TREATMENT of HIV nThe history of HIV infection in the developed world can be divided into 2 eras: u 1.The pre-HAART era (1981 – 1996) u 2.The HAART era (since 1996 – so far) The pre-HAART era n nMonotherapy (NRTI) tresults in viral resistance tshould not be used t with any available AR drug n nTwo AR drugs (NRTIs) tAlso result in viral resistance tIs not recommended n1987 nthe first drug for clinical use n NRTI – AZT (later ZDV) n n n1991-1994 nnext NRTIs (didanosine, zalcitabine, stavudine, lamivudine…) n n n Since 1996 the HAART era nHas been associated with markedly diminished morbidity and mortality n nThree-drug combinations are currently recommended for 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 n ART nEnormous changes in prognosis of HIV/AIDS disease othe introduction of triple combination into clinical practice in 1996 represented a significant step forward in the treatment of HIV infection othe ability of ART regimens has transformed HIV infection into a manageable chronic disease o nART oMaximally and durable supress VL oRestores immunological function oImproves quality of life oReduces HIV-related morbidity and mortality Slide21.gif HAART Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •Maximal and durable suppression of plasma viremia •Restore and preserve immunologic function •Preserves or improves CD4 T lymphocyte (CD4) cell numbers •Confers substantial clinical benefits •Reduce HIV-associated morbidity and mortality ART ART: Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •Prolong the duration and quality of survival •Delays or prevents the selection of drug-resistance mutations •Decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in cohorts with HIV ART ART: Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •ART is recommended for all individuals with HIV, regardless of CD4 T lymphocyte cell count •ART should be initiated as soon as possible ART sken1 CD4+ count primary HIV infection asymptomatic infection, PGL early symptomatic infection late symptomatic infection years ART should be initiated as soon as possible, when the regeneration potential is as high as possible; Patient should not reach AIDS, when is treated on time AIDS Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •After initiation of effective ART, viral load reduction to below limits of assay detection usually occurs within the first 12 to 24 weeks of therapy. •The objective of ART should be to maintain the lowest viral load for as long as possible ART Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •Predictors of virologic success include the following: •Low baseline viremia; •High potency of the ARV regimen; • Tolerability of the regimen; •Convenience of the regimen; • Excellent adherence to the regimen ART Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •After initiation, ART should be continued •Treatment interruption has been associated with rebound viremia, worsening of immune function, and increased morbidity and mortality ART 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 Secondary goal of ART - is to reduce the risk of HIV transmission C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •High plasma HIV-1 RNA is a major risk factor for HIV transmission •When patient is treated •And his viral load of HIV is below limit of assay detection in blood by PCR method, transmission of HIV to another subject is improbable ART 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 40% Global number of people receiving antiretroviral treatment Source: UNAIDS/WHO estimates 23.3 million people with HIV (62%) were accessing antiretroviral therapy (ART) globally, an increase of 1.6 million since 2017 and up from 8 million in 2010. •HIV treatment access is key to the global effort to end AIDS as a public health threat. •People with HIV who are aware of their status, take ART daily as prescribed, and get and keep an undetectable viral load can live long, healthy lives and have effectively no risk of sexually transmitting HIV to their HIV-negative partners. WHO-EN-white-H Increase in people receiving ART over time Source: UNAIDS/WHO estimates WHO-EN-white-H Global ART coverage over time Source: UNAIDS/WHO estimates Secondary goal of ART - is to reduce the risk of HIV transmission C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •The objective of ART should be to maintain the lowest viral load for as long as possible •Eradication of HIV infection cannot be achieved with available antiretrovirals ART nTriple Combination = standard of care n nAdvantages: n oAdditive or synergistic impact on antiviral activity o oDelay in emerging drug-resistance viruses o oDrugs can reach different cellular and body compartments sken1 CD4+ count primary HIV infection asymptomatic infection, PGL early symptomatic infection late symptomatic infection years ART should be initiated as soon as possible, when the regeneration potential is as high as possible; Patient should not reach AIDS, when is treated on time AIDS Primary goal of ART ↓ morbidity and mortality at all stages of HIV infection C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •Maximal and durable suppression of plasma viremia •Restore and preserve immunologic function •Preserves or improves CD4 T lymphocyte (CD4) cell numbers •Confers substantial clinical benefits •Reduce HIV-associated morbidity and mortality ART ART: Secondary goal of ART - is to reduce the risk of HIV transmission C:\Users\Notebook\Documents\2_AKT. TVORBA_7.9..2019\0000_HEP.akad. 21.9\graf OK – kopie.jpg •High plasma HIV-1 RNA is a major risk factor for HIV transmission •When patient is treated •And his viral load of HIV is below limit of assay detection in blood by PCR method, transmission of HIV to another subject is improbable ART The clasess of AR drugs 1.NRTs – nukleoside reverse transcriptase inhibitors 2.NNRTIs – non-nucleoside reverse transcriptase inhibitors 3.InSTI - integrase inhibitors 4.PIs – protease inhibitors 5.FI – fusion inhibitor 6.CCR5 inhibitor – coreceptor inhibitor 05.jpg The main enzymes of HIV are blocked by antiretroviral drugs NRTIs – nucleoside reverse transcriptase inhibitors (NRTIs block of enzyme reverse trascriprase) Generic name Trade made zidovudine (ZDV), azidothymidine (AZT) Retrovir, Azitidin didanosine (ddl) Videx, Videx EC zalcitabine (ddC) Hivid stavudine (d4T) Zerit lamivudine (3TC) Epivir abacavir (ABV) Ziagen ZDV+3TC Combivir ZDV+3TC+ABV Trizivir 3TC+ABV Kivexa emtricitabin (FTC) Emtriva tenofovir (TDF) Viread FTC+TDF Truvada NNRTIs – non-nucleoside reverse transcriptase inhibitors (NNRTIs block of enzyme reverse transcriptase) Genericname 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 InSTI – integrase inhibitor n n n Generic name Trade made raltegravir Isentress elvitegravir Stribild dolutegravir Tivicay II block of enzyme viral integrase FI – fusion inhibitor n n n Generic name Trade made enfuvirtide Fuzeon, T-20 FI blocks of receptor CD4 on surface of cell and block of fusion HIV with CD4 lymphocyte 09.jpg CCR5 inhibitor Generic name Trade made maravirocum Celsentri CCR5 inhibitor blocks of chemokine receptor on surface of cell and block of fusion HIV with CD4 lymphocyte 09.jpg 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 §Truvada + Stocrin (NNRTI) §Co-formulation TDF + FTC in one pill t §Truvada + Kaletra (PI) t §Kivexa + Stocrin §Co-formulation 3TC + ABC in one pill t §Kivexa + Kaletra n n 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 STR – single tablet regimen nIncreasing reductions in pill burden and daily dosages nSignificantly higher comfort for patient nHigher adherence nHigher viral suppression rates nLower risk of hospitalization for complications due to disease progression n nART (HAART, OBT) is very potent nand has a big benefit n nBUT nis unable to completely eradicate nthe virus from the body !!! COMPLICATIONS of ART nAlthough each of the recommended regiments can result in durable suppression of VL, associated with gradual recovery of immunologic function n nEach regimen has specific advantages and potential toxicities of which the patient must be aware n nThree-drug combinations result n in long-term toxicities Major side-effects and complications nNRTIs nmyelosupression (ZDV) nGI intolerance npancreatitis (d4T, ddI) nperipheral neuropathy (d4T, ddC, ddI) nlactic acidosis nneuropsychiatric manifestations nhypersensitivity reaction (ABC) nmitochondrial toxicity nNNRTIs nGI intolerance nskin reaction nneuropsychiatric manifestations (EFV) uNightmares (wild dreams) PIs nGI intolerance, diarrhoea nlipodystrophy nhypercholesterolaemia ninsulin resistance ART (combination of drugs) nIs associated with other possible disease sequelae: §Cardiovascular disease §Changes in body composition §Alterations in glucose and lipid metabolism §Hepatic, renal, bone, neurologic, and oncologic disease complications §Consequences of which have not yet been fully evaluated. „Lipodystrophy syndrome“ in association with HIV n nwas introduced to describe n a complex medical condition including n the apparent §abnormal fat redistribution §and metabolic disturbances nseen in HIV-patients receiving na combination regimens of antiretroviral drugs „Lipodystrophy syndrome“ in association with HIV nPrevalence has been estimated to be n between 30 and 50% nMultifactorial pathogenesis nIs associated with many risk factors n nIs complex interactions between §The effects of chronic HIV infection §Genetically determined disorders §The efects of some antiretrovirals §Lifestyle-induced changes n Definition Lipohypertrophy Visceral Fat Gain Dyslipidemia Lipodystrophy A historical umbrella term that has included multiple, distinct processes Grinspoon & Carr N Engl J Med 2005; 352:48. Carr A et al. Lancet 1999;353:2093-2099. Currier and Havlir. Top HIV Med 2004;12:31. Garg A. N Engl J Med 2004;350:1220. Montessori et al. CMAJ 2004;170:229. Body-Fat Abnormalities Hypercholesterolemia Lipoatrophy Subcutaneous Fat Loss Hypertriglyceridemia Limb lipoatrophy Abdominal fat accumulation Breast hypertrophy Dorsocervical fat pad Lipomatosis Facial lipoatrophy Venomegaly Insulin Resistance Buttock lipoatrophy Hyperinsulinemia Body-Fat Abnormalities buffalo3 Thigh face abdomen Lipoatrophy Lipohypertrophy Morse CG et al. JAMA 2006;296:844-854. Parruti & Torro BMC Infectious Disease 2005;5:80. • Lipoatrophy and lipohypertrophy may co-present • Some characteristics may be irreversible Progression of lipoatrophy over time Grinspoon & Carr N Engl J Med 2005; 352:48. James J et al. Dermatol Surg 2002;11:979–986. Grading nFacial Lipoatrophy Grading n uGrade 1: Mild/localized. Appearance almost normal uGrade 2: Deeper, longer central cheek atrophy. Facial muscles (especially zygomaticus major) u beginning to show through uGrade 3: Deeper, wider atrophic area. Muscles clearly showing uGrade 4: Widespread atrophy. Facial skin lies directly on muscles over a wide area, u extending toward the orbital region Grinspoon & Carr N Engl J Med 2005; 352:48. James J et al. Dermatol Surg 2002;11:979–986. Progression of Lipoatrophy • Definitions based on DEXA or CT scan have not been established in clinical practice • Qualitative grading scales have been utilized 104 nMechanistic pathophysiology of antiretroviral drugs n in lipodystrophy syndrome is very complex and exactly unknown at present nConsequences of this disturbances have not yet been fully evaluated… n nMore signs and symptoms have been described in association with the lipodystrophy syndrome §dry skin, ingrown toenails §aseptic hip necrosis §osteopenia, osteoporosis… §hepatic, renal, bone, neurologic and other disease complications We do not know long-term consequences… It is very likely that the ongoing inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage The morphologic and metabolic effects n nThe fat redistribution and disturbances nin fat and glucose metabolism n– resemble a clinical situation n that is known as n n the „metabolic syndrome“ n n in HIV-negative patients nART is very potent nImproves quality of life nReduces HIV-realted morbidity and mortaliti n nBUT ncan couse nsecondary disorders and complications, nconsequences of which nhave not yet been fully evaluated n n n