Makindo Medical Notes

Related Subjects: |AIDS (HIV) Neurological Disease |AIDS (HIV) Respiratory disease |AIDS Dementia Complex (HIV) |AIDS HIV Infection |AIDS(HIV) Gastrointestinal Disease |Acute Retroviral Syndrome (HIV) |HIV and Post-Exposure Prophylaxis (PEP) |HIV and Pre-exposure prophylaxis |HIV associated nephropathy (HIVAN) |HIV disease Assessment

Many people who are living with HIV have no obvious signs and symptoms at all.

Introduction

• The prognosis of HIV/AIDs is much improved and those who do badly are those whose CD4 count falls due to failure to diagnose and start on therapy before CD4 count falls.
• Early diagnosis is key and the use of HAART at the right time is important. The main causes of death nowadays are coronary artery disease, liver failure (Often have Hep B/C) and lymphoma.
• HAART revolutionised the management of AIDs and converted it from a progressive terminal disease to a long term manageable chronic disease with reduced the incidence of opportunistic infections, deaths, hospitalisations,
• HIV associated cancers and potentially normal mortality. It consists of simultaneous treatment with 3 or more antiretroviral drugs

About

• HIV 1 : worldwide cause of HIV
• HIV 2: less efficiently transmitted though similar. Lower levels of viraemia and transmission and is resistant to NNRTIs

Structure

Details

• Single stranded plus sense RNA lentivirus
• Dense cylindrical core surrounded by a lipid envelope through which virus binds.
• Contains RNA dependent DNA polymerase (Reverse transcriptase) and so is a retrovirus
• Can form a dsDNA molecule which can integrate into host genome
• Gp120: The 120 in its name comes from its molecular weight. It is essential for virus entry into the cells as it plays a vital role in attachment to specific cell surface receptors.
• GP41: It is a subunit of the envelope protein complex of retroviruses including the human immunodeficiencies virus. It is a family of enveloped viruses that replicate in the host cell through the process of reverse transcriptase. It targets a host cell.
• P17 Viral core is made from protein. It is bullet-shaped. Three enzymes required for HIV replication are reverse transcription, integrase and protease.
• P24 is a component of HIV capsid.
• Protease: a retroviral aspartyl protease that is essential for the life cycle of HIV, the retrovirus that caused AIDS. This enzyme cleaves newly synthesized polyproteins at an appropriate place to create nature protein components of infectious HIV virion.
• Integrase Enzyme produced by retrovirus enables its genetic material to be integrated into the DNA of the infected cell.
• RNA All organisms including most viruses store their genetic material on long strands of DNA. Retrovirus is an exception because their genes are composed of RNA

Viral cycle

• Viral gp120 forms a high-affinity bond with the CD4 receptor
• Further bonding with chemokine receptors CCR5 and CXCR4.
• Fusion and entry of the virus into the cell
• Reverse transcriptase makes a dsDNA copy of the viral genome
• This becomes integrated into the host genome by the action of viral integrase
• Host makes viral mRNA which codes viral proteins
• New provirus copies are formed.

Genes

• gag code for core protein structure of the virus
• Pol code for protease, reverse transcriptase, integrase
• Env codes for the envelope and gp120 and gp41
• vif codes for a protein to make the viruses infectious
• vpr - codes for a transport protein
• vpu - codes for protein for virus assembly
• tat, rev

HIV has tropism for the following cells which all have CD4 as a surface receptor

• There is a gradual destruction of these cells
• CD4 +ve T helper cells
• B cells, Macrophages, Microglial CNS cells, Dendritic cells

Transmission

• In the past via blood transfusion or blood products
• Sharing drug needles or syringes.
• Sexual contact including oral, vaginal, or oral who is HIV positive.
• Having other sexually transmitted diseases such as syphilis, herpes, and gonorrhoea seems to increase the risk of being infected by HIV during unprotected sexual contact with an infected partner.
• Babies can be infected by an HIV-positive mother during pregnancy, birth, and breastfeeding.
• The risk of HIV transmission is dependent on the concentration of HIV in the infected fluid. The QUANTITY of fluid introduced into the body. The ACCESS of the infected fluid to the T4 cells.

Epidemiology

• Widespread infection affecting millions mainly in sub-Saharan Africa, China, India and the Western world. Access to treatment is expensive and political.
• Virus is transmitted by blood, semen, vaginal fluid, breast milk.
• A high mutation rate of the viral replication makes treatment more difficult
• Death is due to infection or malignancies which develop in the immunocompromised
• There are two viruses HIV1 and HIV2. HIV 2 is less common than HIV 1 and is mainly found in West Africa. HIV2 is less pathogenic with a slower less severe course
• The use of HAART changed HIV from being a relentlessly fatal disease to one which is a chronic manageable disease using a combination of retroviral agents
• There is a time post-infection when a patient may be antibody negative but be highly infectious and virus-positive. This lasts 2-6 weeks post-infection.

Possible early clues to suggest testing

• Herpes Zoster, B cell lymphoma
• Paul-Bunnell NEGATIVE glandular fever
• Necrotising gingivitis, Dementia
• Active Tuberculosis
• Recurrent pneumococcal pneumonia

List of AIDS defining conditions (HIV): Infections

• Bacterial Infections:
  • Mycobacterium avium complex (MAC) or Mycobacterium kansasii infection
  • Recurrent pneumonia
  • Recurrent Salmonella septicemia
  • Mycobacterium tuberculosis (extrapulmonary or pulmonary)
• Fungal Infections:
  • Candidiasis of bronchi, trachea, or lungs
  • Candidiasis of oesophagus
  • Coccidioidomycosis (disseminated or extrapulmonary)
  • Cryptococcosis (extrapulmonary)
  • Histoplasmosis (disseminated or extrapulmonary)
  • Pneumocystis jirovecii pneumonia (PCP)
• Parasitic Infections:
  • Cryptosporidiosis (chronic intestinal, lasting more than one month)
  • Isosporiasis (chronic intestinal, lasting more than one month)
  • Toxoplasmosis of brain
• Viral Infections:
  • Cytomegalovirus (CMV) disease (other than liver, spleen, or lymph nodes)
  • CMV retinitis (with loss of vision)
  • Herpes simplex virus (HSV) infection causing chronic ulcers (lasting more than one month), or bronchitis, pneumonitis, or oesophagitis
  • Progressive multifocal leukoencephalopathy (PML)
  • Recurrent herpes simplex virus (HSV) infections

List of AIDS defining conditions (HIV): Cancers

• Kaposi's Sarcoma
• Invasive Cervical Cancer
• Non-Hodgkin Lymphoma:
  • Primary central nervous system lymphoma
  • Burkitt's lymphoma
  • Immunoblastic lymphoma

List of AIDS defining conditions (HIV): Other conditions

• HIV-related Encephalopathy
• HIV Wasting Syndrome
• Lymphoid Interstitial Pneumonitis (in children under 13 years old)
• Recurrent Bacterial Infections (in children under 13 years old)

Clinical Categories

• Category A: HIV Seroconversion Illness
  • Mild viral illness/more severe glandular fever-like illness several weeks after infection.
  • Rash and aseptic meningitis. Suspect in pts with risk factors. Take a sexual history.
  • Followed by persisting generalized lymphadenopathy (PGL), nodes > 1 cm in diameter at two or more extra-inguinal sites for more than three months without another apparent cause.
• Category B: Signs Suggestive of HIV Infection
  • Persisting vaginal candidiasis
  • Hairy leukoplakia of the mouth
  • Herpes zoster involving more than a single dermatome
  • Idiopathic thrombocytopenia
  • Pelvic inflammatory disease (PID)
• Category C: Significant Immunosuppression
  • This category indicates significant immunosuppression, CD4 count determines susceptibility to various illnesses.
  • Cytomegalovirus (CMV) and Mycobacterium avium complex (MAC) infections when CD4 count < 100 cells/µL.

General Manifestations

• General: Anorexia, Wasting syndrome, Fever
  
• Hepatic
  • HIV accelerates Hepatitis B and C and can result in end-stage liver disease
  
  

  CNS PML
  

• Neurological
  • Cerebral toxoplasmosis due to toxoplasma gondii - usually several ring-enhancing lesions with oedema on scanning in the cortex and deep brain - basal ganglia and thalamus and is the cause of over 90% of focal CNS lesions. Check IgG serology which is 90% positive. Treat with pyrimethamine plus sulfadiazine. The differential is lymphoma. Interestingly over 22% of UK are seropositive for exposure. From uncooked meats, cat faeces.
  • Cryptococcal meningitis: due to a budding yeast. Indian ink stain. Cryptococcal antigen in blood and serum. CT/MRI and LP are obligatory in most patients with HIV and neurological signs.
  • CNS lymphoma: usually a diffuse, high-grade B cell) and EBV present - several 1-2 lesions in white matter. A single lesion makes it more likely to be lymphoma rather than toxoplasmosis.
  • Progressive Multifocal leukoencephalopathy: diffuse white matter disease due to JC virus in those with very low CD4. MRI shows non enhancing white matter but no oedema. However, the incidence of PML has not fallen markedly with the extensive use of HAART and is even seen in those with a CD4+ count > 200.
  • Neurosyphilis: myelopathy, retinitis, meningitis, meningovascular disease. AIDS-related dementia. Encephalopathy. Sensory polyneuropathy, autonomic neuropathy.
  • Guillain Barre syndrome may be seen in early disease when CD4 count > 150.
• Cardiology
  • Myocarditis
  • Cardiomyopathy may be seen.
  • Needs Echocardiography.
• Haematology
  • Anaemia
  • Low platelets (autoimmune thrombocytopenia)
  
  
• Dermatological
  • Seborrheic dermatitis, Kaposi's sarcoma
  • Zoster infection, Increased Melanoma
  • Molluscum contagiosum especially on the face, cutaneous T cell lymphomas,
  • Stevens Johnson syndrome due to antiretrovirals
  • Anal and nail fold squamous cell carcinoma
• Ophthalmic
  • Cotton wool spots: Fundoscopy and assessment of acuity is vital and one may see retinal cotton wool spots which rarely cause problems,
  • CMV retinitis may be detected which does cause visual loss and can be treated and is usually seen with a CD4 of less than 50. White cottage cheese-like exudate is seen.
  • Chorioretinitis due to toxoplasmosis may also be seen usually along with an associated encephalitis Syphilitic retinitis may be seen but is rare.
• Gastrointestinal
  • HIV enteropathy with diarrhoea and weight loss.
  • Cryptosporidiosis causes a chronic diarrhoea
• Renal
  • Nephrotic syndrome
  • HIV associated nephropathy (HIVAN)
• Endocrine
  • Adrenal insufficiency is seen but uncommon.

Information

• In such a situation the patient should have pre-test counselling which discusses risks, risk of transmission and the implications of a positive result. Once informed consent has been obtained then an HIV test should be performed. However, with an improved survival, this is less dramatic than it once was. The risks and benefits of any test should be explained to patients regardless. In practice the Initial test is an ELISA screening test and If positive then using a new sample repeat using two different immunoassays or Western Blot.

Poor prognosis

• Anaemia
• Low platelets
• Raised Beta₂-microglobulin
• High HIV RNA viral load
• Low CD4+ count < 200x10⁶

Investigations

• Most important test in assessing HIV patients
• Normal values are > 500 cells/mm3
• calculated by multiplying the number of lymphocytes in a full blood count
• Then multiply this by the percentage of CD4+ lymphocytes on flow cytometry
• Repeated every 3-4 months along with a viral load
• CDC definition of AIDs is CD4 count < 200 cells/mm3
• Advanced AIDS is defined by some as a CD4 count < 50 cells/mm3

New HIV Patient Check

• Clinical assessment - mouth, mouth ulcers
• Skin for Kaposi sarcoma, zoster, lymph nodes, chest, fundi, weight
• Check LFTs and U&E eGFR
• Fasting blood glucose, lipids, bone profile, 25(OH)D
• Urinalysis, Dipstick, Urine protein/creatinine

Immunology

• Lymphocyte subsets
• HLA B*5701 status

Virology

• HIV ab, HIV viral load, HIV genotype and subtype
• HAV IgG HBsAg Hep C Ab

Other

• Toxoplasmosis serology
• Syphilis serology
• Sexual transmitted infections screen
• Cervical cytology
• Chest X ray
• Cardiovascular and fracture risk

Neurology Work Up

• FBC, U&E, LFT, TFT, LFT, Ammonia
• Cryptococcal antigen
• CMV DNA PCR
• RPR, FTA-ABS (Syphilis)
• Toxicology, B12
• CD4 count, HIV viral load

CSF

• Cell count, Differential, Gram stain, Protein, Glucose
• Cryptococcal antigen
• EBV, CMV, VZV, HSV DNA PCR
• JC Virus DNA PCR
• Bacterial, TB, fungal stains and cultures

Imaging

• MRI with gadolinium

HAART

• When to Start HAART in HIV positive individuals
  • AIDS defining illness
  • Pregnant woman
  • HIV associated nephropathy
  • Hepatitis B coinfection
  • Risk of transmitting to partner
  • CD4 count < 350
  • CD4 350-500
  • CD4 > 500
• Monitoring
  • Once started on HAART the CD4 should start rising in weeks at an average of 100 cells/mm per year
  • HIV Viral load also falls by 1 log 10 drop by one month and eventually undetectable
• Side effects
  • PIs - raised lipids
  • SJS/TEN: Nevirapine, EFV rare with others
  • Hypersensitivity: Abacavir
  • Skin rash: Nevirapine
  • GI intolerance: PIs, DDI, ZDV
  • Diarrhoea: PIs, NFV
  • Hepatotoxicity; NVP
• Nucleoside and nucleotide RTIs
  • Abacavir (ABC) , Didanosine [Pancreatitis] (ddI), Emtricitabine (FTC), Lamivudine [Myelosuppression](3TC) , Stavudine (d4T) , Tenofovir (TDF) , Zalcitabine (ddC) , Zidovudine [Myelopathy and Myelosuppression] (ZDV, AZT)
  • Bind to viral DNA and inhibit reverse transcriptase
  • Nausea, Mitochondrial dysfunction and lactic acidosis, polyneuropathy
• Non nucleoside reverse transcriptase inhibitors (NNRTI's)
  • Delavirdine (DLV), Efavirenz (EFV), Nevirapine (NVP)
  • Bind directly to Reverse transcriptase
  • Stevens Johnson syndrome, rashes, liver toxicity
• Protease inhibitors (PIs)
  • Effective drugs. Usually combined with low dose Ritonavir which increases the half-life of the drug "Boosting PI" and so can treat with less medication. Drug have a longer half-life.
  • Amprenavir (APV), Atazanavir (ATV) Darunavir (DRV), Fosamprenavir (FPV), Indinavir (IDV) , Lopinavir/ritonavir (LPV/r), Nelfinavir (NFV), Ritonavir (RTV), Saquinavir (SQV), Tipranavir (TPV)
  • Action is on HIV aspartyl protease enzyme involved in viral production
  • Gastrointestinal - diarrhoea, nausea, fat distribution, hyperglycaemia, hepatotoxicity
• Fusion inhibitor
  • Enfuvirtide (T-20)
  • Blocks fusion of the virus with the target cell
  • Local reaction to subcutaneous injections
• Fixed dose combinations
  • Zidovudine Lamivudine Combivir
  • Zidovudine Lamivudine Abacavir Trizivir
  • Lamivudine Abacavir Epzicom
  • Emtricitabine Tenofovir Truvada

References

• BHIVA Guidance on HAART