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Phase 2A > Microbiology 2 > Flashcards

Microbiology 2 Flashcards

1
Q

what is infection?

A

process of foreign organisms invading and multiplying in or on a host
- infectious diseases are the main cause of morbidity and mortality in man, especially in areas where they’re associated with poverty and overcrowding

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2
Q

what has reduced the prevalence of infectious disease in the developed world?

A
  • increasing prosperity, universal immunisation and antibiotics
  • HIV, vCJD, avian influenza and pandemic H1N1 influenza have emerged
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3
Q

what is increased global morbidity being caused by?

A
  • enforced (war, civil unrest and natural disaster)

- voluntary (tourism and economic benefit)

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4
Q

what is the epidemiology of HIV/AIDS?

A
  • first description of AIDS in 1981
  • identification of the causative organism in 1984
  • 20 million deaths
  • 33 million people living with it
  • Sub-Saharan Africa is most seriously affected
  • infection rates rising exponentially in Eastern Europe and parts of central Asia
  • 33% of 15 year olds in high-prevalence countries in Africa will die
  • demographics of the epidemic are influenced by social, behavioural, cultural and political factors
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5
Q

what is HAART? what is its effect on morbidity/mortality of HIV/AIDS?

A

highly active antiretroviral therapy

  • reduced mortality for those who can access care
  • a quarter of those who need treatment are on it
  • for each individual starting therapy, there are two new infections
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6
Q

what are the largest groups of people living with HIV in the UK?

A
  • men who have sex with men (MSM)

- culturally diverse heterosexual populations from sub-Saharan Africa

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7
Q

what percent of people diagnosed with HIV in the UK are women?

A

30%

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8
Q

what is the most common cause of HIV-related morbidity and mortality in the UK?

A
  • 1/4 of those with HIV in the UK are undiagnosed and unaware of their infection
  • leads to late diagnosis, poorer clinical outcomes and onward transmission
  • late diagnosis is most common cause
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9
Q

what are the clinical settings in which all patients should be offered HIV testing?

A
  • GUM/sexual health clinics
  • antenatal services
  • termination of pregnancy services
  • drug dependency programmes
  • healthcare services for TB, hepB, hepC and lymphoma
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10
Q

what are people in whom HIV testing is recommended?

A
  • all patients diagnosed with an STI
  • sexual partners of men and women known to be HIV positive
  • men who have disclosed sexual contact with other men
  • female sexual contacts of MSM
  • IV drug users
  • men and women from a country of high HIV prevalence (>1%)
  • men and women who have sex with people from countries of high HIV prevalence
  • patients presenting for healthcare where HIV enters the differential diagnosis
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11
Q

what are HIV-associated indicator respiratory conditions?

A

TB, pneumocystitis, bacterial pneumonia, aspergillosis

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12
Q

what are HIV-associated indicator neurological conditions?

A
  • cerebral toxoplasmosis
  • primary cerebral lymphoma
  • cryptococcal meningitis
  • progressive multifocal leucoencephalopathy
  • aseptic meningitis/encephalitis
  • cerebral abscess
  • space-occupying lesion of unknown cause
  • Guillain-Barre syndrome
  • transverse myelitis
  • peripheral neuropathy
  • dementia
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13
Q

what are HIV-associated indicator dermatological conditions?

A
  • Kaposi’s sarcoma
  • severe/recalcitrant seborrhoeic dermatitis
  • severe/recalcitrant psoriasis
  • multidermatomal/recurrent herpes zoster
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14
Q

what are HIV-associated indicator gastroenterological conditions?

A
  • peristent cryptosporidiosis
  • oral candidiasis
  • oral hairy leukoplakia
  • chronic diarrhoea of unknown cause
  • weight loss of unknown cause
  • Salmonella, Shigella, Campylobacter
  • hepB and hepC
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15
Q

what are HIV-associated indicator oncological conditions?

A
  • non-Hodgkin’s lymphoma
  • anal cancer
  • anal intraeptihelial dysplasia
  • lung cancer
  • seminoma
  • head and neck cancer
  • Hodgkin’s lymphoma
  • Castleman’s disease
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16
Q

what are HIV-associated indicator gynaecological conditions?

A
  • cervical cancer
  • vaginal intraepithelial neoplasia
  • cervical intraepithelial neoplasia, grade 2 or above
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17
Q

what are HIV-associated indicator haematological conditions?

A

any unexplained blood dyscrasia including thrombocytopenia, neutropenia and lymphopenia

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18
Q

what are HIV-associated indicator opthalmological conditions?

A
  • cytomegalovirus retinitis
  • infective retinal diseases including herpesviruses and toxoplasma
  • any unexplained retinopathy
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19
Q

what are HIV-associated indicator ENT conditions?

A
  • lymphadenopathy of unknown cause
  • chronic parotitis
  • lymphoepithelial parotid cysts
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20
Q

what are HIV-associated indicator miscellaneous conditions?

A
  • mononucleosis-like syndrome
  • pyrexia of unknown origin
  • any lymphadenopathy of unknown cause
  • any STI
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21
Q

what are routes of acquisition of HIV?

A

majority of infections are transmitted via semen, cervical secretions and blood

  • sexual intercourse (vaginal and anal)
  • mother to child (transplacental, perinatal, breast feeding)
  • contaminated blood, blood products and organ donations
  • contaminated needles (IV drug misuse, injections, needle-stick injuries)
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22
Q

what are features of sexual intercourse as a route of acquisition of HIV?

A
  • heterosexual intercourse accounts for the vast majority of infections and co-existent STIs, especially those causing genital ulceration
  • passage of HIV is more efficient from men to women and to the receptive partner in anal intercourse, than vice versa
  • in the UK, sex between men accounts for over half the infections reported
  • in Central and sub-Saharan Africa, the epidemic has always been heterosexual and more than half the infected adults are women
  • South-east Asia and India are having an explosive epidemic, driven by heterosexual intercourse and a high incidence of other STIs
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23
Q

what are features of mother-to-child acquisition of HIV?

A
  • transplacental, perinatal, breast feeding
  • increased vertical transmission is associated with advanced disease in the mother, maternal viral load, prolonged and premature rupture of membranes and chorioamnionitis
  • transmission can occur in utero
  • most infections occur perinatally
  • breast-feeding doubles the risk of vertical transmission
  • in the developed world, interventions to reduce vertical transmission, e.g. use of antiretroviral agents and avoidance of breast feeding, has reduced number of infected children
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24
Q

what is HIV?

A

human immune deficiency virus

  • belongs to the lentivirus group of the retrovirus family
  • two types: HIV-1 and HIV-2
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25
Q

what are features of HIV-1 and HIV-2? where are they most prevalent?

A
  • HIV-1 is the most frequently occurring strain globally
  • HIV-2 is almost entirely confined to West Africa; some spread to Europe, esp. France and Portugal
  • HIV-2 has only 40% structural homology with HIV-1; it’s associated with immunosuppression and AIDS, and takes a more indolent course than HIV-1
  • most drugs used in HIV-1 are ineffective in HIV-2
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26
Q

what is the structure of HIV?

A
  • two molecules of single-stranded RNA are within the nucleus
  • reverse transcriptase polymerase converts viral RNA into DNA (characteristic of retroviruses)
  • protease includes integrase (p32 and p10)
  • p24 (core protein) levels can be used to monitor HIV disease
  • p17 is the matrix protein
  • gp120 is the outer envelope glycoprotein which binds to cell surface CD4 molecules
  • gp41 is a transmembrane protein, influences infectivity and cell fusion capacity
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27
Q

what is the protease in HIV?

A

integrase (p32 and p10)

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28
Q

what is the core protein in HIV? what are its clinical uses?

A

p24 (core protein) levels can be used to monitor HIV disease

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29
Q

what is the matrix protein in HIV?

A

p17

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30
Q

what is the envelope protein in HIV?

A

gp160 = gp120 and gp41 (envelope)

  • gp120 is the outer membrane glycoprotein which binds to cell surface CD4 molecules
  • gp41 is a transmembrane protein indluences infectivity and cell fusion capacity
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31
Q

what are characteristics of retroviruses?

A
  • characterised by possession of the enzyme reverse transcriptase, which allows viral RNA to be transcribed into DNA and incorporated into the host cell genome
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32
Q

what is the action of reverse transcriptase?

A
  • enzyme
  • allows viral RNA to be transcribed into DNA and thence incorporated into the host cell genome
  • error-prone process with significant rate of mis-incorporation of bases; this, with a high rate of viral turnover, leads to genetic variation and diversity of viral subtypes/clades
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33
Q

what are the subtypes of HIV-1?

A
  • represent four independent cross species transfers
  • three (M, N and O) based on chimpanzee related strains of SIV
  • one (P) represents chimpanzee to gorilla to human transmission
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34
Q

what are features of group M (major) subtypes of HIV?

A
  • 98% of infections worldwide
  • high degree of diversity
  • subtypes denoted A-K
  • predominance of subtype B in Europe, North America and Australia
  • areas of Central and sub-Saharan Africa have multiple M subtypes
  • clade C is the commonest subtype
  • recombination of viral material generates an array of circulating recombinant forms (CRFs), which increases the genetic diversity that may be encountered
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35
Q

what are features of group N (new) subtype of HIV?

A
  • mostly confined to parts of West Central Africa e.g. Gabon
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36
Q

what are features of group O (outlier) subtypes of HIV?

A

highly divergent from group M and are largely confined to small numbers centred on Cameroon

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37
Q

what are features of group P subtypes of HIV?

A

related to gorilla strains of SIV has been identified from a patient from Cameroon

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38
Q

how does HIV enter/interact with cells?

A
  • at initial exposure, the virus is transported by dendritic cells from mucosal surfaces to regional lymph nodes where permanent infection is established
  • host cellular receptor that’s recognised by HIV surface glycoprotein gp120 is CD4, which defines the cell populations that are susceptible to infection
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39
Q

what is responsible for HIV entry into cells?

A
  • interaction between CD4 and HIV gp120 surface glycoprotein
  • together with host chemokine CCR5 co-receptors
  • CCR5 CD4 memory T lymphocytes within all body systems are susceptible to infection and depletion; those found in GI tract are heavily infected early in the process and become rapidly depleted leading to compromised mucosal immune function
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40
Q

what is the function of CCR5 CD4 memory T lymphocytes?

A
  • co-receptors that work with HIV gp120 glycoprotein and CD4 to allow entry into cells
  • CCR5 CD4 memory T lymphocytes within all body systems are susceptible to infection and depletion; those found in GI tract are heavily infected early in the process and become rapidly depleted leading to compromised mucosal immune function
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41
Q

what is the HIV half life and virus production like?

A
  • half life of about 6hrs
  • to maintain observed levels of plasma viraemia, 10^8 to 10^9 virus particles need to be released and cleared daily
  • virus production by infected cells lasts for about 2 days and is probably limited to death of the cells
  • HIV replication is linked to the process of CD4 destruction and depletion
  • loss of activated CD4 T lymphocytes is a key factor in the immunopathogenesis of HIV
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42
Q

what is the link between HIV and immunodeficiency? what does this lead to?

A
  • leaves the host open to infections with intracellular pathogens
  • co-existing antibody abnormalities predispose to infections with capsulated bacteria
  • associated with a long-term inflammatory state, which is a key driver of disease progression
  • co-pathogens e.g. cytomegalovirus
  • translocation of microbial products, e.g. LPS, from the gut into into the systemic circulation following HIV destruction of normal mucosal immunity
  • raised level of inflammatory cytokines and coagulation system activation
  • inflammatory responses play a role in HIV-associated end organ damage
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43
Q

when is T cell activation observed in HIV? what does this lead to?

A
  • observed from the earliest stages of infection

- leads to an increase in the numbers of susceptible CD4 bearing target cells that can become infected and destroyed

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44
Q

what are the steps involved in HIV entry and replication in CD4 T lymphocytes?

A
  1. binding: virus binds to host CD4 receptor molecules via the envelope glycoprotein gp120 and co-receptors CCR5 and CXCR4
  2. fusion: subsequent conformational change results in fusion between gp41 and cell membrane of CD4
  3. reverse transcription: entry of viral capsid is followed by uncoating of the RNA. DNA copies are made from both RNA templates. DNA polymerase from host cell leads to formation of dsDNA
  4. integration: in nucleus, virally encoded DNA is inserted into the host genome
  5. transcription: regulatory proteins control transcription; RNA molecule is synthesised from the DNA template
  6. budding: virus is reassembled in the cytoplasm and budded out from the host cell
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45
Q

what is involved in binding of HIV to CD4 T lymphocytes?

A

virus binds to host CD4 receptor molecules via the envelope glycoprotein gp120 and co-receptors CCR5 and CXCR4

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46
Q

what is involved in fusion of HIV to CD4 T lymphocytes?

A

subsequent conformational change results in fusion between gp41 and cell membrane of CD4

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47
Q

what is involved in reverse transcription of HIV in CD4 T lymphocytes?

A

entry of viral capsid is followed by uncoating of the RNA. DNA copies are made from both RNA templates. DNA polymerase from host cell leads to formation of dsDNA

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48
Q

what is involved in integration of HIV in CD4 T lymphocytes?

A

in nucleus, virally encoded DNA is inserted into the host genome

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49
Q

what is involved in transcription of HIV in CD4 T lymphocytes?

A

regulatory proteins control transcription; RNA molecule is synthesised from the DNA template

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50
Q

what is involved in budding of HIV from CD4 T lymphocytes?

A

virus is reassembled in the cytoplasm and budded out from the host cell

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51
Q

how is HIV infection diagnosed?

A

by detection of virus-specific antibodies (anti-HIV) or by direct identification of viral material

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52
Q

what is the recommended UK first line assay? what is an advantage of it?

A

one which tests for HIV antibody and p24 antigen simultaneously
- reduce time between infection and an HIV-positive test result to month; this is several weeks earlier than with sensitive third generation (antibody only detection) assays

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53
Q

what is a fourth generation HIV assay vs third?

A
  • fourth generation ones test for HIV antibody and p24 antigen simultaneously
  • third generation ones test for antibodies only
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54
Q

what are examples of tests used to detect and diagnose HIV?

A
  • detection of IgG antibody to envelope components
  • IgG antibody to p24 (anti-p24)
  • genome detection assays
  • viral p24 antigen
  • isolation of virus in culture
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55
Q

how does the detection of IgG antibody to envelope components test for HIV work?

A
  • most commonly used
  • routine tests for screening are based on ELISA techniques, which may be confirmed Western blot assays
  • up to 3 months may elapse from initial infection to antibody detection (serological window/latency period)
  • IgG antibodies to HIV have no protective function and persist for life
  • anti-HIV crosses the placenta
  • all babies born to HIV-infected women have the anti-HIV antibody at birth
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56
Q

what is STARHS?

A

serologic testing algorithm for recent HIV seroconversions

  • can identify recently acquired infection
  • a highly sensitive ELISA that detects HIV antibodies 6-8 weeks after infection is used on blood in patients with positive oral fluid test
  • in parallel with less sensitive test that identifies later HIV antibodies within 130 days
  • positive result on the sensitive test and negative on the detuned test points to recent infection
  • positive results on both tests point to infection more than 130 days old
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57
Q

how does the IgG antibody to p24 test for HIV work?

A
  • detected from earliest weeks on infection and through the asymptomatic phase
  • lost as disease progresses
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58
Q

how does the genome detection assay for HIV work?

A
  • nucleic acid-based assays that amplify and test for components of the HIV genome exist
  • used to aid diagnosis of HIV in babies of HIV infected mothers or where serological tests may be inadequate
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59
Q

how does the viral p24 antigen test for HIV work?

A
  • detectable shortly after infection but disappears by 8-10 weeks after exposure
  • useful marker in individuals who have been infected recently but have not had time to mount an antibody response
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60
Q

what is isolation of virus in culture for HIV?

A

specialised technique available in some labs to aid diagnosis and as a research tool

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61
Q

what causes the wide spectrum of illnesses associated with HIV infection?

A
  • direct HIV effects
  • HIV-associated immune dysfunction
  • drugs used to treat the condition
  • co-existing morbidity and co-infections
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62
Q

what are categories of the CDC classification of HIV infection?

A

A: asymptomatic or persistant generalised lymphadenopathy or acute seroconversion illness
B: HIV related conditions, not A or C
C: clinical conditions listed in AIDS surveillance case definition

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63
Q

what are levels of absolute CD4 count (/mm^3) used in the summary of CDC classification of HIV infection?

A

> 500
200-499
<200

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64
Q

what are subcategories of A HIV infection (from CDC classification)?

A

A1: >500 CD4 count
A2: 200-499 CD4 count
A3: <200 CD4 count

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65
Q

what are subcategories of B HIV infection (from CDC classification)?

A

B1: >500 CD4 count
B2: 200-499 CD4 count
B3: <200 CD4 count

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66
Q

what are subcategories of C HIV infection (from CDC classification)?

A

C1: >500 CD4 count
C2: 200-499 CD4 count
C3: <200 CD4 count

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67
Q

what are definitions of AIDS?

A

USA: includes individuals with CD4 counts below 200 in addition to clinical classification based on presence of specific indicator diagnoses
Europe: based on diagnosis of specific clinical conditions with no inclusion of CD4 lymphocyte counts

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68
Q

when is progression from HIV to AIDS uncommon?

A

where HAART is available and started before development of severe immunosuppression

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69
Q

what are some AIDS-defining conditions, from C to H?

A 
candidiasis of bronchi, trachea or lungs
candidiasis, oesophageal
invasive cervical carcinoma
disseminated or extrapulmonary coccidioidomycosis
chronic intestinal cryptosporidiosis
cytomegalovirus disease
CMV retinitis
HIV related encephalopathy
herpes simplex, chronic ulcers
disseminated or extrapulmonary histoplasmosis
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70
Q

what are some AIDS-defining conditions, from I to W?

A 
chronic intestinal isosporiasis
Kaposi's sarcoma
Burkitt's lymphoma
immunobasic lymphoma
brain lymphoma
Mycobacterium avium-intracellulare
Mycobacterium TB
Pneumocystis jiroveci pneumonia
recurrent pneumonia
progressive multifocal leucoencephalopathy
recurrent Salmonella septicaemia
toxoplasmosis of the brain
wasting syndrome
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71
Q

what is primary HIV infection? what is involved in it?

A

first 6 month period following HIV acquisition

  • period of uncontrolled viral replication leading to high levels of HIV circulating in the plasma and genital tract
  • high infectiousness
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72
Q

what happens in the weeks after HIV infection?

A

2-4 weeks: may be silent both clinically and seologically

- 3-6 weeks: may be a self-limiting nonspecific ilness

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73
Q

what are symptoms of the self-limiting nonspecific illness that occurs in some people 3-6 weeks after HIV infection? what is its prognosis?

A
  • fever
  • arthralgia
  • myalgia
  • lethargy
  • lymphagenopathy
  • sore throat
  • mucosal ulcers
  • transient faint pink maculopapular rash
  • headache
  • photophobia
  • myelopathy
  • neuropathy
  • encephalopathy (rare)

lasts up to 3 weeks; recovery usually complete

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74
Q

what laboratory abnormalities are there in primary HIV disease?

A
  • lymphopenia with atypical reactive lymphocytes noted on blood film
  • thrombocytopenia
  • raised liver transferases
  • CD4 lymphocytees and the CD4:CD8 ratio is reversed
  • antibodies to HIV may be absent
  • circulating viral RNA is high
  • p24 core protein may be detectable
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75
Q

what is the clinical latency of HIV?

A
  • rate of clinical progression of untreated HIV is variable
  • most people with HIV infection are asymptomatic for some time
  • most people with HIV have a gradual decline in CD4 count over 10 years before progression to AIDS
  • some progress more rapidly, with continued high levels of viral RNA and a rapid decline in CD4 count over 2-5 years
  • other long-term non-progressors, may continue with a normal CD4 count over many years
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76
Q

what are factors affecting clinical latency of HIV?

A
  • older age associated with more rapid progression

- women cope less well

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77
Q

what is persistent generalised lymphadenopathy?

A
  • subgroup of patients with asymptomatic infection have this
  • lymphadenopathy at 2+ extrainguinal sites for more than 3 months in the absence of causes other than HIV infection
  • nodes are usually symmetrical, firm, mobile and non tender
  • may be associated splenomegaly
  • architecture of nodes shows hyperplasia of the follicles and proliferation of the capillary endothelium
  • nodes may disappear with disease progression
  • similar disease progression noted in asymptomatic patients with or without PGL
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78
Q

what are features of symptomatic HIV infection?

A
  • as HIV infection progresses, the viral load rises, CD4 count falls and patient develops signs and symptoms
  • clinical picture is result of direct HIV effects and of associated immunosuppression
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79
Q

what factors do the clinical consequences of HIV-related immune dysfunction depend on?

A
  • microbial exposure of the patient throughout life
  • pathogenicity of organisms encountered
  • degree of immunosuppression of the host
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80
Q

how does microbial exposure of the patient throughout life affect the clinical consequences of HIV-related immune dysfunction?

A
  • many clinical episodes represent reactivation of previously acquired infection, which has been latent
  • geographical factors determine the microbial repertoire of individual patients
  • organisms requiring intact cell-mediated immunity for their control are most likely to cause clinical problems
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81
Q

how does the pathogenicity of organisms encountered affect the clinical consequences of HIV-related immune dysfunction?

A
  • high grade pathogens e.g. Mycobacterium tuberculosis, Candida and the herpesviruses are clinically relevant even when immunosuppression is mild, thus occurring earlier in the course of disease
  • less virulent organisms occur at later stages of immunodeficiency
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82
Q

how does the degree of immunosuppression of the host affect the clinical consequences of HIV-related immune dysfunction?

A
  • when patients are severely immunocompromised (CD4 count <100/mm^3), disseminated infections of organisms of very low virulence e.g. M. avium-intracellulare and Cryptosporidium are able to establish themselves
  • these infections are very resistant to treatment, because there is no functioning immune response to clear organisms
  • hierarchy of infection allows for appropriate intervention with prophylactic drugs
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83
Q

when does infection of the nervous system by HIV occur? what does this include?

A
  • early stage, but clinical neurological involvement increases as HIV advances
  • AIDS dementia complex (ADC), sensory polyneuropathy and aseptic meningitis
  • less common since HAART
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84
Q

what is the pathogenesis of HIV infection causing neurological disease?

A
  • release of neurotoxic products by HIV

- cytokine abnormalities secondary to immune dysregulation

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85
Q

what are the symptoms and features of ADC?

A
  • mild memory impairment and poor concentration to severe cognitive deficit, personality change and psychomotor slowing
  • changes in affect and depressive or psychotic features may be present
  • spinal cord may show vacuolar myelopathy histologically
  • atrophic change in severe cases
  • white matter lesions of increased density on T2 weighted section on MRI
  • EEG shows non specific changes
  • CSF normal, protein may be raised
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86
Q

what are the symptoms of sensory polyneuropathy?

A
  • seen in advanced HIV infection, mainly in the legs and feet, and hands may be affected
  • severe forms cause intense pain, usually in the feet, which disrupts sleep, impairs mobility and generally reduces quality of life
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87
Q

what are the symptoms of autonomic neuropathy?

A
  • may occur with postural hypotension and diarrhoea
  • autonomic nerve damage in the small bowel
  • didanosine and stavudine produce similar neuropathy as a toxic side effect
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88
Q

what are some mucocutaneous manifestations of HIV infection (skin)?

A
  • dry skin and scalp
  • onychomycosis
  • seborrhoeic dermatitis
  • tinea: cruris and pedis
  • pityriasis: versicolor and rosea
  • folliculitis
  • acne
  • molluscum contagiosum
  • warts
  • herpes zoster: multidermatomal and disseminated
  • papular pruitic eruption
  • scabies
  • ichthyosis
  • Kaposi’s sarcoma
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89
Q

what are some mucocutaneous manifestations of HIV infection (mucous membranes)?

A
  • candidiasis: oral and vulvovaginal
  • oral hairy leucoplakia
  • aphthous ulcers
  • herpes simplex: genital, oral, labial
  • periodontal disease
  • warts: oral and genital
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90
Q

how can HIV cause eye disease?

A
  • eye pathology seen in later stages
  • cytomegalovirus retinits: sight-threatening
  • retinal cotton wool spots
  • anterior uveitis: present as acute red eye associated with rifabutin therapy for mycobacterial infections in HIV
  • pneumocystis, toxoplasmosis, syphilis and lymphoma can affect the eye/retina
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91
Q

why is the skin a common site for HIV-related pathology?

A
  • function of dendritic and Langerhans’ cells, both target cells for HIV, are disrupted
  • delayed-type hypersensitivity is reduced or absent even before clinical signs of immunosuppression appear
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92
Q

what are examples of haematological complications caused by HIV? when do they usually occur?

A

common in advanced HIV infection

  • lymphopenia progresses as the CD4 count falls
  • anaemia of chronic HIV infection is usually mild, normochromic and normocytic
  • neutropenia is common and usually mild
  • isolated thrombocytopenia
  • pancytopenia: occurs due to underlying opportunistic infection or malignancies
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93
Q

what are features of isolated thrombocytopenia in HIV?

A
  • may occur early in infection and be only manifestation of HIV for some time
  • platelet counts are moderately reduced
  • circulating antiplatelet antibodies lead to peripheral destruction
  • megakaryocytes are increased in bone marrow but their function impaired
  • effective antiretroviral therapy usually increases platelet count
  • thrombocytopenic patients undergoing dental, medical or surgical procedures may need therapy with human immunoglobin, which increases platelet count, or given transfusion
  • steroids should be avoided
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94
Q

what are examples of myelotoxic drugs?

A
  • zidovudine (megaloblastic anaemia, red cell aplasia, neutropenia)
  • lamivudine (anaemia, neutropenia)
  • ganciclovir (neutropenia)
  • systemic chemotherapy (pancytopenia)
  • co-trimoxazole (agranulocytosis)
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95
Q

what are some GI effects of HIV?

A
  • weight loss and diarrhoea
  • wasting in advanced infection is usually due to anorexia
  • small increase in resting energy expenditure, but weight and lean body mass usually remain normal in periods of clinical latency
  • GI infections are ocmmon
  • villous atrophy with chronic diarrhoea
  • hypochlorhydria in advanced disease
  • rectal lymphoid tissue cells may be resevoirs for infection
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96
Q

what are some renal complications of HIV?

A
  • HIV-associated nephropathy (HIVAN)
  • nephrotic syndrome
  • nephrotoxic drugs used for HIV
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97
Q

what is HIVAN? what are features of it?

A

HIV-associated nephropathy

  • rare
  • causes significant renal impairment, esp. in advanced disease
  • most frequently seen in black males
  • can be exacerbated by heroin use
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98
Q

what are features of nephrotic syndrome caused by HIV?

A
  • subsequent to focal glomerulosclerosis
  • consequence of HIV cytopathic effects on renal tubular epithelium
  • course is usually relentless; dialysis may be needed
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99
Q

what are examples of nephrotoxic drugs used in HIV-associated pathology?

A
  • foscarnet
  • amphotericin B
  • pentamidine
  • sulfadiazine
  • tenofovir
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100
Q

what are some respiratory complications of HIV?

A
  • upper airways and lungs are a physical barrier to air-borne pathogens
  • damage decreases efficiency of protection, leading to an increase in upper and lower respiratory tract infections
  • sinus mucosa may function abnormally, and is a frequent site of chronic inflammation
  • lymphoid interstitial pneumonitis (LIP): paediatric HIV infection
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101
Q

what is LIP? what are features of it?

A

lymphoid interstitial pneumonitis

  • well described in paediatric HIV infection, uncommon in adults
  • infiltration of lymphocytes, plasma cells and lymphoblasts in alveolar tissue
  • Epstein-Barr virus may be present
  • dyspnoea and dry cough
  • reticular nodular shadowing on chest x-ray
  • therapy with steroids
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102
Q

what are some endocrine complications caused by HIV?

A
  • reduced testosterone and abnormal adrenal function
  • intercurrent infection superimposed upon borderline adrenal function precipitates clear adrenal sufficiency, requiring replacement doses of gluco- and mineralocorticoid
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103
Q

what are some cardiac complications of HIV?

A
  • lipid dysregulation associated with antiretroviral medication
  • HDL levels are lower in those with untreated HIV than in HIV-negative controls
  • ischaemic heart disease more common in intermittent ARV therapy than those who maintained viral suppression
  • cardiomyopathy (rare) may lead to congestive cardiac failure
  • lymphocytic and necrotic mycocarditis
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104
Q

what are mechanisms of opportunistic infection in HIV patients?

A
  • defective T cell function against protozoa, fungi and viruses
  • impaired macrophage function against intracellular bacteria
  • defective B-cell immunity against capsulated bacteria
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105
Q

what are some major HIV-associated protozoa?

A 
Toxoplasma gondii
Cryptosporidium parvum
Microsporidia spp. 
Leishmania donovani
Isospora belli
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106
Q

what are some major HIV-associated viruses?

A 
Cytomegalovirus
Herpes simplex
Varicella Zoster
Human papillomavirus
JC polyoma virus
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107
Q

what are some major HIV-associated fungi and yeasts?

A 
Pneumocystis jiroveci
Cryptococcus neoformans
Candida spp. 
Dermatophytes (Trichophyton)
Aspergillus fumigatus
Histoplasma capsulatum
Coccidiodes immitis
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108
Q

what are some major HIV-associated bacteria?

A 
Salmonella spp. 
Mycobacterium tuberculosis
M. avium-intracellulare
Streptococcus pneumoniae
Staphylococcus aureus
Haemophilus influenzae
Moraxella catarrhalis
Rhodococcus equii
Bartonella quintana
Nocardia
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109
Q

what is involved in the initial assessment of HIV-infected patients?

A
  • newly diagnosed patients should be reviewed by an HIV clinician within 2 weeks of diagnosis
  • earlier if they’re symptomatic or has acute needs
  • full medical history, physical examination and lab evaluation should be done to determine stage of infection, presence of co-morbidities and co-infections and to assess overall physical, mental and sexual health
  • details of socioeconomic situation, relationships, family and social support networks and substance misuse
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110
Q

how often are HIV-infected patients monitored?

A

regularly (approx. every 3 months) to assess progression of infection and need for treatment

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111
Q

what is involved in immunological monitoring? what factors affect CD4 counts?

A
  • CD4 lymphocyte counts
  • patients below 200 cells are at greatest risk for HIV-related pathology
  • rapidly falling CD4 counts and those below 350 are indications for HAART
  • factors other than HIV (smoking, exercise, intercurrent infections and diluminal variation) affect CD4 counts
  • CD4 counts are done every 3 months or more if critical levels are being approached
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112
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (haematology)

A

FBC, differential count and film

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113
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (biochemistry)

A
  • serum, liver and renal function including eGFR
  • fasting serum lipid profile, total cholesterol, HDL cholesterol
  • fasting blood glucose
  • serum bone profile including 25 OH vitamin D
  • urinalysis
  • dipstick for blood, protein and glucose
  • urine protein/creatinine ratio
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114
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (immunology)

A
  • lymphocyte subsets

- HLA B*5701 status

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115
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (virology)

A
  • HIV antibody
  • HIV viral load
  • HIV genotype and subtype determination
  • HepA IgG
  • HepB surface antigen and full profile
  • HepC antibody
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116
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (microbiology)

A
  • toxoplasmosis serology
  • syphillis serology
  • screen for other STIs
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117
Q

what is involved in a baseline assessment for a newly diagnosed asymptomatic patient with HIV infection? (other)

A
  • cervical cytology
  • chest x-ray if indicated
  • 10 year cardiovascular risk assessment
  • fracture risk assessment
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118
Q

what is viral load (HIV RNA)?

A
  • HIV replicates at a high rate throughout the course of infection
  • many billion new virus particles produced daily
  • rate of viral clearance is constant and level of viraemia is a reflection of the rate of virus replication; this has prognostic and therapeutic value
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119
Q

what HIV RNA assays for viral load are in current use?

A

viral load encompasses viraemia and HIV RNA levels

  • branched-chain DNA (bDNA)
  • reverse transcription polymerase chain reaction (RT-PCR)
  • nucleic acid sequence based amplification (NASBA)
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120
Q

what is involved in virological monitoring of HIV-infected patients?

A
  • results of assays are given in copies of viral RNA/mL of plasma, or converted to a logarithmic scale
  • good correlation between tests
  • transient increases in viral load are seen after immunisations or in acute intercurrent infection
  • by 6 months after seroconversion to HIV, the viral set point for an individual is established
  • correlation between HIV RNA levels and long-term prognosis, independent of CD4 count
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121
Q

what is involved in genotype determination in HIV?

A
  • clear genotype variations exist within HIV
  • between viral subtypes and also with well-identified point mutations associated with resistance to antiretroviral drugs
  • most appropriate sample for this is one closest to the time of diagnosis and results are used to guide selection of HAART agents
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122
Q

what are limitations to efficacy of HIV treatments?

A
  • inability of current drugs to clear HIV from certain intracellular pools
  • adherence requirements
  • complex drug-drug interactions
  • emergence of resistant viral strains
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123
Q

what are the aims of management in HIV infection?

A
  • maintain physical and mental health
  • improve quality of life
  • increase survival rates
  • restore and improve immune function
  • avoid onward transmission
  • provide appropriative palliative support as needed
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124
Q

what is seroconversion?

A

period in which HIV antibodies first become detectable

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125
Q

what is the immune response to HIV in the first 6 weeks?

A
  • sharp increase and then decrease in viral load, becoming low and staying there at 4-6 weeks
  • sharp increase in antibody to gp120 and CD4 cells, then relative plateau
  • antibody to gp120 increases more than CD4 cell count
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126
Q

what is the immune response to HIV in 6 weeks to 10 years?

A
  • plateau/small increase in viral load
  • small increase then decrease in CD4 cells
  • increase then plateau of antibody to gp120
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127
Q

what is the immune response to HIV in 12 years?

A
  • increase in viral load
  • decrease in CD4 cells
  • plateau/small decrease in antibody to gp120
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128
Q

what is the immune response to antiretroviral therapy at 6-12 weeks?

A
  • sharp decrease in viral load
  • increase in CD4 cells
  • decrease in antibody to gp120
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129
Q

what is required for effective HIV treatment?

A
  • long term maximal suppression of HIV activity using antiretroviral medication and MDT management
  • regular assessment for details of intercurrent medical problems, medications, vaccinations, drug use, sexual history, reproduction, cervical cytology, social situation, employment, benefits and accommodiation
  • mood and cognitive function should be routinely assessed
  • psychological support for patient and family
  • sexual and reproductive health and advice
  • monitoring of weight, BMI, BP and cardiovascular risk
  • dietary assessment and advice
  • general health protection advice
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130
Q

what are potential problems in treating sick HIV-positive patients?

A
  • ADRs
  • acute opportunistic infections
  • presentation or complication of malignancy
  • immune reconstitution phenomenon
  • infection in an immunocompromised host
  • organic or functional brain disorders
  • non-HIV related pathology must not be forgotten
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131
Q

what are things to remember when taking a full medical history of HIV-positive patients?

A
  • ART, prophylaxis, travel, previous HIV-related pathology, potential source of infectious agents (food hygeine, pets, contacts with acute infections, contact with TB, STIs)
  • secure confidentiality
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132
Q

what are things to remember when taking a full physical examination of HIV-positive patients?

A
  • signs of ADRs
  • signs of disseminated sepsis
  • clinical evidence of immunosuppression
  • focal neurological signs and/or meningism
  • evidence of altered mental state - organic or function
  • examine: genitalia, fungi, mouth
  • lymphadenopathy
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133
Q

what are immediate investigations of HIV-positive patients?

A
  • FBC and differential count
  • liver and renal function tests
  • plasma glucose
  • blood gases including acid-base balance
  • blood cultures
  • microscopy and culture of available/appropriate specimens: stool, sputum, urine, CSF
  • malaria
  • serological tests fro cryptococcal antigen, toxoplasmosiss
  • chest x-ray
  • CT/MR scan of brain in focal neurological signs and always before lumbar puncture
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134
Q

what has contributed to consistently improving HIV clinical outcome over time?

A
  • increased potency
  • reduced toxicity
  • greater convenience of formulation
  • compounds with different mechanisms of action
  • improved understanding of drug resistance
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135
Q

what are some types of antiretroviral drugs?

A
  • reverse transcriptase inhibitors
  • protease inhibitors
  • integrase inhibitors
  • fusion inhibitors
  • co-receptor blockers
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136
Q

what are types of reverse transcriptase inhibitors?

A
  • nucleoside/nucleotide analogues

- non-nucleoside analogues

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137
Q

what are nucleoside/nucleotide analogues? what is their mechanism of action? what are some complications?

A
  • NRTIs inhibit the synthesis of DNA by reverse transcription and also act as DNA chain terminators
  • NRTIs need to be phosphorylated intracellularly for activity to occur
  • two drugs of this class are combined to provide the backbone of a HAART regimen
  • NRTIs are associated with mitochondrial toxicity, due to effects on mitochondrial DNA polymerase
  • lactic acidosis is a complication
  • nucleotide analogues have a similar mechanism of action but require 2 intracellular phosphorylation steps (3 for nucleoside analouges)
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138
Q

what are non-nucleoside analogues? what is their mechanism of action? what are some complications?

A
  • NNRTIs interfere with reverse transcriptase by direct binding to the enzyme
  • they’re small molecules that are widely disseminated throughout the body and have a long half-life
  • affect cytochrome P450
  • ineffective against HIV-2
  • level of cross-resistance across the class is high
  • all associated with rashes and elevation of liver enzymes
  • second-generation NNRTIs, e.g. etravirine and rilpivirine,
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139
Q

what are protease inhibitors? what is their mechanism of action?

A
  • act competitively on the HIV aspartyl protease enzyme, which is involved in the production of functional viral proteins and enzymes
  • viral maturation is impaired and immature dysfuntional viral proteins are produced
  • most protease inhibitors are active at low conc. and in vitro are found to have synergy with reverse transcriptase inhibitors
  • cross-resistance can occur across group
  • no activity against human aspartyl proteases, but there are interactions with cytochrome P450
  • abnormalities of fat metabolism and control of blood sugar
  • deterioration in clotting function
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140
Q

what are integrase inhibitors? what is their mechanism of action?

A
  • act as a selective inhibitor of HIV integrase, which blocks viral replication by preventing insertion of HIV DNA into the human genome
  • raltegravir is metabolised by glucuronidation and does not require retroviral drug boosting
  • effective in treating experienced and naive patients
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141
Q

what are co-receptor blockers? what is their mechanism of action? what is required before giving the drug?

A
  • maraviroc is a chemokine receptor antagonist
  • blocks cellular CCR5 receptor by CCR5 tropic strains of HIV
  • strains are found in earlier HIV infection and with time adaptations they allow the CXCR4 receptor to become the more dominant form
  • drug is metabolised by CYP p450 (3A), giving potential drug interactions
  • tropism assays to establish that the patient is carrying a CCR5 tropic virus are required
142
Q

what are fusion inhibitors? what is its mechanism of action?

A
  • enfurvitide
  • injectible peptide derived from HIV gp41 that inhibits gp41-mediated fusion of HIV with the target cell
  • synergistic with NRTIs and PIs
  • no evidence of cross-resistance with other drug classes
  • has an extracellular mode of action
  • few interactions
  • side effects related to subcutaneous route of administration
143
Q

what are examples of NRTIs?

A

tenofovir, abacavir, zidovudine, stavudine, lamivudine, emtricitabine

144
Q

what are examples of NNRTIs?

A

efavirenz, nevirapine, etravirine

145
Q

what are examples of integrase inhibitors?

A

raltegravir

146
Q

what are examples of protease inhibitors?

A

fosamprenavir, atazanavir, darunavir, lopinavir, saquinavir

147
Q

what are examples of CCR5 inhibitors?

A

maraviroc

148
Q

what are examples of fusion inhibitors?

A

enfuvitide

149
Q

what are some characteristics of antiretroviral agents?

A
  • must be taken exactly as prescribed
  • should not be stopped suddenly
  • can be compromised by the introduction of other medications, including other ARVs and vice versa
  • can adversely interact with some herbal, complementary and recreational agents
  • may produce additive toxicities when given with other medications
  • are associated with a range of adverse drug reactions which may be confused with other pathology
  • may exacerbate co-morbidities
150
Q

what patients should start HAART as soon as possible?

A
  • symptomatic HIV disease
  • AIDS
  • CD4 count consistently below 200 cells mm^3

significant risk of serious HIV-associated morbidity and mortality and the longer-term prognosis for patients initiating therapy below 200 CD4 cells/mm^3 is not as good

151
Q

what CD4 counts indicate that patients should start therapy? when should they start therapy as soon as possible?

A
  • around 350 should start

- 200 to 350 should start as soon as possible

152
Q

what is a normal CD4 count?

A

500 cells/mm^3 or above

153
Q

what is a high viral load?

A

> 60000 copies/mL

154
Q

what is a rapidly falling CD4 count?

A

losing more than 80 cells/year

155
Q

with which drugs is HAART treatment initiated?

A

two NRTIs in combination, with either an NNRTI or a boosted protease inhibitor

  • development of fixed-dose coformulations reduces pill burden, increases convenience and facilitates adherence
156
Q

how are NRTIs used in HAART?

A
  • which two NRTIs form the backbone is influenced by efficacy, toxicity and ease of administration
  • availability of OD one-tablet fixed dose combinations, Truvada (TDF/FTC) and Kivexa (ABC/3TC), has led to most patients being prescribed one of these
  • Combivir (ZDV/3TC) is a twice-daily dosing schedule and has lower efficacy and poorer toxicity profile
157
Q

what are some once daily one tablet fixed dose combinations of NRTIs used in HAART?

A

Truvada (TDF/FTC)

Kivexa (ABC/3TC)

158
Q

what is Truvada?

A
  • once daily one tablet fixed dose combination of NRTIs used in HAART
  • TDF/FTC
159
Q

what is Kivexa? when should be used?

A
  • once daily one tablet fixed dose combinations of NRTIs used in HAART
  • ABC/3TC
  • only used in those who are HLAB*5701
160
Q

what is combivir?

A
  • twice daily dosing schedule and poorer toxicity profile than Truvada
  • ZDV/3TC
161
Q

what is stavudine associated with?

A
  • associated with lipodystrophy and peripheral neuropathy and is no longer used as a first-line therapy in the UK
  • used in other parts of the world
162
Q

what are examples of NNRTIs used in HAART?

A
  • efavirenz
  • nevirapine
  • etravirine and rilpivirine
163
Q

what are features of efavirenz?

A
  • NNRTI used in HAART
  • recommended option in the UK
  • good durability over time, potency at low CD4 counts and in high viral loads
  • once-daily dosing
  • associated with CNS side-effects e.g. dysphoria and insomnia and is contraindicated in pregnancy
  • fixed-dose preparation of efavirenz co-formulated with Truvada (Atripla) allows for a one pill once a day regimen
164
Q

what are features of nevirapine?

A
  • NNRTI used in HAART
  • equivalent potency to efavirenz but has a higher incidence of hepatoxicity and rash
  • toxicity is greater in women and in those with higher CD4 counts
  • contraindicated in women with CD4 counts above 250 cells and in men with counts above 400
  • useful alternative to efavirenz if CNS side-effecs are troublesome and in women with lower CD4 counts who wish to conceive
165
Q

what are features of etravirine and rilpivirine?

A
  • second generation NNRTIs
  • used in HAART
  • active against drug-resistant strains and useful in treatment of experienced patients
166
Q

how are protease inhibitors used in HAART?

A
  • used with two NRTIs
  • excellent efficacy in clinical practice
  • usually combined with a low dose of ritonavir which blocks cytochrome P450 metabolism
  • half-life of the active drug is increased, allowing greater drug exposure, fewer pills, enhanced potency and reduced risk of resistance
  • greater pill burden and increased risk of lipid abnormalities, raised fasting TGs
167
Q

what are the most common protease inhibitors used in HAART? what are some side-effects?

A
  • atazanavir, darunavir or lopinavir, boosted with ritonavir are most commonly used as first line therapy
  • all three can cause GI disturbance and lipid abnormalities
  • atazanavir increases unconjugated bilirubin levels and may produce icterus
  • all have interactions with cytochrome P450
168
Q

when should ART be started in primary HIV infection?

A
  • treatment in clinical trial
  • neurological involvement
  • if the CD4 <200 for > months
  • if an AIDS-defining illness is present
169
Q

when should ART be started in established HIV infection, depending on CD4 counts?

A

CD4 <250 treat
CD4 251-350 treat ASAP
CD4 >350 consider enrolment into when to start trial
AIDS diagnosis/CDC stage C - treat (except for TB when CD4 >350)

170
Q

what are the preferred NRTI regimens for HAART?

A
  • tenofovir

- emtricitabine

171
Q

what are the preferred third agents for HAART regimens?

A
  • atazanavir/ritonavir
  • darunavir/ritonavir
  • efavirenz
  • raltegravir
172
Q

what are alternative NRTI regimens for HAART?

A
  • abacavir

- lamivudine

173
Q

what are alternative third agents for HAART regimens?

A
  • lopinavir/ritonavir
  • fosamprenavir/ritonavir
  • nevirapine
  • rilpiverine
174
Q

how can success rates for HAART be measured when first starting therapy?

A
  • by 4 weeks of therapy, the viral load should have dropped by at least 1 log10 copies/mL and by 12-24 weeks should be below 50 copies/mL
  • suboptimal response at either time point demands a full assessment and possible change in therapy
175
Q

how can HAART be monitored once stable on therapy?

A
  • viral load should be routinely measured every 3-4 months
  • CD4 count should be repeated at 1 and 3 months after starting HAART and then every 3-4 months
  • once the viral load is below 50 copies/mL and the CD4 count has been above 350 cells for 12 months frequency may fall to 6 monthly
176
Q

what should regular clinical assessment of HAART include?

A
  • review of adherence to and tolerability of the regimen, weight, blood pressure adn urinalysis
  • monitored for drug toxicity, including FBC, liver and renal function and fasting lipids and gluose levels
177
Q

what should be involved in clinical history taking when monitoring patients on HAART?

A
  • assessment of adherence to medication

- evidence of ART toxicity

178
Q

what should be involved in physical examination on HAART?

A
  • BP
  • weight
  • HIV viral load
  • lymphocyte subsets
  • FBC
  • urinalysis if taking tenofovir
  • liver and renal function
  • fasting lipid profile
  • fasting blood glucose
179
Q

what are additional investigations in monitoring patients on HAART?

A
  • HIV genotype if there is evidence of virological failure

- therapeutic drug level monitoring

180
Q

what are some mechanisms and implications of HIV drug resistance?

A
  1. HIV replicates rapidly and inaccurately; replication in presence of ART leads to selection pressure for mutations which can survive
  2. specific point mutations in the viral reverse transcriptase protease and integrase genes correlate with reduced drug sensitivity
  3. inadequate ARV drug levels fail to suppress viral replication/viral load and percipitate drug resistance
  4. inadequate drug levels
  5. some ARVs have a low genetic barrier
  6. stopping drugs with a long half-life can leave a subtherapeutic drug tail for long enough for resistant strains to develop
  7. therapeutic drug monitoring
  8. introduction of new drugs can impact cytochrome P450
  9. wild type virus reasserts itself without drug selection pressure
  10. resistant variants survive and are archived. reappear if selection pressure is reintroduced.
181
Q

what does HIV replication in presence of ARV drugs lead to?

A

selection pressure for those that can survive

182
Q

what can cause inadequate ARV drug levels? what can this lead to?

A
  • poor adherence, altered GI tract absorption, increased drug breakdown and drug-drug interactions
  • fail to suppress viral replication/viral load and precipitate drug resistance
183
Q

what is a low genetic barrier?

A

small number of mutations that occur rapidly can quickly result in high levels of resistance

184
Q

what can stopping drugs with a long half life lead to?

A
  • leave a subtherapeutic drug tail for long enough for resistant strains to develop
185
Q

what happens without drug selection pressure?

A

wild type virus reasserts itself and resistant variants no longer make up the major circulating viral strains and may not be found on investigation
- genotyping should be done

186
Q

what happens to resistant variants?

A
  • survive and are archived
  • reappear if drug selection pressure is reintroduced
  • all previous genotypes need to be considered when assessing virological failure and planning new therapy
187
Q

what factors affect adherence to HAART?

A
  • side-effects of medications
  • degree of complexity and pill burden
  • inconvenience of the regimen
  • level of motivation and commitment to the therapy
  • psychological wellbeing
  • level of available family and social support and health beliefs
188
Q

what can poor adherence to HAART lead to?

A
  • patients beliefs about their personal need for medicines and their concerns about treatment affect how or whether they take them
  • levels of adherence below 95% have been associated with poor virological and immunological responses
  • poor absorption and low bioavailability leads to levels being inadequate to suppress viral replication
  • even missing a single dose will reduce plasma drug levels a lot
  • patchy adherence facilitates emergence of drug-resistant variants, which lead to virological treatment failure
189
Q

what is failure of ARV treatment caused by?

A
  • persistent viral replication causing immunological deterioration and eventual clinical evidence of disease progression
  • caused by poor adherence, limited drug potency, substances that compromise drug absorption, interaction, limited penetration, side effects etc
190
Q

what are reasons to review HIV therapy?

A
  • rise in viral load
  • falling CD4 count
  • new clinical events that imply progression of HIV disease
191
Q

what is virological failure defined as?

A

two consecutive viral loads of >400 copies/mL in a previously fully suppressed patient

192
Q

when should ARV drugs be stopped?

A
  • cumulative toxicity
  • potential drug interactions with medications
  • poor adherence (stopping completely is preferable to continuing with inadequate dosing, to reduce the development of viral resistance)
  • poor quality of life
  • views of the patient
193
Q

what are features of allergic reactions as complications to HAART?

A
  • abacavir is associated with a potentially fatal hypersensitivity reaction, associated with the presence of HLAB*5701, usually in first 6 weeks
  • may be a discrete rash and fever, malaise and GI/resp symptoms
  • rechallenge with abacavir can be fatal and is contraindicated
  • allergies to NNRTIs (second or third week of treatment) present with widespread maculopapular pruritic rash with fever and disordered liver biochemical tests
  • drugs should be stopped in mucous membrane involvement or severe hepatic dysfunction
194
Q

what are features of lipodystrophy and metabolic syndrome as complications to HAART?

A
  • characteristic morphological changes and metabolic abnormalities
  • loss of subcutaneous fat in the arms, legs and face, deposition of visceral, breast and local fat, raised total cholesterol, HDL cholesterol and triglycerides and insulin resistance with hyperglycaemia
  • associated with increased cardiovascular morbidity
  • PIs and NRTIs have been implicated
  • statins and fibrates recommended, and tesamorelin
195
Q

what are features of mitochondrial toxicity and lactic acidosis as complications to HAART?

A
  • mitochondrial toxicity involes stavudine and didanoside (nucleoside analogues) and leads to raised lactate and lactic acidosis
  • NRTIs inhibit gamma DNA polymerase and other enzymes necessary for mitochondrial function
  • symptoms include anorexia, nausea, abdominal pain and general malaise
  • venous lactate is raised and the anion gap is widened
  • requires immediate cessation of ART and supportive measures until normal biochemistry is restored
196
Q

what are features of bone metabolism as a complication to HAART?

A
  • bone disorders are reported in HIV, e.g. osteoporosis, osteopenia and avascular necrosis
  • varied prevalence
  • ARVs, esp. PIs, have been implicated in the aetiology
197
Q

what is IRIS? what are features of it as a complication of HAART?

A

immune reconstitution inflammatory syndrome

  • occurs in people who have been very immunosuppressed and begin therapy
  • as their immune system recovers, they can mount an inflammatory response, which can exacerbate symptoms
  • unusual mass lesions or lymphadenopathy associated with mycobacteria, deteriorating radiological appearances associated with TB
  • inflammatory retinal lesions in association with cytomegalovirus, deterioration in liver function in chronic hep B carriers and vesicular eruptions with herpes zoster
198
Q

what are examples of complications that can occur from HAART?

A
  • allergic reactions
  • lipodystrophy and metabolic syndrome
  • mitochondrial toxicity and lactic acidosis
  • bone metabolism
  • IRIS
199
Q

what is the use of ART in acute seroconversion?

A
  • unique opportunity for therapy as there’s less viral diversity and the host immune capacity is still intact
  • viral load can be reduced substantially by aggressive therapy at this stage, but it rises when treatment is withdrawn
  • people with severe symptoms during primary HIV infection may gain a clinical improvement on ARVs
200
Q

what is the use of ART in pregnancy?

A
  • in the UK, the mother-to-child HIV transmission rate is 1% for all women diagnosed prior to delivery and 0.1% for women on HAART with a viral load below 50 copies/mL
  • management aim is to deliver a healthy, uninfected baby to a healthy mother without prejudicing future treatment options of the mother
  • breastfeeding doubles the risk of vertical transmission
  • triple therapy is used
  • risk of vertical transmission increases with viral load
  • treatment should start ASAP and continue during delivery
201
Q

what is PEP?

A

post-exposure prophylaxis

  • animal models provide support for use of triple ARVs
  • healthcare workers and those exposed sexually can be given this
  • risk of acquisition of HIV following exposure is dependent upon the risk that the source is HIV positive and the risk of transmission of the exposure
  • may be useful up to 72 hours after exposure
  • in the UK, the standard regimen is Truvada plus Kaletra
  • given for 4 week
  • toxicity should be monitored
202
Q

what are some causes of opportunistic pneumonia in immunocompromised patients?

A
  • pneumocystis jiroveci
  • non-TB mycobacterial species
  • Nocardia spp
  • Aspergillus spp
  • Zygomycetes spp
  • Penicillium spp
  • Cryptococcus spp.
  • Histoplasma capsulatum
  • Coccidomycosis
  • Paracoccidiodomycosis
  • Blastomycosis
  • CMV
  • respiratory syncyitial virus
  • toxoplasma gondii
203
Q

what is the affected patient population of Pneumocystis jiroveci?

A

impaired cell-mediated immunity; HIV infection with CD4 < 200/mm^3, long-term corticosteroid use, immunosuppressant drugs

204
Q

what are the clinical and radiographic features of Pneumocystis jiroveci?

A
  • pneumocystis pneumonia

- perihilar ground-glass shadowing, cysts

205
Q

what is the affected patient population of non-TB mycobacterial species?

A

impaired cell-mediated immunity; HIV infection CD4 usually < 200mm^3
structural lung disease: bronchiectasis, CF, severe COPD

206
Q

what are the clinical and radiographic features of non-TB mycobacterial species?

A
  • varied clinical presentation: non-specific fevers, cough, malaise, lymphadenopathy, hepatosplenomegaly
  • CT findings: nodules, cavitation, thickened airways, tree in bud small airways
207
Q

what is the affected patient population of Nocardia spp?

A

impaired cell-mediated immunity: HIV infection CD4 usually <150/mm^3, chronic corticosteroid use, post-solid-organ transplantation, post stem cell transplantation
structural lung disease: bronchiectasis, CF, severe COPD

208
Q

what are the clinical and radiographic features of Nocardia spp?

A
  • acute sub-acute or chronic pneumonia

- multiple radiographic presentations: lobar infiltrates, abscesses, cavities, pleural effusion, pulmonary nodules

209
Q

what is the affected patient population in Aspergillus, Zygomycetes and Penicillium spp?

A

prolonged neutropenia: post-chemotherapy for haematological malignancy, post-stem cell transplant
impaired cell-mediated immunity: graft-versus-host disease, immunosuppressant therapy
chronic granulomatous disease

210
Q

what are clinical and radiographic features of Aspergillus, Zygomycetes and Penicillium spp?

A
  • invasive fungal pneumonia characterised by cough, haemoptysis, pleuritic pain and fevers
  • CT findings: cavitating consolidation, tree in bud, nodules with ground glass halo and in later stages air-crescent sign (caused by lung necrosis)
211
Q

what is the typical patient population of Cryptococcus spp?

A

impaired cell-mediated immunity: HIV infection CD4 usually <200/mm^3, chronic corticosteroid use, post-solid-organ transplantation, post-stem cell transplantation

212
Q

what are the clinical and radiological features of Cryptococcus spp?

A
  • nonspecific respiratory symptoms of fever, cough, breathlessness
  • usually associated with neurological involvement, isolated pulmonary disease does occur
  • progresses to disseminated disease in immunocompromised patients
  • CT findings: cavitites, nodules, infiltrates
213
Q

what is the typical patient population of Histoplasma capsulatum?

A

impaired cell-mediated immunity: HIV infection CD4 usually <50/mm^3

214
Q

what are the clinical and radiological features of Histoplasma capsulatum?

A
  • fever, fatigue, weight loss
  • cough and dyspnoea are most common respiratory symptoms
  • chest x-ray can be normal in disseminated disease
  • CT findings: diffuse reticular/reticulonodular infiltrates, miliary infiltrates, occasionally mediastinal lymphadenopathy
215
Q

what is the typical patient population of Coccidioidomycosis, Paracoccidioidomycosis and Blastomycosis?

A

impaired cell-mediated immunity: HIV infection CD4 usually <50/mm^3

216
Q

what are the clinical and radiological features of Coccidioidomycosis, Paracoccidioidomycosis and Blastomycosis?

A
  • often presents as disseminated disease (chext x-ray often normal)
  • focal or diffuse pneumonia
  • CT findings: diffuse reticulonodular infiltrates, consolidation, nodules, cavities, mediastinal lymphadenopathy
217
Q

what is the typical patient population of cytomegalovirus?

A

impaired cell-mediated immunity: HIV infection CD4 usually <50/mm^3, post-transplantation on immunosuppressant therapy

218
Q

what are the clinical and radiological features of cytomegalovirus?

A
  • cough dyspnoea and fever

- CT findings: reticular or ground-glass opacities, alveolar infiltrates, nodules/nodular opacities, pleural effusions

219
Q

what is the typical patient population of respiratory syncytial virus, human metapneumovirus, influenza and parainfluenza?

A

impaired cell-mediated immunity: HIV infection CD4 usually <200/mm^3, chronic corticosteroid use, post-solid-organ transplantation, post-stem cell transplantation

220
Q

what are the clinical and features of respiratory syncytial virus, human metapneumovirus, influenza and parainfluenza?

A
  • cough dyspnoea and fever

- CT findings: ground glass opacification, air-space shadowing, tree in bud, airway dilation and wall thickening

221
Q

what is the typical patient population of Toxoplasma gondii?

A

impaired cell-mediated immunity: HIV infection CD4 usually <100/mm^3

222
Q

what are the clinical and radiological features of Toxoplasma gondii?

A
  • isolated pulmonary or disseminated disease
  • dry cough, fever, dyspnoea
  • CT findings: appearance similar to PCP or fungal pneumonia; pleural effusion
223
Q

what are some vaccines that can be used in all HIV-infected adults (all infected)?

A 
anthrax
cholera- WC/rBS
hepatitis A and B
haemophilus influenzae b 
influenza - parenteral
Japanese encephalitis
meningococcus - MenC, ACWY, PPV23
poliomyelitis - parenteral (IPV)
rabies
tetanus-diphtheria
tick-borne encephalitis
typhoid - ViCPS
224
Q

what are some vaccines that are contraindicated in all HIV-infected adults?

A 
cholera - CVD103-HgR (live)
influenza - intranasal (live)
poliomyelitis - oral (OPV) (live)
typhoid - Ty21a (live)
TB (BCG) (live)
smallpox (vaccinia) (live)
225
Q

what are vaccines that can be used only in asymptomatic HIV-infected adults with a current CD4 count >200 cells/mm^3

A

measles, mumps, rubella (MMR)
varicella
yellow fever

226
Q

how is opportunistic infection in HIV-infected patients prevented?

A
  • avoid infection
  • immunisation strategies
  • chemoprophylaxis
227
Q

how can HIV-infected patients avoid opportunistic infections?

A
  • food and hygeine
  • reduce exposure to Salmonella, toxoplasmosis and Cryptosporidium and protected sexual intercourse will reduce exposure to herpes simplex virus, hepatitis B and C and papillomavirus
  • CMV-negative patients should be given CMV-negative blood products
  • travel-related infection can be minimised with appropriate advice
228
Q

what is the use of chemoprophylaxis in preventing HIV OIs?

A
  • many OIs are hard to eradicate using antimicrobials and the recurrence rate is high
  • primary and secondary prophylaxis have reduced incidence of many OIs
229
Q

what are the disadvantages of chemoprophylaxis?

A

potential for toxicity, drug interactions and cost

230
Q

what does primary prophylaxis prevent?

A
  • effective in reducing the risk of Pneumocystis jiroveci, toxoplasmosis and Mycobacterium avium-intracellulare
  • not normally recommended against CMV, herpes viruses or fungi
231
Q

what is CD4/HIV RNA copies like in primary infection?

A
  • high CD4 count (1050 cells/mm^3)

- low HIV/RNA copies (10^2 per ml plasma)

232
Q

what is CD4/HIV RNA copies like in acute HIV syndrome?

A
  • decrease to 500 CD4 count per mm^3 at 6 weeks, then increase to about 600
  • sharp increase in HIV RNA copies, to a peak of about 10^6 per ml plasma at 6 weeks, then a sharp decrease to 10^3.5
233
Q

what is CD4/HIV RNA copies like in clinical latency?

A
  • rise of CD4 count to 700 cells per mm^3 at 12 weeks, then decrease until about 8 years
  • slow increase in HIV RNA copies from 10^3.5 at 9 weeks to 10^4 at 8 years
234
Q

what is CD4/HIV RNA copies like when constitutional symptoms develop?

A
  • slow increase of HIV RNA copies, about 10^4 per ml plasma

- decreasing CD4 count

235
Q

what is CD4/HIV RNA copies like when opportunistic diseases occur and there is death?

A
  • increase in HIV RNA copies, 10^5 when OIs occur and around 10^6.5 at death
  • CD4 counts very low, around 50 when OIs occur and 10 at death
236
Q

what two markers are used to monitor HIV infection?

A
  • CD4 cell count

- HIV viral load

237
Q

when does acute HIV syndrome occur?

A
  • seroconversion
  • usually within 2-4 weeks of infection
  • similar to glandular fever/flu
238
Q

what are symptoms of acute HIV syndrome (seroconversion)?

A
  • fever
  • sore throat
  • myalgia
  • rash
  • vomiting and diarrhoea
  • headache
  • lymphadenopathy
  • weight loss

if symptoms are more severe, their disease will progress more rapidly

239
Q

what should be thought about in patients with fever, rash and non-specific symptoms?

A
  • ask about sexual history

- think of HIV seroconversion

240
Q

what is clinical latency?

A
  • undiagnosed
  • immune system starts to take control and the CD4 cell population increases, and the viral load decreases
  • over time the CD4 population slowly declines until the person is immunosuppressed enough to present with constitutional symptoms and OIs
  • 8 years
241
Q

what are symptoms of clinical latency of HIV?

A
  • no symptoms

- may notice some enlarged lymph nodes -> persistent generalised lymphadenopathy

242
Q

what is persistent generalised lymphadenopathy?

A

enlarged lymph nodes involving at least 2 areas of the body for at least 3 months

243
Q

what are categories of early symptomatic HIV?

A
  • bacterial
  • viral
  • fungal
  • autoimmune
  • constitutional
244
Q

what are bacterial symptoms of early symptomatic HIV?

A
  • pelvic inflammatory disease
  • listeriosis
  • recurrent sinusitis
  • bacterial pneumonia
245
Q

what are viral symptoms of early symptomatic HIV?

A
  • oral hairy leucoplakia
  • shingles
  • cervical dysplasia CIN
  • peripheral neuropathy
  • molluscum contagiosum
  • herpes simplex
246
Q

what are fungal symptoms of early symptomatic HIV?

A
  • oral or vaginal candida (thrush)
  • fungal nail
  • tinea capitis
  • seborrhoeic dermatitis
247
Q

what are constitutional symptoms of early symptomatic HIV?

A
  • chronic diarrhoea
  • pyrexia of unknown origin
  • weight loss
  • lymphadenopathy
248
Q

when should you think about doing a HIV test?

A

when faced with a common problem in:

  • an unexpected patient
  • no clear underlying cause
  • recurring infections
249
Q

what is AIDS defined as?

A

acquired immune deficiency syndrome

  • CD4 <200
  • AIDS defining illness present
250
Q

what is the most common AIDS defining illness?

A

pneumocystis pneumonia (PCP)

  • fungal pneumonia (Pneumocystis jirovecii)
  • 42.6% prevalence in AIDS
251
Q

what are symptoms of pneumocystis pneumonia?

A

fevers, SOB, dry cough, pleuritic chest pain, exertional drop in oxygen sats

252
Q

how can pneumocystis pneumonia be detected?

A

chest xray

  • can be normal
  • if abnormal, variable
  • classically bilateral interstitial changes in perihilar areas

ABG for hypoxia

induced sputum for PCR
- nebulised saline to acquire sputum

253
Q

what is the treatment of pneumocystis pneumonia?

A

co-trimoxazole (trimethoprim + sulfamethoxazole)

- +/- prednisolone (steroids) if hypoxic

254
Q

what is the most common opportunistic infection in HIV?

A

pneumocystis pneumonia

255
Q

what does late diagnosis of HIV lead to?

A
  • increased transmission
  • increased morbidity
  • increased mortality
256
Q

what are bacteria causing respiratory problems in HIV?

A
  • streptococcus pneumonia
  • haemophilus influenzae
  • s. aureus
  • pseudomonas aeruginosa
  • escherichia coli
  • mycobacterium TB
  • non-TB mycobacterium
257
Q

what are fungi causing respiratory problems in HIV?

A
  • pneumocysitis jirovecii (PCP)
  • candidiasis
  • aspergillus spp
  • cryptococcus neoformans
  • histoplasmosis
  • penicillium marneffei
  • coccidioidomycosis
258
Q

what are viruses causing respiratory problems in HIV?

A
  • CMV pneumonitis
  • adenovirus
  • herpes simplex pneumonitis
259
Q

what are parasites causing respiratory problems in HIV?

A
  • stronglyoids stercoralis

- toxoplasma gondii

260
Q

what are non-infectious things causing respiratory problems in HIV?

A
  • Kaposi’s sarcoma
  • lymphoma
  • lung cancer
  • immune reconstitution inflammatory syndromes (IRIS)
  • emphysema
  • pulmonary hypertension
  • interstitial pneumonitis
261
Q

what are CNS presentations of HIV? what are they caused by?

A

mass lesions

  • primary CNS lymphoma
  • M. TB
  • toxoplasmosis

opthalamic

  • toxoplasmosis
  • m. TB
  • CMV

meningitis

  • m. TB
  • pneumococcal meningitis
  • cryptococcal meningitis
262
Q

what are characteristics of CNS mass lesions caused by TB in HIV?

A
  • single mass with surrounding oedema

- lymphocytic CSF

263
Q

what are characteristics of CNS mass lesions caused by toxoplasmosis in HIV?

A
  • reactivation of latent infection
  • seroprevalence 15-50%
  • CD4 <100
  • bilateral ring enhancing lesions on MRI
  • treated with sulphadiazine and pyrimethamine (+ folic acid)
264
Q

what are characteristics of opthalamic CNS damage due to toxoplasmosis in HIV?

A
  • reactivation of latent infection
  • up to half of the UK population will have the infection at some point
  • IgG negative -> IgG positive
  • CD4 <100
  • bilateral ring enhancing lesions on MRI
  • treated with sulphadiazine and pyrimethamine (+folic acid)
265
Q

what are characteristics of opthalamic CNS damage due to toxoplasmosis in HIV?

A
  • ocular TB can involve any part of the eye (e.g. uveitis, retinal, orbit, external eye) and can occur with or without evidence of systemic TB
  • picture is choroidal granuloma
  • histology: granulomas and AFBs
  • develops following hematogenous spread from a primary focus, but in rare cases can also occur as a primary infection following an epithelial injury
266
Q

what is opthalamic CNS damage due to CMV in HIV treated with?

A

(val)ganciclovir

267
Q

what is the presentation of TB meningitis?

A
  • variable presentation as an acute meningitis to a progressive dementia
  • cranial nerve palsies (most often 6th)
  • insidious onset of headache: 1 day to 6 months
  • night sweats and fevers
  • vomiting
  • active pulmonary TB present in 30-60% of cases
  • without treatment, proceeds to coma and death
268
Q

what are histological characteristics of bacterial meningitis?

A
  • neurophil polymorphs
  • high protein
  • low glucose
269
Q

what are histological characteristics of viral meningitis?

A
  • lymphocytes on microscopy
  • high protein
  • variable glucose
270
Q

what are histological characteristics of TB meningitis?

A
  • lymphocytes on microscopy
  • high protein
  • low glucose
271
Q

what are characteristics of pneumococcal meningitis?

A
  • caused by strep pneumoniae
  • common pathogen in immunocompetent meningitis too
  • associated with neurological sequelae
  • patients are immunised against strep pneumo
272
Q

what are characteristics of cryptococcal meningitis?

A
  • gradual onset headache and fever (weeks)
  • little to find on examination and CT
  • very high opening pressure
  • india ink stain to visualise on microscopy
  • treat with amphoteracin B and flucytosine
273
Q

how does HIV affect cancer risk?

A

increases risk of any cancer that’s associated with a virus

  • human herpes virus 8 -> Kaposi’s sarcoma
  • epstein barr virus -> lymphomas
  • human papillomavirus -> cervical, anal, penile carcinoma
  • hepatitis B/C -> hepatocellular carcinoma
  • anal cancer
  • seminoma
  • head and neck cancer
  • Castleman’s disease
  • vaginal neoplasia
  • penile cancer
274
Q

what are features and treatment of Kaposi’s sarcoma?

A
  • caused by human herpesvirus 8
  • usually associated with HIV
  • single -> multiple lesions
  • usually on the skin
  • rarely genetic
  • other sites: mouth, GI tract -> GI bleed, respiratory tract
  • treated with HAART and chemo/radiotherapy
275
Q

what are CNS AIDS illnesses? which ones are AIDS defining? * = AIDS defining

A 
cerebral toxoplasmosis*
TB*
primary CNS lymphoma*
cryptococcal meningitis*
CMV retinitis*
progressive multifocal leukoencephalopathy (JC virus)*
HIV encephalopathy*
viral encephalitis (HSV, CMV*, VZV)
276
Q

what are skin AIDS illnesses? which ones are AIDS defining? * = AIDS defining

A 
persistent HSV*
Kaposi's sarcoma*
shingles (VZV)
molluscum contagiosum
fungal skin infections
severe psoriasis
277
Q

what are micellaneous AIDS illnesses? which ones are AIDS defining? * = AIDS defining

A

wasting syndrome*
recurrent salmonella sepsis*
cervical cancer*
other viral associated cancers

278
Q

what are respiratory AIDS illnesses? which ones are AIDS defining? * = AIDS defining

A 
recurrent pneumonia*
PCP*
TB*
Kaposi's sarcoma*
candidiasis*
CMV or HSV pneumonitis*
lymphoma*
histoplasmosis*
coccidiomycosis*
aspergillus
279
Q

what are GI AIDS illnesses? which ones are AIDS defining? * = AIDS defining

A 
Kaposi's sarcoma*
CMV colititis*
candidiasis* (oral candida isn't AIDS defining)
HSV oesophagitis*
cryptosporidium*
isosporiasis*
disseminated MAI*
280
Q

why does HIV develop drug resistance?

A
  • 1 mutation in every 2 new viruses
  • 1-10 billion new virus particles each day
  • 1-5 billion mutations per day
281
Q

how does HIV develop drug resistance?

A
  1. non adherence

2. drug-drug interactions

282
Q

what are some key points about HIV/AIDS?

A
  1. CD4 and viral load are used to monitor infection
  2. in a patient with fever, rash and non-specific symptoms - ask about sexual history/risks and think of HIV seroconversion
  3. think about doing a HIV test when faced with a common problem in an unexpected patient/no reason for symptoms/recurring infection
  4. PCP is the most common opportunistic infection
  5. consider a lumbar puncture in a seropositive person with a headache
  6. with current HAART regimes, PLWH can live a normal life
  7. good adherence and avoidance of drug interactions are key to avoid drug resistance
283
Q

what was the epidemiology of HIV epidemic in 2018?

A
  • people living with HIV: 37.9 million
  • people newly infected with HIV: 1.7 million
  • HIV related deaths: 770000
  • about 5000 new infections (adults and children) a day
  • 61% in sub-Saharan Africa
  • 500 are among children under 15
  • number of PLWH has steadily increased from 1990s
  • number of deaths in adults and children increased from 1990 and peaked in 2005, then has gradually decreased
284
Q

what are the UNAIDS goals?

A

90/90/90 global target

  • 90% of people living with HIV being diagnosed
  • 90% diagnosed on ART
  • 90% viral suppression for those on ART by 2020
  • 30 million people on treatment
  • fewer than 500000 new HIV infections annually
285
Q

what is the prevalence of HIV in the UK?

A
  • latest MPES estimates showed the number of PLWH as 103800

- estimated 7500 of these people living with an undiagnosed infection

286
Q

how diverse is the HIV epidemic?

A
  • diverse group

- assumptions about the characteristics of those living with HIV should be challenged

287
Q

what are the transmission routes of HIV?

A
  • blood
  • sexual
  • vertical
288
Q

how can HIV be prevented?

A
  • ARV treatment (U=U)
  • PreP
  • circumcision
  • PEP
  • STI control
  • vaccines
  • microbicides
  • HIV diagnosis/partner notification
  • behavioural/condom use
  • screen blood products/needle exchange
289
Q

what is U=U?

A

undetectable = untransmittable

  • review produced 4000 couple-years of follow up
  • combined HIV transmission risk estimate while HIV positive person was virally suppressed, of 0.00 (0.00-0.07) per 100 couple years
  • no cases of linked HIV transmission to sexual partners when the person with HIV was virally suppressed have been documented
290
Q

what is PreP?

A

pre-exposure prophylaxis

  • when people at risk for HIV take daily medicine to prevent HIV
  • can stop HIV from spreading through the body
  • when taken daily, it’s highly effective for preventing HIV from sex or injection drug use
  • less effective when not taken consistently
291
Q

what is PEP?

A

post exposure prophylaxis

  • taking ART after being potentially exposed to HIV to prevent becoming infected
  • used only in emergency situations
  • must be started within 72 hours after a recent possible exposure to HIV
292
Q

what are the risks of sexual acquisition of HIV following exposure from a known HIV+ partner?

A
  • receptive anal intercourse (0.1-3%)
  • receptive vaginal intercourse (0.1-0.2%)
  • insertive vaginal intercourse (0.03-0.09%)
  • insertive anal intercourse (0.06%)
  • receptive oral sex (0-0.04%)
293
Q

what are the benefits of knowing your HIV status?

A
  • access to appropriate treatment and care
  • reduction in morbidity and mortality
  • reduction of vertical transmission
  • reduction of sexual transmission
  • public health
  • cost effective
294
Q

why is early diagnosis of HIV cost effective?

A

savings on social care, lost working days, benefits claimed, costs associated with further onward transmission

295
Q

how can the detection and diagnosis of HIV in non-HIV specialties including primary care be improved?

A
  • be alert to circumstances appropriate to offer and recommend an HIV test
  • patients may have an unacknowledged but identifiable risk, or have signs and symptoms of HIV infection
  • HIV testing in GP would expedite referral directly to HIV services
  • misconceptions create barriers to uptake: pre-test HIV counselling is not a requirement; negative HIV test doesn’t need to be disclosed on applications for insurance
296
Q

why do doctors not test for HIV?

A
  • they don’t think of HIV
  • underestimate the risk of HIV in their patients
  • failure to recognise HIV as a modifiable prognostic indicator
  • misconception that they need pre-test counselling
  • misunderstanding of the implications for insurance, etc
  • fear of offending the patient

these concerns have been overcome in the antenatal setting

297
Q

what are high risk behaviours for HIV?

A
  • sexual contact with people from high prevalence groups - MSM, IVDUs, sub-Saharan Afrca/Thailand/Eastern Europe/USA
  • multiple sexual partners
  • rape in high prevalence localities
  • vertical
  • patients may not admit risk factors or be unaware of their risks
298
Q

what can raise suspicion of HIV?

A
  • generalised lymphadenopathy
  • acute generalised rash
  • glandular fever/flu-like illness
  • think about seroconversion
  • prolonged episodes of herpes simplex
  • persistent frequently recurrent candidiasis
  • oral candida
  • indicators of immune dysfunction
  • recently developed or worsening skin conditions
  • odd looking mouth lesions
  • unexplained weight loss or night sweats
  • persistent diarrhoea
  • gradually increasing SOB and dry cough
  • recurrent bacterial infections including pneumococcal pneumonia
299
Q

what are examples of recurrent, severe or unexplained conditions that may indicate HIV?

A
  • multi-dermatomal shingles
  • unexplained lymphadenopathy
  • unexplained weight loss or diarrhoea, night sweats, PUO
  • oral/oesophageal candidiasis or hairy leukoplakia
  • flu-like illness, rash, meningitis
  • unexplained blood dyscrasias
300
Q

who can offer testing for HIV?

A
  • any competent healthcare professional
  • normalise the test: document verbal consent; determine how results will be given
  • written consent unnecessary
  • pre-test HIV counselling is not required
301
Q

what screening tests can be used for HIV?

A
  • venous blood sample is preferred
  • 4th generation HIV tests include p24 antigen and will detect the vast majority of infections at 4 weeks (if negative, repeat at 8 weeks if high index of suspicion)
  • high sensitivity and specificity
  • salivary antibody screening tests available
302
Q

what are HIV point of care tests?

A
  • finger prick blood
  • lower sensitivity and specificity
  • false positive and negative results
303
Q

what are advantages of point of care HIV testing?

A
  • outreach into community settings/non-specialist clinics
  • increase patient choice
  • increased access to testing and case detection
  • earlier diagnosis in non-healthcare seeking individuals
  • reduce risk of complications
  • reduce transmission
304
Q

what are some pitfalls of self testing for HIV?

A
  • anxiety
  • incubation/window periods
  • misdiagnoses
  • inadequate partner notification: reinfection; onward transmission
305
Q

what is the management of self-testing for HIV?

A

negative test
- repeat if within window period

positive result or result not clear

  • phone sexual health or ID for advice and arrange an appointment for within 48 hours
  • explain test is reactive and needs further investigation
306
Q

how should partners be notified of HIV?

A
  • discuss soon after diagnosis
  • length of look back depends on individual circumstances
  • document discussion of safer sex practices and PEPSE
  • discuss reckless transmission
307
Q

what are retroviruses?

A
  • enveloped viruses
  • viral genetic material is RNA which is copied into DNA by reverse transcription and incorporated into the host cell to allow gene transcription
308
Q

what leads on from retroviridae?

A

orthoretrovirinae -> lentiviruses

309
Q

what are lentiviruses?

A

genus of slow viruses with long incubation period

310
Q

what is in the subfamily of lentiviruses?

A
  • bovine immunodeficiency virus
  • equine lentivirus
  • feline immunodeficiency virus
  • ovine lentivirus visna/maedi virus
  • primate lentivirus group
311
Q

what is included in the subfamily of primate lentivirus group?

A

HIV-1
HIV-2
SIV (simian immunodeficiency virus)

312
Q

what is a group of viruses associated with orthoretrovirinae?

A

deltaretrovirus

- HTLV 1 + 2

313
Q

what are the origins of HIV?

A
  • HIV1 arose from transmission of SIV cpz from chimpanzees to humans pre-1950
  • HIV2 arose from SIV sm
314
Q

what is HIV-1 derived from?

A

simian immunodeficiency virsues (SIVs) circulating in chimpanzees and/or gorillas from west Central Africa

  • SIVcpzPtt (Pan troglodytes troglodytes)
  • SIVgor (gorilla x3)
  • SIVcpzPts (Pan troglodytes schweinfurthii)
315
Q

what are the 4 groups of HIV strains?

A

M (main), N (new), O (outlying), P

316
Q

what are is the main group of HIV strains separated into?

A

A-D
F-H
J-K

  • clade B predominates in Europe and USA
  • clade A in West and Central Africa
  • clade C in Southern Africa
  • some subtypes don’t circulate on their own but as part of a mosaic virus due to genetic recombination
317
Q

what are the steps involved in virus replication?

A
  1. attachment: viral and cell receptors e.g. HIV (gp120 and CD4)
  2. cell entry: only central viral core carrying the nucleic acid and some associated proteins enter the host cell
  3. interaction with host cell: use cell materials (enzymes, amino acids, nucleotides) for their replication; subvert host cell defence mechanisms
  4. replication: may localise in nucleus, cytoplasm or both; production of progeny viral nucleic acid and proteins
  5. assembly: occurs in nucleus, cytoplasm or at cell membrane
  6. release: by lysis of cell or by leaking (exocytosis) from cell over period of time
318
Q

what are the steps involved in HIV replication?

A
  1. attachment
  2. entry
  3. uncoating
  4. reverse transcription (error prone so genomic variability)
  5. genome integration
  6. transcription of viral RNA
  7. splicing of mRNA and translation into proteins
  8. assembly of new virions
  9. budding
319
Q

what are the different coreceptors for HIV?

A

chemokine receptors

  • CCR5 for M-tropic (R5 strains)
  • CXCR4 for T-tropic strains which can predominate in some individuals
  • mutations in CCR5 gene can influence risk of infection
320
Q

what is the structure of the HIV genome? what genes does it encode?

A
  • 9kB
  • RNA genome
  • encodes 9 genes: Gag, Pol, Env, Tat, Rev, Nef, Vif, Vpr and Vpu
321
Q

what HIV genes are essential for its infectivity?

A

Gag, Pol, Env, Tat, Rev

322
Q

what is the role of Gag gene in HIV action?

A
  • encodes structural proteins

- made as a polyprotein and cleaved by HIV protease

323
Q

what is the role of Pol gene in HIV action?

A

encodes the enzymes reverse transcriptase, integrase and protease

324
Q

what is the role of Env gene in HIV action?

A

encodes the envelope proteins

325
Q

what is the role of Nef gene in HIV action?

A

increases infectivity

326
Q

what is the role of Tat gene in HIV action?

A
  • contributes to viral replication

- enhances production of host transcription factors e.g. NF-kB

327
Q

what is the role of Rev gene in HIV action?

A

binds to viral RNA and allows export from nucleus, and regulates RNA splicing

328
Q

what is the cell tropism (cells affected by HIV)?

A

CD4 T cells

  • memory CD45RO+ cells infected preferentially early on
  • naive CD45RA cells infected later on in infection by X4 virus

macrophages (have CD4 and CCR5)

possibly dendritic cells early on
- can trap virus via DC-SIGN and transport virus to lymph nodes to infect T-cells

brain microvascular endothelial cells, CD34+ bone marrow progenitors, astrocytes, renal epithelial cells

329
Q

what is involved in the immune system response to HIV?

A
  • humoral immunity
  • cell-mediated immunity

lack of identification of protective immune responses remains a major barrier to development of an effective vaccine against HIV-1

330
Q

what is involved in humoral response to HIV?

A

neutralising antibodies

  • poor/slow to develop effectively
  • envelope glycoprotein (gp120) is poorly immunogenic and has high genetic diversity
331
Q

what is involved in cell-mediated response to HIV?

A

CD8

  • CTLs against HIV form and cause early decline in virus
  • CTL responses are quantitatively and qualitatively poor
  • virus escapes from CTL responses through mutations

CD4

  • paucity of virus specific CD4+ T lymphocyte responses
  • failure of CD4+ T-lymphocyte proliferation
332
Q

what are long term non-progressors in HIV?

A
  • heterogenous group of individuals that don’t progress to AIDS
  • no symptoms of infection or signs of AIDS after at least 7 years infection with CD4 count >600 cells/ml in the absence of treatment
  • genetic factors (e.g. CCR5 C32), host immune responses (e.g. vigorous CTL responses), differences in MHC I HLAs
333
Q

what are the immune system consequences of HIV?

A
  • progressive decline in number and function of CD4 T-lymphocytes
  • excessive and inappropriate activation of immune system
  • decreased proliferation in response to antigens
  • skewing of CD4+ T cell receptor e.g. preferential involvement of memory T-cells
  • CD8+ T-cells show enhanced activation and decreased cytolytic and non-cytolytic function
  • B cells show enhanced activation and decreased proliferation resulting in increased non-specific but decreased specific Ab production
  • decreased NK, neutrophil and macrophage function
  • perturbed cytokine networks: decreased Th1 responses e.g. IL-2; increased Th2/Th0
334
Q

what are mechanisms of CD4+ T lymphocyte depletion?

A
  • direct cytotoxicity of directly infected cells (but only 1:1000-1000000 cells in periphery directly infected)
  • activation induced death
  • decreased production (infection of CD34+ progenitors in bone marrow and infection of thymocyte progenitors and disruption of thymic microenvironment)
  • redistribution (significant trafficking of CD4+ T cells from periphery to lymphoid tissue)
  • bystander cell killing (gp120 binding to CD4 sensitising cells to apoptosis. Fas ligand upregulation by Tat)
335
Q

how does decreased production of CD4+ lymphocytes lead to depletion?

A
  • infection of CD34+ progenitors in bone marrow

- infection of thymocyte progenitors and disruption of thymic microenvironment

336
Q

how does redistribution of CD4+ lymphocytes lead to depletion?

A

significant trafficking of CD4+ T cells from periphery to lymphoid tissue

337
Q

how does bystander cell killing of CD4+ lymphocytes lead to apoptosis?

A

gp120 binding to CD4 sensitising cells to apoptosis

Fas ligand upregulation by tat

338
Q

what are reservoirs of HIV replication?

A

sanctuary sites

  • genital tract
  • CNS
  • GI tract
  • bone marrow

particular cells

  • macrophages, microglia
  • resting T-cells e.g. CD4+ CD45RO+ memory cells only support replication when activated
339
Q

who is most at risk of HIV?

A
  • MSM
  • heterosexual women
  • injecting drug users
  • commercial sex workers
  • heterosexual men
  • truck drivers
  • migrant workers
340
Q

what are stages of the HIV/AIDS epidemic?

A
  • nascent: <5% prevalence in all known subpopulations presumed to practice high-risk behaviour
  • concentrated: >5% prevalence in one or more subpopulations presumed to practice high-risk behaviour
  • generalised: >5% prevalence in general population
341
Q

what age group is most affected by HIV worldwide?

A

50% of all new infections occurring world-wide are in 15-24 year olds

342
Q

what types of behaviour change and knowing your status for HIV are there?

A

behavioural change

  • education
  • condom use
  • needle exchange

knowing your status
- VCT (voluntary counselling and testing)

343
Q

what are commitments and targets for 2015 for HIV?

A
  1. reduce sexual transmission of HIV by 50% by 2015
  2. reduce transmission of HIV among people who inject drugs by 50%
  3. eliminate new HIV infections among children and substantially reduce AIDS-related maternal deaths
  4. reach 15 million people living with HIV with lifesaving ART
  5. reduce TB deaths by 50%
344
Q

why does circumcision work to prevent HIV infection?

A
  • by removing foreskin, it reduces the ability of HIV to penetrate due to keratinisation of the inner aspect of the remaining foreskin
  • inner part of the foreskin contains many Langerhans cells that are prime targets for HIV; some of these are removed with foreskin
  • ulcers, characteristic of some STIs that can facilitate HIV transmission, often occur on the foreskin. likelihood of acquiring these infections is reduced
  • foreskin may suffer abrasions or inflammation during sex which could facilitate passage of HIV
345
Q

how can microbicidal gel be used against HIV?

A
  • contains 1% tenofovir (drug used in ART)
  • controlled by women
  • decreased risk of HIV by 39%
346
Q

how can drug rehab centres be used against HIV?

A
  • needle and syringe programmes
  • drug dependence treatment - in particular, opioid substitution therapy
  • close compulsory drug detention and rehab centres
  • management of TB and viral hepatitis
347
Q

what is the risk of mother to child transmission of HIV with and without intervention?

A
  • 35% with no intervention

- <1% with HAART and no breast feeding

348
Q

how can MTCT of HIV be reduced?

A

option A

  • antepartum zidovudine (AZT) from 14/40
  • single-dose nevirapine (sd-NVP) at onset of labour
  • AZT and 3TC until 1/52 post partum
  • daily oral nevirapine for infant until all breastfeeding ends

option B

  • 3 drug HAART from 14/40 until all exposure to breast milk has ended
  • daily oral nevirapine to the infant until 6/52 of age

option B+
- life long ART for mother, regardless of CD4 count or clinical stage

349
Q

what problems may be encountered with the delivery of ARV to those in developing countries?

A
  • awareness
  • procurement/delivery
  • clinical services: staff, clinics, testing and monitoring facilities
  • cost/choice of drugs
  • adherence
  • efficacy
  • comorbidities
350
Q

what are goals of HIV testing services?

A

to identify people with HIV through the provision of quality services for individuals, couples and families

  • link individuals and their families to appropriate HIV treatment, care and support, as well as HIV prevention services, based on their status
  • support scale-up of high impact interventions to reduce HIV transmission and HIV-related morbidity and mortality (ART, VMMC, PMTCT, PrEP, PEP)

Phase 2A (28 decks)

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