HIV INFECTION Snopková S, 4/2020 A lecture outline •Definition •Historical chronology •Epidemiology •Transmission •Etiology •Life cycle of HIV •Pathogenesis •Classification of HIV infection • and natural history •Clinical manifestation of HIV infection •Category A – primary HIV infection •Category B •Category C – AIDS •Laboratory tests u DEFINITION oHuman Immunodeficiency Virus (HIV) oInfects human cells and causes gradual loss of immune system function, and these immune alterations predispose to the opportunistic infections, neoplasms, and other conditions (wasting and dementia) oHuman Immunodeficiency Virus infection ois used to describe the cellular and humoral immunodeficiency and the numerous complications that result from the HIV infection oAcquired immunodeficiency syndrome (AIDS) oIs the spectrum of disorders resulting from very advanced HIV infection n HISTORICAL CHRONOLOGY •HIV crossed from chimps to humans in the 1920s in Congo. This was probably as a result of chimps carrying the Simian Immunodeficiency Virus (SIV), a virus closely related to HIV, being hunted and eaten by people living in the area. It happened in the , people got infected from chimpanzees whose meat they ate images (1).jpg • • C:\Users\34212\Desktop\map.jpg •HIV first began to spread along the historic trade routes of the Congo basin in the 1920s from the forest to the cities •The area around Kinshasa is full of transport links, such as roads, railways and rivers. The area also had a growing sex trade around the time that HIV began to spread. The high population of migrants and sex trade might explain how HIV spread along these infrastructure routes. •The first verified case of HIV is from a blood sample taken in 1959 from a man living in what is now Kinshasa in the Democratic Republic of Congo. •The sample was retrospectively analysed and HIV detected. • Spread of HIV infection •until the 1970s there were only sporadic unrecognized cases •since the late 1970s, the infection has spread to all continents n1981 oAIDS was first recognized as a new and distinct clinical entity oAIDS was first reported in previously healthy men oGottlieb and Friedman reported initial cases of Kaposi‘s sarcoma and Pneumocystis carinii jiroveci pneumonia in previously healthy men n1982 oCDC created first definition of AIDS n1983 oa new retrovirus (later called HIV-1) was identified and described as the causative agent of AIDS (formerly HTLV III/LAV) n1985 ofirst antiretroviral drug was discovered (zidovudine - ZDV, formerly AZT) n1986 oInternational committee adopted the name Human immunodeficiency virus (HIV-1) oMontagnier discovered HIV-2 n HIV-1 subtypes nThe most common causes of HIV disease throughout the world is HIV-1, nwhich comprises several subtypes with different geographic distribution n oGeographic distribution oA – Central and East Africa, East Europe oB – America & Europe oC – South Africa & India, Brazil oD – Central, East and South Africa oE – Tchaj-wan & India oF – Romania & Brazil oG, H, O – Western Africa n n n n n n1987 othe first drug for clinical use NRTI – AZT (later ZDV) n1991-1994 onext NRTIs (didanosine, zalcitabine, stavudine, lamivudine…) n1995 othe first protease inhibitor was approved for clinical use n1996 – HAART era othe introduction of HIV therapy into clinical practice represented a significant step forward in the treatment of HIV infection othe ability of HAART regiments have transformed HIV infection into a manageable chronic disease in many patients n n HAART = cART = OBT = ART nThree-drug combinations are currently recommended nfor the initiation of treatment in all patients n nHAART – Highly Active AntiRetroviral Therapy ncART - Combination AntiRetroviral Therapy nOBT - Optimalising Basic Treatment nART - AntiRetroviral Therapy oEnormous changes in prognosis of HIV/AIDS disease omaximally and durably supresses viral load orestores immunological function oimproves quality of life odramatically reduces HIV-related morbidity and mortality Epidemiology HIV – a global health crisis nSince AIDS was recognized as a distinct disease in 1981, the catastrofic nature of this pandemic has been recognized and more fully characterized nSince the beginning of this pandemic q over 78 million individuals worldwide have been infected by HIV-1 q over 40 million people died nNumber of people n living with HIV/AIDS is increasing WHO-EN-white-H Summary of the global HIV epidemic (2018) Source: UNAIDS/WHO estimates 0.8 million HIV-related deaths [0.6 million –1.1 million] 1.7 million people newly infected [1.4 million – 2.3 million] 37.9 million people living with HIV [32.7 million – 44.0 million] 2018 New HIV infections, or “HIV incidence,” refers to the estimated number of people who newly acquired the HIV virus during a year, which is different from the number of people diagnosed with HIV during a year. Some people may have HIV but not know it AIDS by the numbers n↓ 35% decrease in new HIV infection since 2000 n n↓ 42% decrease in AIDS-related deaths since the peak in 2004 n n↓ 58% decrease in new HIV infections among children since 2000 n n↑ 84% increase in access to antiretroviral therapy since 2010 WHO-EN-white-H Decline in HIV incidence and mortality over time Source: UNAIDS/WHO estimates •the highest incidence of HIV infection was in 1997 •3,5 mil people were infected during 1997 •the highest mortality due to HIV infection was in 2004 •2,0 mil people died due to HIV during 2004 WHO-EN-white-H Global number of people newly infected with HIV Source: UNAIDS/WHO estimates 2.8 million 2018 2020 2030 1.7 million < 500 000 Target Target < 200 000 2000 WHO-EN-white-H Global number of HIV-related deaths Source: UNAIDS/WHO estimates 2018 2020 2030 770 000 < 500 000 Target Target < 400 000 2000 1.4 million WHO-EN-white-H Summary of the global HIV epidemic (2018) 37.9 million [32.7 million – 44.0 million] 36.2 million [31.3 million – 42.0 million] 18.8 million [16.4 million – 21.7 million] 17.4 million [14.8 million – 20.5 million] 1.7 million [1.3 million – 2.2 million] 1.7 million [1.4 million – 2.3 million] 160 000 [110 000 – 260 000] 1.6 million [1.2 million – 2.1 million] – – – – 770 000 [570 000 – 1.1 million] 670 000 [500 000 – 920 000] 100 000 [64 000 – 160 000] Source: UNAIDS/WHO estimates People living with HIV in 2018 People newly infected with HIV in 2018 HIV-related deaths 2018 Sub-Saharan Afrika – 25, 7 mil •Is the most affected region India and South and South-East Asia – 5 mil Latin America and North America – 3,4 mil Europe – 2,3 mil Middle East – 350 000 Pacific – 1,5 mil The highest incidences of infection •20.6 million people with HIV (57%) in eastern and southern Africa, •5.0 million (13%) in western and central Africa The vast majority of people with HIV are in low- and middle-income countries. •5.9 million (16%) in Asia and the Pacific •2.2 million (6%) in Western and Central Europe and North America WHO-EN-white-H People living with HIV by WHO region (2018) l Source: UNAIDS/WHO estimates 37.9 million people living with HIV globally 25.7million Africa 3.5 million America 3.8 million South-East Asia 2.5 million Europe Eastern Mediterranean 400 000 1.9 million Western Pacific ˃ 1 mil HIV+ people live in Russia ˃ 64% of all new HIV/year diagnoses in Europe were in Russia Percentage of adults (15+) living with HIV who are female 0 10 20 30 40 50 60 70 Percent female (%) Sub-Saharan Africa GLOBAL Caribbean Asia E Europe & C Asia Latin America 1990 ‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 2007 Year 5 n nHIV+ HIV+ female •In total > 52% •In Sub-Saharan Africa > 62% Þ more HIV+ children TRANSMISSION HIV has been isolated from bodily fluids n nWith high/titer viremia • § blood § semen § cervicovaginal secretion – nThese bodily fluits have been implicated n in the transmission of HIV nWith low/titer viremia • § saliva § tears § urine § CSF – nThese bodily fluits have not been implicated in the transmission of HIV Modes of HIV transmission nHIV is transmitted through nthree primary routes: n 1. sexual 2. parenteral 3. vertical • 1. Sexual rout • •Sexual contact with an infected person is the predominant mode of transmission wordwide • (> 95 % of HIV infection) • •Heterosexual intercourse •The dominant mode (90%) wordwide •Homosexual intercourse (MSM) •Men who have sex with man •Homosexual and bisexual men •The main mode in North America, Europe and Australia C:\Users\Notebook\Desktop\521cfc46a1bdb3c1995241275c88a78db92137edv2_hq.jpg C:\Users\Notebook\Desktop\vlajka_gay.gif Transfusion of infected blood or blood components •as a risk factor for acquiring HIV has dramatically decreases in incidence •secondary to the availability of a screening of all blood products since 1987 2. Parenteral rout (exposure) 1.Blood transfusion and blood products can be infected by HIV •recipients are in risk acquiring of HIV •hemophiliacs, plasma, clotting factors, whole blood, blood cellular components, recipients of tissue, organ transplants, semen • • 2. Parenteral rout (exposure) 2.Contaminated injection and medical equipments 3. •Drug users, sportman •Nosocomila •Health and laboratory workers… • Without antiretroviral therapy is estimated to be 0.3 – 0.5% 2. Parenteral rout (exposure) •The probability transmission of HIV infection after skin puncture with infected materials depends on multiple factors • •High titer viremia of the patients •Amount of blood on the needle •Advanced HIV infection… 2. Parenteral rout (exposure) •Postexposure prophylasis (PEP) •In case of skin puncture with infected materials •Prompt administration of a combination regiment of ART drugs (PEP) •Significantly decreases the likelihood of HIV infection following needle-stick injuries 3. Vertical rout (mother-to-child) •Perinatal transmission may occur 1.During pregnancy (in utero) 2.During delivery (at birth, intrapartum) 3.During breastfeeding 4. •Perinatal transmission rates range •from 22 to 46% (without ART) •In Europe and North America •from 15 to 25% before ART • 05.jpg 3. Vertical rout (mother-to-child) • 04.jpg •Maternal ART has been shown •to decrease vertical transmission •dramatically •in Europe and North American countries • < 1,5% of all newborns • •In 2018 •92% of pregnant women with HIV received ART to prevent transmitting HIV to their babies during pregnancy and childbirth and to protect their own health. •This is compared to 49% in 2010. • 3. Vertical rout (mother-to-child) • 04.jpg •Decreasing • mother-to-child transmission • •Use of ART by the mother and use of AZT by the infant after delivery •Cesarean section •Avoidance of breastfeeding 3. Vertical rout (mother-to-child) •Factors thought to increase risk •of mother-to-child transmission • •High maternal viral load • and no ART •Prolonged membrane rupture •Natural delivery •Prematurity of newborn •Low birth weight of newborn •breasrfeeding AIDS kojení Breastfeeding is very important for HIV transmission. Risk breastfeeding is about 10%. No transmission nHousehold contacts not sexually involved with infected persons are not risk for acquiring HIV nFamily members who shared bathrooms and eating utensils with HIV+ patients did not become infected nMosquitoes do not transmit HIV nNo cases of transmission from human bites have been reported. n Saliva contains neutralizing factors. n ETIOLOGY nHIV nbelongs to the family of human retroviruses and the subfamily n of lentiviruses n nHIV = causativ agent n Family: Retroviridae n Genus: Lentivirus n HIV-1, HIV-2 n SIV… n 04.jpg sken 2 gp120 envelope glycoprotein reverse transcriptase (RT) p24 core antigen RNA Virion structure – very important the main structures of virus Virion structure sken 2 Free virus and possibly virus-infected cells enter the blood during initial infection. The HIV envelope glycoprotein 120 have a high affinity for the CD4 molecule (receptors) on the surface of CD4 cells (helper cells, Th lymphocytes) sken2 Life cycle of HIV 1. Adsorption to CD4+ cell cereptor (and coreceptors) 2. After HIV binds to CD4 receptor, the viral and cellular membranes fuse and the HIV nucleoprotein complex enters the cytoplasm 3. Uncoating follows – into the host cells sken2 4. Using its retroviral reverse transcriptase, the HIV initiates viral DNA synthesis, using its own RNA as a template 5. The double-stranded viral DNA enters into the nucleus of host cell 6. Integration of the DNA into host chromosome is catalyzed by integrase (another retroviral enzyme) 7. When a CD4 cell with integrated provirus (DNA) is activated, retroviral synthesis is begun, directed by the cell´s infected DNA 8. Synthesis of viral proteins is started sken2 9. Mature viral cores are produced through action on viral protease (another retroviral enzyme) 10. New viral particles are produced by budding at the cell plasma membrane 11. The complete virus is extruded into the bloodstream Electron micrograft of HIV budding from a CD4+ cell, The complete virus is extruded into the bloodstream n 03.jpg n n Virion structure sken 2 PATHOGENESIS Free virus and possibly virus-infected cells enter the blood during initial infection. nThe HIV envelope glycoprotein 120 have a high affinity for the CD4 molecule (receptor) on the surface of CD4 cells (helper cells, Th lymphocytes) nProductive viral replication is lytic to infected T cells nLoss of number of CD4 cells is basis of advanced infection CD4+ lymphocytes and HIV Untitled-2 nA decrease in function nas well as number nof CD4 cells nis central nto the immune dysfunction n sken1 CD4+ lymphocytes depletion – gradual loss of number of CD4 cells is basis of advanced infection CD4+ count primary HIV infection asymptomatic infection early symptomatic infection late symptomatic infection final stadium years HIV infects §monocytes, macrophages, B cells §dendritic cells, Langerhans cells in GI §bone marrow cells, myocardial cells… § nInfection by HIV into many cells may contribute greatly nto various clinical syndromes of HIV infection and AIDS n nOther host cells nalso are infected by HIV nthese cells do not appear to be lysed by the virus ncells that do not express CD4 receptor can also be infected by HIV (mechanisms are unknown) n Classification of HIV infection nIn 1993 the CDC issued a revised classification system for HIV nCDC – Centers for Disease Control n and Prevention, Atlanta, USA n nCriteria for HIV infection for adult person include: n § laboratory categories § clinical categories Laboratory categories n nThe three categories corresponding n to CD4+ lymphocyte counts n nThe percentage of CD4+ lymphocyte n also can be use n nNormal values are a mean n of 800 to 1050 cells per µl (mm3) n n n n n Laboratory category CD4+ T-cell count % 1 ≥ 500/mm3 ≥ 29 % 2 200 - 499/mm3 14-28% 3 < 200/mm3 <14% sken1 CD4+ lymphocytes depletion – gradual loss of number of CD4 cells over time CD4+ count primary HIV infection asymptomatic infection early symptomatic infection late symptomatic infection final stadium years 1 2 3 Clinical categories – corresponding to clinical condition uA ● acute primary HIV u ● asymptomatic infection u ● persistent generalized u lymphadenopathy (PGL) u is not typically associated with OI u u Risk for OI begins uB ● symptomatic infection (not A or C condition) uC ● AIDS indicator condition u sken1 CD4+ lymphocytes depletion – gradual loss of number of CD4 cells over time CD4+ count primary HIV infection asymptomatic infection, PGL early symptomatic infection late symptomatic infection - AIDS years A B C Laboratory categories Clinical categories CD4+ T-cell categories A asymptomatitic, acute(primary)HIV or PGL B symptomatic, not A or C conditions C AIDS -indicator conditions 1 ≥500/mm3 A1 B1 C1 2 200-499/mm3 A2 B2 C2 3 <200/mm3 A3 B3 C3 These variants of laboratory and clinical categories are possible. images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS CD4 = immunological mark; VL = virological mark Category A nConsists of one or more of the following n conditions in an adolescent or adult with documented HIV infection n nConditions listed in categories B and C must not have occured n nIncludes: uAcute (primary) HIV infection uAsymptomatic HIV infection uPersistent generalized lymphadenopathy (PGL) n sken1 CD4+ lymphocytes depletion CD4+ count primary HIV infection asymptomatic infection, PGL early symptomatic infection late symptomatic infection final stadium years A B C Acute primary HIV infection (mononucleosis-like syndrome, acute retroviral syndrom) n nOccures: nup to 70% of HIV-infected persons nbetween 2 and 8 weeks after initial infection nacute symptoms last 3 days to 3 weeks na variety of nonspecific signs and symptoms have been associated with the acute retroviral syndrome images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS weeks years images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS •Usually 2 to 8 weeks after infection •Production of antibodies to HIV is started (time of seroconversion) •Significant but transient fall in CD4 cells count •Wide dissemination of virus •Symptoms include a glandular fever-like illness with fatigue, fever lymphadenopathy and seroconversion rash… •Most individuals have no symptoms weeks Signs and symptoms of primary HIV infection nA variety of nonspecific signs and symptoms have been associated nwith the acute retroviral syndrome uFever 77% uLethargy/ fatigue 66% uRash 56% uMyalgia 55% uHeadache 51% uPharyngitis 44% uCervical adenopathy 39% uArthralgia 31% uOral ulcer 29% uPain on swallowing 28% uAxillary adenopathy 24% u Acute primary HIV infection nRash on the back 61 1 nSeborrhoeic dermatitis 61 2 Acute primary HIV infection nHerpetic gingivitis – oral ulcer (trush) nHerpetic gingivitis afty.jpg images.jpg n uWeight loss 24% uNausea 24% uDiarrhea 23% uNight sweats 22% uCough 22% uAnorexia 22% uAbdominal pain 19% uOral candidiasis 17% uVomiting 12% uPhotophobia 12% uMeningitis 12% uGenital ulcer 7% uTonsillitis 7% uDepression 7% uDizziness 6% u Laboratory – in primary HIV infection nLymphopenia nTransient decrease of CD4+ lymphocyte count np24 – HIV core antigen n - may be detected in serum and CSF n within 2 weeks of exposure to HIV n and may persist for weeks or months nanti-HIV n antibodies to HIV usually are detected within 2 months after HIV exposurre not within primary HIV infection n Asymptomatic HIV infection nthe vast majority of individuals infected with HIV are asymptomatic n nthis asymptomatic state n may be prolonged n nthis period of latency is, in fact, n a time of intense viral replication n and immune response images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS weeks years Viral load (VL) = the number of copies of RNA HIV-1 per 1 ml of plasma images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase – clinical asymptomatic phase weeks years • •May last for approxim. 10 years •This not a period of virological and immunological latency •CD4 cell counts gradually fall over time •Immune systém Weakens as viral load increases Predictors of HIV-disease progression clinical immunological virological • oral candidiasis • involution of PGL • constitutional symptoms (fever, night sweats, weight loss…) • ¯ CD4+ cell count • b-2- microglobulin • neopterin • viral load • p24 antigen CLINICAL CATEGORY B sken1 CD4+ lymphocytes depletion CD4+ count primary HIV infection asymptomatic infection early symptomatic infection late symptomatic infection final stadium years A B C images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase weeks years • •CD4 cell counts fall •Viral load increases •Immune system weakens •Clinical symptoms begin to appear Category B = symptomatic HIV infection nConsists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C nExamples of conditions in clinical category B include: n nFever of >38.5 C > 1 month nDiarrhea > 1 month Clinical category B nOropharyngeal candidosis on the bucal mucosa, on the tongue… nOropharyngeal candidosis on the palatum 61 2 D:\Obrázky\Adamicek\dr.Snopková\dodatek poslední\10.jpg n 17 Esophageal candidosis ezofagitida.jpg ezofagitida II.jpg Endoscopic picture nVulvovaginal candidosis nLymphoid interstitial pneumonitis (LIP) nCervical dysplasia or carcinoma in situ nPelvic inflammatory disease (PID) nListeriosis nBacillary angiomatosis nTrombocytopenia nPeripheral neuropathy Clinical category B nBacillary angiomatosis (Bartonella henselae, Bartonella quintana) nOralhairy leucoplacia (cobblestonetongue) 40 n Herpes zoster recurrent or multidermatomal herpes zoster.jpg Clinical caterory C - AIDS nIs the end stage of long-standing, chronic infection with HIV nWithout antiretroviral therapy, approximately 50% of individuals develop AIDS within 10 years after HIV infection n nThe AIDS syndrome is defined by various §opportunistic infections §malignancies §other conditions nsumarized in the CDC definition. sken1 CD4+ lymphocytes depletion CD4+ count primary HIV infection asymptomatic infection early symptomatic infection late symptomatic infection final stadium years A B C images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS-symptomatic AIDS phase weeks years •VL is extremely high – possibly one million copies/ml or more •CD4 counts usually below 200 cells/mm3 and may fall to zero images (16).jpg Natural course of HIV infection (without treatment) •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS-symptomatic AIDS phase weeks years •Symptoms of very advanced infection include opportunistic infections, malignancies and other clinical conditions such as AIDS case definition Category C - AIDS n nIncludes the following clinical conditions as listed in the AIDS case definition n nFor classification purposes, n once a category C conditions has occured, n the person will remain in category C n untill the end of his life Opportunistic infections - Such as AIDS case definition Pneumocystis jiroveci pneumonia – High-resolution CT scan n nShowing ground-glass appearance (image of milk glass) nDestruction of pulmonary parenchymaT (HRCT) scan in 32-year-old woman with HIV infection showing ground-glass appearance due to Pneumocystis jiroveci pneumonia. nCD4+ 4/µl nJirovecii ˃ 100 000 000 kopií DNA/rekaci Pneumocystis jiroveci pneumonia (PCP) showing ground-glass appearanceCT P. jirovecii CD4 lymf. 2 bb/mm3 VL 468000 kopií/ml AIDS – Opportunistic infections nCandidasis esophageal, tracheal, bronchial or pulmonary nHerpes simplex with mucocutaneous ulcer > 1 month nHerpes simplex esophagitis, bronchitis, pneumonia nRecurrent pneumonia with > 2 episodes in 12 month nRecurrent Salmonella bacteremia nChronic intestinal cryptosporidiosis (diarrhea > 1 month) nExtrapulmonary cryptoccocosis nCMV retinitis nGeneralized CMV infection (in other organ than liver, spleen, nodes) n 60 Severe perianal aciclovir-resistant herpes simplex virus 2 infection a-untreated appearance b-healing and re-epithelialization after treatment with foscarnet and institution of HAART AIDS – clical caregory C nHerpes simplex esophagitis nCMV retinitis 15 n 23 AIDS - Extrapulmonary cryptoccocosis - on the skin with cryptoccocomas 16 28 Cryptococcus neoformans in cerebrospinal fluid AIDS – Opportunistic infections nDiseminated or extrapulmonary histoplasmosis nDisseminated coccidioidomycosis nTuberculosis n (pulmonary or extrapulmonary) nDisseminated or extrapulmonary M. avium or M. kansasii infection nAnd others… n Malignancies – AIDS case definition n nKaposi´s sarcoma n Lymphoma t Burkitt´s t Non–Hodgkin lymphoma t Primary lymphoma in brain n Invasive cervical cancer Multiple lesions of Kaposis´s sarcoma Kaposis´s sarcoma Kaposi3 36 dáseň 10.7.09_1.JPG 22 Non-Hodgkin lymfoma (AIDS - category C) Non-Hodgkin - Kopie.jpg AIDS-lymfom Other conditions – such as AIDS case definition n nHIV encephalopathia (dementia) n nWasting syndrome („slim“ disease) n §the introduction of ART has decreased the incidence of opportunistic infections and associated wasting §wasting still remains a common problem in clinical practice §especially in middle income countries n Wasting syndrome associated with HIV/AIDS („slim disease) P1010001 - Kopie.JPG HIV-associated wasting syndrome, „slim disease“ nLoss of body weight together with fever or diarrhea for more than 30 days nIn patient at the time of advanced infection nIn up to 50% of patients in Africa (less in industrialized countries) n nKey etiologic factors nBasal metabolic rate is generally increased at all stages of HIV infection nDisturabances in intermediary metabolism nA reduction in energy intake (nausea, taste disturbance, dysphagia, early satiety, depression, dementia…) nMalabsorption – idiopathic (HIV enteropathy) n - secondary (GI pathogens, OI) n Opportunistic infection in GIT nProtozoa (cryptosporidia, n microsporidia…) nBacteria (Shigella spp., Salmonella spp., n Campylobacter spp.,…) n nProfound anorexia n mediated by cytokine release n accompanies acute OI (not only in GIT) n and results in rapid weight loss. Main laboratory tests for dg. nRecommended for initial evaluation n and follow-up of all patients n 1.Anti-HIV (antibodies to HIV) n ELISA, WB 2.Viral load (the number of copies n of RNA HIV-1) 3.CD4+ lymphocyte count 1. 1.Anti – HIV uenzyme-linked immunosorbent assay (ELISA) tantibodies to HIV tstandard test tprimary screening test for HIV infection n uWB (Western Blot) tif the ELISA anti-HIV test is reactive, u WB is done tmore specific, less sensitive Virion structure sken 2 gp120 envelope glycoprotein reverse transcriptase gp41 transmembrane glycoprotein p24 core antigen RNA anti-HIV • Anti-HIV •Approximately 79% of people with HIV globally knew their HIV status. •The remaining 21% (about 8.1 million people) still need access to HIV testing services. •Testing is an essential gateway to HIV prevention, treatment, care and support services. n2. VL – viral load (viral detection) u u u u u u u u u u •quantitative plasma RNA HIV-1 •the number of copies of RNA HIV-1 per 1 ml plasma •by technique PCR •main virological marker •the most reliable indicator of prognosis C:\Users\Notebook\Desktop\Nový Prezentace aplikace Microsoft PowerPoint.jpg RNA HIV-1 PCR nQuantitative HIV RNA (VL) is useful for: nDiagnosis acute HIV infection nFor predicting probability of transmission nPredicting the rate of progression in chronically infected patiens nFor therapeutic monitoring nis very senstitive nwas developed for monitoring the progression of the disease and the effectiveness of antiretroviral therapy nis not for establishing the diagnosis of HIV infection nshould be repeated from 3- to 4-month intervals during therapy nIn stabile patients it should be repeated every 6 mounths nART nThe objective of ART should be to maintain the lowest VL for as long as possible nWhen an affective AR regimen is initiated in as asymptomatic patient with no previous ART, the VL should decrease to an undetectable level (< 50 copies/ml) within 24 weeks images (16).jpg Natural course of HIV infection •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS weeks years 3. CD4+ Cell (lymphocyte) Count n nThis is a standard test: nto assess prognosis for progression infection nto formulate the differential diagnosis in a symptomatic patient nto make therapeutic decisions regarding antiviral treatment and prophylaxis for opportunistic pathogens n nIt was the most reliable indicator of prognosis until recently nNumber of copies RNA HIV (VL) is considered the most reliable n indicator of prognosis currently n images (16).jpg Natural course of HIV infection •Gradual loss of number of CD4 cells over time •Gradual increase of number of viral copies (increase of viral load) Acute infection Latency phase AIDS weeks years Another screening laboratory tests tComplete blood count tSerum chemistry panel tUrine tSyphilis serology tScreening for other sexually transmitted diseases tTuberculin skin test (Mantoux) tSerology –Hepatitis A, B, C, D, E –Toxoplasmosis –CMV tChest X-ray tEKG tGlucose-6-phosphate dehydrogenase levels (G6-PD) n Glucose-6-phosphate dehydrogenase deficiency nis a genetic disease that predisposes to hemolytic anemia following exposure to oxidant drugs t Dapsone (x lepra, sec.prof. PCP) t Primaqine (x malaria, PCP) t TMP-SMX… (x PCP) nIs found in 10% of black men and in 1% to 2% of black women, in men from Mediterranean area, India and Southeast Asia n n n nThank you for your attention…