor): competitively binds to the viral protein gp41 and thereby prevents fusion with the cell
Side Effects: skin irritation at the site of drug injection - Maraviroc (CCR5-antagonist): blocks the CCR5 coreceptor on T cells and monocytes that is essential to cell infection; for some HIV genotypes (R5 HIV-1) → inhibits gp120 interaction → prevents virus docking
Side Effects: hepatotoxicity, allergic reactions
What are preferred regimes for HIV?
Integrase inhibitor + 2x NRTI
- Biktarvy: bictegravir, tenofovir alafenamide, emtricitabine
- Genvoya: Elvitegravir, cobicistat, tenofovir alafenamide, embtricitabine
- Stibild: Elvitegravir, cobicistat, tenofovir disoproxil, emtrictabine
Drugs to avoid combining
Combinations that should be avoided (due to increased toxicity and/or insufficient/antagonistic effects
- Tenofovir + abacavir
- Lamivudine + emcitrabine
- Stavudine + didanosine
- Tenofovir + didanosine
- Stavudine + zidovudine
Hepatotoxic drug - nevirapine are contraindicated in coinfection with HBV + HCV
A surgeon receives a needle stick injury to his index finger during an operation on an HIV-infected patient. Which of the following would increase the risk of transmission of HIV to the surgeon?
A. The surgeon wearing two sets of gloves
B. Anti-retroviral post-exposure prophylaxis
C. HIV-infected patient taking anti-retroviral therapy
D. Needle stick injury with a hollow-bore needle compared to a solid suture needle
E. Washing the puncture site with water and alcohol-based antiseptic
D. Needle stick injury with a hollow-bore needle compared to a solid suture needle
What are the indications and drugs used for PREP (pre-exposure prophylaxis)
Eligibility:
- Negative HIV test result and no signs or symptoms of acute HIV infection
- Normal renal function test
- Fulfillment at least one indication criteria
Indications
- Men who have sex with men
Any anal sex without condoms in the past 6 months
A bacterial STI (syphilis, chlamydia, or gonorrhoea) diagnosed or reported in the past 6 months
- Heterosexual men and women
Sexually active with an HIV positive partner
Inconsistent or no condom use during sexual activity with one or more sexual partners of unknown HIV status
A bacterial STI in the past 6 months
- Intravenous drug users with high-risk needle behaviour (e.g., sharing needles/equipment) or HIV positive injection partner
Timing: Prior to the exposure to HIV and continued for a month after the exposure, can be on it for a very long time so investigations are more thorough.
Drugs
- Emtricitabine + tenofovir disoproxil fumarate (TDF-FTC) once daily
Follow-up
- HIV test every 3 months
- Renal assessment at baseline and every 6 months
Counseling on adherence and risk reduction
What investigations will need to be checked for patients on PREP.
Baseline
- HIV serology + viral laod
- Hep B+C
- Syphillis
- STI check 3 sites
- FBC/creatinine/LFTs/CK
- egFR
- Urine albumin/creatinine ratio
- Pregnancy test if applicable
Check 90 days after initiation and every 90days - HIV serology, syphilis serology - Asssess SE - STI check 3 sites eGFR + ACR
eGFR and ACR every 6 months
Hep C every 12 months
Indications for PEP and medications used
HIV Post-Exposure Prophylaxis (PEP)
- oPEP - occupational post exposure prophylaxis
- nPEP - non-occupational post exposure prophylaxis
Indications
- Injury with HIV-contaminated instruments or needles
- Contamination of open wounds or mucous membranes with HIV-contaminated fluids
- Unprotected sexual activity with a known or potentially HIV-infected person
Timing: Initiate as soon as possible (ideally within one to two hours after exposure)
- Drugs: A three-drug regimen is recommended (similar to cART treatment). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor
- Start within 72 hours, 28 days.
If >72 hours, need to monitor, not for PEP
- 2 Drug Therapy (if risk <1/1000 and >1/10,000): NRTI Backbone: Tenofovir + Emtricitabine or Lamivudine
- 3 Drug Therapy (if risk >1/1000): 2 drug backbone preference and either dolutegravir daily, raltegravir BD Tenofovir-emtricitabine + dolutegravir
Tenofovir-emtricitabine + raltegravir
Investigations for PEP
Baseline:
- HIV serology + viral load
- Hep B, C, syphillis
- TI check 3 sites
- FBC, Creatinine, LFTs, CK
- Pregnancy test
4-6 weeks
- HIV serology + viral load
- Syphilis serology
- STI check 3 sites
- Cr, LFTs
3 months
- HIV serology + viral load
- Syphilis serology
- STI check 3 site
What is the medication used for HIV post exposure prophylaxis in neonates?
Zidovudine
In pregnant patients where the viral load is >1000/unknown viral load /poor adherence to ARV therapy, when do you deliver?
C section should be scheduled at 38 week and IV zidovudine administered 3 hours before caesarean.
For infant prophylaxis they require cART for 6 week
2 drug: zidovudine + nevirapine
3 drug: zidovudine + lamivudine + either nevirapine or raltegavir
Breastfeeding generally avoided as risk of transmission is 5-20%
Diagnosis of infants: if <18 months, diagnosis is confirmed via PCR not ELISA.
