Cause of HIV
Caused by HIV-1 and HIV-2 (retroviruses)
4 groups of HIV-1 and prevalence worldwide
Groups: M, N, O and P
HIV-1 group M viruses are responsible for the global HIV pandemic. Have 9 subtypes: A-D, F-H, J and K
Which HIV-1 subtype is predominant in Australia?
HIV-1 subtype B (also in America, Western Europe)
subtype C in Africa and India
Where are infections by HIV-2 seen?
Largely confined to West Africa
Most severely HIV-affected region of the world
Sub-Saharan Africa
Basic pathophysiology of HIV infection
- HIV targets & infects CD4+ T-lymphocytes with its primary receptor CD4 and a co-receptor (CCR5 or CXCR4)
- Virus-encoded reverse transcriptase coverts viral RNA genome into HIV DNA
- HIV DNA is transported to the cell nucleus, where virus encoded integrase incoporates HIV DNA into the cell’s DNA
- Once integrated into the host genome, HIV genetic elements are transcribed into mRNA –> HIV proteins (long chains)
- New HIV virions assemble
- The HIV virions bud from the cell wall. HIV proteases digest the long chains, which makes the new virions infectious
- New HIV virions target the next CD4 cell
Each step above can be targeted by antiretroviral medications
Routes of HIV transmission (3)
- Direct sexual contact (semen, vaginal fluid, blood)
- Perinatal transmission
- Direct contact with infected blood (occupational, needle sharing)
Risk factors for HIV transmission
From highest risk to lowest risk
And what disease factor does transmission risk highly depend on?
HIGHLY dependent on the viral load present in the fluid that one is exposed to.
Risk factors:
- Contaminated blood products (back in the day)
- Perinatal transmission without intervention (20% risk)
- Receptive anal intercourse (1.4% per exposure)
- Needle sharing with HIV infected person (0.6% per exposure)
- Occupational needle stick (0.2% per exposure)
- Receptive penile-vaginal intercourse (0.1% per exposure)
- Oral intercourse: low, but not zero
- Biting, spitting, exposure of intact skin (negligible)
- Exposure to fluids from an individual who is HIV infected but undetectable (0% risk)
Clinical presentation
- Acute antiretroviral syndrome
Antiretroviral syndrome (mimics EBV)
- Prolonged fever
- Fatigue
- Cervical adenopathy
- Myalgias
- Arthralgias
- Pharyngitis
When it occurs, painful mucocutaneous ulcerations are one of the most distinctive manifestations of acute HIV infection
Some patients may have no or very mild sx only
May present with aseptic meningitis
Clinical presentation:
- Early infection (first 6 months)
- Chronic HIV infection (6mo - >10 years)
Early infection (acute infection with seroconversion): Asymptomatic, vague, non-specific complaints
Chronic HIV infection:
- Most are asymptomatic
- Sometimes generalised lymphadenopathy
- Mucosal candidiasis common when immune function deteriorates
- Reactivation of VZV –> shingles
- Oral hairy leukoplakia
- Immune-mediated TCP
- Weight loss
Clinical presentation:
- Advanced HIV and AIDS
- Recurrent and stubborn opportunistic infections
- Anorexia with wasting
Prognosis for patients with CD4+ T lymphocyte count <50 (untreated)
Survival average of <18 months
AIDS defining conditions - partial list (13)
Sustained CD4+ TL count of <0.2x10^9/L (<200/uL)
Multiple or recurrent bacterial infections (children <6)
Recurrent pneumonia (>6)
Candidiasis extending beyond the orophraynx to oesophagus/respiratory tract
CMV disease beyond liver, spleen, LNs
HSV infection of oesophagus or respiratory tract
Disseminated infection of non-TB mycobacterium
Kaposi sarcoma
Burkitt or immunoblastic lymphoma
Primary lymphoma of the brain
Pneumocystis jirovecii pneumonia
Progressive multifocal keukoencephalopathy
Toxoplasmosis of the brain
Wasting syndrome
Diagnostic tests for HIV when diagnosis is suspected (i.e. not screening)
- 2 x tests
- Outcomes of these tests and further steps
- HIV immunoassay (tests for HIV p24 antigen AND anti-HIV antibody). Detects >15 days post exposure. Better than antibody only, as antigen can be detected earlier on.
In addition to:
- HIV viral load (quantitative HIV RNA PCR). Detects >5 days post exposure.
The approximate timing of infection can be assessed by the pattern of test results.
Possible outcomes:
A. Negative HIV immunoassay and viral load: HIV infection has not been acquired. Repeat in 2/52 if suspicious
B. Negative HIV immunoassay and positive viral load: usually suggests early infection.
Repeat positive viral load test supports infection. Repeat serology as well in a few weeks to document seroconversion.
Positive serology doesn’t necessarily rule out very recent infection, given serology is now super sensitive (some patients seroconvert within 6 months on modern tests). Consider clinical presentation (i.e. exposure history, recent acute RV syndrome, very high RNA levels) to infer actual timeframe.
A viral load of <1000 copies/mL may be a false positive. Must immediately repeat this.
C. Positive serology and viral load. Next step –> confirmatory HIV-1/2 antibody differentiation assay. If not available in lab, use Western blot.
What test to perform in infants of HIV-infected mothers for diagnosis?
Infants will test HIV seropositive due to presence of transplacental maternal antibodies. Therefore can’t use tests that rely on antibody detection (i.e. 4th gen assay) until maternal antibody clears. HIV assays are so sensitive that this may take up to 15 months.
Therefore, the preferred test for infants is qualitative RNA PCR assay.
Viral RNA level and CD4 count in:
A. Early HIV infection
B. Chronic HIV infection
A. Acute infection = 6 month period post seroconversion
- Viral RNA level usually VERY high (>100,000 copies/mL. Peak is usually at time of seroconversion, usually stabilises by 6 months. This is when HIV-specific CD8+ T cells emerge
- CD4 count can drop transiently in early infection (but opportunistic infections rare)
B. Stable viral RNA levels with progressive decline in CD4 cell count. The rate of CD4 decline is associated with level of viraemia.
Ddx for acute HIV infection
EBV, CMV, toxoplasmosis, rubella, syphilis, viral hepatitis, disseminated gonococcal infection, other viral infections
Consider autoimmune diseases
HIV screening in general population - diagnostic tests
- Fourth generation HIV immunoassay (our regular antigen/antibody test)
THEN, if positive:
- Perform a HIV-1/HIV-2 antibody differentiation immunoassay
This will inform you of a subtype of HIV. If negative or indeterminate (i.e. not consistent with the initial immunoassay):
- Perform HIV RNA PCR (viral load)
If positive, acute HIV-1 infection
If negative, negative for HIV-1
A patient is diagnosed with acute HIV… what investigation should be done next? And what counselling should be given?
Drug resistance testing
20% of newly infected patients have HIV with at least one drug resistance mutation.
Refer to specialist for commencement of therapy. Therapy should not wait for the results of drug resistance testing.
Counselling:
Compliance with medication
Condom use
Avoid sharing needles
Why do HIV patients develop comorbid conditions i.e. CVD, renal disease, OP, cognitive dysfunction & certain malignancies, younger than the general population?
Thought to be due to chronic inflammation, immune activation or immunosenescence
AIDS definition
Acquired immunodeficiency syndrome
Defined by CD4 cell count <200cells/microL or the presence of any AIDS defining conditions
Progression from HIV –> AIDS without ART
Usually gradual over 5-10 years without treatment
Some patients are ‘HIV controllers’ and manage > 10 years (low viral loads, stable CD4)
Some patients are rapid and transition within 1-2 years
Physiological markers of effective ART
- Sustained suppression of HIV RNA
- Improved immunity (CD4 counts)
- Reduced HIV immune activation (proinflam cytokines, chronic inflammation, T cell activation)
Prognosis of HIV with ART
Life expectancy for a person with HIV with virologic suppression on ART approaches that of the general population (provided ART started early with acceptable CD4 count)
