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HIV

Definition
  • Caused by a retrovirus that infects and replicates in human lymphocytes and macrophages
  • Erodes the integrity of the human immune system over a number of years
  • Culminates in:
    • Immune incompetence 
    • Susceptibility to a series of opportunistic and other infections 
    • Development of malignancies
Risk Factors 
  • Needle sharing with IV drug use
    • 67 infections/10,000 exposures to an infected source
  • Unprotected receptive anal intercourse
    • 50 infections/10,000 exposures to an infected source
  • Unprotected receptive penile-vaginal sexual intercourse
    • 10 infections/10,000 exposures to an infected source
  • Percutaneous needle stick injury
    • 30 infections/10,000 exposures to an infected source
  • High maternal viral load (mother to child transmission)
    • The level of HIV RNA at delivery is independently associated with risk of transmission
Differential diagnosis
  • EBV
    • EBV may resemble features of HIV acute seroconversion illness
    • Fever, lymphadenopathy, pharyngitis, and maculopapular rash
  • Cytomegalovirus
    • May resemble HIV acute seroconversion illness 
    • Fever, lymphadenopathy, rash, and splenomegaly
  • Influenza infection
    • No specific differentiating signs
    • Viral infections such as influenza may resemble acute seroconversion illness 
      • Fever, pharyngitis, and lymphadenopathy
  • Common cold
    • No specific differentiating signs
    • Viral infections such as the common cold may resemble acute seroconversion illness 
      • Fever, pharyngitis, and lymphadenopathy
  • Viral hepatitis 
    • RUQ abdominal pain, jaundice
    • Elevated LFTs
  • Secondary syphilis
    • Fever, malaise, pharyngitis, lymphadenopathy, maculopapular rash
    • Condylomata lata on genital areas and oral ulcers
    • May have been preceded by painless genital chancre and inguinal lymphadenopathy (primary syphilis)
    • Can co-exist with HIV
    • VDRL positive
    • Treponema pallidum haemagglutination test positive
Epidemiology
  • AIDS was first identified in the US in 1981
    • The US has the most severe HIV epidemic in the developed world
  • There are 33.3 million people infected worldwide, 22.5 million of whom are in sub-Saharan Africa
    • The Caribbean is the most heavily affected region of the world after sub-Saharan Africa
  • In Central and Western Europe the prevalence of HIV infection in adults is 0.3%
    • An estimated 760,000 people are infected
  • In Western Europe, heterosexual transmission was the largest single route of infection
    • Accounting for 42% of newly diagnosed cases in 2006
    • Most of these heterosexually acquired infections were in migrants or immigrants
    • Around 29% of new infections were attributed to sex between men and 6% to injecting drug use
  • In the UK, 8925 new cases were diagnosed in 2006, almost double the figure for 2001
    • The increase is attributed to rising numbers of infections in men who have sex with men
    • Also an increase in heterosexual acquisition in high-risk countries
    • Also improved reporting
  • 49% percent of all newly diagnosed HIV infections in the US in 2006 were among men who have sex with men
  • In contrast, the sub-Saharan epidemic is predominantly heterosexual
    • Women comprise 60% to 70% of those living with HIV
  • Overall, globally, the HIV incidence rate is believed to have peaked in the late 1990s 
    • Changes in incidence along with rising AIDS mortality have caused global HIV prevalence to level off
  • However, the numbers of people living with HIV have continued to rise
    • Due to population growth 
    • And, more recently, to the life-prolonging effects of antiretroviral therapy
Aetiology
  • HIV is a retrovirus that infects and replicates primarily in human CD4+ T cells and macrophages
  • HIV can be transmitted via blood, blood products, sexual fluids, other fluids containing blood, and breast milk
  • Most individuals are infected with HIV:
    • through sexual contact
    • before birth or during delivery
    • during breastfeeding
    • when sharing contaminated needles and syringes (IV drug users)
  • Sexual intercourse is the most common, albeit inefficient, mode of HIV transmission
  • The risk of transmission per exposure is low
    • Estimates are on the order of 0.1% per contact for heterosexual transmission
Clinical features 
  • Fevers and night sweats
    • Unexplained fever and night sweats for more than 1 month (with no response to antibiotics)
    • These symptoms may indicate TB, which should be excluded
    • Malaria should be excluded in endemic areas
  • Weight loss
    • Unexplained involuntary weight loss of less than 10% of body weight is a WHO stage 2 symptom
    • If more than 10% of body weight is lost this indicates more severe immunocompromise
    • Loss of weight may result from malnutrition, TB infection, and HIV wasting syndrome
  • Skin rashes and post-inflammatory scars
    • Rashes may occur throughout HIV disease and close attention should be paid to the skin
    • Rashes are the most common sign of WHO stage 2 disease, including:
      • herpes zoster (shingles)
      • seborrhoeic dermatitis
      • pruritic papular eruptions
      • fungal skin and nail infections (tinea corporis or unguium)
  • Oral ulcers, angular cheilitis, oral thrush, or oral hairy leukoplakia (OHL)
    • The mouth should always be thoroughly examined
    • Both thrush and OHL indicate WHO stage 3 or CDC category B disease
    • Recurrent painful oral aphthous ulcers indicate WHO stage 2, as does angular cheilitis
  • Diarrhoea
    • Unexplained diarrhoea of more than 1 month in duration (with no pathogen diagnosed)
  • Wasting syndrome
    • Unexplained weight loss (>10% of body weight) 
    • or Wasting together with either unexplained fever (lasting >1 month) 
    • or Unexplained chronic diarrhoea (for >1 month)
  • Recent hospital admissions for an infectious disease
    • Bacterial infections (such as pneumonia, meningitis, bone or joint infection, severe PID, septicaemia)
    • TB
    • Fungal or viral infections
  • TB
    • The risk of TB increases with worsening immunosuppression
    • In severe immunosuppression, TB may be present without a positive sputum (smear-negative TB)
  • Medical comorbidities
    • For example, a patient with renal disease will require adjustment of antiretroviral doses
    • Consideration of drug interactions with antiretroviral therapy and all medicines should be given
  • Sexual activity
    • HIV is largely spread through heterosexual intercourse in sub-Saharan Africa
    • Homosexual intercourse, especially in the receptive partner, is a risk factor for HIV transmissio
  • Generalised lymphadenopathy
    • Painless enlarged nodes, in 2 or more non-contiguous sites of greater than 1 cm for more than 3 months
  • Oral Kaposi's sarcoma (KS) 
    • KS may present as a pink or violaceous patch on the skin or in the mouth
    • It is an AIDS-defining condition
  • Genital STDs
    • Chronic herpes infection, that is, progressive painful genital or anal ulceration for more than 1 month
  • Shingles
    • Occurs in WHO stage 2 or CDC category B disease
  • Headaches
    • Headaches may be indicative of CNS disease
  • Changes in mental status or neuropsychiatric function
    • Change in mental status could be due to organic disease in late-stage HIV (WHO stage 4/CDC category C)
    • Toxoplasmosis and cryptococcal disease should be excluded.
    • In the absence of another condition to explain symptoms, HIV encephalopathy may be diagnosed
  • Periodontal disease
    • Poor oral hygiene with loosening of teeth, bleeding of gums, and bad odour indicates gingivitis or periodontitis
  • Retinal lesions on fundoscopy 
    • Medical emergency and requires immediate referral for sight-saving intervention if CMV retinitis
  • SOB on exertion, cyanosis on exertion, dry cough, silent chest on auscultation
    • These are clinical features of Pneumocystis jirovecii pneumonia
  • Malnutrition 
    • Malnutrition results in further immune suppression and possibly more rapid progression of HIV disease
  • Hepatomegaly or splenomegaly
    • May indicate acute HIV syndrome, opportunistic infection, or non-benign illness, for example, lymphoma
Pathophysiology 
  • The virus gains entry to the cells by attaching to the CD4 receptor and a co-receptor 
    • Via its envelope glycoproteins
  • It is called a retrovirus because it encodes the enzyme reverse transcriptase
    • Allows a DNA copy to be made from viral RNA
  • The reverse transcriptase enzyme is inherently error-prone, resulting in a high rate of HIV mutation,
    • Can rapidly lead to viral resistance in those on treatment
  • Once integrated into the cellular DNA the provirus resides in the nucleus of infected cells 
    • Can remain quiescent for extended periods of time
  • Alternatively it can become transcriptionally active (especially where immune activity is occurring) 
    • Can use the human host cell machinery to replicate itself
  • Viral RNA is then spliced singly or multiply to make a variety of structural and regulatory and accessory proteins
  • Viral proteases further process proteins
  • Mature viral particles are formed when the virus buds through the host cell membrane
  • Within a few weeks of infection there is a high level of viral replication in the blood 
    • Can exceed 10 million viral particles per microlitre of plasma
    • There is a concomitant decline in CD4 T cells
  • However, an immune response to HIV develops that curtails viral replication
    • Results in a decrease in viral load and a return of CD4 T-cell numbers to near normal levels
  • The immune control is thought to be dependent on killer T cells and neutralising antibodies
  • Depending on how effective this control is, the viral load is known as the set point
    • This is thought to be prognostic of natural history outcomes for the infected person
  • Research suggests that the host's initial response to HIV infection is critical and genetically determined
    • Five percent of patients show unusually slow or no immune damage
      • These non-progressors are being carefully studied 
Investigations
  • Serum HIV ELISA
    • ELISA should be ordered when HIV testing is indicated
    • False negatives may occur during window period immediately after infection before antibodies to HIV have occurred
    • A positive result should be confirmed with a Western blot or second ELISA
    • The window period can be reduced to 2 to 4 weeks by using fourth-generation tests and those that include IgM antibodies to HIV
  • Serum HIV rapid test
    • Point of care test
    • Staff should be trained to do the rapid test
    • Should be ordered when HIV testing is indicated
    • False-negatives may occur during window period immediately after infection before antibodies to HIV have occurred
    • A positive result should be confirmed with a second rapid test
  • HIV non-invasive tests
    • Most often used in surveillance
    • Most frequently sample buccal saliva
    • Both rapid and ELISA varieties are available
  • Serum Western blot
    • Expensive, so most often used as a confirmatory test following a positive ELISA or rapid test
    • During the window period result may be falsely negative or indeterminate
  • Serum p24 antigen
    • p24 protein is present during high viral replication and so is detectable in the blood during acute infection and again during late stages of infection
    • Its use, therefore, is as a supplementary test during the window period
  • Serum HIV DNA PCR
    • By HIV DNA PCR, qualitative pro-viral DNA in peripheral blood mononuclear cells can be used to make diagnosis of HIV especially during the window period
    • This is more costly than antibody-based diagnostic tests
  • CD4 cell count
    • Indicates immune status and assists in the staging process
    • Ideally more than 1 CD4 count should be completed before treatment-initiating decisions are made
    • Levels:
      • CD4 count of more than 500 cells/mL: patients are usually asymptomatic
      • CD4 count of less than 350 cells/mL: implies substantial immune suppression
      • CD4 count less than 200 cells/microlitre: places the patient at risk of most opportunistic infections
  • Serum viral load
    • May help to assess whether treatment should be initiated
    • An important test for establishing a baseline viral load before therapy and monitoring response to highly active antiretroviral therapy (HAART)
    • Quantitative viral RNA in plasma is used to confirm acute retro viral syndrome (i.e., symptomatic patients before the HIV antibody test is positive)
    • Detectable levels of less than 1000 copies/mL may indicate a false positive result and should be repeated in 1 month along with antibody tests
    • However, if the result is well over 1000 copies/mL, then the diagnosis is confirmed
    • Quantitative viral RNA is not recommended as a diagnostic test in other clinical scenarios because it can be falsely positive
    • Levels:
      • Recently infected people may attain levels in the millions of copies/mL
      • During control of infection, viral load may be controlled in the thousands or hundred of thousands
      • End stages of infection viral loads increase again into millions
  • Pregnancy test
    • All women of childbearing potential should have a pregnancy test to enable access to prevention of mother-to-child transmission strategies
    • Urine beta-hCG would be sufficient to detect pregnancy
  • Serum hepatitis B serology
    • Should be performed at baseline, before starting HAART, or if liver functions are abnormal
  • Serum hepatitis C serology
    • In some countries, for example, the US, hepatitis C is tested on all patients at baseline
  • Serum VDRL
    • Non-treponemal antibodies will detect primary and early syphilis
    • Titre reduces with adequate treatment
    • Lack sensitivity in late stages of syphilis
  • Treponema pallidum haemagglutination test
    • Good screening for all stages after primary syphilis
    • Remains positive after treatment.
    • Follow-up tests are fluorescent treponemal antibody absorption test, RPR, or enzyme immunoassay
  • RPR
    • Follow-up test
    • Positive in patient with syphilis infection
  • Tuberculin skin test
    • Indicated to establish evidence of exposure to, and infection with, TB
    • False-negatives may occur in anergic patients (advanced HIV)
    • A reaction of more than 5 mm in a patient who has been screened for TB disease may require TB prophylaxis
  • CXR
    • Should be requested if there are symptoms or signs of TB, P jirovecii pneumonia, or other pulmonary illness
    • Findings:
      • Pneumocystis jirovecii pneumonia: interstitial to extensive alveolar shadowing
      • TB: many abnormalities possible including apical fibrosis/scarring, pleural effusion, hilar adenopathy, miliary pattern, lobar or patchy opacification
      • Bacterial pneumonia: lobar or patchy opacification
  • Tests requested before initiation of HAART and monitored while on therapy
    • LFT
    • FBC
    • Serum creatinine
    • Urinalysis

Management

a) conservative
  • Counselling
b) medical
  • Treatment for co-existing conditions
    • TB
    • P jirovecii
    • Hepatitis
  • Immunisations
  • CD4 count <350 cells/microlitre or AIDS or pregnant or HIV nephropathy or hepatitis B => HAART
    • Multiple combinations of antiretrovirals may be effective in any given patient
    • Additionally, older drugs are now given in off-label doses to facilitate adherence, and new classes of drugs have been introduced
    • Because of this complexity, HIV-treatment prescribing is best individualised by an HIV-experienced clinician
      • The complexity of the regimen may affect adherence
    • Patients must be ready to adhere to treatment and their readiness should be established through counselling
    • Classes of antiretrovirals used include:
      • nucleoside reverse transcriptase inhibitors (NRTIs)
      • non-nucleoside reverse transcriptase inhibitors (NNRTIs)
      • protease inhibitors (PIs)
      • fusion inhibitors (e.g., enfuvirtide)
      • CCR5 antagonists (e.g., maraviroc)
      • integrase inhibitors (e.g., raltegravir)
    • In acute HIV infection or seroconversion within the last 6 months, HAART is optional and decision to start treatment should be made between the physician and patient
  • Virological failure
    • Defined as:
      • a confirmed HIV RNA level greater than 400 copies/mL after 24 weeks or greater than 50 copies/mL after 48 weeks
      • or a repeated detectable HIV RNA level after prior suppression of viraemia
    • Patients with virological failure should be referred back to an HIV-experienced clinician or infectious diseases consultant
      • further drug-resistance testing
      • adherence assessment
      • optimisation of treatment regimens based on drug resistance patterns
    • These patients should also be referred to their consultant for assessment of current medicines, untreated co-infections, and serious medical conditions
c) surgical
  • Stem cell transplantation?
    • One case report from Berlin
Prognosis
  • The majority of HIV-infected individuals are able to regulate viral replication for many years because of an effective immune response
  • There is a steady decline over time of CD4 numbers and slow destruction of the immunity
    • Leads to gradual onset of constitutional symptoms followed by opportunistic infections (OIs) and malignancies
  • Patients may progress through the stages consecutively, but in many cases may move to a stage, skipping a clinical stage in between
    • Individuals do not revert to a previous stage even if treated
  • Antiretroviral therapy, when used appropriately, can reduce HIV replication to levels that are undetectable by laboratory assays
  • This allows the restoration of even advanced immune deficiency to safe levels in the vast majority of treated persons
  • Highly active antiretroviral therapy (HAART) can also reduce HIV transmission and prevent initial infection (post-exposure prophylaxis)
  • As long as appropriate HAART is taken as prescribed without default, the benefits of the viral suppression will be sustained
  • Poor adherence is the most common cause for failure of a regimen
    • Leads to development of drug resistance, leading to breakthrough replication and immune damage once more
    • Under these circumstances, a new regimen must be found with non-resistant agents, which can then, if taken correctly, lead to viral suppression once more
  • The central goal of HIV therapy then is suppression of viral replication sufficient to prevent the selection of viral resistance mutations
    • Long-term adherence remains the key to the efficacy of all HIV regimens
  • A small proportion of individuals are able to control HIV viral load without assistance of HAART
    • Many have low-to-undetectable viral loads and well-preserved CD4 counts for many years
    • This appears in part to be due to a robust immunity to HIV
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