Background
- A chronic immunodeficiency resulting from infection with the human immunodeficiency virus (HIV)
- Acquired immune deficiency syndrome (AIDS) is a severe form of HIV characterized by low CD4 count resulting in characteristic infections
Microbiology
- A member of the Retroviridae family
- Clades or subtypes:
- HIV-1: by far the most common species worldwide
- M group
- Clade A: common in East Africa
- Clade B: is common in Canada, Americas, Europe
- M group
- HIV-2: essentially confined to West Africa and certain parts of southern Europe and Asia
- HIV-1: by far the most common species worldwide
Life Cycle
- Two phases: initial viral attachment, fusion, reverse transcription, and integration; and the following lifetime of the viral infection
- Initial cellular infection
- Binding or attachment of the virion gp120 Env surface protein to the CD4 receptor with CCR5 or CXCR4 coreceptor (on macrophage or T-cell, respectively).
- Binding the receptor triggers a conformational change that exposes the fusion domain on gp41, which facilitates fusion and viral entry. The proceeding viral disassembly requires viral protein p24 to bind to cellular cyclophilin A.
- In the cytoplasm, reverse transcriptase converts viral RNA into viral DNA. The RNA is degraded, then the complementary strand of DNA created.
- The preintegration complex of double-stranded DNA is imported into the nucleus using viral Gag, viral protein R (Vpr), and integrase. Unlike other retroviruses, HIV does not require active replication to enter the nucleus.
- Viral DNA is integrated into the host genome with viral integrase.
- Viral DNA in the host genome is transcribed into mRNA and translated into viral proteins, including Gag.
- Protease cleaves the Gag protein, which facilitates virion budding and release.
- Infection of lymphoid cells and lymph nodes, especially gut-associated lymphoid tissue (GALT)
- Infection therefore kills a large proportion of CD4 cells in the gut
- HIV enters from the mucosa to infect activated Langerhans macrophages, which then get to the local lymphoid tissue
Epidemiology
- 63,000 Canadians living with HIV in 2016, of which 14% are unaware of their serostatus
- Mode of transmission in Canada
- Sex among men who have sex with men (MSM) (52% of cases)
- People who inject drugs (17% of cases)
- Heterosexual sex (33% of cases)
- However, heterosexual sex is the most common mode of transmission worldwide
Risk Factors
- High-risk exposures
- Men who have sex with men (MSM)
- Multiple partners
- Injection drug use
- Sex work
- Indigenous Canadians (2.7x higher incidence)
- African and Caribbean people (endemic countries)
- Prior sexually-transmitted infection
- Blood transfusion before 1983 or 84
Clinical Manifestations
Stages
CDC
- Developed by the CDC to provide some risk stratification for opportunistic infection
- Patients are classified based on the most advanced stage ever reached, and not reclassified based on response to therapy
| Stage | Laboratory Evidence | Clinical Evidence |
|---|---|---|
| 0 | negative/indeterminate HIV test within 180 days before first confirmed positive HIV test, or sequence of tests that demonstrate the presence of HIV-specific viral markers 0 to 180 days before or after antibody test that had a negative/indeterminate result | no AIDS-defining illnesses |
| 1 | laboratory-confirmed HIV infection, with CD4 >500 or ≥29% | no AIDS-defining illnesses |
| 2 | laboratory-confirmed HIV infection, with CD4 200-499 or 14-28% | no AIDS-defining illnesses |
| 3 | laboratory-confirmed HIV infection, with CD4 <200 or <14% | OR AIDS-defining illnesses |
| unknown | laboratory confirmed HIV infection, but no information about CD4 count or percentage | no AIDS-defining illnesses |
WHO
| Clinical Stage | Symptoms | CD4 |
|---|---|---|
| 1 | asymptomatic, or persistent generalized lymphadenopathy | ≥500 |
| 2 | unexplained weight loss <10%, recurrent respiratory tract infections, herpes zoster, angular cheilitis, recurrent oral ulcers, papular pruritic eruption, fungal nail infections, seborrheic dermatitis | 350-499 |
| 3 | unexplained weight loss >10%, unexplained diarrhea >1 month, unexplained fever >1 month, persistent oral candidiasis, oral hairy leukoplakia, pulmonary tuberculosis, severe bacterial infections, acute necrotizing ulcerative stomatisis, gingivitis, or periodontitis, unexplained anemia <80, unexplained neutropenia <0.5, unexplained thrombocytopenia <50 | 200-349 |
| 4 | HIV wasting syndrome, Pneumocystis jirovecii, recurrent severe bacterial pneumonia, chronic herpes simplex infection >1 month, esophageal candidiasis, extrapulmonary tuberculosis, Kaposi sarcoma, CMV infection, CNS toxoplasmosis, HIV encephalopathy, extrapulmonary cryptococcosis, disseminated non-tuberculous mycobacteria, progressive multifocal leukoencephalopathy, chronic cryptosporidiosis or isosporiasis, disseminated endemic mycosis, CNS lymphoma, B-cell non-Hodgkin lymphoma, symptomatic HIV-associated nephropathy, symptomatic HIV-associated cardiomyopathy, recurrent bacteremia, invasive cervical carcinoma, atypical disseminated leishmaniasis | <200 or <15% |
Acute HIV
- Incubation period 2 to 6 weeks
- Usually presents as an influenza- or mononucleosis-like illness, corresponding to very high viral load (in the millions) and acute decrease in CD4
- Infectivity is highest due to the very high viremia
- Most common symptoms include fever, lymphadenopathy, pharyngitis, and rash
- Other common symptoms include myalgias, arthralgias, headache, diarrhea, oral ulcers, leukopenia, thrombocytopenia, and mild hepatitis
- Can rarely cause encephalopathy or neuropathy
- Illness lasts 10 to 15 days, followed by recovery of CD4 and suppression of viral load over weeks to months
Chronic HIV
- Following acute infection, there is a long latency period before development of overt symptoms and opportunistic diseases
- Progression from HIV infection to AIDS takes on average 10 years
- Speed of progression is proportional to viral load
- Some people progress quickly to AIDS in 5 years, and others are long-term nonprogressors that remain asymptomatic without treatment
- Non-progressors may have detectable viremia but normal CD4 counts, but with a CD4 count that eventually decreases
- Elite controllers are non-progressors that have no detectable viremia despite infection, and maintain CD4 counts
- Symptoms depend on severity of immunodeficiency; refer to WHO staging above for a long list of possible symptoms, but commonly include:
- Fevers
- Weight loss
- Dyspnea, cough, hemoptysis
- Dysphagia, diarrhea
- Anemia, neutropenia, thrombocytopenia
- Metabolic derangements
- Opportunistic infections
- Direct effects of HIV infection include:
- Neuropsychiatric: HIV-associated neurocognitive disorders (must be differentiated from progressive multifocal leukoencephalopathy or other opportunistic infections), neuropathy, radiculopathy (usually lumbosacral polyradiculopathy), myelopathy, HIV-associated retinopathy
- Cardiovascular: HIV-associated cardiomyopathy, early atherosclerosis
- Pulmonary: HIV-associated pulmonary hypertension, possibly emphysema
- Gastrointestinal: HIV-induced enteropathy, possibly non-alcoholic fatty liver disease
- Renal: HIV-associated nephropathy
- Endocrine: impaired lipid and glucose metabolism, HIV wasting syndrome, lipodystrophy, possibly hypogonadism and premature ovarian failure
- Musculoskeletal: myopathy, myositis
- Hematologic: anemia of chronic disease, possibly coagulopathy
- Dermatologic: possibly eosinophilic folliculitis
Advanced HIV/AIDS
- Acquired immunodeficiency syndrome (AIDS) occurs when the cell-mediated immunodeficiency progresses to the point where opportunistic infections and malignancies occur (AIDS-defining illnesses)
- Medial survival if untreated is 12 to 18 months (38 to 40 months once CD4 counts drops below 200)
Diagnosis
- HIV serology
- Can test for HIV antibodies (usually combined IgM/IgG) and p24 antigen
- Window period of 3-4 weeks exists before antibodies are positive, and is shortened to 2-3 weeks with antigen testing (included in fourth-generation testing)
- If concern for acute seroconversion syndrome (within 2-4 weeks of exposure), may need to repeat serology
- Standard testing in Ontario includes HIV 1+2 antigen/antibody ELISA screen, followed by confirmatory p24 antigen ELISA
- HIV qualitative PCR
- Indicated in cases of suspected acute seroconversion (with negative serology), previous indeterminate antibody results, or a newborn of an HIV-infected mother
- More specific than quantitative PCR for viral load
- Can be done from dried blood spot
- Generally only done for HIV-1 outside of a reference lab
| Ab/Ag | Ab | Ag | RNA | Interpretation |
|---|---|---|---|---|
| – | HIV negative, or within serologic window period (2-3 weeks) | |||
| – | + | HIV positive, within the serologic window period (2-3 weeks) | ||
| + | + | HIV positive, following a 3-4 week window period | ||
| + | – | + | HIV positive, within the serologic window period for antibodies (3-4 weeks) |
Investigations
- See Initial assessment for patients with HIV for baseline bloodwork
Management
Initial management
Follow-up
- See also Routine follow-up for patients with HIV
- HIV viral load
- Every 4 to 6 weeks until undetectable
- Then every 3 months until undetectable for 1 year
- Then every 6 months
- CD4 count
- Every 3 to 4 months until viral load undetectable and CD4 count >350 for 1 year
- Then every 6 months until viral load undetectable for at least 2 years and CD4 count > 500
- Then stop monitoring routinely unless evidence of treatment failure
- Assess for failure if RNA level remains detectable at 24 weeks or if it increases to above 50 at any time
- Repeat RNA level within 4 weeks
Failure
- Several types of failure:
- Clinical failure is the development of new or recurrent clinical events indicating severe immunodeficiency (WHO stage 4) after 6 months of antiretroviral therapy
- Immunologic failure is CD4 count falling below baseline, or is persistently below 100 cells/mm3
- Virologic failure is a viral load over 1000 copies/mL in two consecutive viral loads after 3 months of antiretroviral therapy
- May have "blips" of low-level viremia above the lower limit of the assay, but these blips do not constitute virologic failure
- The differential for failure includes:
- Non-adherence
- Decreased absorption or altered metabolism, including from drug-drug interactions (e.g. proton pump inhibitors), mistimed medication, not taking with food (e.g. rilpivirine), taking with food, diarrhea or other GI illness that can decrease absorption
- Drug resistance
