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HIV1 infection; human immunodeficiency virus-1 infection

Etiology: - see infectivity of HIV Epidemiology: 1) predominant HIV1 strain in US & Europe is group M subtype B 2) HIV1 group M subtype B originated in central Africa & spread Haiti in about 1966 (1962-1970) [20] 3) spread to the US (& elsewhere around the world) emerged after a single migration of HIV1 out of Haiti in about 1969 (1966-1972) [20] 4) 1.2 million people in the US infected with HIV1 (2009-2014) [3,73] - 47,500 new cases in 2010 in the US (CDC) - 13% of the 1.2 million people with HIV1 infection in the U.S. have undiagnosed infection [73] - 30-40% of patients with known HIV1 infection are not getting regular care [74] - prevalence of HIV1 infection ranges from 0.1% (Iowa) to nearly 4% (District of Columbia) [73] 5) majority of cases in US occur in men who have sex with men; heterosexual transmission is 2nd most common cause [3] 6) patients with known HIV1 infection, but not virally suppressed account for 61% of transmissions; undiagnosed patients account for 30% of transmissions; virally suppressed patients account for 2.5% of transmissions [69] - 80% of new HIV1 infections transmitted by persons either unaware of HIV1 infection or not receiving HIV1 care [103] 7) 26% of new HIV infections in the U.S. are in people 13-24 years of age [41] - male-to-male sexual contact accounts for ~75% of new HIV infections among youth - ~60% of new HIV infections among youth are in African Americans. - 13% of high school students have been tested for HIV - 35% of people 18-24 years of age have been tested for HIV 8) 10% of new diagnoses in patients >= 50 years of age a) 48% of older infected adults diagnosed when CD4 count < 200 cells/uL b) men who have sex with men account for 40% of diagnosed older adults 9) 62% of foreign-born HIV persons in U.S. with HIV1 infection acquired it in the U.S. [93] 10) diagnosis is often delayed [31] - 60% with a previous negative test - 42% within a year before of diagnosis - 21% from 1-2 years before - 37% >2 years before 11) overall reduction in new cases of HIV1 2001-2012 [51,62] - increase in HIV1 cases in young men who have sex with men [62] 12) a new strain of HIV-1 (CRF19-cpx) progresses to AIDS within 3 years identified in Cuba [68] 13) surveillance case definition for HIV infection [60] 14) HIV1 infection can be spread by a) contact with infected blood or other body fluids - sexual contact, blood transfusion, shared needles, occupational exposure b) perinatal transmission [3] 15) reducing HIV1 RNA viral load to undetectable eliminates risk of transmission during sex [81] 16) increasing resistance to HIV1 antiretroviral agents [89] 17) HIV infections in the U.S. fell by 15% from 2008 to 2015 [97] - HIV1 infections due to heterosexual contact & injection drug use fell, but remained stable among men who have sex with men 18) Alabama, Arkansas, Kentucky, Mississippi, Missouri, Oklahoma, South Carolina & with highest rates of new HIV1 infection (2018) [102] Pathology: - RNA virus encoding a reverse transcriptase, with subsequent insertion of nascent DNA into cellular genome, thus causing latent & persistent infection - HIV binds to CD4 in the presence of a coreceptor - either CCR5 or CXCR4, on the cell surface of T-helper lymphocytes, monocytes, macrophages & other cells - alternative coreceptors: APLNR, CCR2, CCR3, CCR8, CCR9, CX3CR1, CXCR7, GPR1, GPR15 - with disease progression, CD4+ lymphocytes decline; below 200 cells/mm3, there is an increased risk of opportunistic infections - early symptomatic HIV infection generally occurs when the CD4 count begins to decline & the CD4/CD8 ratio inverts - disease generally progresses over a period of 10-14 years - ongoing viral replication throughout the entire course of infection, including asymptomatic periods - 100 million to 10 billion new virions produced daily - > 99% of virions produced from acutely infected CD4+ cells - 1/2 life of virus in plasma is estimated to be about 1.2 days - initially, several hundred million CD4 cells are produced daily in response to rapid viral replication - acutely infected individuals are viremic & contagious [14] - eventually, the immune system fatigues with increased viremia, decreased CD4 production, & opportunistic infection - low-lvel virus replication within chronically infected monocytes, macrophages & dendritic cells - B-cell dysfunction occurs early in HIV infection - defective neutrophil chemotaxis, phagocytosis & bactericidal activity - preserved monocytic antimicrobial function [95] - also see resistance to HIV1 Clinical manifestations: 1) primary infection a) often asymptomatic b) acute retroviral syndrome c) presentation may be atypical - gastrointestinal & CNS manifestations most common [77] - opportunistic infections (CMV) account for 24% of atypical presentations (7% overall) [77] 2) cutaneous manifestations of early disease a) genital warts b) genital Herpes c) psoriasis d) mild seborrheic dermatitis e) tenia, onychomycosis 3) oral mucosal lesions a) aphthous ulcers b) oral hairy leukoplakia c) gigivitis, periodontitis 4) signs/symptoms may increase in severity with time [21] a) lymphadenopathy b) fever, chills, night sweats c) chronic diarrhea d) weight loss e) cough f) dyspnea g) fatigue h) skin lesions i) blurred vision j) headache 5) peripheral neuropathy 6) nephropathy 7) persistently enlarged glands may be 1st sign of AIDS Laboratory: 1) all adolescents and adults should be tested for HIV at least once [61] - WHO recommends self-testing be offered as another method to test for HIV1 [87] 2) HIV Ag/Ab Combo assay to detect both HIV1 p24 antigen in serum & HIV1 + HIV2 Ab in serum FDA-approved 6/21/10 - HIV 1+2 Ab & HIV1 p24 Ag in serum/plasma/blood 3) HIV1 serology (older assay) a) specific HIV-1 antibodies* are not detectable until 4-12 weeks after initial infection b) HIV1 antibody in serum - screening with HIV1 EIA/ELISA* for antibody to HIV-1 (99% sensitivity & specificity) c) Oraquick Rapid HIV-1 Antibody Test available 2003 - HIV1 antibody in saliva d) confirmatory HIV1 western blot* for antibodies to virus- specific proteins: a positive HIV1 western blot consists of the presence of bands for: - HIV1 p24 Ab in serum - HIV1 gp41 Ab in serum - HIV1 gp120 Ab in serum or HIV1 gp160 Ab in serum e) seronegative HIV1 infections are rare, but potentially lethal [3] f) repeat HIV1 testing if no documentation [3] 4) HIV1 antigen in serum/CSF - HIV1 p24 antigen in serum - p24 antigen testing# is generally positive just after onset of symptoms of seroconversion, before development of antibodies 5) quantitative HIV-1 RNA levels# a) reverse-trancriptase polymerase chain reaction (RT-PCR) b) branched chain DNA (bDNA) assay c) nucleic acid sequence-based assay (NASBA) d) high levels of HIV-1 RNA (500,000- 21 million copies/mL) are detected in plasma before the detection of specific anti-HIV-1 antibodies e) the high level of viremia decreases 100-10,000 fold coincident with the development of the specific anti-HIV-1 humoral immune response - it is thought that cytotoxic T-cells are responsible for this decline in HIV1 viral load f) post-seroconversion viral load (HIV RNA determined by PCR) is the best predictor of long-term prognosis g) post-seroconversion HIV RNA > 30,000 copies/mL are associated with a high risk of disease progression h) identification of acute HIV infection with quantitative HIV-1 RNA levels combined with aggressive early treatment may 1] reduce severity of chronic infection 2] prevent transmission to sexual contacts [14] i) HIV1 viral load 1] independent predictor of disease progression [3] 2] poorly predicts decline in CD4 count [17] 3] responds to initiating or changing therapy within 4-8 weeks (>= 1 log decrease in HIV RNA) 4] a decrease in HIV RNA of > 1 log is associated with treatment benefit 5] an undetectable viral load reduces HIV1 transmission via sexual intercourse to zero or close to zero [3] j) frequent monitoring of HIV-1 RNA levels for the 1st year to detect treatment failure [26] k) routine every 3-4 months & monthly after change in therapy 6) complete blood count (CBC) with differential a) lymphopenia may develop during acute seroconversion b) atypical lymphocytosis may follow resolution of symptoms associated with seroconversion c) anemia d) thrombocytopenia [3] 7) serum chemistries (baseline, every 6-12 months or change in ART) a) renal function tests: nephropathy b) serum transaminases c) serum glucose; HgbA1c - do not use HgbA1c for diagnosis of diabetes when patient taking ART [3] d) lipid panel 8) urinalysis [3] - HIV nephropathy is generally nephrotic syndrome due to focal segmental glomerulosclerosis 9) other serology a) serologic testing for syphilis - testing for other STDs b) Toxoplasma gondii IgG c) Cytomegalovirus (CMV) IgG (high risk) d) hepatitis A serology, hepatitis B serology & hepatitis C serology e) screen for hepatitis C infection yearly [72] f) varicella virus serology (high risk) [3] 10) CD4 count a) best predictor of risk of disease progression b) average rate of decline is 80-90/uL/year c) viral load does NOT predict decline [17] d) routine every 3-4 months [3] - results of routine CD4 counts constribute nothing to medical decision making [44] e) CD4 count of < 200 cells/uL establishes diagnosis of AIDS [3] f) rarely used in treatment decisions for patients with with virologic suppression on antiretroviral therapy [64] g) many older patients with suppressed viral loads continue to have CD4 counts ~ 200/mm3 after years of antiretroviral therapy [35] h) in patients with undectable HIV1 viral load & normal CD4 count, further monitoring of T-cell subsets is not recommended [3] 11) tuberculin skin testing or Quantiferon TB test annually [3] unless PPD+ or with active tuberculosis 12) Papanicolaou (Pap) smear for women 13) glucose-6-phosphate dehydrogenase (G6PD) in erythrocytes (baseline) 14) HIV1 genotyping 15) genotypic HIV1 resistance testing - all HIV1 patients at baseline & treatment failure [3,26] - done while patient is receiving no therapy or ineffective therapy [3] 16) same day HIV testing & antiretroviral therapy initiation beneficial in newly diagnosed patients with HIV1 infection [92] 17) see ARUP consult [36] * informed consent for testing must be obtained & arrangements should be made for a follow-up visit to discuss results; results of HIV testing should not be given over the phone # HIV-1 RNA & p24 antigen testing preferred for diagnosis [3] * also see HIV laboratory testing Radiology: - Dexa scan screening for osteoporosis men > 50 years - HAART containing tenofovir disoproxil fumarate associated with greater decline in bone mineral density than other regimens [114] Complications: - immune reconstitution inflammatory syndrome occurs after initiation of antiretroviral therapy due to inflammatory response to pre-existing underlying infection - see complications in patients with HIV disease Management: 1) antiretroviral therapy a) indications 1] all HIV1-infected patients [36,37,61,76] - treatment beginning at the time of diagnosis reduces risk of serious illness or death (RR < 0.5) [71,98] - initiation of antiretroviral therapy within 1 year improves likelihood of normal CD4 counts [66] - if viral load is low & CD4 count is high & patient does not agree to treatment, it is safe to defer treatment pending further discussion [3] 2] older recommendations a] start antiretroviral therapy if symptomatic, regardless of CD4 cell count [26] b] start antiretroviral therapy if pregnant, regardless of CD4 cell count [3] c] asymptomatic patients should start at CD4 counts of <= 500/mm3 [3, 26,30] d] CD4 count < 200/mm3 [11] (200-350/mm3 [6], 350/mm3 [21,27]) e] post-seroconversion HIV RNA load of > 5000 copies/mL (10,000-100,000 copies/mL [6]) f] rapid rate of CD4 count decline, HIV viral load of > 100,000 copies/mL, hepatitis B or hepatitis C coinfection, HIV-associated neuropathy or cardiovascular risk factors even if CD4 count is > 350/mm3 [22] g] early treatment of asymptomatic patients (48 weeks of therapy) associated with higher CD4 counts at 4 years [42] b) initial therapy should consist of a 3-drug combination from 2 different classes individualized according to the results of HIV1 resistance testing - 2 drug regimens also available [112] c) preferred initial regimen is an integrase inhibitor + 2 nucleoside reverse transcriptase inhibitors (NRTIs) [82] - preferred NRTIs: tenofovir* +lamivudine (3TC) or emtricitabine (FTC) [110] - regimens that don't require boosting with ritonavir or cobicistat [99] - regimens with a high barrier to resistance - 2nd-generation integrase inhibitors dolutegravir & bictegravir offer the most advantages for HIV1 treatment [99] - dolutegravir + lamivudine (Dovato) 1st line if HIV1 RNA < 500,000/mL & no hepatitis B coinfection [112] d) multiple agents are used to prevent emergence of viral resistance - most regimens at least 3 agents - 2 agent regimens approved if no coinfection with hepatitis B [112] - dolutegravir/lamivudine (Dovato) - dolutegravir/rilpivirine (Juluca) - cabotegravir/rilpivirine (Cabenuva) e) QUAD HIV therapy (4 drugs, once a day) non-inferior to standard of care regimens - 3 one pill once a day regimens [48] a] efavirenz/FTC/tenofovir* (Atripla) b] efavirenz-containing regimens formerly recommended, now alternative [70] c] elvitegravir/cobicistat/FTC/tenofovir* (Stribild) f) recommended regimens [3,70] - tenofovir*/lamivudine (3TC) plus dolutegravir (DTG) [105] - tenofovir*/emtricitabine (FTC) plus dolutegravir (DTG) - tenofovir*/emtricitabine (FTC)/cobicistat plus elvitegravir (EVG/c) - tenofovir*/emtricitabine (FTC) plus raltegravir (RAL) - tenofovir*/emtricitabine (FTC) plus bictegravir (Biktarvy) - abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTG) g) alternative regimens [70] - abacavir (ABC)/lamivudine (3TC) & atazanavir (ATV/r) - abacavir (ABC)/lamivudine (3TC) & efavirenz (EFV) - tenofovir*/emtricitabine (FTC) plus atazanavir (ATV/r) - tenofovir*/emtricitabine (FTC) plus darunavir (DRV/r) h) pregnancy or HIV1/tuberculosis coinfection - tenofovir*/lamivudine (3TC) plus dolutegravir (DTG) [105,112] - tenofovir*/emtricitabine (FTC) plus dolutegravir (DTG) [112] - tenofovir*/emtricitabine (FTC) plus raltegravir (RAL) [112] - tenofovir (TDF))/lamivudine (3TC) & efavirenz 400 or 600 mg (EFV) [112] i) newer FDA approvals - dolutegravir/rilpivirine (Juluca) PO QD, FDA-approved Nov 2017 [94] - dolutegravir/lamivudine (Dovato) PO QD, FDA-approved April 2019 - cabotegravir/rilpivirine (Cabenuva) injection 2 in injection IM every 4 weeks - ibalizumab (Trogarzo) FDA-approved March 2018 for multidrug-resistant HIV1 infection j) long-acting injectables - cabotegravir/rilpivirine (Cabenuva) IM every 4 or 8 weeks [90,108] - if no coinfection with hepatitis B [112] - every 4 weeks non inferior to daily antiretroviral [107] k) see AIDS for antiretroviral regimens l) goal of therapy is to achieve HIV1 RNA levels below limits of detectability, formerly < 500-5000 copies/mL - effective treatment diminishes emergence of resistance (the most important principle) [3] - HIV1 RNA levels become undetectable within a few months of effective antiretroviral therapy - effective antiretroviral therapy reduces perinatal transmission in pregnant women - goal of HIV1 viral load suppression more commonly achieved in older patients vs younger patients [35] m) treatment diminishes CSF viral load [19] n) early antiretroviral treatment protects sex partners [32,100] - no risk of HIV1 transmission in virally-suppressed patients with or without condom during heterosexual or homosexual intercourse [81,100] o) early combination antiretroviral therapy (for ~ 3 years) may enable some patients to maintain a very low or undetectable HIV1 viral load years after stopping antiretroviral therapy [47] p) early antiretroviral therapy in infant may lead to antiretroviral-free virologic control [53] q) same day antiretroviral therapy initiation beneficial in newly diagnosed patients with HIV1 infection [92] r) antiretroviral therapy as effective in the elderly as in younger patients [35] s) high-dose multivitamin in conjunction with HAART not helpful, perhaps harmful [39] t) immune reconstitution inflammatory syndrome may occur as the patient regains immune function 2) prophylactic antiretroviral therapy a) exposure to potentially infectious tissue or body fluids b) see post-exposure HIV prophylaxis c) see pre-exposure HIV prophylaxis 3) treatment failure a) re-emergence of detectable HIV1 viral load b) HIV1 resistance testing while continuing current antiretroviral therapy [3,50] - agents active in the setting of drug resistance: - fostemsavir, maraviroc, ibalizumab, enfuvirtide c) 30% of HIV-infected Americans achieve viral suppression - majority not virally suppressed either not diagnosed or not linked to HIV care [67] d) older patients taking > 15 medications (polypharmacy) have lower chance of viral suppression [111] 4) medication compliance may be an issue a) suppression of HIV1 viral load in plasma is common at adherence levels of >70% [38] b) new HIV1 replication may occur within cells, despite suppression of HIV1 viral load in plasma [38] c) goal is > 95% compliance [5] d) older patients are more likely to be compliant with antiretroviral therapy than younger patients [35] e) direct observation benefits are not sustained past the period of direct observation [34] f) interruption of antiretroviral therapy is associated with increase in cardiovascular events including death & infectious complications [3] 5) prophylaxis for opportunistic infections a) Pneumocystis jirovecii 1] CD4 count < 200 cell/uL 2] Bactrim DS QD or 3X/week b) toxoplasmosis 1] CD4 count < 100 cell/uL & positive serum Toxoplasma IgG 2] Bactrim DS QD c) Mycobacterium avium 1] CD4 count < 50 cell/uL 2] azithromycin 1200 mg/week no longer recommended if taking HART [3] d) latent tuberculosis 1] tuberculin skin test > 5 mm induration or positive Quantiferon TB test 2] INH 300 mg/day for 9 months (after chest X-ray rules out active tuberculosis) e) discontinue prophylaxis (excepting latent tuberculosis) when CD4 count > 200/uL & HIV1 viral load undetectable for > 3 months [3] 5) health maintenance including routine immunizations & cancer screening for the most part as per uninfected persons a) immunizations (unless immune or CD4 < 200 mm3) - measles-mumps-rubella vaccine (MMR) - varicella vaccine b) other vaccinations (not live virus) as indicated for the general public - pneumococcal vaccination (PCV15 & PPSV23 in this order or PCV20) - hepatitis B vaccine - recombinant Herpes zoster vaccine (Shingrix) - meningococcal vaccine (MenACWY/Menveo,Menomune/Menactra: all HIV1 patients) - other vaccinations as indicated for the general public - Tdap - hepatitis A vaccine - HPV vaccine - influenza virus vaccine annually b) aggressive cardiovascular risk reduction for patients on antiretroviral therapy including HIV1 protease inhibitor [3] - pravastatin & pitavastatin are the least likely statins to interfere with antiretroviral therapy [104] - avoid simvastatin & lovastatin [14] - atorvastatin or rosuvastatin mya be considered [104] - even patients at low to moderate cardiovascular risk benefit from statin [113] c) tuberculin skin testing annually unless PPD+ or with active tuberculosis (see AIDS) d) exclude active infection with Mycobacterium avium [3] e) zoledronic acid 5 mg IV with initiation of anti-retroviral therapy reduces bone loss at 24 weeks (assessed by plasma C-terminal telopeptide of collagen) [83] 6) follow-up every 6 months in early HIV infection 7) experimental therapies a) interleukin-2 (IL-2) may be of some benefit in increasing CD4 counts & diminishing viral loads in HIV positive patients b) HIV vaccine stimulating cytotoxic lymphocyte responsiveness to the HIV GAG protein show promise (results in monkeys) [7] c) transfection with short interfering double-stranded RNA (siRNA) shows promise [8] d) CMV/HIV1IV virus vaccine may be effective on infected mucosal cells early in the course of HIV1 infection [33] e) broadly neutralizing antibodies reduce HIV viral load [40,75] f) gene therapy using reinfused cells genetically modified ex-vivo (in vitro) [58] - a zinc-finger nuclease renders CCR5 gene permanently dysfunctional in CD4 cells collected by leukopheresis - the reinfused cells were found in the endovascular space as well as trafficking into tissues 8) bone marrow transplantation / allogeneic stem cell transplantation not curative [57,62] 9) case reporting required in California (local health department) [9] 10) patient education a) a stable partnership is associated with a better prognosis [10] b) stop smoking: - smoking associated with more years of life lost than from the HIV1 virus itself (12.3 vs 5.1) [43] c) phone calls reminding patients to take their medications of no benefit [65] d) voluntary assisted partner notification should be offered to patients with HIV1 [87] 11) prognosis: a) non-HIV related deaths becoming more common [16] b) although HIV1 has been transformed from a fatal disease to a chronic disease, life expectancy is diminished for even the healthiest HIV patients (72 years most favorable estimate) [23] c) seropositive HIV1 patients able to maintain an HIV RNA viral load of < 50 copies/mL without antiretroviral therapy are called 'elite controllers' d) excess mortality in untreated HIV even with CD4 counts of > 350/uL [28] e) older patients diagnosed with HIV1 infection 3-fold more likely to die within 1 year than younger patients [35] * tenofovir disoproxil fumarate (TDF) is associated with risk for renal tubular nephrotoxicity & reduced bone mineral density * tenofovir alafenamide should be used preferentially in patients at risk for kidney disease or osteoporosis [3] Comparative biology: - vectored immunoprophylaxis protects humanized mice from HIV1 [59] Notes: - treatment of HIV-infected patients in serodiscordant couples is cost-effective [52] - risk for HIV transmission from an infected man not virally suppressed to an uninfected woman is 8 per 10,000 episodes of unprotected vaginal sex [91] - no instances of HIV transmission during unprotected sex in serodiscordant couples in which infected partner was virologically suppressed [91] - HIV1 RNA in semen of men without detectable HIV1 RNA in blood - unknown whether this poses a risk for transmission [91] - financial incentives (< $300/year) improves viral suppression rates [88] - HIV remission after receiving a stem cell transplant for lymphoma from a donor with a mutation in HIV coreceptor CCR5 [102] - current threshold for health care providers allowed to participate in higher-risk healthcare-associated procedures is < 200 copies/mL for HIV1 RNA [109]

Interactions

disease interactions

Related

acute retroviral syndrome; acute HIV1 infection antiretroviral therapy (ART) complications in patients with HIV1 infection HIV infection during pregnancy HIV laboratory testing HIV1-discordant couples HIV1/hepatitis C-coinfection HIV1/malaria coinfection HIV1/tuberculosis coinfection hospice guidelines for determining prognosis, HIV human immunodeficiency virus-1 (HIV-1) human immunodeficiency virus-2 (HIV-2) infectivity of HIV oral lesions of HIV & AIDS perinatal transmission of HIV prevention of HIV resistance & susceptibility to HIV1 safe sex (prevention of HIV1 & other STDs) screening for HIV1 surgery in HIV patients

Useful

HIV treatment failure outpatient management of HIV related pneumonia

Specific

Acquired Immuno-Deficiency Syndrome (HIV infection stage 3, AIDS) HIV/AIDS in the elderly

General

HIV infection; human immunodeficiency virus infection

References

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