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