Virology and Immunology: The Basics. Dr Tristan Barber

Transcription

1 Virology and Immunology: The Basics Dr Tristan Barber

2 Objec9ves HIV life cycle Stages of HIV Infec7on Virology Immunology Basics of resistance

3 Life Cycle

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5 Stages of Infec9on

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7 Stages of HIV infec9on Primary HIV infec7on Asymptoma7c HIV infec7on Symptoma7c HIV infec7on AIDS diagnosis

8 Primary HIV Infec9on Inflammatory response HIV- specific CD4 cells are infected An7body tests are nega7ve An7gen posi7ve HIV viral load elevated

9 Primary HIV Infec9on Inflammatory response HIV an7bodies (within 6 wks but <3 mths) Window period High levels of HIV in blood, sexual fluids and/ or breast milk Highly infec7ous!

10 Asymptoma9c HIV infec9on This stage lasts for an average of ten years Free from major symptoms Viral load drops from seroconversion but remains infec7ous HIV an7body posi7ve Not dormant, very ac7ve in the lymph nodes

11 Symptoma9c HIV infec9on Over 7me immune system becomes severely damaged The lymph nodes and 7ssues become damaged HIV mutates and becomes more pathogenic CD4 cells become depleted Symptoms start mild and increase in severity Emergence of opportunis7c infec7ons

12 Immunology

13 Basics CD4 cells What do they do? What s normal? Numbers or percentage? CD8 cells Any other tests? HLA B5701

14 Opportunis9c infec9ons CD4 > 500 cells/mm 3 - usually not at risk CD cells/mm 3 - Candidiasis (Thrush) - Kaposi s Sarcoma (KS) - Tuberculosis (TB) - Lung infec7ons

15 Opportunis9c infec9ons cells/mm 3 - Toxoplasmosis - Cryptosporidiosis - Cryptococcal Infec7on - Cytomegalovirus (CMV) <50 cells/mm 3 - Mycobaterium Avium complex (MAC)

16 Virology

17 Virology An7bodies and an7gens Hepa77s from A. To Z? HIV viral load What does it mean? How quickly should it go away? What s a log drop?

18 Resistance (is useless)

19 Resistance What is resistance? Why does it mager? What strategies do we use to reduce development of resistance?

20 HIV - replica9on and muta9on Approx 5000 new virions per ml of blood per day (30 million+ virions) No checking mechanism Rapid muta7on rate Viral escape mutants A replica9ng virus is a muta9ng virus lead to theory of HAART

21 What is a muta9on? HIV enzymes (reverse transcriptase, protease ) are made up of proteins The subunits of proteins are amino acids Each amino acid is coded for by a triad of nucleosides A, C, T, G Hence AZT, 3TC, d4t etc 1 muta7on = change in 1 nucleoside that may or may not change the amino acid A muta7on is a change in the gene7c code of an organism, which may change the way in which the organism looks and behaves

22 Discussion Why does treatment failure occur? Why does resistance occur?

23 Why do resistance and treatment failure occur? Commonly for 4 reasons: A random occurrence Drug interac7on decreasing effec7veness Malabsorp7on Nonadherence to the treatment regimen Pa7ent choice Side effects Life events

24 HIV drugs and resistance Some drugs have a low gene7c barrier to resistance One point muta7on may confer resistance to a par7cular drug or en7re drug class e.g. some nucleoside drugs (NRTIs) or non- nucleosides (NNRTIs) Some drugs have high gene7c barrier Step wise accumula7on of resistance muta7ons need to develop resistance e.g. boosted protease inhibitors (PIs)

25 Barriers to resistance Single PI Small change per mutation BUT Low drug levels NNRTIs High drug levels BUT Large change per mutation Boosted PIs Small change per mutation AND High drug levels High trough High trough Low trough EC 50 EC 50 Increasing EC 50 Increasing number of mutations

26 Minimizing resistance Use combina7on therapy (HAART) Use boosted PIs Maximise adherence (>95%) Tolerable Simple Alarms/other adherence support Use drugs with long/matched half lives Don t interrupt therapy

27 Types of failure Clinical Immunological Virological

28 Types of resistance Clinical resistance HIV mul7plies in your body even though you are taking an7viral drugs Genotypic resistance The gene7c code of HIV has muta7ons that are linked to drug resistance Phenotypic resistance HIV mul7plies in a test tube when an7viral drugs are added

29 Genotypic tes9ng Gene7c code of sample virus compared to wild type Each codon defines an amino acid used to build a new virus Currently sequence genes coding for reverse transcriptase (RT) and protease enzymes Legers and numbers are used to describe muta7ons

30 3TC Resistance ATG to ATA ATG = methionine ATA = valine Hence M184V Old amino acid New amino acid Position of mutation ie. 184 th amino acid Along chain

31 Phenotypic tes9ng Sample of HIV grown in the laboratory Dose of an an7retroviral drug is added Growth rate of HIV is then compared to wild type virus If sample grows more than normal it is resistant to the drug Results reported as fold resistance This is a direct measure of in vitro resistance

32 Virtual phenotype Perform genotype Compare results to phenotypes of viruses with similar pagern Less expensive Faster Dependent on database

33 Ques9ons

34 BREAK

35 Working. Together. Dr Tristan Barber

36 Personal Experiences

37 Being an HIV doctor Holis7c Global Pa7ent focussed Progressive Evolving Challenging Liberal Boundaries C.A.M.P. (yes, really) Teaching The bigger picture sharing our model

38 Working in the NHS Pride Cost effec7ve Opportuni7es Collabora7on Centres of excellence Joined up care Virtual consulta7ons Holis7c Preven7on Threats Commissioning Uncoupling from sexual health Losing local services to bigger centres Staff pressures

39 Working Together

40 An holis9c approach... If a pa-ent only sees a clinician, they only get half the story Dr Simon Edwards Mor7mer Market Centre

41 Working together User interac7on is essen7al in HIV services How can doctors and advocates work together?

42 What is it? Can be local/na7onal/interna7onal Not always NGO/voluntary sector; can be clinic/pa7ent based Individual/group Different role in urban vs. rural sewngs Pa7ent focussed May involve aspects of role modelling living posi7vely, managing meds/side effects Management/poli7cal level Mee7ngs, campaigning, advoca7ng Voluntary or paid

43 What s gained? Understanding of needs pa7ent/community Biological, psychological, social Ability to beger public health and preven7on strategies Encouraging adherence/agendance Personal empowerment Leverage with funding threats Extra weight to commissioning of services S7gma reduc7on Experiences shared Diagnosis Disclosure Rejec7on S7gma and discrimina7on

44 Mulitple possibili9es Direct client involvement and support Wri7ng pa7ent informa7on/leaflets Telephone advice Maintaining websites Quality control Campaigning locally, na7onally, interna7onally Human rights New drugs (mul7) media

45 Self s9gma Self- s7gma amongst people at risk for, and living with HIV, results in self- discriminatory decisions or ac7ons that can include: self- isola7on from family, friends and support depression self- harming prac7ces and risk taking missed HIV tes7ng opportuni7es, clinic appointments, necessary treatments hospitalisa7ons suicidal idea7on and ac7ons

46 Pa9ent Reps: Bloomsbury Clinic Employed pa7ent reps Peer support, advice, advocacy and means of engagement One on one appointments as well as coordina7ng the pa7ent network Workshops, forums, courses and social events Administering emergency financial funds Represent pa7ents on external commigees, advisory panels, working par7es and on the boards of chari7es

47 Varied roles Social isola7on and exclusion Disclosure and confiden7ality issues Social and psychological issues Diagnosis and life expectancy Star7ng treatment and adherence Physical health and well- being Dental care and GPs Pregnancy, paren7ng, adop7on and fostering Onward referrals for legal advice, immigra7on, employment, benefits, housing and homelessness Onward referrals to our own health advisors and psychology department or external counselling

48 Peer HUH Informed by mentor mothers (PUK) and mothers2mothers programme Peer Navigator posts recruited from local cohort; MAC AIDS grant Based on early ini7a7ve in Global South Can it work it London, can it be genericised? To ensure needs are met, PLWHIV have to be able to effec7vely navigate various health and social care networks/systems In this cohort, there are mul7ple barriers that restrict effec7ve access to care, including some men7oned but also en7tlement to treatment Therefore people in most need struggle to navigate effec7vely, which can impact on their overall health outcomes Peer Navigators enable people to navigate the various systems effec7vely and appropriately

49 Conclusions Rolediversely implemented in different areas (and clinics) User involvement helps at individual level as well as at service provision/poli7cal level Strengthening of pa7ent centred care Peer support helps come to terms with diagnosis Empowerment through informa7on Skills and coping mechanisms Development of inner strengths and resources User involvement key at pa7ent level as well as at na7onal/ interna7onal poli7cal level Supplement and enhance pa7ent care

50 Ques9ons