Download - Pharmacotherapy of HIV management
![Page 1: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/1.jpg)
PHARMACOTHERAPY OF HIV MANAGEMENT
Dr. Sourav ChakrabartyPost-graduate trainee
Department of Pharmacology
![Page 2: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/2.jpg)
Overview• Introduction• HIV virus• Pathophysiology of AIDS• Anti-retroviral drugs• Principles of anti-HIV chemotherapy• WHO 2013 guideline• Conclusion
![Page 3: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/3.jpg)
Introduction• HIV/ AIDS- a global threat to mankind
• 33 millions of HIV infected worldwide
• Cripples immune system, affects CNS, Kidney, vascular system, mucosa.
• Still no cure, • No vaccine
![Page 4: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/4.jpg)
HIV virus
![Page 5: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/5.jpg)
Life cycle of HIV virus
![Page 6: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/6.jpg)
History of natural disease
![Page 7: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/7.jpg)
Acquired Immune Deficiency Syndrome
• Two parameters:1. Clinical conditions 2. CD4+ T lymphocyte count at blood
• AIDS- if one or more specific opportunistic illness has been diagnosed OR CD4 T+ Lymphocyte <200/µl
![Page 8: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/8.jpg)
Conditions defining AIDS
![Page 9: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/9.jpg)
Anti-retroviral drugs- sites of action
![Page 10: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/10.jpg)
History of anti-retroviral drugs
• Zidovudine – synthesized in 1964 Anti-HIV activity- 1985
• Saquinavir – 1995
• NNRTI- 1998
• Raltegravir- 2007
![Page 11: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/11.jpg)
Anti-retroviral drugsNucleoside Reverse Transcriptase Inhibitors(NRTI)
Zidovudine (AZT)
Stavudine (d4T)
Tenofovir disoproxil (TDF)
Lamivudine(3TC)
Didanosine (ddl)
Zalcitabine(DDC)
Emtricitabine (FTC)
Abacavir (ABC)
Non-nucleosideReverse Transcriptase Inhibitors(NNRTI)
Nevirapine(NVP)
Delavirdine (DLV)
Efavirenz (EFV)
Etravirine (ETV)
![Page 12: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/12.jpg)
Contd………Protease Inhibitors
Saquinavir (SQV)
Ritonavir (RTV)
Amprenavir (APV)
Atazanavir(ATV)
Indinavir (IDV)
Nelfinavir (NFV)
Lopinavir (LPV/r)
Fosamprenavir (FPV)
Tipranavir (TPV)
Darunavir (DRV)
Entry Inhibitors
Enfuvirtide (T-20)
Maraviroc (MVC)
Integrase Inhibitor
Raltegravir (RAL)
![Page 13: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/13.jpg)
Nucleoside/ Nucleotide Reverse Transcriptase
Inhibitors(NRTI)
![Page 14: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/14.jpg)
Intracellular activation of NRTIs
![Page 15: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/15.jpg)
![Page 16: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/16.jpg)
Zidovudine• Active against HIV 1 & 2, HTLV 1 & 2.• more active in lymphocytes than in
monocyte-macrophage cells• Dose- 300 mg twice a day• Crosses placenta & BBB.• Untoward Effects-1. fatigue, malaise, myalgia, nausea,
anorexia, headache and insomnia.2. Bone marrow suppression3. nail hyperpigmentation, myopathy4. Serious hepatic toxicity
![Page 17: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/17.jpg)
Lamivudine• First line NRTI• manufactured as the pure
2Rcis(−)enantiomer• More active in resting cells• Dose- 300 mg once daily
• Untoward Effects- Neutropenia, headache, and nausea
• caution in using in co-infection with HBV
![Page 18: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/18.jpg)
Tenofovir• only nucleotide analog• Available only as the disoproxil prodrug• Incomplete ribose ring• Dose- 300mg OD
• Untoward Effects-well tolerated, rarely acute renal failure and Fanconi’s syndrome
• Drug interaction with Didanosine
![Page 19: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/19.jpg)
Emtricitabine• chemically related to lamivudine• one of the least toxic anti-retroviral drugs
Abacavir• Dose: 600 mg once daily• eliminated by metabolism by alcohol
dehydrogenase, and by glucuronidation• fatal hypersensitivity syndrome(HLA-
B*5701 genotype)
![Page 20: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/20.jpg)
Didanosine• Dose-200 mg twice daily
• Acid labile, hence needs antacid buffer
• Not well tolerated
• peripheral neuropathy and pancreatitis
![Page 21: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/21.jpg)
Non-Nucleoside Reverse Transcriptase
Inhibitors(NNRTI)• Active against HIV 1 only
• No activity against host cell DNA polymerases.
• 4 agents- Nevirapine/Efavirenz/ Delavirdine/ Etravirine.
• Susceptible to high-level drug resistance
• Cross-resistance
![Page 22: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/22.jpg)
Mechanism of action
![Page 23: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/23.jpg)
Pharmacokinetics
![Page 24: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/24.jpg)
Efavirenz• First line NNRTI
• Once daily dosing
• Highly teratogenic
• Adverse effect- CNS toxicities
• Rash
![Page 25: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/25.jpg)
Nevirapine• First line ART both for active treatment and for PPTCT
• Induces own metabolism
• Untoward Effects- Rash, increased liver enzymes
• Severe & fatal hepatitis in pregnancy.
• PPTCT- A single oral intrapartum dose of 200 mg nevirapine followed by a single dose given to the newborn
![Page 26: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/26.jpg)
HIV Protease Inhibitors• Inhibit virus aspartyl protease
• Highly variable pharmacokinetics
• Metabolised by CYP 3A4
• Potential for metabolic drug interactions
• ADR-nausea, vomiting, and diarrhea
![Page 27: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/27.jpg)
Mechanism of action
The viral maturation is
inhibited
The production of the viral particle is inhibited
Act as protease inhibitor in
which block the action of protease
![Page 28: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/28.jpg)
Pharmacokinetics
![Page 29: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/29.jpg)
Saquinavir• First approved Protease inhibitor• Poor oral bioavailability• Dose- 600 mg TDS
Lopinavir• Active against both HIV-1 and HIV-2• Extensive metabolism by CYP 3A4• lopinavir/ritonavir co-formulation in a fixed 4:1
ratio• ADRs- loose stools, diarrhea, nausea, and
vomiting
![Page 30: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/30.jpg)
Ritonavir• Mostly used as a pharmacokinetic
enhancer (CYP 3A4 inhibitor)• Dose- antiretroviral treatment 600 mg
twice dailyBooster dose-100/ 200 mg once or
twice daily
• ADRs- GI upset, lipodystrophy
![Page 31: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/31.jpg)
Entry Inhibitors• Two drugs- Enfuvirtide and Maraviroc
• gp 41 and CD4 interactions- enfuvirtide
• gp 120 and CCR5 interactions- maraviroc
![Page 32: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/32.jpg)
Maraviroc
![Page 33: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/33.jpg)
Contd……..• Active only against CCR5-tropic strains of
HIV
• Three different starting dose-1. with most CYP3A inhibitors- 150mg BD2. with most CYP3A inducers- 600mg BD3. With other- 300mg BD
• generally well tolerated
![Page 34: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/34.jpg)
Enfuvirtide• only approved parenteral antiretroviral drug
• Evolved first as vaccine• High cost to manufacture
• ADRs- injection-site reactions, lymphadenopathy , pneumonia
• Indication- only in treatment-experienced adults
![Page 35: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/35.jpg)
Mechanism of action
![Page 36: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/36.jpg)
Integrase Inhibitors
![Page 37: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/37.jpg)
GUIDELINES FOR HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART):HOW TO USE THE DRUGS?
Based on:Rapid Advice: antiretroviral therapy for HIV infection in adults and adolescentGuidelines For The Management Of Adult HIV Infection With Antiretroviral Therapyhttp://www.who.int/hiv/pub/arv/rapid_advice_art.pdf
![Page 38: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/38.jpg)
HAART
Highly active antiretroviral therapy (ART) using 3 or more active anti HIV drugs from at least 2 different class with the
aim of achieving durable viral suppression to undetectable levels, the
therapeutic goal under most clinical circumstances.
![Page 39: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/39.jpg)
BEFORE STARTING THE REGIMEN• Past treatment history Any resistance to medications Current CD4 and viral load counts Compliance to medication Pregnancy/lactation Concurrent illness (TB/HBV)• HIV tropism assay
![Page 40: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/40.jpg)
GUIDELINES TO START ART
• Start ART in all individuals with a CD4 < 500/µl
• Priority to severe or advanced HIV disease and CD4 < 350/µl
• ART at any CD4 count in PLHIV Active TB disease HBV co-infection with severe chronic
liver disease HIV nephropathy HIV-positive partners in sero-
discordant couples Pregnant and breastfeeding women Children younger than five years of
age Stage 3 or later in WHO clinical
staging
![Page 41: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/41.jpg)
First-line ARTPreferred first-line regimens
Alternative first-line
RegimensAdults(including pregnant andbreastfeeding women and adults with TB and HBV coinfection) TDF + 3TC (or FTC)
+ EFV
AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVP
Adolescents (10 to 19 years) ≥35 kg
AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVPABC + 3TC + EFV (or NVP)
Children 3 - 10 years and adolescents <35 kg
ABC + 3TC + EFV
ABC + 3TC + NVPAZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + EFVTDF + 3TC (or FTC) + NVP
Children <3 yearsABC orAZT + 3TC + LPV/r
ABC + 3TC + NVPAZT + 3TC + NVP
![Page 42: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/42.jpg)
• People receiving NVP discontinue because of adverse events
• With EFV no increased risk of birth defects compared with other ARV drugs during the first trimester of pregnancy
• TDF/FTC or TDF/3TC are the preferred NRTI backbone for
HIV + HBV HIV with TB and pregnant women. • EFV is the preferred NNRTI for HIV & TB (pharmacological
compatibility with TB drugs) HIV +HBV coinfection (less risk of
hepatic toxicity) and Pregnant women, including first
trimester.
![Page 43: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/43.jpg)
ART for PMTCT
![Page 44: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/44.jpg)
Simplified Infant Prophylaxis doses
Drug Infant age Daily dosing
NVP
Birth to 6 weeks• Birthweight 2000−2499 g• Birthweight ≥2500 g
10 mg once daily15 mg once daily
> 6 weeks to 6 months 20 mg once daily
> 6 months to 9 months 30 mg once daily
> 9 months until breastfeeding ends
40 mg once daily
AZTBirth to 6 weeks• Birthweight 2000−2499 g • Birthweight ≥2500 g
10 mg twice daily15 mg twice daily
If toxicity from NVP requires discontinuation or if NVP is not available,infant 3TC can be substituted.
![Page 45: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/45.jpg)
Timing of ART with TB• ART should be started in all TB patients,
including drug-resistant TB, irrespective of the CD4 count
• ATD should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment.
• HIV-positive TB patients with profound
immunosuppression (CD4 <50) should receive ART immediately within the first 2 weeks of ATD .
.• Preferred NNRTI is EFV in patients starting
ART while on ATD .
![Page 46: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/46.jpg)
ART FOR HIV/HBV CO-INFECTION
• Start ART in all HIV/HBV co-infected individuals who require treatment for their HBV infection, irrespective of CD4 cell count or WHO clinical stage
• Start tenofovir and lamivudine or emtricitabine (2 NRTIs = BACKBONE) containing antiretroviral regimens in all HIV/HbV co-infected individuals needing treatment
![Page 47: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/47.jpg)
HIV-2 infection• HIV-2 is naturally resistant to NNRTIs
• Treatment-naive people coinfected with HIV-1 and HIV-2 should be treated with three NRTIs TDF + 3TC / FTC + AZT or AZT + 3TC + ABC or a ritonavir-boosted PI plus two NRTIs.
• In PI-based regimen, the preferred option is LPV/r
• SQV/r and DRV/r are alternative boosted-PI options, but they are not available as heat-stable fixed-dose combinations.
![Page 48: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/48.jpg)
WHO definitions of Treatment failure
Failure Definition Comments
Clinical failure
Adults and adolescentsNew or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) after 6 months of effective treatment--------------------------------------------------ChildrenNew or recurrent clinical event indicating advanced or severe immunodeficiency (WHO clinical stage 3 and 4 clinical condition with exception of TB) after 6 months of effective treatment
differentiate from IRIS
For adults, certain WHO clinical stage 3 conditions (PTB and severe bacterial infections) also indicate treatment failure
![Page 49: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/49.jpg)
Immunologicalfailure
Adults and adolescentsCD4 count falls to baseline (orbelow) or Persistent CD4 <100 ------------------------------------------Children < 5 yearsPersistent CD4 <200 or <10% >5 yearsPersistent CD4 <100
Without concomitant or recent infection to cause a transient fall in CD4
Virologicalfailure
Plasma viral load >1000 based on two consecutive viral load measurements after 3 months, withadherence support
Must be on ARTfor at least 6 months before declaring failure
![Page 50: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/50.jpg)
Preferred second-line ART regimens
for adults and adolescents Target population Preferred second-line regimen
Adults andadolescents(≥10 years)
If d4T or AZT was used in first-line ART TDF + 3TC (or FTC) + ATV/r or LPV/r
If TDF was used in first line ART AZT + 3TC + ATV/r or LPV/r
Pregnant women Same regimens recommended for adults and adolescents
HIV and TBCoinfection
If rifabutin is available Standard PI-containing regimens
If rifabutin is not availableSame NRTI plus double-dose LPV/r (ie, LPV/r 800 mg/200 mg ) or standard LPV dose with an adjusted dose of RTV(i.e, LPV/r 400 mg/400 mg )
HIV +HBVcoinfection AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
![Page 51: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/51.jpg)
Third-line regimens• National programs should develop policies for
third-line therapy that consider funding, sustainability and the provision of equitable access to ART
• Third-line regimens should include new drugs likely to have anti HIV activity such as integrase inhibitors (eg. Raltegravir) and second generation NNRTIs (eg. Etravirine) and PIs (eg. Darunavir)
• Patients on a failing second-line regimen with no new antiretroviral options, should continue with a tolerated regimen
![Page 52: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/52.jpg)
52
• All NRTIs**– Lactic acidosis/fatty
liver*– Lipoatrophy (loss of
subcutaneous fat)
• Anemia– Zidovudine (AZT,
ZDV)• Pancreatitis*
– didanosine (ddI)• Neuropathy
– didanosine (ddI)– stavudine (d4T)
*Potentially life-threatening**d4T > ddI, AZT > ABC, TDF, 3TC
Serious Adverse Effects of NRTIs
![Page 53: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/53.jpg)
53
Serious Adverse Effects of NNRTIs
• All NNRTIs–Hepatitis*–Skin rash
• CNS symptoms– efavirenz
• Stevens-Johnson syndrome*– nevirapine
*Potentially life-threatening
![Page 54: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/54.jpg)
54
Serious Adverse Effects of PIs
• All PIs– Insulin resistance hyperglycemia and
diabetes
– Elevated serum lipids
– Abnormal fat accumulation
– Liver toxicity**Potentially life-threatening
![Page 55: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/55.jpg)
Conclusion• HIV replication is controllable
• ART is always lifelong
• Minimum 3 drugs
• Best combination- NRTI+ NRTI+ NNRTI
• NNRTI + PI- Should not be given
• But above all, Prevention from HIV is the best way
![Page 56: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/56.jpg)
VACCINE???IS THERE ANY VACCINE AVAILABLE??
IS IT POSSIBLE TO MANUFACTURE ONE??
![Page 57: Pharmacotherapy of HIV management](https://reader035.vdocuments.us/reader035/viewer/2022062412/5873fcc81a28abb1528b7457/html5/thumbnails/57.jpg)
THANK YOU