HIV Flashcards
HIV structure & classification
Family: Retroviridae
Subfamily: Lentiviridae
Genus: Lentivirus
2 segments of (+)ssRNA whose replication involves RNA-dependent DNA synthesis via reverse transcription.
Baltimore: VI
Capsid core with lipid enveloped derived from host.
Viral glycoproteins: gp120 surface and gp41 transmembrane.
HIV genes and proteins coded
- Structural proteins:
A. gag- Matrix, Capsid, Nucleocapsid
B. env- Surface envelope glycoproteins (gp 120) binds CD4
& Transmembrane envelope glycoprotein (gp 41)
C. pol - Rt, integrase, protease
- Regulatory proteins:
A. tat - trans-activator of transcription - transcription
B. rev - Regulator of virion protein expression - post transcriptional regulation and exposure of viral RNA from nucleus.
HIV subdivisions
HIV 1: 4 lineages M,N,O,P
M group divided into 9 subtypes: A,B,C,D,F,G,H,J,K
HIV 2: 9 lineages A to I
Most common HIV subtype globally
C - 42%
HIV CRF
Circulating recombinant form - hybrid of 2 subtypes
HIV life cycle
Infection of cells mediated by gp120 envelope glycoproteins.
Receptor- T cells have CD4 receptors - lymphocytes, monocytes, macrophages.
Other receptors used - CCR5 and CXCR4 - CCR5 inhibitors useful here.
Once HIV binds to CD4 + other receptors, gp41 fuses the virus and it enters into the cytoplasm - fusion inhibitors useful here.
In the CYTOPLASM, RNA undergoes reverse transcription to ssDNA and then to dsDNA. dsDNA forms a complex with the viral and host proteins and is transported to the nucleus.
dsDNA integrates into host genome by DNA splicing by viral integrase or forms DNA circles.
The integrated virus is called PROVIRUS. Transcription of viral RNA occurs by host RNA polymerase. Mature virions are assembled.
HIV protease is activated and is needed for viral maturation - encapsulation of the viral proteins.
Elite controller
A small subset of individuals exhibit persistently low plasma HIV RNA levels less than 50 copies/mL without ART.
High proportion of HLAb 5701 -65%- seen in this cohort - CD8 T cell driven viral control.
CD4 counts every 6 months & VL 6-12 months.
BHIVA recommends ART given low level viral replication if:
- Declining CD4
- Inverted CD4:8 ratio
- Any HIV related complications
- Coinfection with HBV,HCV, or HTLV
- Significant comorbidities including cancer
- Immunosuppression
- Pregnancy
Berlin & London patients
Underwent HSCT with a donor homozygous for delta 32 CCR5 mutations - leads to lack of CCR5 expression on cells.
Berlin patient has undetectable for 10 years - then started PrEP, so don’t know longer term outcome.
HIV testing window periods
Based on 99th percentile
4th gen - 45 days
3rd gen - 60 days
POCT - Determine HIV1/2 (3rd gen), INSTI HIV1/2, Oraquick Rapid HIV1/2 antibody test - 90 days
HIV screening assays timings
Infection - D0
RNA - D10
P24 capsid antigen - D14 to D20
IgM (EIA/CLIA) - D20 to D23
IgG (EIA/CLIA) - D28 onwards
HIV avidity
Offered by Colindale for suspected recent infections
HIV reporting
SEE ALBUM
HIV assay generations
1 through 5 - see ALBUM
HIV screening SMI algorithm
Diagnosis should be made on 3 CE (UKCA from 2025!) marked 4th gen assays in an ISO 15189 lab.
2 CE marked 4th gen test should detect HIV1/2 and a 3rd CE marked test should differentiate HIV 1 vs 2 (typing).
See ALBUM
HIV-1 usual regimens
Usual:
1. Dolutegravir (II)+ emtricitabine (NRTI)/tenofovir AF (NRTI) OR
Dolutegravir + emtricitabine/tenofovir DX
Bone/renal caveats for tenofovir DX
- Dolutegravir (II)/lamivudine (NRTI)
No baseline resistance, VL < 500k, CD4 > 200
- Dolutegravir (II)/lamivudine (NRTI)/abacavir (NRTI)
HLAB5701 negative and QRISK < 10%
HIV-1 regimen in drug resistance, Rapid ART, and High VL
- Standard genotyping resistance testing for RT and protease for all ART naive patients.
Baseline integrase resistance if suspicion of transmitted resistance or pregnancy or other mutations identified.
Regimen: Tenofovir + lamivudine/emtricitabine + dolutegravir/bictegravir/boosted darunavir
- SAME REGIMEN FOR RAPID ART (When there is no time for baseline resistance testing).
- SAME REGIMEN FOR HIGH VL
HIV1 TWO drug regimen in virological suppression
- Dolutegravir (II) + lamivudine (NRTI)
- Dolutegravir (II) + rilpivirine (NNRTI)
- Darunavir (B PI)+ lamivudine (NNRTI)
Injectables:
Cabotegravir (II)+ rilpivirine (NNRTI)- 2 monthly injections and 2 monthly VL monitoring
BMI < 30
NON A1/6 subtypes if baseline resistance unavailable
HIV ART classes
8 main types SEE IMAGE IN ALBUM
- NRTI- inhibit RT
Used as backbone
Abacavir
Tenofovir
Emtricitabine
Zidovudine
Lamivudine
- NNRTI - inhibits RT
Efavirenz
Nevirapine
Rilpivirine
Doravirine
- Integrase inhibitors
Dolutegravir
Cabotegravir
Bictegravir
Raltegravir
- Protease inhibitors
Darunavir
Atazanavir
Lopinavir - only available as Lopinavir/ritonavir
- Boosters
Ritonavir
Cobicistat
- Entry inhibitors& fusion inhibitors
CCR5 inhibitors - Maraviroc
gp41 fusion inhibitor - Enfuvirtide
Leronlimab- anti CCR5
- Post attachment inhibitor
Ibalizumab - anti CD4 antibody
- Capsid inhibitor
Lenacapavir
HIV1 treatment - suppression vs blips vs failure vs IVR vs rebound
Suppression - achieving & manyinaijg undetectable VL (below LL detection).
IVR - VL>200 on 2 consecutive tests >24 hours after ART.
Rebound - failure to maintain undetectable VL on 2 consecutive tests.
Blip - single VL 50-200 followed by undetectable is not cause for concern
Low level Viraemia or recurrent blips - resistance testing
Failure - VL > 200 - resistance testing
HIV-2 treatment
2 NRTIs + integrase inhibitor or boosted PI
Preferred - Tenofovir DX + emtricitabine + Dolutegravir OR Darunavir (r)
Abacavir + lamuvidine + Dolutegravir OR Raltegravir
NNRTIs - intrinsic resistance
HIV PrEP
Tenofovir + Emtricitabine preferred for ongoing risk.
HIV testing every 3 months while on PrEP.
PrEP stopped if HIV infection, HBV co infection, suboptimal adherence.
NEW:
MHRA in May 2024 approved two new formulations of the medicine cabotegravir (Apretude 30 mg film-coated tablets and Apretude 600 mg prolonged-release suspension for injection) for PrEP.
Cabotegravir 600 mg long-acting injection is administered by a nurse or doctor into the buttock muscle six times a year. Initially, patients receive one injection each month for two months, followed by one every two months. Before starting the injections, patients can take cabotegravir 30 mg tablets daily for a month in consultation with their doctor to assess whether it’s appropriate to proceed with injections (oral lead-in).
HIV PrEP efficacy
TDF-FTC - 86% in IPERGAY randomised double blinded placebo controlled trial in MSM.
Also 86% in the PROUD study in the UK - randomised open label study.
Cabotegravir PrEP efficacy
two main studies that compared cabotegravir to standard PrEP (tenofovir disoproxil fumarate/emtricitabine) for preventing HIV over a period of approximately 3 years (153 weeks). In one study involving around 4,500 HIV-negative cisgender men and transgender women who have sex with men, there was a 66% reduction in HIV-1 incidence among those who received cabotegravir compared to the standard treatment. In the second study, involving over 3,200 HIV-negative cisgender women, there was an 88% reduction in HIV-1 incidence among those taking cabotegravir compared to standard PrEP.
HIV ART in pregnancy
tenofovir DF or abacavir with emtricitabine or lamivudine as a nucleoside backbone.
It is recommended that the third agent in cART should be efavirenz or atazanavir/r, as these are agents with the most safety data in pregnancy.
Rilpivirine (25 mg od), raltegravir (400 mg bd) or darunavir/r (600/100 mg bd) may be used as alternatives.
• As soon as they are able to do so in the second trimester where the baseline viral load ≤30,000 HIV RNA copies/mL;
• At the start of the second trimester, or as soon as possible thereafter, in women with a baseline viral load of 30,000–100,000 HIV RNA copies/mL;
• Within the first trimester if viral load >100,000 HIV RNA copies/mL and/or CD4 cell count is less than 200 cells/mm3 .
All women should have commenced cART by week 24 of pregnancy.
Management of an untreated woman presenting in labour at term.
• All women should be given a stat dose of nevirapine 200 mg;
• and commence oral zidovudine 300 mg and lamivudine 150 mg bd;
• and raltegravir 400 mg bd;
• and receive intravenous zidovudine for the duration of labour.
HIV pregnancy modes of delivery & breast feeding
- VL < 50 @ 36 weeks - normal
- 50-400 @ 36 weeks - consider LSCS
- > 400 @ 36 weeks - LSCS
Formula feeding recommended. Women who are virologically suppressed on cART with good adherence and who choose to breastfeed should be supported to do so, but should be informed about the low risk of transmission of HIV through breastfeeding in this situation and the requirement for extra maternal and infant clinical monitoring.
HIV RNA viral load testing during and for 2 months after stopping breastfeeding.
Indications for intrapartum zidovudine
- Untreated HIV
- VL > 1000
- Consider in VL 50-1000
Neonatal HIV PEP
- Very low risk - mum has been on 10 weeks ART, has 2 VL < 50 4 weeks apart one of which is @ or after 36 weeks
Zidovudine for 2 weeks
- Low risk - Prem but mum’s VL < 50 or if doesn’t fully fit criteria for very low
Zidovudine for 4 weeks
- High risk - mum’s VL > 50
Zidovudine + lamivudine + nevirapine for 4 weeks
HIV2 PEP in neonate
Zidovudine + lamivudine + raltegravir
Nevirapine - intrinsic resistance
Neonate HIV testing
PCR:
<48 hours & before discharge
2 weeks - HIGH RISK
6 weeks
12 weeks
BREASTFED:
Monthly if breast fed
4 & 8 weeks after cessation of BF
Antibody:
At birth
24 months for seroconversion
Adjunct testing in HIV
- HLAB5701 screening for abacavir
- CD4 counts
- CD8 counts
- Lipid profile
- Bone profile
- Co-receptor tropism if using maraviroc
FLAIR trial
Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection
Phase III randomized, open-label trial
Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir–abacavir–lamivudine with regard to maintaining HIV-1 suppression.
Lenacapavir
Capsid inhibitor by Gilead
Not used routinely in the NHS due to cost concerns
3 major trials:
- CAPELLA - Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. Phase III RCT.
In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo.
- CALIBRATE - Study to Evaluate the Safety and Efficacy of Lenacapavir in Combination With Other Antiretroviral Agents in People Living With HIV (CALIBRATE)
A Phase 2 Randomized, Open Label, Active Controlled Study
At week 54, viral suppression was similar across the four study arms, ranging from 85% in the two-drug treatment arms to 92% in the control arm.
- PURPOSE 1
Phase 3, Double-Blind, Multicenter, Randomized Study
evaluating the safety and efficacy of twice-yearly, subcutaneous lenacapavir for pre-exposure prophylaxis (PrEP) and once-daily oral Descovy® (emtricitabine 200mg and tenofovir alafenamide 25mg; F/TAF) in more than 5,300 cisgender women and adolescent girls aged 16-25 across 25 sites in South Africa and three sites in Uganda
GILEAD PRESS RELEASE JAN 2024 - Independent Data Monitoring Committee Recommended That Gilead Stop the Blinded Phase of the PURPOSE 1 Trial at Interim Analysis and Offer Open-Label Lenacapavir to All Participants
PURPOSE 2 - Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection
Phase 3, Double-Blind, Multicenter, Randomized Study in Cisgender Men, Transgender Women, Transgender Men, and Gender Nonbinary People ≥ 16 Years of Age Who Have Sex With Male Partners and Are at Risk for HIV Infection.
HIV1 ONLY injectable regimen
Cabotegravir (II)+ rilpivirine (NNRTI)- 2 monthly injections and 2 monthly VL monitoring
BMI < 30
NON A1/6 subtypes if baseline resistance unavailable
