Human Immunodeficiency Virus

Background

  • Thought to originate from primates, the HIV virus first infected humans ~100 years ago.  Since then, it has been responsible for over 30 million deaths
    • Its impact has been most devastating in sub-Saharan Africa (2/3 of all HIV cases)
  • There are different strains/subtypes of the HIV
    • M (major- worldwide); O (outlier); and N (non-major and non-outlier) groups
      • O and N are found almost exclusively in Western Africa
      • Group M has 9 subtypes (A-D; F-H, J and K)
        • Subtype C most common, particularly in Africa
        • Subtype B common in Western Europe, Americas and Australia

Epidemiology

  • The total number of people living with HIV in 2011 was ~34 million, the number of new cases was ~2.5 million and there were ~1.7 million deaths related to HIV.
  • Since the introduction of ART (see below), AIDs related deaths have declined but the number of people living with HIV has risen.
  • Incidence is generally decreasing but HIV is increasing in areas such as Eastern Europe, North Africa and the Middle East- thought to mainly be due to IV drug use

Transmission

  • Sexual contact
    • Worldwide, the major mode of transmission is heterosexual sex
  • Exposure to blood/blood products
  • Vertical (either in utero or by breast-feeding)
  • Note that the highest risk of transmission is via contaminated blood products or vertical transmission (remainder are <1%).  However, the frequency of unprotected sex outfactors the small risk.

Virology/Immunology

  • HIV is an enveloped RNA retrovirus containing 2 copies of genomic RNA and 3 viral enzymes (reverse transcriptase, protease and integrase)
    • Once in the host, it is transported to lymph nodes and infection is established
    • Followed by viraemia and infection of lymphoid tissues/organs, where viral replication occurs
  • HIV can only infect CD4-receptor expressing cells
    • T-helper lymphocytes
    • Monocyte-macrophages
    • Dendritic cells
    • Microglial cells in the CNS
  • By directly infecting cells of the immune system, the immune system cannot mount a response
    • It also evades destruction by a process called antigenic variation.  This is caused by a high error rate of reverse transcriptase which causes a huge variation in the genetic structure of HIV strains within a single patient.  This swamps the immune system and renders it effectively useless at attempting to clear the virus
  • HIV DNA is incorporated into the cells DNA and HIV can then replicate using the cell’s own mechanisms
  • An important consequence of this process is that it reduces the cell life-span to around 1 day.
  • Patients with HIV are estimated to lose 10^9 CD4 lymphocytes every day and produce more than 10^10 virions each day

HIV_gross_cycle_only

  • A small number of T helper lymphocytes do not assist with HIV replication but enter a latent phase (post-integration)
    • This is important because these cells are not targeted by the body’s natural defenses nor by current treatments
  • The body’s T cells (CD8) mount an cellular and humoral defense against active CD4 cells (not latent cells)
    • Rise in CD8 cells initially, but then decline
    • Patient becomes susceptible to opportunistic infections

Diagnosis/Investigation

  • Combined antibody and p24 antigen test (PCR) is most commonly used for screening HIV (very accurate, takes 4 weeks)
  • When/who to offer testing?
    • If the patient asks for it
    • In settings where HIV is a possible/important diagnosis e.g.
      • GUM/STI clinics
      • Antenatal services/TOP clinics
      • Illicit drug use services, services for those with Hep B, Hep C, TB etc
      • Patients with an STI, sexual partners of people with HIV or of men who sleep with men (MSM)
      • Patients with a history of drug use
      • Patients from a country of high HIV prevalence
      • Blood donors, dialysis patients, organ transplant donors/recipients
  • Pretest/Posttest counselling
    • Pretest
      • Discuss the meaning of both positive and negative results
      • Emphasise confidentiality and identify person/people to whom a positive result could be disclosed to
        • In some cases, the partner of the patient may be informed without the patient’s consent (see here for more information)
      • Explore knowledge and explain natural history of HIV; transmission and risk reduction
      • Assess patient coping strategy
      • Explain the test procedure and obtain informed consent
    • Post test- negative
      • Discuss transmission and need for any behaviour modification / risk reduction
      • Advise for further testing 3 months after last exposure and welcome the patient back for testing if they have been/worried about having been exposed
    • Post-test – positive
      • Explain meaning (use suitable skills for breaking bad news)
      • Organise suitable follow up
      • Assess coping strategy
      • Stress importance of disclosure
      • Explain value of antiretroviral therapy
      • Provide written information/internet resources
      • Discuss confidentiality issues
      • Organise support networking (names/numbers)
      • Offer to facilitate notification of sexual partners

Further investigations

  • Screen for other transmissable diseases e.g. Hep B and Hep C; Full workup including FBC, LFTs and U&Es; urinalysis; STI screen
  • CD4 counts (flow cytometry)
    • <200 cells/mm³ is significant; although %age of CD4 (to total count) may also be a useful calculation
    • used in combination with clinical stage to decide the requirement of treatment
  • Viral load (HIV PCR)
    • Main use is response to treatment
    • Higher the viral load, the faster the decline in CD4 count

Hiv-timecourse

Natural History/Staging

  • Staging
    • Clinical staging should be performed at diagnosis (provides prognostic information and key as to whether ART/infection prophylaxis is started).
    • Two staging systems available.  Note that for both, patients CANNOT be downstaged i.e. if a patient recovers from a major opportunistic infection, they are still stage III/IV

Hiv-timecourse

  • Primary Infection (seroconversion)
    • 2-4 weeks after exposure, around 50% of patients will experience a flu-like illness (often very similar to glandular fever) which lasts 10-14 days
    • Drop in CD4 count but dramatic rise in CD8 count (if this is strong- associated with good prognosis
    • Features include
      • Fever
      • Maculo-papular rash (often differentiating)
      • Pharyngitis
      • Lymphadenopathy
      • Myalgia/arthralgia
      • Diarrhoea
      • Headache
      • More rarely: Oral/genital ulcerations; meningo-encephalitis or Bell’s palsy
    • If patients present with features similar to EBV infection, but have a negative EBV mononuclear spot test, consider testing for HIV
      • there may be a transient lymphopenia (cf EBV lymphocytosis) which may predispose to fungal infections e.g. cadidiasis, or more severe infections e.g. pneumocystis pneumonia.
  • Latency
    • Once seroconversion is over, CD8 count drops and CD4 count rises (clinical latent period)
    • Can last days, weeks, months or years
    • CD4 count gradually declines as the HIV replicates
  • Presentation
    • Pneumonia (pneumocystis) is the most common presentation (40% of AIDS defining illness is pneumocystis)
      • Dry cough, dyspnoea, fever, general malaise
      • Chest x-ray shows bilateral mid- and lower zone interstitial shadowing
      • Treat with high dose cotrimoxazole or IV pentamidine
    • Oesophageal candidiasis occurs in >10%

Management

  • Patients should be started on treatment when
    • They have symptomatic HIV disease
    • They have rapidly falling CD4 counts; but before CD4 count falls below 200 cells/ml (usually when count is <350)
    • They have a high viral load
  • Treatment is with 3 drugs
    • 2 nucleoside reverse transcriptase 1A inhibitors (NRTI) plus
      • either a ritonavir-boosted protease inhibitor OR
      • an NNRTI OR
      • an intense inhibitor
    • NB Side effects of protease inhibitors are multiple: including pancreatitis, abdominal pain, fat redistribution, blood disorders (pan- (or individual)- cytopenia), metabolic effects e.g. hyperlipidaemia, insulin resistance and hyperglycaemia, buffalo hump, P450 enzyme inhibition)
    • NB Side effects of NRTIs include peripheral neuropathy; anaemia, myopathy and black nails (zidovudine) and pancreatitis (didanosine)
  • Zidovudine should be given in pregnancy during labour (IV) and to the neonate (oral syrup) for the first 6 weeks of life

NB For healthworkers who are exposed to HIV via needlestick injury, zidovudine has been shown to reduce the risk of seroconversion

HIV in Pregnancy

  • Some antivirals have been shown to be teratogenic but not all
    • pregnant women with HIV should be given the latter, ideally combination treatment of non-teratogenic drugs, because antiretrovirals will decrease the chance of vertical transmission by 68% (from 25.5% to 8.3% monotheraphy and <2% combination therapy)
    • Also
      • Intrapartum zidovudine infusion
      • Oral zidovudine for the baby until 6 weeks
      • Elective C section
    • Breastfeeding increases the risk of vertical transmission so is actually discouraged

Infections of AIDs and Management

  • Pneumocystis jiroveci
    • Cotrimoxazole
  • Cerebral toxoplasmosis
    • Ring-enhancing lesions most commonly seen in the basal ganglia
    • Pyrimethamine + Sulphasiazine (standard)
      • Co-trimoxazole or pyrimethamine and clindamycin
      • If no response- brain biopsy
  • Intestinal Cyclosporiasis
    • Cyclospora cayetanensis (intestinal protozoan)
    • Acute watery diarrhoea in immunocompetent; chronic diarrhoea and severe weight loss in HIV patients
    • Cotrimoxazole (often prolonged course)
  • Cryptococcal meningitis
    • Cryptococcus neoformans (yeast)- affects lungs and meninges
    • Amphotericin B and Flucytosine in meningitis (-flucytosine in respiratory only disease)
  • Babesia microti
    • Parasite acquired via tick bites
    • Quinine + clindamycin +/- exchange transfusion
  • Intestinal microsporidiosis
    • Albendazole for treatment
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s