HIV symposium Flashcards
Where did HIV come from?
Origins traced back to chimpanzees (HIV-1) & sooty mangabeys (HIV-2)
‘Bushmeat practices’ - cross species transmission during killing or butchering
Transfer to humans beginning of 20th century in central & W. Africa
Social changes / migratory routes / urbanisation
How did HIV cross from Africa to the west?
Stored specimens test positive early as 1959
Introduced to Haiti by individuals working in the DR Congo ~ 1966 – outbreak followed
Transferred to US ~ 1969-72
Increase in international travel / transfusion / blood products / IVDU
Rapid spread within gay community
1st clinical cases 1981
Early 1980s
HIV discovered
- Institut Pasteur 1983
- Robert Gallo 1984
Increasing reports of Pneumocystis & KS
- developed world, gay men
- IVDUs, haemophiliacs
- developing world
Antibody test in 1985
Management
- treatment of infections
- palliative care
Late 1980s
AZT - zidovudine (monotherapy)
- first manufactured in 1964
Patient activism
Management:
- prevention opportunistic infections
- nebulised pentamidine 1989
- palliative care
Widespread prevention campaigns
- reduction in STIs
- needle exchange
1991-1992
More HIV tests than any other time
- Mark Fowler diagnosed with HIV on East Enders
- Freddy Mercury died
- Arthur Ashe, Kenny Everett, Holly Johnson all HIV +
Resistance to AZT documented in people who had never taken AZT
1993-1994
Concorde - AZT monotherapy ineffective
Dual therapy (addition of ddC) ineffective
Therapeutic nihilism
Treatment limited to treatment and prophylaxis of OIs
Reduction in HIV testing
1994
ACTG 076
- antenatal & intrapartum AZT
- post partum AZT to neonate
- decreased transmission 25% -> 8%
Current practice
- combination therapy (3 drugs)
- normal vaginal delivery if VL <40
- transmission rates <1%
1994-1996
More ARVs approved +++
1994/5: dual therapy works (Delta)
1996: everything changes ……
1996/7
Protease inhibitors Triple therapy Nevirapine, ritonavir, indinavir Vancouver AIDS conference (July) "Lazarus Syndrome” - ward closures Viral load testing
HAART (highly active anti-retroviral therapy)
HAART = ART = combination therapy = ‘triple’ therapy = usually at least 3 anti-retroviral drugs (ARVs)
Aim to reduce viral load to ‘undetectable’ levels - allowing immune system to partially recover
Need to take all the drugs, on time
Need to think about food restrictions, drug interactions
1997-2000: ART side effects
lipodystrophy hyperlipidaemia and CVD Glucose intolerance / diabetes Loss bone mineral density Gastrointestinal – N&V, diarrhoea Peripheral neuropathy, CNS side effects Hepatotoxicity Renal – nephrolithiasis, proteinuria Skin rash / hypersensitivity
2000-2016
Improvement in tolerability of ART
Improvement of toxicity of ART
Improvement of formulation of ART
Reduced daily dosing
Co-formulation
Shift towards earlier treatment
HIV lifecycle
1) binding, 2) fusion, 3) reverse transcription, 4) integration, 5) replication, 6) assembly, and 7) budding.
Viral dynamics and resistance
10 billion viruses produced/person/day 10,000 bases in viral genome Mutations every 10,000 bases Every mutation likely to occur each day Just one mutation can cause resistance Pools of resistant virus exists before exposure to drug therapy Combination antivirals essential
Viral load
- Lower the better
- Higher viral load associated with more rapid disease progression
- Very high levels in early infection (>10,000,000 copies/ml)
- Viral load marker of treatment success: aim for “undetectable” (<40)
CD4 Count
Measure of immune function
Higher the better
Decreasing count associated with increasing risk of disease progression
Normal values >500
Significant risk of morbidity/ mortality if CD4 count < 200
Aims of treatment of HIV
To start as soon as possible
To reduce HIV transmission
To prevent further damage to the immune system ( ‘CD4 count’)
Reduce risk of opportunistic infections, tumours, direct effects e.g. HIV neurocognitive impairment
Prolong healthy life
Untreated HIV infection
Seroconversion
Then later on TB, Kaposi’s Sarcoma, shingles, oral thrush, seborrhoeic dermatitis
Then later on Pneumocystis pneumonia, toxoplasmosis, lymphoma
Then MAC, CMV, PML, CNS lymphoma
HIV treatment effect
Reduced morbidity and mortality
HIV patients now living very long
As long as have no comorbidities
Global statistics
In 2017:
36.9 million globally were living with HIV
New HIV infections have fallen by 35% since 2000
1.8 million became newly infected with HIV
AIDS-related deaths have fallen by 48% since the peak in 2005
940,000 died from AIDS-related illnesses
Global ARV rollout
Made possible by generic drug production
£60 per year vs £10,000
‘3 by 5’ target - 3 million on ARVs by 2005
‘15 by 15’ target - 15 million people taking ARVs by 2015 was reached in June 15
21.7 million accessing ARVs (2017)
Clinical response similar in all settings
Next target 90:90:90 by 2020
What is the 2020 90-90-90 target?
By 2020, 90% of all people living with HIV will know their HIV status. By 2020, 90% of all people with diagnosed HIV infection will receive sustainedantiretroviral therapy. By 2020, 90% of all people receiving antiretroviral therapy will have viral suppression.
by 2020 and by 2030…
Fewer than 500 000 people newly infected with HIV (currently 1.8m)
Fewer than 500 000 people dying from AIDS-related causes (currently ~1m)
Elimination of HIV-related discrimination
75:79:81 globally
48% of all PLWH have supressed virus
Reduce the number of new HIV infections by 89% by 2030 and the number of AIDS-related deaths by 81%
Combination prevention
Treatment as prevention - TasP
Pre-exposure prophylaxis- PrEP
Expansion of HIV testing
Condoms wherever possible
What is U=U
Undetectable=Untransmittable
ART is now so effective that those who are treated and have an undetectable viral load (<200 copies) have levels of virus that are untransmissible, even if having sex without condoms. This is sometimes referred to as U=U.
The Swiss Statement 2008
Partner study - zero transmissions after >58,000 episodes sex without condoms when viral load was undetectable <200
Test and treat programmes
Aim for 90% of new diagnoses to be taking ARVs by 90 daysAim for 98-100% PLWH to be taking effective treatmentAim for 100% PLWH have undetectable viral loads
What is PrEP?
Pre-exposure prophylaxis (or PrEP) is when people at very high risk of HIV take daily HIV medicines to reduce the chances of getting infected
It works – trials showed 86% effective, but actually 100% for those who took it
Historical lack of availability on NHS…
Truvada (tenofovir/emtricitabine)
PrEP impact trial
10,000 patients (then 13,000, now 26,000) 3 years Generic Truvada – daily or event based GUM clinics across UK Open for recruitment
Other Prevention strategies
HIV testing
Sexually transmitted infection treatment - 40% reduction (1)
Circumcision - South Africa, Kenya, Uganda - 58% reduction
What kind of surfaces are the best for HIV entry
Most of the pathogens that cause the deaths of large numbers of people are those of mucosal surfaces or enter the body through these routes. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS.
Which cells are the main host cells for HIV?
CD4 T cells are the main host cells for HIV.
Entry: CD4/gp120
& CXCR4/CCR5
What are activated CD4 T cells in the terminal ileum?
Activated CD4 T-cells are primary targets for infection. Activated CD4 T cells in the terminal ileum are CCR5+
HIV can use CCR5 (‘R5 viruses’)
CXCR4 (‘X4 viruses’)
Or both (‘R5X4 viruses’)
Differential targetting of CD4 T cells by HIV
During primary HIV infection (mostly R5), effector CD4 T cells are eliminated rapidly owing to their high expression of CCR5 and their highly activated state, which supports lytic viral replication. Although CD4 T-cells are essentially depleted from the effector lymphoid tissues, most of the CD4 T cells residing in the inductive lymphoid tissues are spared owing to their lack of CCR5 expression.
R5 viruses
R5 viruses are the strains most commonly transmitted sexually. This is in agreement with the high resistance to infection of individuals lacking CCR5.
After about five years, viruses that are able to use CXCR4, with or without concurrent use of CCR5, evolve in about 50% of patients. These viruses would now be called R5X4 and X4 viruses, respectively.
What are the main ways through which CD4 T cells are depleted?
Cytopathic effects
Apoptosis
CTL mediated killing
Importance of intestinal mucosal infection
60% or so of all CD4 T cells are in the gut, a minority is in the blood (think of other compartments: lung, spleen etc.)
The main mucosal sites for HIV entry are oral, rectal, and vaginal mucosa.
Depletion of CD4 T-cells in the gut is rapid (weeks in the monkey model)
What can measure intestinal leakage?
Bacterial translocation is a good measure of intestinal leakage and hence a measure for the destruction of the gut mucosal immune system after HIV infection.
Development of AIDS
Early conditions: Rash, fever, myalgia, arthralgia Guillian-Barre syndrome, chronic demyelinating neuropathy, Bell’s palsy, Sjogren’s syndrome
Intermediate: gingivitis, warts, TB, herpes Zoster, oral candidiasis, Kaposi’s sarcoma
Late: Pneumocystitis, toxoplasmosis, cryptococci
Early changes
Poor CD4 T cell proliferation after stimulation by specific antigen
Normal CD8 T cell activity
Reduced ability of TH1 cells to proliferate
Some histological abnormalities in lymph nodes
Elevated IgG and A (but non-specific), reduced IgM
Small changes in cytokine levels
Late changes
Dramatic loss of CD4 T cells and function
Reduction of cytotoxic capacity of CD8 T cells
Complete loss of tuberculin-type response
Major histological disruption of lymph nodes & loss of DCs
Eventual loss of anti-HIV antibody
Significant change from TH1 to
TH2 type cytokine production
Who needs a HIV test?
Anyone who has ever been exposed to even a small risk of HIV infection needs an HIV test. It is better to test more people than not enough, because a positive test always requires action. Widespread testing is the best way to stop the virus from being passed on.
Detecting HIV infection
HIV antibody and HIV p24 ELISA
So-called ‘fourth-generation’ HIV tests have been successfully used for the past decade.
Compared with third-generation assays, fourth-generation assays have greater sensitivity because of their ability to detect p24 antigen as well as conventional HIV antibodies.
