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  1. CURRENT NATIONAL GUIDELINE IN THE PHARMACOTHERAPY OF HIV/AIDS Pharm. Shomuyiwa Rasheed .T (B.Pharm. Olabisi Onabanjo University) FEDERAL MEDICAL CENTER ,LOKOJA, KOGI STATE. Supervisor : Dr. (Mrs) Ugo Adaobi Pharm.D (Uniben))
  2. Outline ‒Introduction ‒Opportunistic infection ‒Hiv transmission ‒Hiv life cycle ‒ Laboratory Diagnosis of HIV Infection ‒Pharmacotherapy of Hiv ‒Baseline treatment of ARV’s ‒Classification of ARV’s ‒Recommend ART regimen for Adults, Adolescent and children ‒Conclusion ‒Reference
  3. Introduction Human immunodeficiency virus (HIV) is an infection that attacks the body’s immune system, specifically the white blood cells called CD4 cells (500-1400 per cubic meter). HIV destroys these CD4 cells, weakening a person’s immunity against opportunistic infections, such as tuberculosis and fungal infections, severe bacterial infections and some cancers. AIDS (acquired immune deficiency syndrome) is the name used to describe a number of potentially life-threatening infections and illnesses that happen when your immune system has been severely damaged by the HIV virus.
  4. Introduction  Hiv was first recognized in 1981 and the virus was identified in 1983.  There are two main types, HIV-1 and HIV-2 ─ HIV-1 is responsible for AIDS in America, Europe, and Asia ─ HIV-2 occurs mainly in western Africa  There were an estimated 38.4 million [33.9–43.8 million] people living with HIV at the end of 2021  Two thirds of whom (25.6 million) are in the WHO African Region.
  5. Opportunistic infections (OIs)  Opportunistic infections (OIs) are illnesses that occur more frequently and are more severe in people with HIV. This is because they have damaged immune systems.  Today, OIs are less common in people with HIV because of effective HIV treatment.  But some people with HIV still develop OIs because ─ They may not know they have HIV ─ They may not be on HIV treatment ─Their HIV treatment may not be working properly.
  6. Common Opportunistic Infections ─ Candidiasis ─ Herpes simplex virus (HSV) ─ Encephalopathy, HIV-related ─ Kaposi’s sarcoma (KS) ─ Lymphoma ─ Tuberculosis (TB) ─ Pneumocystis pneumonia (PCP)
  7. HIV Transmission • Blood • Semen • Vaginal Secretions • Breast milk Comes into contact with: mucous membranes, damaged tissue, or is injected into the body Through: Vaginal, anal, or oral sex Contaminated needles IV drug use
  8. HIV Transmission  HIV is NOT transmitted by casual contact ─ Working or playing with an HIV positive person ─ Closed mouth kissing ─ Shaking hands ─ Public pools ─ Hugging ─ Public toilet  HIV is not transmitted by air, food, or mosquito and does not survive long outside the body.
  9. Laboratory Diagnosis of HIV Infection Antibody Assays Enzyme-Linked Immunosorbent Assay (ELISA) or Enzyme Immunoassay (EIA) for blood Screening Nucleic Acid-based Testing ─HIV DNA Polymerase Chain Reaction (PCR) ─Viral Load Assay- Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)
  10. Staging of HIV Infection The WHO classified HIV infection clinically into: Asymptomatic stage 1 Mild symptom stage 2 Advanced symptoms stage 3 Severe symptoms stage 4
  11. Manifestations at the clinical stages Stage 1 Asymptomatic, gneralised lymphadenopathy Stage 2 weight loss <10%, fungal nail infection, herpes zoster, recurrent UTIs, prurigo Stage 3 weigh loss>10%, chronic diarrhoea, fever, oral candidiasis, pulmonary TB, severe bacteria infections. Stage 4 AIDS-defining illnesses such as brain toxoplasmosis, candida oesophagitis, extra pulmonary TB, Karposi sarcoma, non-hidgkin lymphoma.
  12. Pharmacotherapy of HIV/AIDS Antiretroviral therapy (ART) is the treatment of HIV infection using a combination of antiretroviral drugs (ARVs). ART should be initiated in a patient if: CD4+ cell count =<350cells/mm3 including pregnant women irrespective of clinical symptoms WHO stage 3 or 4 irrespective of the CD4+ count
  13. Pharmacotherapy of HIV/AIDS Co-infected with TB as soon as possible irrespective of CD4 count (within 8 weeks after the start of TB treatment) HIV patient who require treatment for HBV infection irrespective of CD4 cell count or WHO clinical staging HIV positive pregnant women with CD4 count<350 ARV prophylaxis should be provided
  14. Baseline Assessment for ART The baseline assessment and preparation of patients for ART should include: Re-testing for HIV to verify HIV positive status A comprehensive history and clinical examination Assessment of patient's readiness for initiation of ART (regimen, dosage, scheduling, benefits, adverse effects, follow up, monitoring visits and age-appropriate disclosure) Development of patient-centred adherence strategy  Baseline laboratory assessment
  15. Classification of Antiretroviral Drugs (ARVs) CLASS DRUGS Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Abacavir (ABC) , Emtricitabine (FTC); Lamivudine (3TC) Tenofovir Disoproxil fumarate (TDF); Zidovudine (AZT, ZDV), Didanosine (ddI) Stavudine (d4T) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz (EFV), Etravirine (ETR); Nevirapine (NVP), Rilpivirine (RPV) Protease Inhibitors (PI) Atazanavir (ATV), Darunavir (DRV) Lopinavir (LPV), Fosamprenavir (FPV); Indinavir (IDV) Nelfinavir(NFV) Protease Inhibitors (PIs) boosters Ritonavir (RTV), Cobicistat (COBI) Integrase Strand Transfer Inhibitors (INSTIs) Dolutegravir (DTG), Elvitegravir (EVG); Raltegravir(RAL), Cabotegravir (CAB)
  16. Classification of Antiretroviral Drugs (ARVs) CLASS DRUGS Attachment Inhibitors Fostemsavir, Ibalizumab, Anti CD4 adnectin Fusion Inhibitors Enfuvirtide; Anti-GP41 Adnectin; Combinectin Chemokine receptor antagonists Maraviroc; Vicroviroc; Cenicriviroc
  17. MECHANISM OF ACTION:NRTI’S Interrupt HIV replication cycle via competitive inhibition of HIV reverse transcriptase and termination of the DNA chain These compete with host nucleotides to serve as the substrate for reverse transcriptase chain elongation.  Absence of 3'OHgroup on sugar moiety prevents the addition of another nucleotide, resulting in chain termination, abortion of viral DNA chain elongation and cessation of viral replication.
  18. SIDE EFFECTS DRUGS ( NRTI’S) SIDE EFFECTS ABACAVIR Hypersensitivity reaction, increase in cholesterol DIDANOSINE Nausea, vomiting abdominal pain, peripheral neuropathy, EMTRICITABINE Rash and skin darkening of palms or soles LAMIVUDINE Skin rash STAVUDINE Peripheral neuropathy and lactic acidosis TENOFOVIR DISIPROXIL FUMARATE Kidney and bone damage ZIDOVUDINE Anemia, nausea, vomiting, lactic acidosis, increase in cholesterol, fat loss in arms, legs or face, fatty liver
  19. MECHANISM OF ACTION:NNRTI’S  NNRTI’s are generally hydrophobic molecules that bind to an allosteric binding site. Binding to this allosteric site locks the neighboring substrate-binding site into an inactive conformation. Inhibit HIV reverse transcriptase by binding a hydrophobic pocket close to the active site thereby locking the site in an inactive conformation.
  20. SIDE EFFECTS DRUGS(NNRT’S) COMMON SIDE EFFECT EFAVIRENZ Anxiety, depression, insomnia, skin rash, liver damage ETRAVIRINE Skin rash , Nausea NEVIRAPINE Skin rash CABOTEGRAVIR/RILPIVIRINE Headache, tiredness, trouble sleeping, nausea Doravirine Skin rash, weight gain
  21. MECHANISM OF ACTION:PI HIV protease is a 99-amino-acid, aspartic acid protein Inhibit HIV protease by binding to its active site, preventing the cleavage of gag and gag-pol precursor. Virions are produced but they are incomplete and noninfectious.
  22. SIDE EFFECTS: P.I ─ Nausea ─ vomiting ─ Diarrhea, ─ Jaundice ─ Gall bladder and kidney stones ─ liver damage ─ Skin rash ─ Increase in cholesterol ─ Changes in heart rhythm
  23. Pharmacokinetic enhancers/ PI boosters  These are drugs used in HIV treatment to increase the effectiveness of certain classes of ARV drugs. The PIs are metabolized by cytochrome P450 (CYP) 3A enzymes; and intentional inhibition of the enzymes' lead to higher drug exposure, lower pill burden and simplified dosing schedules.  In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat.  These agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir.
  24. INTEGRASE INHIBITORS It’s also known as Integrase Strand Transfer Inhibitors (INSTI). HIV integrase Responsible for transport and attachment of proviral DNA to host-cell chromosomes, allowing transcription of viral proteins and subsequent assembly of virus particles  Raltegravir , Elvitegravir & Dolutegravir
  25. Mechanisms of Action: Integrase Inhibitors The INSTI mechanism of action is to prevent HIV integrase from incorporating proviral DNA into the human host cell, thus inhibiting the HIV-catalyzed strand transfer step. This step has no human homolog, making it a specific and effective HIV drug target with excellent tolerability and minimal toxicity
  26. SIDE EFFECTS:INSTI ─ Insomnia ─ Depression ─ Skin rash ─ Weight gain ─ Fever ─ Fatigue ─ Muscle or joint ache ─ Swelling in eyes, mouth and face
  27. Entry Inhibitors Entry Inhibitors block the mechanisms by which HIV gains access into the cytoplasm of CD4+ cell molecule bearing cell. There are 3 classes: Attachment inhibitors: These agents complex with glycoprotein 120 and prevent it from interacting with the CD4+ molecule thus, the attachment of the virus to the cell is blocked.
  28. Entry Inhibitors  Chemokine Receptor Antagonists: These are agents that complex with cell membrane receptors that serve as fusion proteins i.e. CXCR4, CCR5. Fusion inhibitors: These are agents designed to compete with the viral GP41. GP41 is the viral protein that is capable of fusing with cellular membrane molecules called chemokine receptors. The interaction of fusion inhibitors with GP41 blocks the fusion of viral membrane with cellular membrane
  29. Highly Active Antiretroviral Therapy (HAART) Highly active antiretroviral therapy (HAART) are medications used to treat HIV. These medications may also be called antiretroviral drugs (ART), antiretrovirals (ARVs), or anti-HIV drugs.  HAART is used to describe a combination of three or more anti-HIV drugs. HAART prevents the HIV virus from making copies of itself and limits how much virus is in the body. The level of virus in the blood is called ‘viral load’.
  30.  Recommended ART Regimen for Adults, Adolescents and Children ‒ First-line ART regimens for adults and adolescents Two NRTIs + INSTI Abacavir (600mg) | Lamivudine (300mg) + Dolutegravir (50mg) ABC + 3TC (or FTC) +DTG
  31. Alternatively Tenofovir(300mg) | Lamivudine (300mg) | Dolutegravir(50mg) TDF + 3TC +DTG
  32. A switch to a second-line regimen is recommended when FIRST-LINE THERAPY FAILURE  Clinical failure is recognized  Immunological failure is recognized  Virological failure is recognized.
  33. Adult & Adolescent Second Line ART regimens TWO NRTIs + TWO PIs Tenofovir (300mg) | Lamivudine (300mg) +Lopinavir 200mg Ritonavir (50mg) ‒ Tenofovir (300mg) | Lamivudine (300mg) + Atazanavir (300mg) | Ritonavir (50mg)
  34. Adult & Adolescent Third Line ART regimens TWO NRTIs + TWO PIs + INSTI Tenofovir (300mg) | Lamivudine (300mg) + Darunavir (800mg)| Ritonavir (100mg) + Dolutegravir (50mg)
  35. Paediatric First Line (0-9yrs) < 20kg ─Tenofovir | Lamivudine 60mg | Dolutegravir (TLD) ─ Abacavir 120mg | Lamivudine 6omg + Dolutegravir ─ Abacavir 120mg | Lamivudine 60mg + Lopinavir | Ritonavir - 100/25mg ─Zidovudine 6omg| Lamivudine 60mg + Lopinavir |Ritonavir - 100/25mg ─Abacavir | Lamivudine + Lopinavir | Ritonavir - 40/10mg
  36. Paediatric Second Line (0-9yrs) ‒Abacavir | Lamivudine + Raltegravir ‒ Zidovudine | Lamivudine + Raltegravir ‒Abacavir | Lamivudine + Lopinavir | Ritonavir ‒ Zidovudine | Lamivudine + Lopinavir | Ritonavir  HIV-exposed infants ‒ Nevirapine Suspension 10mg/ml ‒ Zidovudine 10mg/ml + Nevirapine 10mg/ml
  37. PROPHYLAXIS Pre-Exposure Prophylaxis Pre-exposure prophylaxis (PrEP) is the pre-emptive use of ARVs to reduce the probability of HIV negative individuals acquiring HIV infection, especially in persons who are deemed at substantial risk. Post-Exposure Prophylaxis Post-Exposure Prophylaxis (PEP) is the short-term use of ARVs to prevent HIV infection in persons accidentally exposed to a potential risk of acquiring HIV infection.
  38. Pre Exposure Prophylaxis (PrEP) ─ Tenofovir (300mg) | Emtricitabine(200mg) ─ Tenofovir (300mg) | Lamivudine (300mg) Adult & Adolescent Post Exposure Prophylaxis (PEP) ‒ ‒ Tenofovir (300mg) | Lamivudine (300mg) | Efavirenz (600mg) ‒ Tenofovir (300mg) | Lamivudine (300mg) | Dolutegravir (50mg)
  39. Paediatric Post Exposure Prophylaxis (PEP) ‒ Zidovudine | Lamivudine + Dolutegravir ‒ Abacavir | Lamivudine + Dolutegravir  TB/HIV Prophylaxis ─Co-trimoxazole |Isoniazid |Pyridoxine (960/300/25mg) ─ Isoniazid (INH) 300mg ─Isoniazid (INH) 100mg
  40. HIV Treatment Adherence Taking HIV medicines every day prevents HIV from multiplying, which reduces the risk that HIV will mutate and produce drug-resistant HIV. Skipping HIV medicines allows HIV to multiply, which increases the risk of Drug resistance and HIV treatment failure. Poor adherence to an HIV treatment regimen also allows HIV to destroy the Immune system. A damaged immune system makes it hard for the body to fight off infections and certain cancers.
  41. CONCLUSION ‒HIV attacks and weakens the immune system, reducing its ability to fight infection. ‒Main transmission routes are sexual, parenteral, vertical. ‒The four phases of HIV disease are acute, asymptomatic, symptomatic, and full-blown AIDS. ‒HIV is recognized mainly by testing antibodies formed to fight the virus. ‒ART can prevent OIs and slow progression of AIDS.
  42. REFERENCES National guidelines for hiv prevention treatment and care Nigeria. 2020 New Mexico AIDS Education and Training Center: "Taking Current Antiretroviral Drugs." U.S. Dept. of Health and Human Services: "Side Effects of Anti-HIV Medications." U.S. Dept. of Health and Human Services: "Enfuvirtide." World Health Organization Fact Sheet . 2020. Global Update on the Health Sector Response to HIV. Geneva World Health Organization; Joint United Nations Programme on HIV/AIDS (UNAIDS) and United Nations Children Fund (UNICEF)