Human immunodeficiency virus

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
  • 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
  1. 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).
  2. 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.
  3. In the cytoplasm, reverse transcriptase converts viral RNA into viral DNA. The RNA is degraded, then the complementary strand of DNA created.
  4. 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.
  5. Viral DNA is integrated into the host genome with viral integrase.
  6. Viral DNA in the host genome is transcribed into mRNA and translated into viral proteins, including Gag.
  7. 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

• 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 >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