HIV INFECTION ! AIDS.jpg Human Immunodeficiency Virus (HIV) n nInfects human cells n and causes gradual loss of immune n system function, n and these immune alterations predispose n to the opportunistic infections, n neoplasms, and other conditions n (wasting and dementia) nThe term n nHuman Immunodeficiency Virus syndrome n nis used to describe nthe cellular and humoral immunodeficiency nand the numerous complications nthat result from the HIV infection Acquired immunodeficiency syndrome (AIDS) n n n nIs the spectrum of disorders n resulting from n very advanced HIV infection 1996 – HAART era nthe introduction of HIV therapy into clinical practice represented a significant step forward in the treatment of HIV infection n nthe ability of HAART regiments have transformed HIV infection into n a manageable chronic disease n in many patients n n HAART = cART = OBT = ART nThree-drug combinations nare 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 n ART nEnormous changes in prognosis nof HIV/AIDS disease umaximally and durably u supresses viral load urestores immunological function uimproves quality of life udramatically reduces HIV-related morbidity and mortality n •Global summary of the AIDS epidemic | 2014 •36.9 million [34.3 million – 41.4 million] •34.3 million [31.8 million – 38.5 million] •17.4 million [16.1 million – 20.0 million] •2.6 million [2.4 million – 2.8 million] • • •2.0 million [1.9 million – 2.2 million] 1.8 million [1.7 million – 2.0 million] •220 000 [190 000 – 260 000] • • •1.2 million [980 000 – 1.6 million] 1.0 million [760 000 – 1.8 million] •150 000 [140 000 – 170 000] •Number of people living with HIV •People newly infected •with HIV 2014 •AIDS deaths in 2014 •Total •Adults •Women •Children (<15 years) • • •Total •Adults •Children (<15 years) • • •Total •Adults •Children (<15 years) Czech republic 31.8.2016 nCzech citizens 2836 nForeigners n with long-lasting stay in CR 416 n nTotal number 3252 n nDeath due to AIDS 352 • 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 • I. Sexual route nSexual contact with an infected person nis the predominant mode nof transmission wordwide n 1.Homosexual intercourse §Men who have sex with men §Homosexual and bisexual men t u The main mode in North America, u Europe and Australia 2.Heterosexual intercourse n §The dominant mode (90%) wordwide §As a risk factor for acquiring HIV has dramatically increased II. Parenteral route (exposure) 1.Blood transfusion and blood products can be infected by HIV n - recipients are in risk acquiring of HIV §hemophiliacs, plasma, t clotting factors §whole blood, t blood cellular components §recipients of tissue, t organ transplants, semen nTransfusion of infected blood nor blood components nas a risk factor for acquiring HIV has n ndramatically decreased in incidence n nsecondary to the availability nof a screening of all blood products nsince 1987 2.Contaminated injection and medical equipments n §drug users, sportsman §nosocomial §health and laboratory workers The probability transmission of HIV infection nafter skin puncture with infected materials ndepends on multiple factors §high titer viremia of the patients §amount of blood on the needle §advanced HIV infection… nWithout antiretroviral therapy nis estimated to be 0.3 – 0.5 % n n n Postexposure Prophylaxis (PEP) nPrompt administration nof a combination regimen of AR drugs (PEP) nsignificantly decreases the likelihood nof HIV infection nfollowing needle-stick injuries n III. Vertical route (mother-to-child) n nPerinatal transmission may occur 1. 1.During pregnancy (in utero) 2.During delivery n (at birth, intrapartum) 3.During breastfeeding No transmission n nHousehold contacts not sexually involved with infected persons are not risk n for acquiring HIV n nFamily members who shared bathrooms and eating utensils with HIV+ patients did not become infected nMosquitoes do not transmit HIV n nNo cases of transmission from n human bites have been reported. n Saliva contains neutralizing factors. PATHOGENESIS Virion structure sken 2 • •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) • • • Virion structure sken 2 • • • • • nProductive •viral replication •is lytic •to infected T cells • nLoss of number of CD4 cells is basis of advanced infection 37 CD4+ lymphocytes and HIV nA decrease in function nas well as number of 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 CLASSIFICATION OF HIV INFECTION n nCriteria for HIV infection for adult person include: n § laboratory categories § clinical categories 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 u is not typically associated with OI u Clinical categories – corresponding to clinical condition uRisk for OI begins u uB ● symptomatic infection u (not A or C condition) u uC ● AIDS indicator condition u nThe AIDS syndrome is defined by various n §opportunistic infections §malignancies §other conditions n nsumarized in the CDC definition. 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 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 CLINICAL CATEGORY A Category A nConsists of one or more of the following n conditions n in an adolescent or adult n with documented HIV infection n nConditions listed in n categories B and C must not have occured Category A nIncludes: n uAcute (primary) HIV infection u uAsymptomatic HIV infection u uPersistent generalized lymphadenopathy (PGL) 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 Signs and symptoms of primary HIV infection 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% uWeight loss 24% uNausea 24% uDiarrhea 23% uNight sweats 22% uCough 22% uAnorexia 22% uAbdominal pain 19% u u u uOral candidiasis 17% uVomiting 12% uPhotophobia 12% uMeningitis 12% uGenital ulcer 7% uTonsillitis 7% uDepression 7% uDizziness 6% n nA variety n nof nonspecific signs and symptoms n n have been associated n nwith the acute retroviral syndrome CLINICAL CATEGORY B 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 nVulvovaginal candidosis nLymphoid interstitial pneumonitis (LIP) nCervical dysplasia or carcinoma in situ nPelvic inflammatory disease (PID) nListeriosis nBacillary angiomatosis nTrombocytopenia nPeripheral neuropathy CLINICAL CATEGORY C AIDS 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 AIDS nIs the end stage of long-standing, n chronic infection with HIV n nWithout antiretroviral therapy, n approximately 50% of individuals n develop AIDS within 10 years n after HIV infection n nThe syndrome is defined by various n uopportunistic infections umalignancies uother conditions n nsumarized in the CDC 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 Opportunistic infections n nsuch as AIDS case definition • Pneumocystis carinii jiroveci pneumonia •Pneumocystis carinii jiroveci pneumonia (PCP) PCP – High-resolution CT scan (EP 20.11.2014) nshowing ground-glass appearanceCT (HRCT) scan i32-year-old man with HIV infection showing ground-gdue to Pneumocystis carinii pneumonia. nCD4+ lymfocyty 4/µl, MI…………..IF……… nJirovecii ˃ 100 000 000 kopií DNA/rekaci AIDS - OI n nCandidasis esophageal, tracheal, bronchial or pulmonary n nHerpes simplex with mucocutaneous ulcer > 1 month n nHerpes simplex esophagitis, bronchitis, pneumonia AIDS - OI nCMV retinitis nGeneralized CMV infection (in other organ than liver, spleen, nodes) n nProgresive multifocal leukoencephalopathy (PML) AIDS - OI n nRecurrent pneumonia with > 2 episodes in 12 month n nRecurrent Salmonella bacteremia n nChronic intestinal cryptosporidiosis (diarrhea > 1 month) n nExtrapulmonary cryptoccocosis n 28 •Extrapulmonary •cryptoccocosis •- CSF AIDS - OI nDiseminated or extrapulmonary histoplasmosis n nDisseminated coccidioidomycosis n nTuberculosis n (pulmonary or extrapulmonary) n nDisseminated or extrapulmonary M. avium or M. kansasii infection 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 • n 31 •Kaposis´s sarcoma Other conditions - AIDS case definition n n nHIV encefalopathia (dementia) n nWasting syndrome („slim disease“) • D:\Obrázky\Adamicek\KICH\Snopková\105.jpg Wasting syndrome („slim disease“) n HIV-associated wasting syndrome, „slim disease“ n nLoss of body weight together with fever n or diarrhea for more than 30 days n nIn patient at the time of advanced infection n nIn up to 50% of patients in Africa (less in industrialized countries) nthe introduction of ART n has decreased the incidence of OI n and associated wasting n nwasting still remains a common problem in clinical practice n nespecially in middle income countries n LABORATORY TESTS 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.Anti – HIV uenzyme-linked immunosorbent assay n (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 n n2. VL – viral load (viral detection) u uquantitative plasma RNA HIV-1 uthe number of copies of u u RNA HIV-1 per 1 ml plasma u uby technique PCR umain virological marker uthe most reliable indicator of prognosis n nQuantitative HIV RNA (VL) is useful for: n nDiagnosis acute HIV infection nFor predicting probability of transmission nPredicting the rate of progression in chronically infected patiens nFor therapeutic monitoring n Viral load (VL) 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 n it should be repeated every 6 mounths n n ART nThe objective of ART should be to maintain n the lowest VL for as long as possible n 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 3. CD4+ Cell (lymphocyte) Count 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 CD4 Cell Count n It was the most reliable n indicator of prognosis until recently n nNumber of copies RNA HIV (VL) n is considered the most reliable n indicator of prognosis currently TREATMENT The clasess of AR drugs 1.NRTs – nucleoside n reverse transcriptase inhibitors 2.NNRTIs – non-nucleoside n reverse transcriptase inhibitors 3.PIs – protease inhibitors 4.FI – fusion inhibitor 5.CCR5 inhibitor – coreceptor inhibitor 6.II - integrase inhibitors 05.jpg • • The main enzymes of HIV are blocked • by antiretroviral drugs • NRTIs block of enzyme reverse trascriprase NRTIs – nucleoside reverse transcriptase inhibitors Generic name Trade made zidovudine (ZDV), azidothymidine (AZT) Retrovir, Azitidin didanosine (ddl) Videx, Videx EC zalcitabine (ddC) Hivid stavudine (d4T) Zerit lamivudine (3TC) Epivir Generic name Trade made abacavir (ABV) Ziagen ZDV+3TC Combivir ZDV+3TC+ABV Trizivir 3TC+ABV Kivexa emtricitabin (FTC) Emtriva tenofovir (TDF) Viread FTC+TDF Truvada •NNRTIs block of enzyme reverse transcriptase NNRTIs – non-nucleoside reverse transcriptase inhibitors Generic name Trade made nevirapine (NVR) Viramune delavirdine (DLV) Rescriptor efavirenz (EFV) Stocrin, Sustiva rilpivirine (RPV) Edurant PIs – protease inhibitors Generic name Trade made saquinavir (SQV-hgc) Invirase saquinavir (SQV-sgc) Fortovase ritonavir (RTV) Norvir indinavir (IDV) Crixivan nelfinavir (NFV) Viracept amprenavir (APV) Agenerase •PIs block of enzyme viral protease PIs – protease inhibitors Generic name Trade made lopinavir/ritonavir (LPV/r) Kaletra atazanavir Reyataz fosamprenavir Telzir tipranavir Aptivus darunavir Prezista II – integrase inhibitor n n n Generic name Trade made raltegravir Isentress elvitegravir Stribild dolutegravir Tivicay •II block of enzyme viral integrase 09.jpg • CCR5 • • • Inhibitor •- maravirocum •Fusion inhibitor •- enfuvirtide nThree-drug combinations are currently recommended for the initiation of treatment in all patients n nWhen HIV diagnoses is established regardless on CD4 lymphocyte count n nThe most widely used combination is n n two NRTIs with one II, PI or NNRTI STR – single tablet regimen nThe most advanced way of treatment n nComplete ART for once-daily dosing - in one pill n nSTR co-formulation for once-daily dosing is the highest level of ART simplification achieved so far Co-formulations of drugs for STR tAtripla •TDF/FTC/EFV t tEviplera •TDF/FTC/RPV t tStribild •TDF/FTC/EVG/COBI • tTriumeq •ABC/3TC/DTV tGenvoya •TAF/FTC/EVG/c ncART (HAART, OBT) is very potent n nBUT nis unable to completely eradicate nthe virus from the body !!!