HIV Flashcards
What are examples of human retroviruses?
Retriviral DNA exists in human genome as product of evolution. Does not produce infectious virus
Family - retrovirus Sub-family - orthoretrovirinae Genus - lentivirus Species - HIV1 HIV2 - West Africa, less virulent
Family - retrovirus
Sub-family - orthoretrovirinae
Genus - deltavirus
Species - HTLV1/ HTLV2 - West Indies/ Japan.
Also known has tropical spastic paraparesis. T- cell leukaemia
What is structure of HIV virus
GP41/ GP120 envelope glycoproteins
Lipid mebrane - host derived
Matrix protein p17
Single stranded RNA
RT
Integrase
Virion core proteins - p7, p9, p 24
HIV nuclear material is two copies of positive sense SS RNA.
It codes for virion proteins/ regulatory proteins.
What virion proteins does it code for?
LTR
gag
pol
env
HIV nuclear material is two copies of positive sense SS RNA.
It codes for virion proteins/ regulatory proteins.
What regulatory proteins does it code for?
nef
rev
tat
vif
vpr
vpu
What do these HIV virion proteins code for?
LTR
gag
pol
env
LTR - long terminal repeat promotes transcription/ replication
gag - virion core proteins -
- p7
- p9
- p17 - matrix
- p24 - nucleocapsid
pol - RT, integrase, protease
env - gp160 glyocprotein which is cleaved into gp120 and gp41
gp 41 and gp 120 formed from env gene.
What are their roles?
gp 120 - attachment protein
gp 41 - fusion protein
What do these HIV regulatory proteins code for?
nef
rev
tat
nef - negative regulatory factor - important for virulence
rev - promote export viral RNA from nucleus
tat - transactivator protein regulates viral transcription
What do these HIV regulatory proteins code for?
vif
vpr
vpu
What do these HIV regulatory proteins code for?
vif - virion infectivity factor
vpr - weak transcriptional activator
vpu - for efficient budding
What is replication cycle of HIV?
Absorption of HIV gp120 onto CD4 cell Fusion via GP41 Penetration Uncoating Reverse transcription of positive sense ssRNA into DNA Integration into host DNA - now provirus
Transcription of viral mRNA and progeny RNA
Translation of viral proteins
Assembly of virions
Budding via envelope proteins
HIV also binds to dendritic cells/ macrophages, which transport to lymph nodes, which helps spread infection to other CD4 cells
Most CD4 cells die. Only few survive to continue HIV virion production
HIV-2 confined to West Africa, originally zoonosis from sooty mangabeys
HIV-1 has different groups, what are they?
During transmission from chimpanzees, groups evolved.
M - major. 90% of cases, worldwide distribution. Emerged between 1910-1930 in West Africa
N - new. West Africa. Very rare
O - outlier. West Africa
P - only one case ever
HIV1 group M (major), has further subtypes, based on geographical spread. What are they?
Subtype A: Central and East Africa, Eastern Europe
Subtype B: West and Central Europe, the Americas, Australia, South America, and several southeast Asian countries (Thailand, and Japan), as well as northern Africa and the Middle East. Most common in UK
Subtype C: Sub-Saharan Africa, India, and Brazil.
Subtype D: North Africa and the Middle East.
Subtype F: South and southeast Asia.
Subtype G: West and Central Africa.
Subtypes H, J, and K: Africa and the Middle East
CRF - circulating recombinant types, due to recombination between different subtypes
HIV virus uses gp120 to bind to CD4 receptor on which cell types?
T-helper cell Monocyte Dendritic cell Langerhans cell Microglia
HIV virus binds gp120 to CD4. What other receptors are required for entry?
chemokine co-receptor CCR5 absolutely required
CXCR4 co-receptor is also desired by virus
If CCR5 gene deletion, host can be resistant to HIV progression- elite controllers 0.3%.
Once infected Th rests in lymphoid tissue, it can continue to produce new virions. If Th cell becomes activated, cell will die.
What is immune response to HIV infection?
CD8 T cells which kill infected cells
B cells produce antibodies directed towards infected cells
CD4 Th cells directly killed by virus, undergo apoptosis, damaged by CD8/ B cells
As Th count decreases, immune response wanes, and HIV load rises
Why does having another STI increase risk of HIV transmission?
Other STIs cause genital ulcers/ discharge, which can provide route for HIV transmission
Uncircumcised males more likely to be affected
What are transmission routes of HIV?
Blood transfusion - haemophiliacs
IVDU/ tattoo/ accupuncture/ needlestick
Sex
Vertical - up to 50% of HIV mothers will pass on to children (if untreated). Avoid breast-feeding, perform C-section
What are initial symptoms of HIV infection?
fever
malaise
maculopapular rash
lymphadenopathy
Can invade CNS and cause self-limiting aseptic meningitis
After initial HIV exposure, what tests can be used to diagnose HIV, and when are they used in timeline?
Can also perform genome sequencing to assess antiretroviral drug resistance and tropism (CCR5/ CXCR4)
p24 antigen - 1-8 weeks after exposure, then levels will drop as Ab produced
HIV antibody - 4 weeks 95% will test positive. If negative, can check up to 12 weeks after exposure
Diagnosis is infants is difficult as passively acquired IgG will be detected up to 12 months after birth. Test infant at various intervals from 12-24 months
Tests available:
p24 antigen
HIV RNA
HIV proviral DNA - check mother will always remain positive
HIV antibody
Point-of-care tests - less sensitive/ specific
How is HIV viral load measured?
RT-PCR of HIV RNA
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are viral opportunistic infectious?
CMV - retina, brain, GI
HSV - lungs, GI, CNS, skin
JC - brain PML
EBV - hairy leukoplakia, primary cerebral lymphoma
HHV8 - Kaposi sarcoma
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are bacterial opportunistic infectious?
Mycobacterium tuberculosis - disseminated/ extrapulmonary
Mycobacterium avium
Salmonella dissemninated
Also higher risk of common bacterial pathogens - streptococcus/ haemophilus
AIDS is when:
- patient with HIV antibodies
- develops opportunistic infections (usually CD4 <200)
What are protozoal/ fungal opportunistic infectious?
Cryptococcus neofromans - CNS
Coccidioides
Histoplamosis
PCP
Toxoplasma
Cryptosporidium
Isospora
What are ways to reduce HIV spread?
Combatting HIV/ AIDS was 6th Millenium Development Goal
Change sexual behaviours - condoms
Pregnant women start ART after first trimester
Treat other STIs
Clean needles
Blood product screening
HIV transmission can be explained via R0 equation. What are factors in this?
R0 >1 epidemic spread can occur
R0 <1 infection will eliminate
R0 is proportional to C x beta x D
C - is the average rate of contact between susceptible and infected
individuals
beta - transmissibility - probability of HIV transmission per given exposure e.g anal intercourse has 1.65 % risk transmission
D - duration of infectious period
What are risk factors for more rapid progression of HIV?
Female Older Depression Poor pre-morbid nutritional state Certain HLA types Co-infection HBV/HCV/ TB can alter immune system
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms (CD4 <500)
Clinical stage 3 - moderate symptoms (CD4 200-500)
Clinical stage 4 - severe symptoms (CD4 <200)
On average, untreated it will take 8-10 years from HIV acquisition to AIDS. WHO staging does not use CD4 count
What symptoms might primary/ clinical stage 1 have?
Asymptomatic - time from acquisition of virus, to development of HIV antibody, HIV p24 antigen or HIV RNA
Viral illness - fever, malaise, sore throat, lymphadenopathy, maculopapular rash - approx 50% of patients
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 2 have?
Moderate weight loss - <10% body Recurrent URTI VZV Angular chellitis Recurrent oral ulceration Sebhorrhoeic dermatitis Fungal nail infections
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 3 have?
Unexplained weight loss >10% body
Chronic diarrhoea - two or more loose stools per day
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary TB
Severe bacterial infections - pneumonia, meningitis
WHO HIV staging is grouped into:
Primary HIV infection
Clinical stage 1 - asymptomatic
Clinical stage 2 - mild symptoms
Clinical stage 3 - moderate symptoms
Clinical stage 4 - severe symptoms
What symptoms might primary/ clinical stage 4 have?
HIV wasting syndrome - >10% weight loss and diarrhoea PCP Recurrent severe bacterial pneumonia Oesophageal candidiasis Extrapulmonary TB KS CMV Toxoplasmosis HIV encephalopathy Cryptococcus Cryptosporidiosis Isosporiasis Coccidiomycosis Histoplasmosis Non-typhoidal salmoneall Lymphoma - cerebral or B-cell non Hodgkin Cervical carcinoma HIV neuropathy
What are the UNAIDS 90-90-90 targets?
90% living with HIV, know their status
90% diagnosed with receive ART
90% on treatment will have suppressed viral loads
What is U=U in regards to HIV?
Undetectable viral load = transmissible
Data on 58 000 episodes of unprotected sex in HIV individuals, showed no transmission
Patient presents 8 weeks after unprotected sex, with fever, sore throat.
HIV p24 positive
HIV antibody negative
What steps should you take next
Diagnosis is primary HIV infection
Need to refer to HIV specialist and start ART within 2 weeks
Early ART is associated with better preservation of immune function, CD4 count, morbidity associated with high viraemia, and reduced risk of transmission. It may also prevent HIV developing a reservoir in deep lymph nodes.
If initial HIV test positive, what are next steps labs take to confirm this?
Initial diagnosis on Architect
Use same sample to confirm on VIDAS
New sample to confirm on Archiect
Geenius to check HIV1/HIV2 as different treatment
Viral load by PCR
Whole genome sequencing for resistance pattern
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What are HIV related tests?
Confirm HIV1/HIV2
Viral load
Genotypic resistance testing
CD4 T cell count
Viral tropism test is sometimes performed, if considering CCR5 inhibitor as first line therapy
If PCP - consider G6PD if needing dapsone/co-trimxoazole/primaquine as contraindicated otherwise. African/ mediterranean/ Chinese
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What are other infectious agents to test for?
viral/ bacterial/ protozoal
Viral
HAV IgG
HBV surface antigen/ core antibody
HCV IgG
EBV/ CMV - serology initially, but can be negative in HIV. Check viral load buy PCR
Measles IgG - if no history of vaccine/ infection
Varicella IgG - if no history of vaccine/ infection
Rubella IgG - in women of child-bearing age
Note - vaccine preventable diseases -
HAV/ HBV/ Measles/ varicella/ rubella
Bacteria
Chlamydia NAAT
Gonorrhoea NAAT
Syphilis serology
IGRA
Sputum for AAFB - BAL
Protozoa/ fungal CrAg Toxoplasmosis Strongyloides Giardia Beta-d-glucan/ galactomannan
Must screen partner/ children
After initial HIV diagnosis, baseline laboratory tests are required.
HIV related/ other infectious/ metabolic
What metabolic tests are required?
FBC U+Es LFTs Bone Lipids Glucose
Urinalysis
Urine PCR - if proteinuria
Pregnancy test
HLA-B*57:01 - if abacavir being considered
When do perform HIV resistance testing?
At baseline
At commencement of ART if there is a delay
Suboptimal viral load response to therapy - <1 log10 drop in 4 weeks
Virological failure - viral load >200 copies/ml on two samples while on ART. Always perform whilst on ART - as otherwise resistant strain will become smaller part of opulation
On CSF samples if CSF viral load detectable on therapy
Pregnancy - if detectable viral load at week 36 of pregnancy
If on CCR5 antagnoist, and has virological failure, check tropism to ensure no tropism switch
Pregnant women with HIV, starting ART.
When should repeat viral load be measured?
Baseline 2-4 weeks after starting ART (first trimester) Second trimester 36 weeks (third trimester) Time of delivery
Children born to HIV infected mothers.
When should HIV testing be performed?
HIV proviral DNA or RNA PCR -
- Within 48 hours of birth
- 6 weeks of age - after completing 4 weeks anti-retroviral prophylaxis
- 12 weeks of age - two months after completing prophylaxis
- Monthly if breastfeeding is taking place, to detect late transmission
HIV antibody testing -
- 18 months - following loss of maternal antibodies at this time
- 6 weeks after stopping breastfeeding
What are elite controllers?
What are negatives to this?
Have HIV antibodies, but no HIV RNA in blood, and normal CD4 count.
Usually lacking CCR5 gene, so HIV cannot bind
Studies show they are in low grade inflammatory state, and may have more issues with illness compared to those on ART
When must HIV post-exposure prophylaxis be taken?
Within 72 hours of exposure
Patient commenced on ART, 4 weeks later viral load has not dropped by 1log10. Resistance testing initially negative
What is the next step?
Check medication compliance/ drug side effects
Re-check HIV resistance testing. Testing can detect resistant species if make up 25% of virus population. So if <25% of population, will not be detected. Once ART given, these resistant strains can emerge, and become dominant population, which can be detected.
When checking CD4 count and viral load, how often do you need to check CD4 count?
If patient has CD4 count >350, on two occasions, with low viral load, then no longer need to check. As we can presume CD4 will be higher than this.
Re-check if new symptoms, or signs of treatment failure.
When should ART be initiated?
Within two weeks from diagnosis, regardless of CD4 count
Hold if TB meningitis
What classes of ART exist?
NRTI - nucleoside/ nucleotide reverse transcriptase inhibitor
NNRTI - non-nucleoside reverse transcriptase inhibitor
Protease inhibitor
Fusion inhibitor
INSTI - integrase strand transfer inhibitors
How do NRTIs work?
Act as false nucleotides (ATCG)
RT attempts to convert viral RNA into DNA, but NRTI inserts and causes chain termination
What are examples of NRTIs?
Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (ZDV) - sometimes known as AZT
How do NNRTIs work?
Non-competitive inhibitors of RT, by binding to allosteric site on enzyme
HIV-2 naturally resistant
What are examples of NNRTIs?
Efavirenz (EFZ)
Nevirapine (NVP)
Rilpivirine (RPV)
How do protease inhibitors work?
Inhibit protease enzyme preventing cleavage of essential proteins (gag proteins) necessary for viral maturation and budding from cell membrane
What are examples of protease inhibitors?
Atazanavir (ATZ)
Darunavir (DRV)
Lopinavir (LPVr)
All are prescribed with ritonavir which boosts action
How do fusion inhibitors work?
What is an examples of this?
- CCR5 inhibitor
- fusion inhibitor
CCR5 inhibitor -Interfere with binding/ fusion of virus to cell membrane through co-receptor CCR5. Virus can switch from CCR5 to CXCR4 - so tropism assay is required prior to starting this class
-Maraviroc (MVC)
Fusion inhibitor - binds to GP41 on CD4, preventing HIV binding
- Enfuvirtide (ENF, T-20)
How do INSTI - integrase strand transfer inhibitors work?
Inhibit viral enzyme integrase, which is essential for integration of viral DNA into host cell DNA
What are examples of INSTIs?
Dolutegravir (DAG)
Raltegravir (RAL)
Elvitegravir (EVG) + cobicistat (COBI)
cobicistat is a PK (pharmacokinetic enhancer), which blocks breakdown of other drug
HAART is usually made of 3 drugs.
Two NRTIs + third drug (NNRTI/ PI/ INSTI)
2xNRTIs are normally fixed drug combinations.
What drugs make up these combinations -
Truvada
Descovy
Kivexa
Combivir
Truvada - tenofovir disoproxil fumarate (TDF) + emtricitabine
Descovy - tenofovir alafenamide (TAF) + emtricitabine
Kivexa - abacavir + lamivudine. Recommended only if viral load < 100 000, or any level if used with dolutegravir
Combivir - Zidovudine + lamivudine
When is tenofovir contraindicated?
When is abacavir contraindicated?
When is efavirenz contraindicated?
If CrCl <70ml/min
If HLA-B*57:01 positive
Mental health disorder
What are examples of third drug added to 2xNRTIs backbone for HAART?
NNRTI
NNRTI -
Nevirapine
Efavirenz
Rilpivirine - only if viral load <100 000
What are examples of third drug added to 2xNNRTIs backbone for HAART?
PI
PI - atazanavir/ ritonavir atazanavir/ cobicistat darunavir/ ritonavir darunavir/ cobicistat
PI interact with PPIs. So switch omeprazole to ranitidine
What are examples of third drug added to 2xNNRTIs backbone for HAART?
INT
INSTI -
Dolutegravir
Raltegravir
Elvitegravir + cobicistat
When starting ART, when do blood tests need to be monitored?
2 weeks post ART - metabolic tests to ensure no reaction
4 weeks post ART - viral load/ CD4 - expect two-log VL drop
6 months - VL should be undetectable
Once established on ART - check VL every 6 months, and CD4 once a year
Patient has HIV and HBV.
What are treatment options?
Tenofovir + emtricitabine is recommended NRTI backbone
Patient has HIV and HCV
What are treatment options?
ART
If CD4 count ok, treat HCV first, then HIV, to reduce drug-drug interactions
Pregnant women, when should be commenced on ART?
If presenting late, treatment should be started immediately. What are options?
Prior to 24 weeks
Combination -
Zidovudine/ lamivudine
Raltegravir
Nevirapine - stat dose
Why do ART drugs affect liver function/ have multiple itneractions?
All metabolised via cytochrome p450 pathway
If patient on NRTI + NNRTI, and is failing, what is next step?
Switch to NRTI + PI
Patient with TB and HIV. After waiting 2 weeks, what drugs should be started?
RIPE for TB (not need to switch to rifabutin)
ART -
abacavir + lamviduine + dolutegravir
What is given to protect against opportunistic infections PCP in HIV?
Co-trimoxazole 480mg OD
Co-trimoxazole 960mg M/W/F
Dapsone
Pentamidine nebuliser
Co-trimoxazole is preferred, as also protects against diarrhoeal disease, and some effect against toxoplasma
Prophylaxis can be stopped if CD4 >200 for 3 months, with undetectable viral load
What advice is given to avoid toxoplasmosis?
If CD4 <50, how often retinal screening for CMV?
Avoid raw meat/ cat litter
Every 3 months
PCP can present with SOB, fever, fatigue. SOB worsens quickly on exertion - can check patients saturations.
Normal CXR does not exclude PCP.
PaO2 <9.3 or Sp02 <92% - severe infection
How to diagnose PCP?
Sputum analysis - either induced sputum/ BAL.
Grocott methenamine silver stain.
PCP stays in samples up to 10 days after starting treatment, so do not delay treatment awaiting diagnosis
What is first line treatment of PCP?
Co-trimoxazole for 21 days
Oral if mild
IV if severe
Alternatives:
Atovaquone
Clindamicin + primaquine
Pentamadine IV
Steroids if severe. Prevents IRIS to dead fungi.
Prendisolone 40mg BD 5 days
Prednisolone 40mg OD 5 days
Prednisolone 20mg OD for next 11 days
Can take 7 days before seeing response
When is second line PCP treatment required?
What is the treatment?
Clinical failure to first line - no improvement after 5 days (remember to consider alternative diagnosis)
Sulpha allergy
Patient toxicity
Clindamicin/ primaquine
Pentamidine IV
Trimethoprim/ dapsone
Atovaquone
What is treatment for toxoplasmosis?
Often have ring-enhancing lesion on CTB
Retinal exam shows retinitis
Sulphadizine + pyrimethamine
Give with folinic acid
6 weeks treatment, then lower dose long term prophylaxis
Anti-epileptics may be required
Second line -
clindamicin + pyrimethamine
co-trimxazole
What are side effects of sulphadiazine used to treat toxoplasmosis?
Cause crystal uropathy and renal dysfunction - need to be hydrated
Cryptococcal meningitis causes raised ICP by preventing CSF reabsorption.
When performing LP, how much fluid is removed?
Aim closing pressure <20cm H2O
Or if very high, aim for half the pressure. e.g 50cm H2O aim 25cm H2O
Daily LP may be required. If persistingly high pressure, or hydrocephalus, will need shunt/drain
ventriculo-peritoneal shunt (if hydrocephalus)
lumbar-periotenal shunt
external lumbar drainage
How to diagnose cryptococcal infection?
Serum CrAg
CSF CrAg
India ink staining
What is treatment for cryptococcal infection?
Liposomal amphotericin + flucytosine for 2 weeks, then
High dose fluconazole 10 weeks
Normal dose fluconazole long term prophylaxis
Which organs can CMV affect?
Retina - 75% cases
Lungs
GI
CNS
What eye symptoms does CMV cause?
How does it appear on fundoscopy?
Reduced visual acuity, can lead to blindness
Necrotising retinitis - pizza pie appearance
How to diagnose CMV infection?
Fundal exam
CMV DNA titre does not necessarily indicate organ disease, if no symptoms. But DNA levels useful for monitoring response to treatment.
What are treatment options for CMV infection?
oral valganciclovir 900mg BD for 2-4 weeks
900mg maintenance until CD4 >100, and VL <40
IV options -
ganciclovir
foscarnet
cidofovir
Intravitreal anti-CMV treatment injections can be used
Mycobacterium avium complex is a group of common environmental organisms (mycobacterium avium and mycobacterium intracellularae). Cannot be spread person-person. Found in water, soil, dust
Causes non-specific symptoms such as night sweats, fever, diarrhoea. Typically patiets CD4< 50.
How is MAC diagnosed?
Sputum culture
98% diagnosed if two sets of blood cultures taken for mycobacterium culture
What is treatment for MAC?
Clarithromycin + ethambutol
Rifabutin is added in severe cases
Treat until at least symptom free for 3 months, and CD4 >100
May require lifelong treatment
What are patterns of disease causes by MAC?
Pulmonary MAC - usually underlying lung disease
Disseminated MAC - AIDS patient, any organ
Lymphadenitis MAC - children with immunodeficiency causes swelling of lymph nodes
What is treatment for -
oral candidiasis
genital candidiasis
oesophageal candidiasis
candidaemia
oral candidiasis - nystatin
genital candidiasis - clotrimazole
oesophageal candidiasis - oral fluconazole
candidaemia - IV fluconazole
Candida albicans is most common fungus. Other species such as C krusei or C glabrata are resistant to fluconazole, and need itraconazole
Stage 4 AIDS - what are causes of diarrhoeal disease?
Lymphoid tissue in gut has high levels of CD4 lymphocytes - so high risk GI disease
Cryptosporidia - nitazoxanide/ paromomycin
Cyclospora - co-trimoxazole
Isospora belli – co-trimoxazole
Microsporidia – albendazole
ART side effects - particularly protease inhibitors
Stage 4 AIDS - what are empirical treatments for diarrhoeal disease?
Cryptosporidia - nitazoxanide/ paromomycin
Cyclospora - co-trimoxazole
Isospora belli – co-trimoxazole
Microsporidia – albendazole
Starting ART is treatment for all diarrhoeal disease
What are general side effects of NRTIs?
In general -
anaemia, lipodystrophy, lactic acidosis, liver cirrhosis/ hepatitis, pancreatitis, peripheral neuropathy
What are side effects of these NRTIs?
Lamivudine
Stavudine
Tenofovir
Zidovudine
Lamivudine - well tolerated
Stavudine - no longer used as multiple side effects
Tenofovir - renal disease, osteoporosis
Zidovudine - anaemia, lipodystrophy, lactic acidosis, liver cirrhosis/ hepatitis, pancreatitis, peripheral neuropathy
What are general side effects of NNRTI?
Nausea Diarrhoea Hepatotoxicity Fever Rash
What are side effects of these NNRTIs?
Efavirenz
Nevirapine
Efavirenz (EFV) – psychiatric symptoms
Nevirapine (NVP) – rash – SJS/ TEN (CD4 >250 count puts more at risk)
What are side effects of protease inhibitors?
diarrhoea
diabetes
lipodystrophy
hepatitis
After starting ART, what other drugs should be commenced?
IPT - isoniazid preventative therapy 6 months, if no active TB
Co-trimoxazole - until CD4 count improved
2x NRTI combinations - what drugs are in these combinations?
Combivir
Kivexa
Truvada
Combivir - zidovudine/ lamivudine
Kivexa - abacavir/ lamivudine
Truvada - tenofovir/ emtricitabine
2x NRTI and 1x NNRTI come as combination drugs. What drugs are in these combinations?
Trioday
Viraday
Trioday - tenofovir/ lamivudine/ efavirenz
Viraday - tenofovir/ emtricitabine/ efavirenz
If on NRTIx2/ NNRTI, and have virological failure, what steps would you take?
Change one of the NRTI
Switch NNRTI to PI
Why does HIV resistance emerge?
Replicates 1 billion times/day. Reverse transcription is error prone. Selective pressure – rapid emergence of resistance
Can be infected with resistant strain, but usually resistant virus is not as “fit” as wild virus
Which ART drugs are at high risk of having resistance emerge?
NRTI - emtricitabine/ lamivudine/ tenofovir/ zidovudine
NNRTI - efavirenz/ nevirapine
Which ART drugs do not show much resistance?
Protease inhibitors
How does HIV evade immune system?
Hide - in sanctuary sites (Brain/ testes)
Run - high levels virus turnover, high mutation rate
What is pathogenesis of IRIS in TB for example?
Low CD4 count - macrophages contain TB, but cannot be fully activated
CD4 count increases due to ART
IFN-gamma and other cytokines stimulate macrophages
Macrophages produce overwhelming cytokine response - TNFalpha, IFNgamma, IL6
Excessive inflammation causes tissue destruction
HIV most important risk factor for reactivation of TB.
New diagnosis HIV, how should you screen patient?
- Check for active symptoms - then CXR if suspicious of active pulmonary TB
- If no symptoms symptoms - IGRA.
IGRA positive - CXR check for active TB
IGRA negative - give patient 6 months isoniazid prophylaxis
Active - give RIPE
Latent - 6 months isoniazid prophylaxis
Why are sputum samples less reliable in advanced HIV?
Why is IGRA less reliable in advanced HIV?
Reduction in smear positive cases, as no immune response/ cavitation. Use Genexpert
HIV may give false negative IGRA test as cannot produce antibodies
Rifampicin is potent enzyme inducer, used in TB treatment
How does this affect ART?
- No interaction between rifampicin and NRTI
- NNRTI
Efavirenz (nNRTI) – levels only reduced slightly, does not need dose adjustment
Nevirapine (nNRTI) – rifampicin reduces levels greatly. Give higher dose of nevirapine – but risk of hepatotoxicity. Only use if have to - LMIC
Rifampicin is potent enzyme inducer, used in TB treatment
How does this affect ART?
- PI
- Integrase inhibitor
Lopinavir/ atazanavir (protease inhibitor) – reduces levels greatly. Severe hepatotoxicity, can only give ritonavir. Switch rifampicin to rifabutin (if need to be on protease inhibitor)
Raltegravir/ dolutegravir (integrase inhibitor) – reduces levels greatly. Double the dose
What are the 5Cs of HIV testing?
consent confidentiality counselling correct results connection to services
Neurological disease can occur in HIV due to infections.
What are other causes of non-infectious neurological disease?
Stroke - 5x more likely in HIV
HIV associated neurocognitive disorder (HAND) – neuronal damage due to CNS inflammation (IRIS/ ARVs/ HIV replication CNS), direct neurotoxic effect of HIV
What drug is used for pre-exposure prophylaxis?
When is is taken?
Truvada - tenofovir/ emtricitabine
Descovy - tenofovir/ emtrictabine
70-99% effective
Every day dosing
or
Event based dosing (EBD)
take 2 pills 2 – 24 hours before sex
take 1 pill 24 hours later
take 1 more pill 24 hours after that
or
Holiday PrEP
7 days daily dosing before the period
7 days daily dosing during the period (or for as long as the specific period lasts)
7 days daily dosing after the period.
What are downsides to pre-exposure prophylaxis?
Increased risky sexual behaviour
Does not protect from other STIs
Need HIV test before treatment, and every 3 months
What drugs are included in post-exposure prophylaxis?
Must take within 72 hours
Course lasts 28 days
Re-test for HIV at 3 months
Truvada + Raltegravir
Vertical transmission - approx 30% transmission risk in pregnancy, 20% transmission risk breast feeding
What are risk factors for increasing transmission?
High viral load
Maternal malnutrition
Placental infection
STI
Premature birth
Low birth weight
Longer breast feeding
Breast abscess/ mastitis
How are these ART drugs affected in pregnancy?
NRTI
NNRTI
Integrases
Protease inhibitors
NRTIs/ NNRTIs - dose normal in pregnancy
Pregancny - on antacids/ iron replacement - integrases don’t work as bind to metals. Normal dose in pregnancy
Protease inhibitors effect reduced in pregnancy
Why do HIV infected children progress rapidly to AIDS?
Immature T cells, so cannot suppress viral load
How do HIV infected children present?
Malnutrition/ stunted growth
Oral thrush
Severe infection - pneumonia
Which vaccines to avoid in HIV?
Vacccines are less effective in HIV due to weakned immune response
BCG Measles/ Mumps/ Rubella Rotavirus Typhoid Varicella Yellow fever
Any live attenuated vaccine
