HIV

Introduction

• Leading cause of infectious disease death worldwide
• Up to 1/20 in sub-Saharan Africa
• Risk factors
  • MSM
  • IVDU
  • Heterosexual exposure
  • Receipt of blood transfusion prior to 1985
  • Maternal HIV infection

Pathophysiology

• Cytopathic retrovirus
• HIV-1: Major subtype. Causes AIDS
• HIV-2: Causes similar immune syndrome but primarily in West Africa
• Central RNA with reverse transcriptase protein surrounded by a core protein and lipid bilayer envelope
• Primarily attacks CD4+ T cells
• RNA converted to DNA by reverse transcriptase and DNA incorporated into host genome
• Get death of CD4+ T cells, qualitative defects in CD4+ function and autoimmune phenomena

Acute retroviral syndrome  – Seroconversion illness

• Occurs in 50-90% of patients
• Missed in 75% of cases as resembles flu or mononucleosis
• Usually 2-4 weeks after exposure and can last 2-10 weeks
• Fever (>90%), fatigue (80%), pharyngitis (70%), rash, headache, lymphadenopathy, weight loss, diarrhoea
• Seroconversion and detectable antibodies usually by 3-8 weeks
• Asymptomatic phase then may have only generalised lymphadenopathy (enlarged nodes in at least 2 non-contiguous sites other than inguinal)
• Mean time to AIDS if untreated is 8 years for adults and 2 years for children <5yo

Progression of disease

• In untreated patients, AIDS within 9 years (median)
• 5% are long-term non-progressors (>15 years)
• Early in course of chronic HIV infection, virus present in lymphoid tissues bound to follicular dendritic cells. As immune response fails, viral replication increases and other cells become infected (macrophages, microglial cells of nervous system and CD4+ T cells)

Progression of disease

Progression of disease

• Balanced CD4+ production and death until HIV replication increases resulting in drop in CD4+ count
• HIV viral load and CD4+ count are the most predictive variables for disease progression
• Early (CD4+ >500)
  • GBS, chronic demyelinating neuropathy, idiopathic thrombocytopaenia, Reiter’s syndrome, Polymyositis, Sjogren’s, Bell’s palsy
• Early symptomatic infection (CD4+ 200-500)
  • Thrush, tinea, onychomycosis, seborrhoeic dermatitis, molluscum contagiosum, Herpes zoster, TB, sinusitis, peripheral neuropathy, cervical dysplasia, recurrent herpes zoster and ITP
  • Usually CD4+ <500
  • Not AIDS-defining illnesses
• AIDS (Stage 3) – CD4+ usually <200
  • Opportunistic and AIDS-defining illnesses
  • Oral candidiasis, Hairy leukoplakia, Herpes simplex, Cryptococcus, MAC, CMV

AIDS-defining illnesses

• Bacterial infection – multiple or recurrent
• Candidiasis of bronchi, trachea, lungs, oesophagus
• Invasive cervical cancer
• Coccidioidomycosis – disseminated or extrapulmonary
• Cryptococcus – Extrapulmonary
• Cryptosporidiosis, chronic intestinal
• CMV (other than liver, spleen or nodes)
• CMV retinitis
• HIV encephalopathy
• Herpes simplex: Chronic ulcers or bronchitis, pneumonitis, oesophagitis
• Histoplasmosis – Disseminated or extrapulmonary
• Isosporiasis – Chronic intestinal

AIDS-defining illness

• Kaposi’s sarcoma
• Lymphoma – Burkitt’s, immunoblastic, primary CNS
• MAC or M. kansasii – Disseminated or extrapulmonary
• TB
• Pneumocystis jirovecii pneumonia
• Pneumonia – Recurrent
• Progressive multifocal leukoencephalopathy
• Salmonella septicaemia – Recurrent
• Toxoplasma of brain
• HIV wasting syndrome

Diagnosis

• Standard is HIV antibodies by ELISA (99% specific; 98.5% sensitive) followed by Western blot (100% sens and spec)
• Acute HIV cannot be diagnosed by above methods (as is period prior to seroconversion)
  • Can diagnose with HIV viral load, p24 antigen and rapid antigen testing
• Mean time to positivity
  • HIV viral load (positive at 17 days)
  • P24 antigen (positive at 22 days)
  • ELISA (25 days)
  • Western blot (31 days)

Diagnosis

• Benefits of diagnosing early
  • Can limit risk of transmission (critical as often high viral load in acute HIV)
  • Start ART to slow disease progression
• CD4 counts
  • CD4+ <200 cells/mm3 and viral load >50 000 copies/mm3 are associated with increased risk of AIDS-defining illness
  • Total lymphocyte count <1700 cells/mm3 correlates to CD4 <200

Diagnosis

• Source of fever if no obvious source
  • CD4+ >500: Sources similar to non-immunocompromised
  • CD4+ 200-500: Early bacterial respiratory infections most common
  • CD4+ <200: P. jirovecii pneumonia, central line infection, MAC, TB, CMV, drug fever and sinusitis, endocarditis, lymphoma, Histoplasma capsulatum, Cryptococcus neoformans
  • Fever due to HIV alone tends to occur in afternoon or evening and responds to antipyretics

Disseminated MAC

• Mostly CD4+ <100 and not on ART or prophylactic azithromycin
• Persistent fever, night sweats, weight loss, diarrhoea, malaise
• Dissemination to bone marrow, liver and spleen results in anaemia and raised ALP
• Treatment reduces bacteraemia and symptoms but does not eradicate disease

Immune reconstitution syndrome

• Lymphadenitis, fever
• Usually weeks after ART initiated, often during TB therapy
• Continue ART, anti-inflammatories and consider steroids in severe cases

Non-infectious fever

• Non-Hodgkin’s lymphoma is most common  neoplasm
  • Change in CNS status + fever requires neuroimaging
• IVDU
• Drug fever

Neurological complications

• Toxoplasmosis is the most common cause of encephalitis in HIV
  • CSF toxoplasma serology
  • Multiple ring-enhancing subcortical lesions on contrast CT +- non-con
  • Rx: Pyrimethamine + sulfadiazine + folinic acid +- dexamethasone for oedema
• DDx of ring enhancing lesions in HIV
  • Lymphoma: Normally single lesion in periventricular white matter or corpus callosum
  • Cerebral TB: Inflammatory appearance with exudate in basal cisterns
  • Fungal infection: Cryptococcal meningitis normal neuroimaging typically

Neurological complications

• AIDS dementia, Toxoplasmosis, Cryptococcus
• Fever, meningismus, ALOC and headache are independent predictors of space-occupying lesions
• If CD4+ <200, isolated headaches require neuroimaging
• Non-contrast CT head is first-line imaging modality
  • If results equivocal or negative, add contrast to identify abscess/malignancy
• CSF testing
  • Opening pressure, cell count, glucose, protein, Gram stain, India ink, bacterial culture, viral culture, fungal culture, toxoplasmosis/Cryptococcus antigen assays, coccidioidomycosis titer

Neurological complications

• AIDS dementia
  • 20-40% of HIV positive patients with subtle memory disturbance
  • Often confused with depression, anxiety or substance abuse in early phase
  • Later mental status changes, aphasia or motor abnormalities
  • Always consider systemic or CNS pathology if any decline in mental status in patient with confirmed HIV-associated dementia
  • Antiretroviral therapy is the most effective therapy

Neurological complications

• Toxoplasmosis
  • Common cause of focal encephalitis in AIDS
  • Mostly CD4+ <100
  • Serological tests not very helpful as antibodies exist in general population
  • CSF antibodies makes diagnosis likely but false negatives are common
  • Non-contrast CT: Multiple subcortical lesions with predilection for basal ganglia
  • Contrast-CT: Multiple ring-enhancing lesions with surrounding oedema
  • MRI more sensitive
  • DDx: CNS lymphoma, fungal infection and cerebral TB

Neurological complications

• Cryptococcosis
  • Focal or diffuse meningoencephalitis
  • Mostly in CD4+ <50
  • Neuroimaging usually normal
  • CSF cryptococcal antigen testing (100% sens and specific), culture or India ink stain
  • Raised CSF opening pressure and pleocytosis with lymphocyte predominance
• CNS lymphoma
  • Typically single ring-enhancing lesion on neuroimaging

Neurological complications

• Peripheral neuropathy
  • May be due to HIV-neuropathy or due to ART
  • Changing ART agents may be helpful
  • Short-term opioids in severe cases

Ophthalmic complications

• 75% of patients with AIDS develop ocular complications
• Retinal microvasculopathy
  • Retinal cotton-wool spots (as seen in HTN and DM)
  • Retinal microaneurysms
  • Can be difficult to differentiate above from early CMV retinitis

Ophthalmic complications

• CMV retinitis
  • Most frequent and serious ocular opportunistic infection
  • Leading cause of blindness in AIDS
  • May be asymptomatic early but then changes in visual acuity, visual field loss, photophobia, scotoma, eye redness and eye pain
  • Fluffy white perivascular lesions with haemorrhage
  • 10% of affected patients ultimately go blind

Ophthalmic complications

• Herpes zoster ophthalmicus
  • Paraesthesia and discomfort in V1 followed by typical zoster rash
  • Ocular complications include conjunctivitis, episcleritis, iritis, keratitis, secondary glaucoma and rarely retinitis

Pulmonary complications

• Most common causes are CAP, PJP, tuberculosis, CMV, Cryptococcus, histoplasmosis and neoplasms
• Diffuse interstitial pattern: PJP, CMV, TB, MAC, histoplasmosis, coccidioidomycosis, lymphoid interstitial pneumonitis
• Focal consolidation: Bacterial pneumonia, Mycoplasma, PJP, TB, MAC
• Nodular lesions: Kaposi’s sarcoma, TB, MAC, Fungal infection, Toxoplasmosis
• Cavitary lesions: PJP, TB, bacterial pneumonia, fungal pneumonia
• Adenopathy: Kaposi’s sarcoma, lymphoma, TB, cryptococcus

Pulmonary complications

• Pneumocystis jirovecii
  • Most common opportunistic infection in AIDS
  • 70% of HIV patients have PJP at some stage and is often the first AIDS-defining illness
  • Fever, cough (typically dry) and SOB + Fatigue
  • Negative CXR in 15-25% but usually diffuse interstitial pattern
  • Exercise desaturation in excess of CXR findings is pathognomonic
  • Bactrim +- prednisolone as initial therapy

Pulmonary complications

• TB
  • Typically CD4 200-500
  • Classically cough with haemoptysis, night sweats, weight loss, prolonged fever and anorexia
  • With more profound immunosuppression often have less classic features
  • Classic upper lobe cavitary lesions are less common as late-stage AIDS occurs
  • Negative tuberculin skin testing due to immunosuppression
  • Extrapulmonary TB becomes more common typically affecting peripheral lymph nodes, bone marrow, CNS, GI and urogenital system

GI complications

• Oral and oesophageal complications
  • Oral candidiasis
    • Potential clinical marker of high viral load, dropping CD4+
    • Seen in >80% of AIDS patients
    • Mostly managed with oral nystatin
    • Must differentiate from oral hairy leukoplakia on lateral tongue border)
  • Other oral lesions
    • HSV (vesicular)
    • Kaposi’s sarcoma (non-tender, well circumscribed, slightly raised violaeceous lesion)

GI complications

• Oesophageal
  • Odynophagia and dysphagia suggests oesophagitis
  • Usually CD4+ <100 with Candidiasis, HSV or CMV
  • Oral azole therapy as presumptive for candidiasis with endoscopy if refractory to rule out HSV/CMV
• Diarrhoea
  • Enterobacteriaceae, Entamoeba, MAC, C. diff, Giardia, Cryptosporidium, Isospora, CMV, HSV, HIV, Histamoeba, Cryptococcus
  • Stool MCS + OCP
  • Acid-fast staining of stool can identify Cryptosporidium and Isospora
  • In end-stage AIDS, CMV and MAC are most common and require biopsy for diagnosis

GI complications

• Hepatic
  • Hepatomegaly in 50% often with raised ALP but not jaundiced
  • Co-infection with HepB and C is common
  • Opportunistic CMV, Cryptosporidium, MAC and TB can all cause hepatitis
  • Proctitis often due to N. gonorrhoeae, C. trachomatis, Treponema pallidum and HSV

Cutaneous complications

• Seen in 90% of patients with HIV
• Dry skin, seborrheic eczema and pruritic are common
• Staph aureus: Bullous impetigo, folliculitis
• Pseudomonas aeruginosa: Chronic ulcerations and macerations
• Syphilis
• HPV warts
• Intertriginous Candida or Trichophyton
• HSV
• VZV
• Scabies
• Kaposi’s sarcoma: Painless, raised, brown or purple papules and nodules that do not blanch. Commonly on face, chest, genitals and oral cavity

Psychiatric complications

• Search for underlying cause of delirium
• AIDS psychosis should be treated as like any other
• Depression in 81%
• Mania occurs in early and late-phase HIV infection
  • Late-stage strongly associated with dementia

Antiretroviral therapy

• 5 Classes
  • Nucleoside reverse transcriptase inhibitors (e.g. zidovudine)
  • Non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz)
  • Protease inhibitors e.g. indinavir
  • Entry inhibitors e.g. enfuvirtide
  • Integrase inhibitors e.g. raltegravir
• Usually initial therapy is 2 nucleoside RT inhibitors + 1 other

Antiretroviral therapy

• Indication for therapy
  • CD4 <350 or history of AIDS-defining illness
  • Pregnancy
  • HIV-associated nephropathy
  • Hepatitis B co-infection requiring therapy

Antiretroviral therapy

• Common adverse effects
  • Stevens-Johnson syndrome, pancreatitis, peripheral neuropathy, lactic acidosis, dyslipidaemia, hyperglycaemia
  • NRTI’s associated with fatigue, fat wasting, lactic acidosis and peripheral neuropathy
  • NNRTI’s – Skin rash (mild through to SJS)
  • Hepatotoxicity in 10%

Post-exposure prophylaxis (PEP)

• Risk of transmission if known HIV positive source not on ARV
  • Receptive anal intercourse
    • Ejaculation (1/70); Withdrawal (1/155)
  • Shared needles 1/125
  • Insertive anal intercourse uncircumcised 1/160
  • Insertive anal intercourse circumcised 1/900
  • Receptive vaginal intercourse 1/1250
  • Insertive vaginal intercourse 1/2500
  • Receptive or insertive oral intercourse – Extremely low
  • Needlestick injury 1/440
  • Mucous membrane or non-intact skin exposure <1/1000

PEP

• HIV seroprevalence in Australia
  • MSM 8-10%
  • IVDU 0.5%
  • MSM + IVDU 30%
  • Heterosexuals <0.003%
  • Female sex workers <0.1%
  • Overall 0.14%
• Overseas prevalence
  • 26% in Southern Africa
  • 40% of IVDU in Sth East Asia

PEP

• RASP tool (Risk Assessment Stratification Protocol)
  • Total score (Z) = A x B x C
  • Basic risk = 1/ Z
  • Total risk = Basic Risk x Modifier (D)
• A = Identify source population
  • Acute AIDS = 1
  • Asymptomatic = 10
  • Unknown HIV status high-risk (suspected HIV, IVDU, unknown needle with high local prevalence of HIV) = 100
  • Low-risk = 1000

PEP

• B = Inoculum type
  • Fresh blood = 1
  • Body fluids = 10
  • Dried old blood = 100
  • Low-risk (tears, saliva, urine) = 1000
• C = Method of transmission
  • IV = 1
  • Deep IM = 10
  • Deep transcutaneous with visible bleeding = 100
  • Superficial transcutaneous with no visible bleeding = 200
  • Mucosal only = 500
  • Intact skin = 1000

PEP

• D = Estimate volume of inoculum
  • Massive (transfusion) = 100
  • Measurable (>1mL) = 10
  • Large bore hollow needle >22g = 5
  • Small bore hollow needle <22G = 3
  • Suture needle = 1
• Risk level
  • >1/1000 = Definitely indicated
  • 1/1000 to 1/10000 = Recommended but optional
  • 1/10000 to 1/100 000 = Optional but not recommended
  • <1/100 000 = Not indicated

PEP

• Non-occupational exposure to known HIV positive
  • 3 drug regime recommended for all except oral intercourse (unless breach in mucous membrane OR if viral load KNOWN to be undetectable
• Non-occupational exposure to unknown HIV status
  • 2 drug regime if source MSM or from high-prevalence country
  • Not recommended for oral sex, mucous membrane exposure or discarded needlestick injury

PEP

• Must inform patients
  • Not 100% effective
  • Importance of adherence
  • Potential adverse effects
  • Measures for preventing re-exposure
  • Follow-up HIV testing requirements
  • HIV seroconversion signs and symptoms
  • Discuss PrEP

PEP

• 2-drug regime
  • Tenofovir + lamivudine
  • Tenofovir + Emtricitabine
• 3-drug regime
  • Above + Dolutegravir, Raltegravir or Rilpivirine
  • Increases risk of drug-drug interactions, adverse reactions and rhabdomyolysis (Raltegravir)

Switching from PrEP to PEP

• Recommended only if:
  • Exposure warrants 3-drug PEP AND
  • Adherence to PrEP has been <4 doses in the week of exposure AND
  • The last exposure event occurred in 72 hour PEP window

PEP following sexual assault

• Should always be offered for male-to-male sexual assault
• Not recommended routinely for heterosexual assault as prevalence is likely around <0.1%
• Multiple assailants, trauma or assailant from HPC may change risk benefit ratio though
• Always offer emergency contraception

PrEP

• Daily PrEP with tenofovir + emtricitabine (Truvada) is safe and effective for IVDU, MSM, heterosexual adults in those that are deemed high risk
• High adherence efficacy of 92% in homosexual men and 84% in heterosexuals
• Indicated for high and ongoing risk of HIV in proven seronegative state (within 7 days of prescription)

Last Updated on October 2, 2020 by Andrew Crofton