Antiretroviral therapy and its complications

GOAL OF ANTIRETROVIRAL THERAPY • maximally and durably suppress plasma HIV viral load, • restore and preserve immunologic function (CD4), • reduce HIV-associated morbidity and prolong survival, • improve quality of life, and • prevent HIV transmission. HIV suppression with antiretroviral therapy may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other comorbidities

WHAT CAN NOT BE ACHIEVED WITH ARV THERAPY cure lack of infectivity of a person living with HIV Reservoirs (sanctuaries) of the virus: - central nervous system - lymph nodes - urogenitary tract

When to start ARV treatment? 2019 - all guidelines All patients

Groups of ARV drugs Reverse transcriptase inhibitors nucleotide NtRTI nucleoside NRTI non nucleoside NNRTI Protease inhibitors PI Fusion inhibitors Integrase inhibitors Co-receptors inhibitors (CCR5)

ARV drugs Highly active antiretroviral therapy – HAART 1996 Basic regimens 2 NRTI + PI/r 2 NRTI + NNRTI 2 NRTI +InI Salvage regimens We give what we can

Nucleoside reverse transcriptase inhibitors (NRTI) Generic name Abbreviation Trade name Zidovudine AZT „ Retrovir” Emtricitabine FTC „Emtriva” Lamivudine 3TC „Epivir” Didanosine ddI „Videx” Stavudine d4T „Zerit” Abacavir ABC „Ziagen” 2019-04-20

NRTIs may cause mitochondrial toxicity NRTIs may cause mitochondrial toxicity. The most serious symptom of mitochondrial toxicity is a life-threatening condition - lactic acidosis. Other symptoms - pancreatitis - polyneuropathy, - lipoatrophy - bone marrow suppresion (pancytopenia) - miopathy - hepatotoxicity .

Nucleotide reverse transcriptase inhibitor (NtRTI) Tenofovir TDF „Viread” TAF Tenofovir Alafenamide („Descovy” : F/TAF) Non nucleoside reverse transcriptase inhibitors (NNRTI) Nevirapine NVP „Viramune” Efavirenz EFV „Stocrin” „Sustiva” Etravirine „Intelence” Rilpivirine „Edurant” 2019-04-20

Non nucleoside reverse transcriptase inhibitors NNRTI Adverse effects: - hepatitis - rash (hypersensivity)

Protease inhibitors Saquinavir SQV „Invirase” Indinavir IDV „Crixivan” Atazanavir ATV „Reyataz” Fosamprenavir FPV „Telzir” Ritonavir RTV „Norvir” Lopinavir LPV „Kaletra” (LPVr) Tipranavir TPV „Aptivus” Darunavir DRV „Prezista” 2019-04-20

Protease inhibitors may cause : - abnormal distribution of fatty tissue (lipodystrofy) - diabetes, - increased cholesterol and TG concentration CHD - increased bleeding in hemophiliacs - diarrhoea, nausea, abdominal pains - hepatitis

Fusion inhibitor Enfuvirtide ENF „Fuzeon” Administered subcutaneously, topical symptoms

Raltegravir „Isentress” Integrase inhibitors Raltegravir „Isentress” Elvitegravir only with other drugs in one pill „Stribild or Genvoya ” Dolutegravir „Tivicay” Bictegravir „Bictervy” Co-receptors antagonists (CCR5) Maraviroc „Celsentri”

EACS

What is important in highly active antiretroviral therapy Combined treatment with at least 3 drugs Combining drugs from different groups Lifelong treatment Adherence > 95%

Importance of adherence Adherence „Full” suppresion of the virus >95 % 81 % 90 – 95 % 65 % 80 – 90 % 50 % 70 – 80 % 25 % <70 % 6 % Paterson D et al Conference on retrovirus and Opportunistic Infections Chicago 1999 2019-04-20

Evidence for efficacy of ARV decrease in HIV viremia < 20 copies/ml increase in CD4 count patient`s general condition improved

Failure of ARV therapy Increase in HIV viremia Decrease in CD4 count Occurrence of opportunistic infections Causes: Too low drugs concentration Immergence of the resistant strain of virus - improper dosing, drug-drug interactions, malabsorption - poor adherence

Definition of Antiviral Drug Resistance Presence of viral mutations that reduces drug susceptibility compared with the susceptibility of wild-type viruses. Selection of resistance requires viral replication in the presence of sub-optimal drug concentrations

When do we switch to another ARV regimen Therapeutic failure Improve adherence Resistance testing : genotyping phenotyping Toxicity of the drugs 2019-04-20

Drug – drug interactions ARV drugs have many interactions with other drugs and between themselves. PIs and NNRTIs are inhibitors or substrats of CYP 450 and that results in increasing or decreasing plasma concentration of other ARVs or concomitant drugs. E.g. Rifamycin decreases PI plasma concentration by 80 % Some herbs have similar effect (St.John`s wort, garlic) 2019-04-20