View source for Lentivirus humimdef1

{{DISPLAYTITLE:''Lentivirus humimdef1''}}

==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 [[Family::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
**HIV-2: essentially confined to West Africa and certain parts of southern Europe and Asia

===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

{| class="wikitable"
!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====
{| class="wikitable"
!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 [[Usual 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 [[Has symptom::fever]], [[Has symptom::lymphadenopathy]], [[Causes::pharyngitis]], and [[Has symptom::rash]]
*Other common symptoms include [[Has symptom::myalgias]], [[Has symptom::arthralgias]], [[Has symptom::headache]], [[Has symptom::diarrhea]], [[Has symptom::oral ulcers]], [[Has symptom::leukopenia]], [[Has symptom::thrombocytopenia]], and mild [[Has symptom::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 in HIV|Opportunistic infections]]
*Direct effects of HIV infection include:
**Neuropsychiatric: HIV-associated neurocognitive disorders (must be differentiated from [[progressive multifocal leukoencephalopathy]] or other [[Opportunistic infections in HIV|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

{| class="wikitable"
!Ab/Ag!!Ab!!Ag!!RNA!!Interpretation
|-
| style="text-align:center;" |–
|
|
|
|HIV negative, or within serologic window period (2-3 weeks)
|-
| style="text-align:center;" |–
|
|
| style="text-align:center;" | +
|HIV positive, within the serologic window period (2-3 weeks)
|-
| style="text-align:center;" | +
| style="text-align:center;" | +
|
|
|HIV positive, following a 3-4 week window period
|-
| style="text-align:center;" | +
| style="text-align:center;" |–
| style="text-align:center;" | +
|
|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===

*[[Initial assessment for patients with HIV]]
*[[Single-tablet regimens for HIV]]
*[[HIV treatment]]

===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 &gt;350 for 1 year
**Then every 6 months until viral load undetectable for at least 2 years and CD4 count &gt; 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/mm<sup>3</sup>
** 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
** [[Antiretroviral resistance in HIV|Drug resistance]]

[[Category:HIV]]
[[Category:Retroviridae]]