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 may resemble features of HIV acute seroconversion illness
Fever, lymphadenopathy, pharyngitis, and maculopapular rash
May resemble HIV acute seroconversion illness
Fever, lymphadenopathy, rash, and splenomegaly
No specific differentiating signs
Viral infections such as influenza may resemble acute seroconversion illness
Fever, pharyngitis, and lymphadenopathy
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
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