HIV

Question 1

Disease Feature

Answer 1

Answer

Question 2

HIV Epidemiology in 2023

Answer 2

40 million PLHIV, 1.3 new infections, 630,000 deaths - this is a reduced incidence and death rate compared with 2010. Incidence, duration of disease, and prevalence are interrelated - in steady state and with low prevalence. As treatment increases, we expect duration to rise and incidence to fall, and HIV prevalence will continue to rise or be stable for some time to come. Role of HIV exposure and HIV infection in aetiology and management of other conditions becomes increasingly important to consider

Question 3

HIV Early reports

Answer 3

1981 opportunistic infections in gay men, 1982 OI in Americans of Haitian descent, IVDU and people receiving blood transfusions. 1983 HIV-1 identified

Question 4

HIV Origin

Answer 4

Likely origin of HIV in Central HIV, HIV found in blood sample from 1959 (Belgian-Congo), Transmission to Haiti and the US, deaths prior to 1981 in Europe, US, Africa now believed to be HIV related

Question 5

HIV Stigma

Answer 5

Deeply homophobic and stigmatising response to HIV in US, activist groups including ACT UP and Treatment Action Group fount against stigma and homophobia. One result: change in US clinical trial regulations to include ‘parallel track’ for PLHIV to receive experimental drugs (1990)

Question 6

HIV WHO 2030 targets

Answer 6

95% diagnosed 95% on treatment 95% virologically suppressed

Question 7

HIV HIV-2

Answer 7

Distinct virus closely related to HIV-1. Much less common, most prevalent in West Africa and places with close ties to West Africa. Usually more indolent, higher CD4/lower VL, intrinsic NNRTI resistance

Question 8

HIV Transmission

Answer 8

Sexual (semen, vaginal fluid, blood, anal mucus), parenteral (skin or blood/blood products), MTC (during pregnancy, labour, breastfeeding)

Question 9

HIV Variable risk per 10,000 exposures

Answer 9

Parenteral higher (blood transfusion 9250, Needle sharing IVDU 63, Percutaneous needlestick 23) than sexual (receptive anal 138, insertive anal 11, receptive vaginal 8, insertive vaginal 4), and MTC 2260

Question 10

HIV Treatment and prevention tools

Answer 10

Treatment U=U, Combination prevention - behaviour change (consistent condom use), biomedical interventions (voluntary medical male circumcision, PrEP), supportive political and healthcare environment. Prevention of MTCT

Question 11

HIV Concentrated vs generalised epidemics

Answer 11

Concentrated: HIV has spread rapidly in one or more defined subpopulation but is not well established in the general population (proxy 5% in at least one defined subpopulation but <1% among pregnant women) Generalised: HIV is firmly established in the general population (proxy >1% among pregnant women, most generalised HIV epidemics are mixed in nature, in which certain (key) subpopulations are disproportionately affected. Mixed epidemics people are acquiring HIV infection in one or more subpopulations AND in the general population - mixed epidemics are therefore one or more concentrated epidemics within a generalised epidemic

Question 12

HIV Five key populations

Answer 12

Sex workers, people who inject drugs, MSM, people in prisons or other closed settings, transgender people. Also region-or country populations at elevated risk: migrant populations, occupational groups (fisherfolk, truck drivers, miners), adolescents

Question 13

HIV Package of services

Answer 13

Health sector interventions (condoms, harm reduction, HIV testing, prevention and care, and sexual and reproductive health care) and Strategies for an enabling environment (decriminalisation of behaviours, addressing stigma and discrimination, and addressing violence)

Question 14

HIV HIV prevalence among sex workers

Answer 14

Zimbabwe 56%, Nigeria 14%

Question 15

HIV Why are adolescent girls at risk

Answer 15

Biological vulnerability (higher per-act risk of sexual transmission, higher STI prevalence, anatomical development), Behavioural vulnerability (risky sexual behaviour), Social and structural vulnerability (gender based violence, lack of access to services increase risk and decrease access to PrEP and other HIV prevention)

Question 16

HIV Populations, epidemics and services

Answer 16

Global declines in HIV incidence mask worrying trends in vulnerable subpopulations. HIV epidemics are mixed, with multiple populations at elevated risk in ‘generalised’ epidemic settings - within key population groups, some subgroups more vulnerable. Consider intersecting vulnerabilities and resilience factors. Prevention guidance focuses on structural protection (decriminalisation, stigma reduction, community building) as well as reducing transmission probability and promoting medical interventions. Finally, increasing attention needed to comorbidities and specific health needs of PWHIV to ensure health and wellbeing for life

Question 17

HIV Virology

Answer 17

Retroviridae, Lentivirus, ss+RNA virus, gag (p24), pol (PR/RT/IN) and env (gp41 gp 120)

Question 18

HIV Replication

Answer 18

Receptor binding > Fusion > Nuclear import > Reverse transcription > Integration > Transcription > Nuclear export > Translation > Assembly > Budding > Release > Maturation

Question 19

HIV Pathogenesis

Answer 19

Infection of mucosal tissues (spread of infection throughout the body, immune response > partial control of viral replication) > death of mucosal memory CD4 T cells (clinical latency > establishment of chronic infection: virus concentrated in lymphoid tissues, low level virus production) > infection established in lymphoid tissues eg LN > increased viral replication > destruction of lymphoid tissues and depletion of CD4 T cells > AIDS

Question 20

HIV Lab testing

Answer 20

2x 4-5th generation assays + immunotyping, viral load +/- proviral DNA or Western blot

Question 21

HIV POCT testing

Answer 21

2/3rd generation Ab only - important as longer window period - 90d (compared with 45d with 4th gen)

Question 22

HIV Drug resistance concepts

Answer 22

Mixed population including drug-resistant minority variants. Subtherapeutic drug levels (eg adherence issues), selection pressure -> resistant variants flourish. Usually not ‘fitter’ than wild-type. Take away drug (ART cessation/onward transmission) -> wildtype takes over again, archived resistance, compartmentalisation (CNS)

Question 23

HIV Virology summary

Answer 23

HIV crossed over from primates to humans multiple times. HIV-1 M group caused a pandemic with global subtype diversity. Retroviruses hijack the host cell by reverse transcribing viral RNA to proviral DNA and integrating it into the human chromosome. 3 HIV enzymes involved in replication (reverse transcriptase, integrase, protease) are common drug targets. HIV infects cells including macrophages, CD4 T lymphocytes -> extensive reservoir -> clinical latency. Immune system responses achieve only temporary partial control prior to CD4 decline and viral escape. Rapid, error-prone replication -> viral diversity -> selection of immune escape mutants and drug resistance. HIV test = 2x Ag/Ab assays and immunotyping (window period 45 days, 90 days for POCT). Combination therapy ART can achieve viral suppression and peripheral CD4 restoration (but NB adherence, archived resistance, compartmentalisation)

Question 24

HIV Clinical manifestations

Answer 24

1 Primary HIV infection (acute viral illness or asymptomatic) 2 Chronic viral infection: direct viral effects and inflammation (adenopathy, haematological, skin disorders. Higher risk of non-HIV cancers, cardiovascular disease, osteoporosis. HAND, wasting syndrome, HIVAN). 3 Opportunistic infections and cancers: impaired cellular immunity (many pathogens, related to CD4 count). ART-associated effects (IRIS, toxicity)

Question 25

HIV WHO Clinical Staging asymptomatic/mild CD4 350-500

Answer 25

Primary: Asymptomatic, acute retroviral syndrome. Clinical stage 1: Asymptomatic, persistent generalised lymphadenopathy. Clinical stage 2: Moderate unexplained weight loss (10% body weight), recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis), herpes zoster, angular cheilitis, recurrent oral ulceration, papular pruritic eruptions (eosinophilic folliculitis), seborrhoeic dermatitis, fungal nail infections

Question 26

HIV WHO Clinical Staging: higher OI risk CD4 200-350

Answer 26

Clinical stage 3: unexplained severe weight loss (>10% body weight), unexplained chronic diarrhoea for longer than one month, unexplained persistent fever (above 37.6oC for longer than one month), persistent oral candidiasis, oral hairy leukoplakia, pulmonary tuberculosis, severe bacterial infections (pneumonia, empyema, pyomyositis, bone infection, meningitis, bacteraemia), acute necrotising ulcerative stomatitis, gingivitis, or periodontitis. Unexplained anaemia (<80), neutropaenia (<0.5) or thrombocytopaenia (<50)

Question 27

HIV WHO Clinical Staging: Severe (AHD) CD4 <200

Answer 27

HIV wasting syndrome(>10% body weight plus >1 month fever or diarrhoea), pneumocystis pneumonia, recurrent severe bacterial pneumonia, chronic herpes simplex infection, oesophageal candidiasis, extrapulmonary TB, Kaposi’s sarcoma, CMV disease (retinitis, colitis, encephalitis), CNS toxoplasmosis, HIV encephalopathy, extrapulmonary cryptococcosis including meningitis, Disseminated NTM infection, progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, chronic isosporiasis, disseminated mycosis (dimorphic fungal), recurrent non-typhoidal Salmonella bacteraemia, lymphoma (cerebral or B-cell non-Hodgkin), invasive cervical carcinoma, atypical disseminated leishmaniasis, HIV-associated nephropathy or cardiomyopathy

Question 28

HIV Acute retroviral syndrome

Answer 28

Symptomatic presentation of acute HIV infection, prevalence varies 23-92%, onset 2-4w from exposure. Duration and severity associated with higher viral set point and more rapid HIV progression.

Question 29

HIV Persistent generalised lymphadenopathy

Answer 29

Early HIV: symmetrical, modestly enlarged, mobile, painless. >=2 non-contiguous sites for 3-6 months. Always investigate if constitutional symptoms, asymmetrical, very large

Question 30

HIV Approach to lymphadenopathy in HIV

Answer 30

Any CD4 TB/TB IRIS, Syphilis, Lymphoma, KS/Castleman’s, NTM. CD4<100 Nocardia, Dimorphic fungal infection (Histo, emergo, talaro, sporotrichosis), Cryptococcus. Always sample with FNA TB GeneXpert, Histology (PAS, HHV8), Culture (TB and fungal)

Question 31

HIV Herpes zoster

Answer 31

Reactivation of VZV, often first presentation. Diagnosis clinical (painful, can be disfiguring, does not cross midline, but can be disseminated, VZV PCR on swab) Early treatment: valaciclovir preferred, IV if ocular/facial or disseminated/progressive

Question 32

HIV Papular pruritic eruption

Answer 32

Eosinophilic folliculitis, occurs at any CD4 count. Uncomfortable++ can lead to scarring. No specific treatment: antihistamines, symptomatic management. Easily confused with dimorphic fungal infection - always biopsy if CD4 <100 or constitutional symptoms

Question 33

HIV Molluscum contagiosum

Answer 33

Pox virus infection, spread by contact (including sexual), common in childhood, seroprevalence ~25%, chronic, localised infection: firm dome shaped papules, central indentation/umbilication - can become widespread (IRIS). Differential diagnosis: Crypto, Histoplasma, Talaromycosis, MPox. Treatment is ART, no evidence based therapy for recalcitrant disease

Question 34

HIV Aphthous ulcer

Answer 34

Odynophagia, dysphagia, otalgia. Management: minor ulcers: topical analgesics, topical corticosteroids or betamethasone spray, chlorhexidine based mouth wash. Severe cases: oral corticosteroids or thalidomide. Differential diagnosis: lymphoma and KS, HSV, CMV, TB, Syphilis, Deep fungal infection, leishmaniasis, rheumatologic diseases and IBD

Question 35

HIV Oropharyngeal candidiasis

Answer 35

Usually C albicans, pseudomembranous form most common (white plaques). Diagnosis clinical or microscopy of tongue scrapings. Management: mild nystatin drops 7d, moderate/severe fluconazole 200mg/d for 7d

Question 36

HIV Oral hair leukoplakia

Answer 36

EBV-related, hairy or feathery looking with prominent folds, unable to scrape (unlike candida), not pre-malignant, no treatment

Question 37

HIV Respiratory illness

Answer 37

Increases in HIV regardless of CD4, Bacterial CAP 70% pneumococcus, 5% Haemophilus, 15% atypical, 5% GN, 5% S aureus

Question 38

HIV Pneumocystis

Answer 38

Fungal biology is challenging - the ascus (cystic) form is transmissible, thick cell wall containing beta-D-glucan and causes immune reaction, the trophic forms which replicate and are more abundant in the lungs are ‘wall-less’, contain cholesterol (not ergosterol) in cell wall, hence difficulty treating, and are immune evasive. WHO clinical case definition: dyspnoea on exertion or nonproductive cough, tachypnoea and fever AND CXR diffuse bilateral interstitial infiltrates AND no evidence of bacterial pneumonia. Diagnosis: Gold standard Bronch not available in most high risk settings, sputum based tests not accurate enough, most patients started on empiric therapy. qPCR good rule out test on induced sputum (NPV 96%) and oral wash (NPV 91%), Grey-zone remains challenging, optimal cutoff not defined. BD-glucan - after a negative test rules out PCP with 95% certainty up to a pre-test probability of 50%. After a positive test, increases chance of PCP to ~70% for any HIV-associated pneumonia. Treatment SXT for 21d high dose. Evidence for duration is very limited

Question 39

HIV Mediastinal adenopathy

Answer 39

TB, lymphoma, dimorphic fungal, cryptococcus, nocardia, NTM

Question 40

HIV Pleural effusion

Answer 40

TB, bacterial, KS, cryptococcus, lymphoma (KSHV-related)

Question 41

HIV TBM

Answer 41

Heterogeneous clinical presentation (mild subacute headache -> coma, associated vasculitis, hydrocephalus, hyponatraemia). Difficult to diagnose (variable CSF findings, lymphocytosis and low glucose not always present, paucibacillary (smear, culture, Xpert poor sensitivity) Poor outcomes despite TB treatment - 40-50% mortality with treatment.

Question 42

HIV TBM treatment and prevention

Answer 42

Standard HRZE 9-12 months, steroids are MAYBE (benefit in HIV-infected is not as clear), Data on ART timing is unclear, most would delay initiation until around 1-2 months after initiation of TB treatment and give steroid cover. TB preventive therapy in HIV-positive individuals may help prevent development of TB meningitis

Question 43

HIV Lymphocytic meningitis DDx

Answer 43

TBM, Crypto, Viral, Bacterial (pneumococcus, meningococcus), Listeria, Syphilis

Question 44

HIV Intracranial mass lesion DDx

Answer 44

TB, Toxoplasmosis, Nocardia, Pyogenic brain abscess, Lymphoma, Cryptococcus, Syphilis

Question 45

HIV TB-HIV Management

Answer 45

TB: susceptible 2HRZE/4HR MDR BPaL/M 6-9 months. ART start within 2 weeks for CD4<50, Start within 8 weeks for higher CD4. Delay ~6w in TBM. Drug-drug interaction with rifamycins and DTG. Steroids in pericarditis, TBM, TB IRIS

Question 46

HIV Severe weight loss

Answer 46

Opportunistic diseases (TB, NTM, lymphoma, deep fungal, leishmaniasis), HIV wasting syndrome, GI pathology (painful oral/oesophageal lesions, severe chronic diarrhoea), other malignancy, depression (very common and often unrecognised), lack of financial resources to buy food

Question 47

HIV Chronic diarrhoea

Answer 47

Small bowel = large volume watery with bloating/pain - cryptosporidium, isospora, NTM, HIV enteropathy, microsporidiosis. Large bowel = small volume blood, mucus, inflammatory with tenesmus - CMV, TB, Schistosomiasis, Amoebiasis

Question 48

HIV Summary

Answer 48

CD4 count major determinant of OI risk. ART not completely protective (TB, IPD still more common), AHD persistent problem with high mortality. Non-specific clinical presentations and possibility of multiple concurrent Ois with challenges for diagnosis. Limited diagnostic capability for most severe OIs (EPTB, PCP). Optimal management not yet defined for most severe OIs

Question 49

HIV Meningoencephalitis DDx

Answer 49

Toxoplasmosis, Cryptococcal meningitis, CMV, VZV, TB meningitis, PML, Primary CNS lymphoma, Bacterial meningitis

Question 50

HIV LP

Answer 50

The only contraindication to LP in most high HIV-prevalence settings is focal neurological deficit (excluding CN palsies) suggesting mass lesions. The risk/benefit ratio almost always favours immediate LP.

Question 51

HIV CNS OI

Answer 51

Investigations: Malaria film, FBC, EUC, BC, HIV test and CD4 count if not already done. LP with opening pressure, appearance, cell count and differential, protein and glucose. Pathogen detection tests on CSF: Stains (Gram, AFB, India Ink), Bacterial, mycobacterial and fungal culture, CrAg, Xpert Ultra (MTB/Rif)

Question 52

HIV Cryptococcal meningitis

Answer 52

Commonest cause of adult meningitis in most sub-Saharan Africa and much of SE Asia. Severe OI in patients with late stage HIV, often subacute presentation with headache, meningism (~50%), fever, focal neurology (CN VI), abnormal mental status. Diagnosed using CrAg, India Ink staining, culture. Mortality 30-50% even with antifungal treatment. Treatment: AMBITION trial - single dose amphotericin plus flucytosine and fluconazole 1200mg/d for 2 weeks, then Fluconazole 800mg/d for 8 weeks, then Fluconazole 200mg/d until CD4>200 and virally suppressed. Don’t give steroids (worsens outcomes - CryptoDEX). Start ART 4-6 weeks after initiating antifungal therapy to avoid IRIS. Amphotericin toxicity: renal impairment, K/Mg wasting, anaemia, thrombophlebitis, raised ICP common (75%) daily LPs until OP<25mmH2O. CrAg detectable in blood for several months before cryptococcal meningitis develops - screen all individuals with CD4<100 and initiate pre-emptive antifungal treatment. Ideally CrAg positive individuals should undergo LP to assess for meningitis.

Question 53

HIV Cryptococcal pneumonia

Answer 53

Respiratory Alveolar macrophages – phagocytose, try to kill it, but the polysaccharide capsule protects it within the macrophage, produces melanin which protects against oxidative burst in macrophage – these strategies are to survive phagocytosis by amoeba – can survive inside alveolar macrophages, presents to CD4 T cells  killed or walled off as granuloma – similar process to TB, and if CD4 declines granulomas break down and reactivation occurs

Question 54

HIV Cryptococcus raised ICP

Answer 54

Thick capsule sheds and clogs arachnoid granulation which reduces CSF resorption, pressure goes up, and communicating hydrocephalus – management to drain CSF daily until opening pressure <25mmHg Draining 1ml drops by 1cm – can take 30-40ml of CSF in a single LP to normalise the pressure There is no risk of coning in communicating hydrocephalus when draining CSF

Question 55

HIV Cerebral toxoplasmosis

Answer 55

No 1 parasitic disease of advanced HIV, usually CD4<100. Focal CNS lesion(s) or toxoplasmosis encephalitis. 5-10% mortality on treatment. Initial treatment pyrimethamine plus sulfadiazine, SXT high dose much more widely available. Secondary prophylaxis initiate ART without delay, longterm SXT prophylaxis until sustained CD4>200 for >6m. Steroids (maybe - ideally avoid as can confuse therapeutic trial), Anticonvulsants (give if presents with seizures, consider giving pre-emptively in those with suspected toxoplasmosis and no seizures). Biopsy - if deterioration or no clinical or radiological improvement by 2 weeks consider stereotactic brain biopsy to confirm or look for alternative diagnosis - very high risk in most LMICs. Toxo facilitates its own transmission by changing the behaviour of its host – mouse becomes less afraid of cat

Question 56

HIV Primary CNS Lymphoma

Answer 56

Consider if toxo-type presentation but no response to toxo Rx, particularly if solitary lesion on imaging. Definitive diagnosis by biopsy. CSF EBV may be positive. Often no peripheral involvement, occurs in very advanced HIV disease CD4 <50. Prognosis better since ART, but still poor - chemoradiotherapy and ART

Question 57

HIV Progressive multifocal leukoencephalopathy

Answer 57

JC virus, insidious onset, occurs at CD4<100, progressive focal neurology (mainly motor), normal CSF (JC PCR usually positive), MRI is diagnostic. No known effective treatment, give ART

Question 58

HIV CNS DDx

Answer 58

Other than the common ones: CMV encephalitis, HSV/VZV encephalitis, neurosyphilis, HIV encephalitis, CD8 encephalitis

Question 59

HIV Approach to CNS infections in resource limited settings

Answer 59

Clinical manifestations are non-specific, there is a broad differential - not always narrowed by available imaging and CSF analyses. Effective diagnosis is based on: epidemiology, clinical history and examination, basic tests, treatment. In areas of high prevalence - no CT/MRI scans, no CSF PCR/serology/immunology. Survival depends on fast and accurate diagnosis and early administration of effective treatment

Question 60

HIV Talaromycosis

Answer 60

T marneffei, CD4<100, major cause of HIV-associated OI in South and SE Asia, leading cause of HIV-associated bloodstream infection and death in Vietnam and southern China. Clinical presentation: disseminated infection involving multiple organ systems, fever, weight loss, hepatosplenomegaly, lymphadenopathy, skin lesions (40-70%), pulmonary (40%), GI (30%), significant hepatosplenomegaly (70%), coinfections with other OIs common (TB in up to 22%). Diagnosis by Microscopy of skin lesions, LN, BM. BC may take up to 28d, yield is highest from bone marrow and skin lesions. PCR whole blood sens 99% in those with fungaemia, 55% without, 88% overall. Rapid antigen testing, Treatment Amphotericin B> Itraconazole

Question 61

HIV Histoplasmosis

Answer 61

H capsulatum. Endemic in Americas, but will find elsewhere, CD4<100, annual incidence up to 5% in endemic areas. Major cause of HIV-associated OI in parts of Latin America where it is estimated to cause more deaths than TB, Prevalence in Africa and Asia not known. Clinical: progressive disseminated infection. Fever, fatigue, weight loss and hepatosplenomegaly, cough, chest pain and dyspnoea ~50% of patients, CNS, GI and cutaneous manifestations in smaller percentage of patients. If CD4 >300, histoplasmosis is often limited to the respiratory tract with cough, pleuritic chest pain and fever. Diagnosis: Microscopy 2-4um budding yeast, Culture blood, BM, resp. PCR. Ag detection (urine>blood) sens 95%, spec 97% - addition of urinary Histoplasma antigen testing increased the diagnosis of disseminated histoplasmosis by 54% in comparison with classical mycological methods in Brazil. Treatment Amphotericin > Itraconazole

Question 62

HIV CMV

Answer 62

dsDNA herpesvirus, worldwide distribution, frequent exposure with latency then reactivation, disseminated or localised end-organ disease in individuals who have very advanced HIV CD4<50 (retinitis, colitis, pneumonitis, encephalitis). Before ART an estimated 30% of patients with AIDS experienced CMV retinitis. The incidence of new cases of end-organ disease has declined by >95% with the advent of potent ART. BUT - CMV viraemia remains common in AHD and is associated with poor outcomes. The cause/effect relationship remains unclear. Diagnosis: PCR, treatment: valganciclovir

Question 63

HIV Kaposi’s sarcoma

Answer 63

Patch, plaque, nodular, tumour, may also have visceral involvement, respiratory and GI tract. Treatment Paclitaxel if available

Question 64

HIV & TB Granulomas

Answer 64

CD4 are critical in developing granulomas, and granulomas are critical in the immune control of TB. CD4 depletion -> lose control of granuloma formation. Well formed granulomas with preserved CD4 count, with advancing HIV infection decreased CD4, decreased epithelioid cells, decreased Langhan’s cells, and increased MTB the granulomas are less well organised. In very advanced HIV infection increased necrosis, increased neutrophils and increased MTB - granulomas are poorly organised or absent.

Question 65

HIV & TB Epidemiology

Answer 65

6.3% of TB is associated with HIV+ = 600,000 people. Coinfection responsible for 167,000 deaths in 2022. As CD4 lowers, much higher risk of TB. There is also a higher risk of TB in HIV with higher CD4 counts compared with non-HIV patients. HIV is associated with poorer outcomes with TB

Question 66

HIV & TB Clinical

Answer 66

People without HIV - usual presentation is pulmonary TB, upper lobe infiltrates with cavities, EPTB less common, mild immunosuppression (eg CD4 >350) is similar. In advancing HIV as the CD4 declines the presentation may include thoracic lymphadenopathy and pleural effusions -> EPTB more common with declining CD4 counts -> disseminated disease, lower zone nodules, non-cavitating or normal CXRs

Question 67

HIV & TB Diagnosis

Answer 67

Essentially the same approach as HIV negative Clinical specimens (sputum, LN, urine, pus, CSF, pleural/pericardial fluid, ascites) -> microscopy, culture, molecular techniques, antigen detection. Supportive diagnostic criteria: CXR (also consider chest/abdo US, CT/MRI brain, TTE, CT CAP), Clinical features = fever, weight loss, night sweats, cough, examination features of EPTB, RF for active TB disease, haematology/biochemistry

Question 68

HIV & TB What is different in TB for sputum diagnostics

Answer 68

More difficult to diagnose in HIV due to different immunopathology. Higher proportion of patients unable to produce sputum samples (20-50% unable), EPTB is more common. Clinical/empirical treatment is more common

Question 69

HIV & TB Non-sputum based testing

Answer 69

Urine LAM (lipoarabinomannan 30-50% sens 92-95% spec). Urine Xpert US (sens 30-50%, sens >98%). Stool Xpert (sens 60-80%, spec >99%)

Question 70

HIV & TB TB screening in HIV

Answer 70

People living with HIV should be systematically screened for TB disease at each visit to a health facility (WHO Strong recommendation). 1 WHO 4 symptom screen (cough, fever, weight loss, night sweats 80-90% sens 40% spec), 2 CRP >5 (sens 90% spec 50%), 3 CXR (sens 93% spec 20%) 4 WHO recommended molecular diagnostic (medical inpatients sens 70% spec 98%)

Question 71

HIV & TB US

Answer 71

Focussed assessment with sonography for HIV/TB (FASH) - pleural fluid, pericardia fluid, ascites, focal liver lesions, focal splenic lesions

Question 72

HIV & TB Treatment

Answer 72

Standard 2HRZE4HR - common side effects: hepatitis, rash, arthropathy (pyrazinamide), optic neuritis (ethambutol), peripheral neuropathy (isoniazid)

Question 73

HIV & TB TBM

Answer 73

Treat for 12 months, no benefit of steroids in HIV associated TBM or pericardial TB

Question 74

HIV & TB Drug interactions

Answer 74

Rifampicin: backbone of TB Rx - potent CYP450. Many ART drugs are metabolised by CYP450. 3 strategies to overcome this: use ART without significant interactions, replace rifampicin with rifabutin (less induction), increase doses of ART drugs. Use Liverpool HIV drug interaction database. Essentially TDF/3TF/DTG is still first line, but DTG is BD

Question 75

HIV & TB When to start ART

Answer 75

ART should be started as soon as possible within two weeks of initiating TB treatment, regardless of CD4 cell count, among people living with HIV. Exception is TBM - wait 4-8 weeks0

Question 76

HIV & TB TB-IRIS

Answer 76

8% have paradoxical IRIS after starting ART. Usually worsen pulmonary infiltrates/enlarging LNs. 25% hospitalised, 2% mortality. Prednisolone reduces severity/hospitalisation/need for procedures. RF: low CD4 count, high viral load, EPTB, early ART (but mortality lower), prophylactic prednisolone reduces IRIS by 30%

Question 77

HIV & TB TPT

Answer 77

TB preventive therapy - strong evidence that it reduces TB. Poorly implemented (drug interactions, pill burden, concerns about resistance, availability), limited duration of benefit in high TB burden settings. IGRA/TST doesn’t predict benefit from TPT

Question 78

HIV & TB Summary

Answer 78

Some progress on incidence/deaths from HIV/TB, but still lots to do. Public health interventions have had biggest impact. HIV & TB collaborative activities are key: integrated services, bidirectional screening, TB and HIV preventative therapies. Improve diagnostics. Treatment can be complex - need for integrated care

Question 79

HIV & TB Key message

Answer 79

Microscopy needs 10-1000 cfu/ml in sputum, in advanced HIV don’t generally have that degree of TB in sputum, they don’t mount the immune response and don’t have the cavitations. Xpert needs 100 cfu/ml to detect, therefore is more sensitive

Question 80

HIV Basics

Answer 80

HIV is a retrovirus. HIV drugs = antiretrovirals (ARVs). Antiretroviral therapy = ART. CD4 (cells/mm3) - Main HIV target, orchestrate the immune system, Marker of immune function, improves with ARVs, Normal >500, low <350, very low <200 - Diagnosed with CD4 <350 is the definition of ‘late presentation’. Viral load or HIV-RNA (copies/mL): Amount of virus in blood, Used to monitor treatment (goal = ‘undetectable’ eg<50), below 200 is enough to prevent onward sexual transmission

Question 81

HIV Virology

Answer 81

HIV particle binds to two surface receptors on the target CD4 cell. CD4 receptor and the coreceptor. Binding of viral envelope induces conformational change and the virus ejaculates its material into the cell. RNA to DNA, then into the host cell nucleus, integrase inserts viral DNA into the host – the cell is turned over to an HIV factory. Protease packages up into new viral particles

Question 82

HIV Ibalizumab

Answer 82

European licence withdrawn, eyewateringly expensive, can be life saving in those with no treatment options, available in the US

Question 83

HIV Maraviroc

Answer 83

Maraviroc binds the co-receptor

Question 84

HIV Enfuvirtide

Answer 84

Enfuvirtide fusion inhibitor prevents the fusion to the membrane, BD subcut, superseded by modern agents, and will be discontinued

Question 85

HIV NRTI

Answer 85

first Zidovudine, they mimic nucleotides, and because they aren’t real nucleotides, and the replication ceases. It pretends to be natural building block of natural part of human, the older ones were fraught with metabolic toxicities, lipoatrophy, pancreatitis, neuropathy, mimicking endogenous – cause mitochondrial toxicity, can inhibit part of the mitochondrial activity

Question 86

HIV NNRTI

Answer 86

in the late 1990s, mainstay for subsequent decade, target the same step but in different way, they bind the enzyme at a distant site and change its shape, they don’t pretend to be genetic building blocks

Question 87

HIV Lenacapavir

Answer 87

Lenacapavir Capsid inhibitor – six monthly subcut injection, recent study in PrEP every 6 months could be a gamechanger – iAS are calling upon Gilead to make it available (but still needs regulatory approval) – but will become an issue, because it will be available in 70 LICs, but MIC and HIC countries will have more difficulty accessing – this may also be a lifesaver for those without treatment options

Question 88

HIV Core principle

Answer 88

Single core principle is to use at least two drugs from different drug classes

Question 89

HIV START study

Answer 89

RCT, CD4>500 randomised to start immediately or until it had fallen ~350 – despite this, there was significant benefit to starting early

Question 90

HIV U=U

Answer 90

HPTN052 – HIV negative sexual partner, randomised the person living with HIV to early vs later starting, and in the earlier group there were no transmissions except. Undetectable = <200  zero risk of transmission. Destigmatised, can motivate adherence for those with difficulty taking ART. Vertical transmission is not quite U=U, it’s a very low risk esp in breastfeeding. This can be useful to help start someone on ART.

Question 91

HIV When to start ART

Answer 91

US: Start ART at diagnosis (when possible) to increase uptake, decrease time to linkage and virologic suppression, and to improve the rate of virologic suppression. EACS: offer same day ART in primary HIV infection, patient wishes to do so, loss to follow up more likely if not started. BHIVA: same day ART recommended in primary HIV infection, patient wishes to, is ready and has no clinical contraindications. WHO: rapid ART initiation should be considered

Question 92

HIV When is rapid ART NOT recommended?

Answer 92

Cryptococcal meningitis (Increased mortality with immediate ART, Defer until 4-6W after CM treatment start) and TB meningitis (Delay ART for at least 4W but start within 8W of anti-TB treatment, Consider adjuvant steroids)

Question 93

HIV Potential pros and cons of rapid ART

Answer 93

Pros: ART uptake, suppression, retention, transmission, ‘control’. Cons: No baseline tests, counselling, adherence, retention, capacity (ie the team to routinely be able to do this)

Question 94

HIV HIV/HBV

Answer 94

Tenofovir is first line in those with HBV coinfection

Question 95

HIV Weight

Answer 95

Weight gain in women on DTG vs EFV – conclusion DTG driving weight gain, but probably isn’t, EFV had been causing a previously unrecognised weight suppression. Confidence is that EFV has well described pharmacokinetics and pharmacogenomics – there are people with particular polymorphisms who metabolise it faster and those with lower, and looked at say the fast metabolisers with the lowest level gained the same weight as those on DTG, those with the highest EFV levels (low metabolisers) have reduced weight. Dose response relationship

Question 96

HIV TDF v TAF

Answer 96

More weight gain on TAF, conflicting opinion on what is driving this. Many believe that TDF is causing weight suppression. TDF prevention vs placebo – people on TDF didn’t gain weight, and those on placebo gained 0.5kg per year (roughly expected). TAF 2.5kg weight gain in the first year. Gained weight because they are healthier, often it’s a return to what is normal for their family, but when the guidelines say that TAF may be associated with excessive weight gain, then patients are wanting to switch away, and there is no good evidence that this is effective for weight management. Not convinced TAF is driving weight gain, but there are lipid differences (TDF lowers lipids) but some would argue that this is a TDF toxicity, as is the weight suppression. More important to find the patients with baseline CKD, they are at higher risk of TDF toxicity, rather than the Cr as a test to monitor TDF itself

Question 97

HIV Bone

Answer 97

All ART, see a small drop in bone density after starting, this plateaus, no one really knows why it happens, but seems that when immune reconstitution the bone eating cells boost before the bone creating cells. May be mitochondrial toxicity of bone forming cells, its all not well understood

Question 98

HIV Adherence

Answer 98

If someone doesn’t adhere, think about what the clinic could have done to improve the management. Assume that missing tablets is normal, start from the assumption that missing tablets is normal, and invites honesty. In the era of universal treatment, loss to care has gone up – programmatically something is not going right. We have the tools to reach zero, but we are not going to achieve this unless we improve programmatic

Question 99

HIV Treatment

Answer 99

DTG/TDF/3TC (or FTC) as first line. Alternative firstline TDF/3TC/EFV (EFV should not be used where national estimates of pre-treatment resistance to EFV are >10%. If DTG is not available, then boosted PI should be used

Question 100

HIV Monitoring on treatment

Answer 100

Recommended: HIV VL at 6m, 12m, then annually, Cr and eGFR for TDF, Pregnancy test for women of child-bearing potential. If suspected ART failure, check HBVsAg before switch off TDF if not done pre-treatment. In settings in which routine viral load monitoring is available, CD4 count monitoring can be stopped for individuals who are established on ART. If viral load testing is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure.

Question 101

HIV HBV & HCV screening

Answer 101

WHO: at enrolment into care and initiation of ART, at treatment failure and switching ART regimen, at re-engagement following care interruption

Question 102

HIV Prevention is better than cure

Answer 102

New HIV infection have been reduced by 60% since the peak in 1995. In 2023 1.3 million people were newly infected with HIV, compared to 3.3 million people in 1995

Question 103

HIV How can we prevent HIV?

Answer 103

Combination prevention approach. Population specific. Reflecting the epidemiology of the setting. Evidence based. Community owned. Sustainable. Cannot prevent HIV without tackling stigma. Address intersecting inequalities relating to race, immigration status, gender and sexuality. Needs to be normalised

Question 104

HIV Male circumcision

Answer 104

50% risk of transmission. Women benefit indirectly from VMMC programmes. Lower HIV incidence and prevalence among circumcised men. Women benefit directly – reduced risk of transmission if an HIV-positive male partner is circumcised. Two observational cohorts among serodiscordant couples – 41% lower risk of infection. RCT found a higher risk of HIV transmission in the first six months after the procedure, particularly if the couple resumed sex more than five days before the circumcision wound had healed. Among 4.8 million men seen at VMMC services in 12 countries during 2013-2016 nearly all were tested for HIV, and less than 1% were positive

Question 105

HIV Treatment as prevention (TasP)

Answer 105

HPTN052 study - treatment reduced risk of transmission by 96%. 2017 Partner study - zero transmissions after >58,000 episodes sex without condoms when viral load was undetectable <200

Question 106

HIV PrEP

Answer 106

Efficacy is very dependent upon the adherence. Women – study in PrEP in women, found that the women were not taking the TDF/FTC. VOICE study: no detectable drug at any quarterly visit in approximately half of women tested. For women to have enough level in the vaginal mucosa – need to be taking it every day. CAPRISA – topical PrEP 12h before and 12h after sex – again not used. MTN-020/ASPIRE & IPM-027 Dapivirine Vaginal ring for HIV prevention in women, similar concept to vaginal contraceptive ring, silicone ring. HPTN084 IM CAB LAPrEP – superior to TDF/FTC in cisgender women, there were no on-injection breakthrough infections. Oral PrEP adherence declines over time. PURPOSE study – lenacapavir (capsid inhibitor), twice yearly subcut injection – cisgender adolescent girls and young women comparing LEN with oral TDF/FTC or TAF/FTC, no infections in the LEN group, 16 breakthrough infections in the TDF/FTC group. PURPOSE2 study – cisgender men, transgender women, gender nonbinary who have sex with partners assigned male at birth, x2 incident infections in LEN group, 9 in TDF/FTC group. PURPOSE5 study – cisgender MSM, transgender women, transgender men, plus cisgender women and nonbinary people who are at an increased likelihood of HIV acquisition, LEN vs TDF/FTC (UK and France)

Question 107

HIV Prevention of MTC transmission

Answer 107

Globally 1.3 million women and girls living with HIV become pregnant each year. In the absence of intervention, the rate of transmission of HIV from a mother living with HIV to her child during pregnancy, labour, delivery or breastfeeding ranges from 15 to 45%. The earlier you start ART in pregnancy, the more likely of being suppressed at the time of birth. Women present late. Women seroconvert during pregnancy. Women are at higher risk of gender based violence and domestic abuse while pregnant. MDT approach. Manage anxiety and work together with women. Often a motivator. Work closely with midwives, obstetrics and paediatrics

Question 108

HIV Breastfeeding

Answer 108

Depends where baby is born. Risk of HIV vs water sanitation. Breastfeeding advised where risk of malnutrition/GI disease outweighs risk of HIV transmission. In higher income countries no substantial data therefore no clear guidance - extremely difficult for mothers and clinicians to advise. UK guidelines for breastfeeding: Mother and infant should be reviewed monthly in clinic for HIV RNA viral load testing during, and for 2 months after stopping BF. Maternal ART (rather than infant pre-exposure prophylaxis) is advised to minimise HIV transmission and safeguard mothers’ health. Infant BF HIV Ab testing for seroreversion should be checked at age 18-24 months. Infant BF for as short a time as possible, exclusively for the first six months, and 24 months cease if signs of breast infection/mastitis, mother or infant has gastrointestinal symptoms or blip in maternal viral load

Question 109

HIV HIV prevention for women is complex

Answer 109

Women need to be aware of their risk. HCPs need to understand who is at risk. Knowledge. Specific messaging to individual populations. Accessible. Peer support. Need other STI and pregnancy prevention too. Safe sex for women in some cultures means ‘testing together’. Overcome gender bias

Question 110

HIV Prevention Summary

Answer 110

HIV prevention viewed as a toolkit encompassing education, circumcision, PEP and PrEP. PrEP is not one size fits all – prevention programmes need to be culture specific and gender specific with a view to providing individualised care and choice. Messaging and information targeted to specific groups. Community owned and sustainable. Pharmacological interventions just a part of HIV prevention programmes. Longacting CAB and LEN for PrEP looking very positive (but don’t forget simple strategies too..). Women must be included in studies – including while pregnant and breastfeeding. Transwomen also need to be prioritised. Think about where HIV prevention is situated/accessibility

Question 111

HIV Consideration of the person

Answer 111

Think about the person – to appreciate and understand the experience of living with HIV for the rest of your life, the stigma from other people and within, and how healthcare professionals interactions can have a massive impact upon their experience to share what is going on in their lives, and support them to have the lifelong treatment