Antiretroviral

Pharmacology: Chemotherapy, Anti HIV Drugs

1. ANTIRETROVIRAL DRUGS Dr. Ankita Bist Assistant professor Dept. of pharmacology

2. STRUCTURE OF HIV VIRION gp120 gp41 Gag, pol, env genes

3. ANTI-RETROVIRUS DRUGS Established targets for anti-HIV drugs : Chemokine coreceptor (CCR5) on host cells : provide anchorage for the surface proteins of the virus . Fusion of viral envelope with plasma membrane of CD4 cells : through which HIV- RNA enters the cell . HIV reverse transcriptase : Which transcripts HIV - RNA into proviral DNA . HI V - integras e : V iral en z yme which integrates th e proviral DNA into host DNA . HIV protease: Which cleaves the large virus directed polyprotein into functional viral proteins .

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5. Classes of ARV Drugs

6. Nucleoside and Nucleotide Analogs Nucleoside analogs (NRTI) act as competitive inhibitors or chain terminators at the substrate binding site of RT. The first anti-HIV drug approved was the NRTI known as AZT or Zidovudine (1987).

7. Nucleoside reverse transcriptase inhibitors (N R TI s ) T hymidine analogue (azido- thymidine, AZT), the prototype NRTI P hosphorylation in the host cell—zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase Single-stranded viral RNA Virus directed reverse transcriptase ( inhibited by zidovudine triphosphate) Double-stranded proviral DNA Resistance : point mutations

8. ZIDOVUDINE Pharmacokinetics: The oral absorption is rapid, bioavailability is ~ 65% It is quickly cleared by hepatic glucuronidation (t1 ⁄2 = 1 hr); 15–20% of the unchanged drug along with the metabolite is excreted in urine . CSF level is ~50 % of that in plasma It crosses placenta and is found in milk . AZT also reduces neurological manifestations of AIDS and new Kaposi’s lesions do not appear while on treatment with this .

9. Adverse effects: Anaemia , neutropenia . Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are common at the start of therapy, diminish later. Myopathy , pigmentation of nails, lactic acidosis, hepatomegaly , convulsions and encephalopathy - infrequent ZIDOVUDINE

10. LAMIVUDINE Inhibits HIV reverse transcriptase as well as HBV DNA polymerase Oral bioavailability is high and plasma t1⁄2 longer (6–8 hours). Synergizes with most other NRTIs for HIV & is an essential component of all first line triple drug NACO regimens . Side effects are few—fatigue, rashes , abdominal pain Pancreatitis and neuropathy are rare Hematological toxicity does not occur

11. Abacavir (ABC) A guanosine nucleoside analogue . Indicated for the therapy of HIV-1 infection in adults and children. Adverse effects: Anorexia , nausea, vomiting, malaise , headache, and insomnia. A potentially fatal hypersensitivity reaction ( approx 5% of patients ) .

12. TENOFOVIR Is the only nucleotide analogue, relatively newer . It is also active against HBV Due to good tolerability profile, it is now included in first line regimens . Renal toxicity is to be watched.

13. Non-Nucleoside reverse transcriptase inhibitors (NNRTI’s) Nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase No need for intracellular phosphorylation. Bind at the allosteric non-bonding site of RT, causing a conformational change of the active site. More potent than AZT on HIV-1, but do not inhibit HIV-2. Resistance : point mutations General ADR’s: R ashes including Stevens Johnson syndrome, elevated liver enzymes.

14. Either NVP or EFV is included in the first line triple drug regimen used by NACO. Cross- resistance between NVP and EFV is common . Enzyme inducers and Inhibitors Nevirapine (NVP) and Efavirenz (EFV)

15. Adverse effects NEVIRAPINE Rashes are the commonest , followed by nausea and headache . Occasionally severe skin reaction . P otentially hepatotoxic . EFAVIRENZ Side effects are headache, rashes, dizziness, insomnia and a variety of neuropsychiatric symptoms. Because of its longer plasma t 1⁄2 , occasional missed doses of EFV are less damaging . Teratogenic on animals .

16. P rotease inhibitors (PIs) Acts at a late step in HIV replication . Bind to the active site of protease molecule, interfere with its cleaving function . M ore effective viral inhibitors than AZT . E ffective in both newly as well as chronically infected cells . Nelfinavir , lopinavir and ritonavir induce their own meta bolism, Ritonavir used in booster dose . Also metabolism of PIs is induced by rifampicin and other enzyme inducers rendering them ineffective.

17. Most prominent adverse effects of PIs are gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes . Lipodystrophy , dyslipidaemia and insulin resistance are of particular concern . Diabetes may be exacerbated . Indinavir crystallizes in urine and increases risk of urinary calculi. P rotease inhibitors (PIs)

18. Ritonavir (RTV) Drug interactions. More commonly employed as a booster drug in a low dose. Nausea, diarrhoea , paresthesias , fatigue and lipid abnormalities are prominent . Ritonavir (RTV)

19. Entry (fusion) Inhibitor-Enfuvirtide B inds to HIV 1 envelope transmembrane glycoprotein (gp41) involved in fusion of viral and cellular membranes entry of virus into host cell is blocked Not active against HIV 2 Pharmacokinetics: Administered s.c twice daily Used as add on drug in earlier regimens Adverse reactions: Local nodule/ cyst at injection site , rash, pneumonia like sym.

20. CCR5 receptor inhibitor-Maraviroc Targets the host cell chemokine -CCR5 receptor and blocks it attachment and entry of virus is inhibited Used in highly treatment experienced patients Adverse reactions: I mpaired immune surveillance Increased risk of infection/malignancy Hepatotoxicity Skin rashes

21. Integrase inhibitor-Raltegravir HIV Integrase nicks the host chromosomal DNA and integrates the proviral DNA with it Active against both HIV 1 and 2 and causes improved CD4 cell count Uses : As a component of drug regimen along with other drugs in treatment experienced patients Adverse effect: myopathy

22. HIV treatment principles & guidelines Greater the suppression of viral replication, lesser is the chance of emergence of drug resistant virus. Monotherapy is contraindicated . HAART: highly active antiretroviral therapy with a combination of 3 or more drugs is indicated . The current NACO guidelines (2017) on when to start ART: All persons diagnosed with HIV infection should be initiated on ART regardless of the CD4 count or WHO Clinical Staging or age group or population sub-groups. Proper counselling .

23. First line therapy R egimen should have 2 NRTI+ 1NNRTI and treatment is life long . Efavirenz is indicated for patient with hepatic dysfunction and concurrently taking rifamp ic in . It is contraindicated in pregnancy . PI containing regimen: 2NRTI+PI or NRTI+NNRTI +PI ( low dose ritonavir boosted PIs are used) Development of drug toxicity: no dose reduction Either entire regimen should be interrupted Or the offending drug should be changed

24. First-line ARV Regimen guidance

25. Changing a failing regimen An ART regimen is considered to have failed when: Plasma HIV-RNA count is not rendered undectable (<50 copies/μl) with in 6 months therapy . Repeated detection of virus in plasma after initial supression to undectable levels despite continuation of drug regimen . Clinical deterioration,fall in CD4 cell count , serious opportunistic infection while continuing drug therapy .

26. Second line regimen Drugs with known overlapping viral resistance should not be used. Indinavir should not be substituted for nelfinavir or saquinavir Efavirenz should not be replaced by nevirapine Viral resistance testing is recommended for selecting the salvage regimen . A boosted PI is nearly always included .

27. List of second line regimens (NACO) NRTI component Standard regimen 1.Lopinavir 2. Atazanavir Tenofovir + Abacavir Didanosine + Abacavir Tenofovir + Zidovudine Tenofovir + Lamivudine 3.Saquinavir 4.Indinavir 5. Ne l finav i r Special circumstances Didanosine + Zidovudine Didanosine + Lamividine PI component ..

28. Third-line ART regimens Third-line regimens should include new drugs with minimal risk of cross-resistance to previously used regimens such as Integrase inhibitors and second-generation NNRTIs and PIs. Accordingly, such a regimen is Raltegravir (400 mg) + Darunavir (600 mg) + Ritonavir (100 mg); one tablet each twice daily.

29. Antiretroviral combination avoided Zidovudine + stavudine Pharmacodynamic antagonism ; inhibits phosphorylation of Stavudine Stavudine + didanosine Increased toxicity ( neuropathy , lactic acidosis ) Lamivudine + didanosine Clinically not additive

30. WHO Recommended Post exposure prophylaxis(PEP) regimens For adults and adolescents Preferred 2 NRTI Tenofovir 300mg daily ± Emtricitabine 200mg daily ± Preferred PI Lopinavir /r (400+ 100mg) or Atazanavir /r (300+ 100mg) daily Alternative 3 rd drug Darunavir /r or Raltegravir or Efavirenz For children ≤ 10 yrs Preferred 2 NRTI Zidovudine + lamivudine Preferred PI Lopinavir /r Alternative 3 rd drug Atazanavir /r or Darunavir /r or Raltegravir or Efavirenz

31. Pre exposure prophylaxis Drug regimen Tenofovir 300mg daily ± Emtricitabine 200mg daily Key risk groups Homosexual men Sex workers Injection drug users Transgender Uninfected partner of a heterosexual serodiscordant couples

32. Perinatal HIV prophylaxis : Vertical transmission: Highest rate of transmission (2/3 rd ) through placenta, during delivery or breast feeding . All HIV positive pregnant women including those presenting in labour and breast feeding should be initiated on a triple drug ART and continue lifelong ART . Nevirapine prophylaxis to HIV exposed infant: minimum 6 weeks and extended to 12 weeks, if the duration of ART in pregnant mother falls less than 4 weeks before delivery. Drugs safe in pregnancy: Zidovudine , Lamivudine , Nevirapine , Nelfinavir , Saquinavir

33. HIV / TB co-infection ART should be initiated as soon as possible in all HIV/TB- co-infected patients with active TB . If an NNRTI-based regimen is used, EFV would be the preferred drug . Except for SQV/r, PIs are not recommended during TB treatment with Rifampicin , even then Rifampicin should be substituted with Rifabutin .

34. Thank you