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PHARMACOTHERAPY OF HIV/AIDS
Dr Manjeeta Gupta
Structure of HIV
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 2
Antigenic strains : HIV-1 & HIV-2
HIV-1(virulent strain) Worldwide
HIV-2 (less virulent) West Africa
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 3
Genetic design
Life cycle of HIV
Pathophysiology
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 5
- HIV attaches to T-cells & monocytes/macrophages
- CD4 cell count ↓ --- immunodeficiency --- opportunistic infections
- Macrophages --- ↓ migration response to chemoattractants --
defective intracellular killing of organisms
- Impaired Ag presentation
- Excessive production of TNF α --- dementia, wasting,
unexplained fever
Diagnostic tests
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 6
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 7
Revised WHO clinical staging of HIV/AIDS for adults and adolescents
Prevalence
People living with HIV/AIDS in 2014 36.9 million
Women living with HIV/AIDS in 2014 51%
Children living with HIV/AIDS in 2014 2.6 million
People newly infected with HIV in 2015 2.0 million
Children newly infected with HIV in 2014 2.2 lacs
AIDS deaths in 2014 1.2 million
Child AIDS deaths in 2014 1.5 lacs
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 8
Leading cause of death
HIV + TB  leading cause of death in 2013 (13% of new TB + HIV)
The Global HIV/AIDS Epidemic Jul 31, 2015
Status of HIV epidemic in India
◦ 2.4 million (Adult prevalence -- 0.31%)
• 1986: 1st case detected in Chennai
• 1990: HIV/AIDS Cell set up by MoHFW
• 1992: NACP-I launched
• 1992: National AIDS Control Organisation (NACO)
• 1999-2006: NACP-II launched
• 2007-2012: NACP-III launched
• NACP IV (2012-2017)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 9
Declining Trends of HIV Epidemic in India
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 10
22.5 21.9 21.4 21.1 20.9
0.33
0.31
0.30 0.28 0.27
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.0
5.0
10.0
15.0
20.0
25.0
2007 2008 2009 2010 2011
AdultHIVPrevalence(%)
NumberofPLHIV(Lakhs)
Estimated Adult HIV Prevalence & Number of PLHIV, India, 2007-11
Number of PLHA (Lakhs) Adult HIV Prevalence (%) Female: 39%; Children: 7%
Technical Report India HIV Estimates 2012, NACO & NIMS
Classification of
Antiretroviral Drugs
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 11
Guidelines for starting ART
◦ All symptomatic patients
◦ Asymptomatic patients with CD4 count < 350/μl
◦ All HIV patients co-infected with HBV/HCV
◦ All pregnant HIV positive women
◦ All patients with HIV nephropathy
PLUS NACO guidelines:
◦ All HIV patients with WHO clinical stage 3-4
◦ All patients tested HIV positive 6-8 years ago
◦ History of TB/or Herpes
◦ HIV infected partners of AIDS patients
◦ All HIV positive children < 15years
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 12
HAART
◦ Highly Active Anti-Retroviral Therapy (1995)
◦ 3 ART (1 NRTI + 1 NNRTI + 1 PI with ritonavir or 2 NRTI + 1 PI with ritonavir)
Goals:
◦ Achieve virologic suppression (viral load < 50 copies/ml)
◦ Reverse decline in CD4 count
◦ Reconstitute & preserve immunologic function (↓ opportunistic infections)
◦ Improve quality of life
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 13
First line NACO recommended
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 14
Preferred regimen
Lamivudine + Zidovudine + Nevirapine
Alternative regimens
Lamivudine + Zidovudine + Efavirenz
Lamivudine + Stavudine + Efavirenz
Lamivudine + Stavudine + Nevirapine
Others
Lamivudine + Tenofovir + Nevirapine
Lamivudine + Tenofovir + Efavirenz
Lamivudine + Zidovudine + Tenofovir
Second line regimens
NRTI PI
Standard regimens
Tenofovir + Abacavir Lopinavir
Didanosine + Abacavir Atazanavir
Tenofovir + Zidovudine Saquinavir
Tenofovir + Lamivudine Indinavir
Nelfinavir
Special circumstances
Didanosine + Zidovudine
Didanosine + Lamivudine
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 15
The Value of Innovation in HIV/AIDS Therapy, Boston healthcare, Sept. 2014
NRTIs (Nucleoside reverse transcriptase inhibitors)
◦ Prevent infection of susceptible cells
◦ Phosphorylation
◦ Lack 3’ hydroxyl group
◦ Competitive inhibition
◦ Renal excretion (except AZT & ABC)
◦ ADR: Bone marrow suppression, GI
intolerance, fatigue, headache, anorexia,
insomnia, lactic acidosis, hepatic & renal
toxicity, myopathy, pancreatitis, peripheral
neuropathy
◦ Inhibit human DNA polymerase γ
◦ Less drug interactions
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 16
Pharmacotherapy of HIV
Pharmacotherapy of HIV
Pharmacotherapy of HIV
Zidovudine (AZT/ZVD) – 1st ART approved in 1987 --- BM suppression (anemia/neutropenia),
pigmentation of nails
Stavudine (d4T) -- hepatic steatosis, lipodystrophy
Didanosine (ddI) -- optic neuritis, pancreatitis, hyperuricemia
Zalcitabine (DDC) – diarrhea, stomatitis, oesophageal ulceration (Production stopped in 2006)
Lamivudine (3TC) – Least toxic, well tolerated
Emtricitabine (FTC) -- hyperpigmentation of skin
Tenofovir (TDF) -- Nucleotide analogue, Available as tenofovir disoproxil fumarate (prodrug),
Well tolerated, Flatulence (OATP drug transporter)
Abacavir (ABC) -- Fatal hypersensitivity syndrome, genetic (release of TNFα) --- Onset 1-6 weeks (2-
9%), ↑ MI episodes (alcohol dehyrogenase)
Combivir -- AZT+3TC
Trizivir -- AZT+3TC+ ABC
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 20
NNRTIs (Non Nucleoside reverse transcriptase inhibitors)
◦ Potent, highly effective
◦ Active against HIV-1
◦ Non-competitive inhibition
◦ Do not require phosphorylation
◦ No activity against host DNA polymerase
◦ Hepatic metabolism
◦ ADR: Hepatotoxic, rash, GI intolerance,
fever, headache, fatigue, somnolence
◦ Fatal: Steven’s Johnson Syndrome
◦ Long term use: fat accumulation
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 21
Pharmacotherapy of HIV
Pharmacotherapy of HIV
Nevirapine (NVP) – Maculopapular rash (1st 6 weeks), fulminant hepatitis (↑ incidence in
women with CD4 count >250), Steven’s Johnson Syndrome…extended release tablets
available
Efavirenz (EFV) – teratogenic, morbiliform rash, neuropsychiatric symptoms (seen with
1st dose)
Delavirdine (DLV) – neutropenia (not used)
Etravirine (ETV) – Newer agent (CYP3A4 inducer, CYP2C9 & CYP2C19 inhibitor)
Rilpivirine – Newer agent for HIV-1, Only for treatment naïve patients. Depression,
headache, insomnia, QTc prolongation
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 24
PIs (Protease inhibitors)
◦ Peptide-like
◦ Competitively inhibit viral aspartyl protease
◦ High inter-individual variability
◦ Highly plasma protein bound
◦ P-glycoprotein substrate, OATP drug
transporter
◦ CYP3A4 (except Nelfinavir)
◦ Potential for drug interactions
◦ ADR: GI intolerance, rash, paresthesia
◦ Long term use: lipodystrophy & insulin
resistance, ↑ TGs, ↑ cholesterol
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 25
Pharmacotherapy of HIV
Pharmacotherapy of HIV
“Boosted Ritonavir”
◦ Potent CYP3A4 inhibitor
◦ Inhibits 1st pass & systemic clearance
◦ ↑ bioavailabilty (longer T1/2)
◦ Reduces dose & frequency
◦ Overcomes deleterious effects of food on Indinavir
◦ Cannot be combined with nelfinavir
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 28
◦ Saquinavir (SQV) -- 1st PI (1995) -- Available as hard gel capsules
◦ Indinavir (IDV) -- Crystalluria, nephrolithiasis, alopecia, metallic taste, hemolytic anemia
• Nelfinavir (NFV) -- CYP2C19 (Only PI not boosted by ritonavir), Safe in pregnancy
◦ Ritonavir (RTV) – bitter taste
◦ Lopinavir (LPV) -- Only PI FDC (4:1)
◦ Atazanavir (ATV) -- unconjugated hyperbilirubinemia (inhibits hepatic glucuronyl transferase), ↑ PR
interval (1st degree heart block), ↑ bleeding episodes in hemophilics
◦ Fosamprenavir (FPV) – Prodrug, better tolerated
◦ Darunavir (DRV) -- Use only in treatment experienced patients (newer)
◦ Tipranavir (TPV) -- intracranial hemorrhages; Use only in treatment experienced patients (newer)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 29
Entry inhibitors
Enfuvirtide
Enfuvirtide (T-20) -- 2003
◦ Subcutaneous injection BD
◦ Synthetic polypeptide, binds to gp41 subunit of HIV-1 (fusion inhibitor)
◦ 84% bioavailability, 98% plasma protein bound
◦ Only in treatment experienced
◦ ADR: Local injection site reactions, rash, eosinophilia, ↑ risk of bacterial pneumonia, hypersensitivity (fatal)
Maraviroc (MVC) – 2007
CCR5 antagonist blocks binding of HIV outer envelope protein gp120 to CCR5 chemokine receptor
◦ Bioavailability 30%, 76% plasma protein bound, CYP3A4
◦ Treatment experienced CCR5-tropic MDR-HIV-1 strains
◦ ADR: Cough, fever, rash, abdominal pain, rhinitis, dizziness, sleep disorder
◦ Serious events (< 2%): hepatic failure, viral meningitis, osteonecrosis, rhabdomyelitis
◦ Lab abnormalities: ↑ bilirubin, amylase/lipase, AST/ALT
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 31
Entry inhibitors
Integrase inhibitors
Raltegravir (RAL) -- 2011
◦ Blocks catalytic activity of integrase 
prevent insertion of HIV genetic material into
host genome
◦ Biphasic elimination, Glucuroidation (UGT1A1)
◦ 83% plasma protein bound
◦ Antacids & iron bind to integrase (2 hrs dose
interval)
◦ Adverse Events: GI intolerance, fever,
headache, creatine kinase elevation
(myopathy, rhabdomyolysis), exacerbation of
depression
◦ Treatment experienced patients
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 32
Elvitegravir (2012)
◦ Available only as FDC (cobicistat, emtricitabine, tenofovir)  requires boosting cobicistat (PK enhancer,
inhibits CYP3A4 & intestinal transport proteins) or ritonavir
◦ C/I in renal disorder
Dolutegravir (2013)
◦ Retains activity against virus resistant to raltegravir & elvitegravir for HIV-1
◦ UGT1A1 & CYP3A
◦ Inhibits renal organic cation transporter (OCT2)
◦ > 12yrs
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 33
Maturation Inhibitors
Bevirimat (Phase III)
◦ Semisynthetic derivative of Chinese herb (syzigium claviflorum)
◦ Inhibits viral maturation – released viruses cannot infect other host cells
◦ Well tolerated (nausea, headache)
◦ Glucuronidation
◦ Cross resistance with PI
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 35
Azithromycin “Off-label”
◦ Prevent: Disseminated MAC  primary & secondary prophylaxis, syphilis
◦ Treat: toxoplasmosis, MAC, bacterial enteric infections (campylobacteriosis, shigellosis), bacteremia, osteomyelitis,
syphilis
Foscarnet
◦ Inhibits HIV reverse transcriptase
◦ In resistant cases, markedly ↓ plasma HIV load & improves immunological status
◦ Foscarnet induction therapy – 5 g iv BD for 6 weeks + antiretroviral regimen
Hydroxyurea
◦ 1st ART targeting cellular factor (novel, inexpensive HIV combination therapy)
◦ Resistance resistant (impedes resistance to NRTIs)
◦ Cytostatic, immunomodulatory effects -- reduce activated HIV target cells (long-term treatment)
◦ Hydroxyurea-based regimens  Effective, potent (sustained viral suppresion), well tolerated in primary & chronic HIV
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 36
Post Exposure Prophylaxis (PEP)
◦ Initiate as soon as possible
◦ 2 drug regime (low risk): 3TC (150 mg) + AZT (300 mg) BD for 4 weeks
◦ Expanded 3 drug regime (high risk): Above + IDV/r 800 mg TDS* 4 weeks
◦ Serology: 0, 6, 12 weeks, 6, 12 months
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 37
Pregnancy
◦ 2nd trimester
◦ AZT (300 mg) + 3TC (150 mg) + NFV (1250 mg) BD
◦ Efavirenz – teratogenic
◦ Nevirapine - ↑ hepatotoxicity in CD4 > 250
Perinatal prophylaxis
◦ Intra-partum: AZT 2 mg/kg; 1 mg/kg/hr until delivery
◦ Post-partum: (Infant) AZT syrup 2 mg/kg QID or 1.5 mg/kg IV QID for 6 weeks
◦ Single dose of NVP (200 mg) --- onset of delivery + neonate within 1st 3 days (2 mg/kg)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 38
Pocket Guide Adult HIV/AIDS Treatment January 2006
Hepatitis Co-infection
HBV
◦ Tenofovir, Lamivudine (LMV), Emtricitabine (FTC)
◦ Hepatocellular inflammation “Flares”  LMV or FTC + entecavir
◦ In early HIV, treat HBV only: adefovir/entecavir
HCV
◦ ART excluding didanosine with ribavirin
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 39
Opportunistic infections
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 40
TB (latent) > 5mm INH 300 mg//day + pyridoxine 50 mg/day
PCP CD4 < 200/mm3 or CD4% <14, oral thrush TMP-SMX 1 tab/day
Toxoplasmosis CD4 < 100/mm3 + anti-Tox IgG TMP-SMX 1 tab/day
MAC CD4 < 50/mm3 Azithromycin 1200 mg/wk Clarithromycin
500 mg BD
Varicella Exposure to chickenpox/zoster VZIG 6.25 mL IM < 96 hr
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 41
Pneumocystis carinii pneumonia
Acute therapy
◦ TMP-SMX 15-20 mg/kg/day IV for 21 days
Chronic maintenance therapy
◦ TMP-SMX
◦ Alternative: Dapsone 100 mg/day
◦ Dapsone 50 mg/day + pyrimethamine 50 mg + leucovorin 25 mg/wk
◦ Dapsone 200 mg + pyremethamine 75 mg + leucovorin 25 mg/wk
◦ Pentamidine aerosol 300 mg/month
◦ Atovaquone 1500 mg/day
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 42
Toxoplasma gondii Encephalitis
Acute therapy: Pyrimethamine 200 mg, then
50 mg (< 60 kg)/day + sulfadiazine
1,000 (<60 kg) QID + leucovorin
10-20 mg/day
Disseminated Mycobacterium Avium Complex Disease (MAC)
At least 2 drugs as initial therapy
◦ Clarithromycin 500 mg BD + Ethionamide 15 mg/kg/day
◦ Consider adding a 3rd agent (CD4 < 50, high mycobacterial load, absence of ART); Rifabutin 300 mg/day
◦ Chronic maintenance therapy
◦ Clarithromycin 500 mg BD + Ethionamide 15 mg/kg/day +/- Rifabutin 300 mg/day lifelong until sustained
immunity
Cryptosporidiosis
Acute therapy
◦ Amphotericin B 0.7 mg/kg/day IV + Flucytosine 25 mg/kg QID for 2 weeks followed by fluconazole 400
mg/day for 8 weeks/until CSF sterile
◦ Chronic maintenance therapy
◦ Fluconazole 200 mg/day
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 43
Immune Reconstitution Inflammatory
Syndrome (IRIS)
◦ Initiation therapy with low CD4 or advancing disease
◦ Associated with better virological response to therapy Paradoxical worsening
◦ Onset: <1 week to years
◦ Incidence: 10-25%
◦ Implicating pathogens: TB, other mycobacterial diseases, cryptococcosis, HBV, HCV,
Pneumocystis pneumonia
◦ Symptomatic relief
◦ Defer ART 1-3 weeks (depending on CD4 count)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 44
CID 2004;38:1159-66
Salvage Therapy
◦ Treatment interruptions
◦ Multi-drug Rescue
◦ Drug selection based on past exposure & resistance, treatment failure
◦ Foscarnet induction
◦ Mega-HAART
◦ Typically 5-9 drugs
◦ Boosted PI
◦ 1-2 NNRTIs
◦ Several NRTIs
◦ Hydroxyurea
◦ Adherence > 95% required
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 45
3rd International Workshop on Salvage Therapy for HIV infection HIV/AIDS eJournal 6(3),2000
Investigational Agents
NRTIs
◦ Apricitabine
◦ KP-1461
◦ Stampidine
◦ Racivir
◦ Fozivudine tidoxil
NNRTIs
◦ Elvucitabine (Phase III)
◦ Capravirine (Phase II)
◦ Lersivirine
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 46
aidsinfo.nih.gov
Entry Inhibitors
◦ Vicriviroc (Phase III)
◦ Cicriviroc
◦ Apraviroc (Banned)
◦ AMDO70
◦ PRO 140
◦ Peptide T
◦ Ibalizumab
◦ BMS-488043
◦ PRO 542
Integrase Inhibitors
– GS 9137
Recent advances
◦ Gene modification
◦ Tesamorelin (INN) -- synthetic GHRH, used in HIV-associated lipodystrophy (↓ excess abdominal fat)
◦ Portmanteau inhibitor -- combination of 2 drugs, each being type of inhibitor (reverse transcriptase inhibitor +
integrase inhibitor) & (integrase inhibitor + CCR5 entry inhibitor– 2011)
◦ Vaccines -- Viral gp120--RV 144 (Phase I/II), Live vector viruses– Adeno V520 (Phase II), pure gp120 protein +
killed canary pox (Phase II)
◦ Vaginal rings (contraception + anti- HIV property)
◦ 1% Tenofovir vaginal gels (↓ risk of HSV-2 -----↓ risk of HIV)
◦ Pre-exposure prophylaxis (PrEP) -- FDC tenofovir disoproxil fumarate 300 mg + emtricitabine 200 mg (High risk)
◦ Combination pills
Tenof-EM -- FTC + TDF (1 tablet OD)
Trustiva -- EFV + FTC + TDF (1st 3-drug combination – July 2006) (1 tablet OD)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 48
Crofelemer
- Oral proanthocyanidine oligomer  relieves symptoms of diarrhea in HIV/AIDS in patients on ART.
- It acts by voltage independently blocking 2 structurally unrelated chloride channels in the gut (CFTR – cystic fibrosis
transmembrane conductance regulator) and calcium activated channel anoctamin 1.
- Inhibition  few chloride ions excreted in gut  ↓ Na & H2O  improve stool consistency  ↓ duration of
diarrhoea
- Not absorbed in the gut……excreted with stool.
Somatrem and Somatropin
- Recombinant growth hormone for AIDS related wasting
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 49
India’s AIDS programme disintegrating?
◦ NACP-IV (2012-17)--- World Bank funded $250 million
◦ Supply of antiretroviral drugs, erratic since December 2013. Without replenishments,
stocks depleted rapidly in 2014, eventually resulting in empty shelves from January.
Over last 9 months, every ART centre in country has run out of at least 1 drug for
several weeks. (Feb 2015)
http://www.livemint.com/Politics/n2svOmWwLqMsZuViMKwHmJ/IsIndiasAIDSprogrammedisintegrating
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 51
Is HIV curable?
◦ Homozygous CCR5 allele  inactive CCR5 gene product --- high
resistance against HIV1
◦ In 40 year patient with AML (1998), allogeneic stem cell transplantation from
HLA matched donor --- complete chimerism -- non–CCR5tropic variant ----
discontinuation of HAART ≥ 20 months, HIV1 virus remained undetected
◦ Central role of CCR5 receptor during HIV1 infection & disease progression
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 52
Long Term Control of HIV by CCR5 Delta32/Delta32 Stem Cell Transplantation — NEJM
◦ Mississippi baby (2010) – HIV at birth from HIV-positive mother, In 2013
thought to be cured of HIV -------- July 10, 2014
◦ Timothy Ray Brown, The Berlin patient, first and only person 'cured' of HIV-
--stem cell transplant from a donor naturally resistant, off antiretroviral
therapy since 1st day of his stem cell transplant (2008)
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 53
nejm.org february 13, 2014
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 54
References
◦ Goodman Gillman 12th edition
◦ Katzung 13th edition
◦ Rang and Dale 7th edition
◦ KD Tripathi 7th editon
◦ KK Sharma 2nd edition
◦ NACO Annual Report 2014-15 (www.naco.gov.in)
◦ WHO-UNAIDS Report 2014-15. (www.unaids.org)
◦ Interim who clinical staging of hiv/aids and hiv/aids case definitions for surveillance.
◦ http://aidsinfo.nih.gov/guidelines on 9/14/2015
16-09-2015
MIMER Medical College Talegaon
Department of Pharmacology 55

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Pharmacotherapy of HIV

  • 2. Structure of HIV 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 2 Antigenic strains : HIV-1 & HIV-2 HIV-1(virulent strain) Worldwide HIV-2 (less virulent) West Africa
  • 3. 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 3 Genetic design
  • 5. Pathophysiology 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 5 - HIV attaches to T-cells & monocytes/macrophages - CD4 cell count ↓ --- immunodeficiency --- opportunistic infections - Macrophages --- ↓ migration response to chemoattractants -- defective intracellular killing of organisms - Impaired Ag presentation - Excessive production of TNF α --- dementia, wasting, unexplained fever
  • 6. Diagnostic tests 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 6
  • 7. 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 7 Revised WHO clinical staging of HIV/AIDS for adults and adolescents
  • 8. Prevalence People living with HIV/AIDS in 2014 36.9 million Women living with HIV/AIDS in 2014 51% Children living with HIV/AIDS in 2014 2.6 million People newly infected with HIV in 2015 2.0 million Children newly infected with HIV in 2014 2.2 lacs AIDS deaths in 2014 1.2 million Child AIDS deaths in 2014 1.5 lacs 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 8 Leading cause of death HIV + TB  leading cause of death in 2013 (13% of new TB + HIV) The Global HIV/AIDS Epidemic Jul 31, 2015
  • 9. Status of HIV epidemic in India ◦ 2.4 million (Adult prevalence -- 0.31%) • 1986: 1st case detected in Chennai • 1990: HIV/AIDS Cell set up by MoHFW • 1992: NACP-I launched • 1992: National AIDS Control Organisation (NACO) • 1999-2006: NACP-II launched • 2007-2012: NACP-III launched • NACP IV (2012-2017) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 9
  • 10. Declining Trends of HIV Epidemic in India 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 10 22.5 21.9 21.4 21.1 20.9 0.33 0.31 0.30 0.28 0.27 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.0 5.0 10.0 15.0 20.0 25.0 2007 2008 2009 2010 2011 AdultHIVPrevalence(%) NumberofPLHIV(Lakhs) Estimated Adult HIV Prevalence & Number of PLHIV, India, 2007-11 Number of PLHA (Lakhs) Adult HIV Prevalence (%) Female: 39%; Children: 7% Technical Report India HIV Estimates 2012, NACO & NIMS
  • 11. Classification of Antiretroviral Drugs 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 11
  • 12. Guidelines for starting ART ◦ All symptomatic patients ◦ Asymptomatic patients with CD4 count < 350/μl ◦ All HIV patients co-infected with HBV/HCV ◦ All pregnant HIV positive women ◦ All patients with HIV nephropathy PLUS NACO guidelines: ◦ All HIV patients with WHO clinical stage 3-4 ◦ All patients tested HIV positive 6-8 years ago ◦ History of TB/or Herpes ◦ HIV infected partners of AIDS patients ◦ All HIV positive children < 15years 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 12
  • 13. HAART ◦ Highly Active Anti-Retroviral Therapy (1995) ◦ 3 ART (1 NRTI + 1 NNRTI + 1 PI with ritonavir or 2 NRTI + 1 PI with ritonavir) Goals: ◦ Achieve virologic suppression (viral load < 50 copies/ml) ◦ Reverse decline in CD4 count ◦ Reconstitute & preserve immunologic function (↓ opportunistic infections) ◦ Improve quality of life 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 13
  • 14. First line NACO recommended 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 14 Preferred regimen Lamivudine + Zidovudine + Nevirapine Alternative regimens Lamivudine + Zidovudine + Efavirenz Lamivudine + Stavudine + Efavirenz Lamivudine + Stavudine + Nevirapine Others Lamivudine + Tenofovir + Nevirapine Lamivudine + Tenofovir + Efavirenz Lamivudine + Zidovudine + Tenofovir Second line regimens NRTI PI Standard regimens Tenofovir + Abacavir Lopinavir Didanosine + Abacavir Atazanavir Tenofovir + Zidovudine Saquinavir Tenofovir + Lamivudine Indinavir Nelfinavir Special circumstances Didanosine + Zidovudine Didanosine + Lamivudine
  • 15. 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 15 The Value of Innovation in HIV/AIDS Therapy, Boston healthcare, Sept. 2014
  • 16. NRTIs (Nucleoside reverse transcriptase inhibitors) ◦ Prevent infection of susceptible cells ◦ Phosphorylation ◦ Lack 3’ hydroxyl group ◦ Competitive inhibition ◦ Renal excretion (except AZT & ABC) ◦ ADR: Bone marrow suppression, GI intolerance, fatigue, headache, anorexia, insomnia, lactic acidosis, hepatic & renal toxicity, myopathy, pancreatitis, peripheral neuropathy ◦ Inhibit human DNA polymerase γ ◦ Less drug interactions 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 16
  • 20. Zidovudine (AZT/ZVD) – 1st ART approved in 1987 --- BM suppression (anemia/neutropenia), pigmentation of nails Stavudine (d4T) -- hepatic steatosis, lipodystrophy Didanosine (ddI) -- optic neuritis, pancreatitis, hyperuricemia Zalcitabine (DDC) – diarrhea, stomatitis, oesophageal ulceration (Production stopped in 2006) Lamivudine (3TC) – Least toxic, well tolerated Emtricitabine (FTC) -- hyperpigmentation of skin Tenofovir (TDF) -- Nucleotide analogue, Available as tenofovir disoproxil fumarate (prodrug), Well tolerated, Flatulence (OATP drug transporter) Abacavir (ABC) -- Fatal hypersensitivity syndrome, genetic (release of TNFα) --- Onset 1-6 weeks (2- 9%), ↑ MI episodes (alcohol dehyrogenase) Combivir -- AZT+3TC Trizivir -- AZT+3TC+ ABC 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 20
  • 21. NNRTIs (Non Nucleoside reverse transcriptase inhibitors) ◦ Potent, highly effective ◦ Active against HIV-1 ◦ Non-competitive inhibition ◦ Do not require phosphorylation ◦ No activity against host DNA polymerase ◦ Hepatic metabolism ◦ ADR: Hepatotoxic, rash, GI intolerance, fever, headache, fatigue, somnolence ◦ Fatal: Steven’s Johnson Syndrome ◦ Long term use: fat accumulation 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 21
  • 24. Nevirapine (NVP) – Maculopapular rash (1st 6 weeks), fulminant hepatitis (↑ incidence in women with CD4 count >250), Steven’s Johnson Syndrome…extended release tablets available Efavirenz (EFV) – teratogenic, morbiliform rash, neuropsychiatric symptoms (seen with 1st dose) Delavirdine (DLV) – neutropenia (not used) Etravirine (ETV) – Newer agent (CYP3A4 inducer, CYP2C9 & CYP2C19 inhibitor) Rilpivirine – Newer agent for HIV-1, Only for treatment naïve patients. Depression, headache, insomnia, QTc prolongation 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 24
  • 25. PIs (Protease inhibitors) ◦ Peptide-like ◦ Competitively inhibit viral aspartyl protease ◦ High inter-individual variability ◦ Highly plasma protein bound ◦ P-glycoprotein substrate, OATP drug transporter ◦ CYP3A4 (except Nelfinavir) ◦ Potential for drug interactions ◦ ADR: GI intolerance, rash, paresthesia ◦ Long term use: lipodystrophy & insulin resistance, ↑ TGs, ↑ cholesterol 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 25
  • 28. “Boosted Ritonavir” ◦ Potent CYP3A4 inhibitor ◦ Inhibits 1st pass & systemic clearance ◦ ↑ bioavailabilty (longer T1/2) ◦ Reduces dose & frequency ◦ Overcomes deleterious effects of food on Indinavir ◦ Cannot be combined with nelfinavir 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 28
  • 29. ◦ Saquinavir (SQV) -- 1st PI (1995) -- Available as hard gel capsules ◦ Indinavir (IDV) -- Crystalluria, nephrolithiasis, alopecia, metallic taste, hemolytic anemia • Nelfinavir (NFV) -- CYP2C19 (Only PI not boosted by ritonavir), Safe in pregnancy ◦ Ritonavir (RTV) – bitter taste ◦ Lopinavir (LPV) -- Only PI FDC (4:1) ◦ Atazanavir (ATV) -- unconjugated hyperbilirubinemia (inhibits hepatic glucuronyl transferase), ↑ PR interval (1st degree heart block), ↑ bleeding episodes in hemophilics ◦ Fosamprenavir (FPV) – Prodrug, better tolerated ◦ Darunavir (DRV) -- Use only in treatment experienced patients (newer) ◦ Tipranavir (TPV) -- intracranial hemorrhages; Use only in treatment experienced patients (newer) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 29
  • 31. Enfuvirtide (T-20) -- 2003 ◦ Subcutaneous injection BD ◦ Synthetic polypeptide, binds to gp41 subunit of HIV-1 (fusion inhibitor) ◦ 84% bioavailability, 98% plasma protein bound ◦ Only in treatment experienced ◦ ADR: Local injection site reactions, rash, eosinophilia, ↑ risk of bacterial pneumonia, hypersensitivity (fatal) Maraviroc (MVC) – 2007 CCR5 antagonist blocks binding of HIV outer envelope protein gp120 to CCR5 chemokine receptor ◦ Bioavailability 30%, 76% plasma protein bound, CYP3A4 ◦ Treatment experienced CCR5-tropic MDR-HIV-1 strains ◦ ADR: Cough, fever, rash, abdominal pain, rhinitis, dizziness, sleep disorder ◦ Serious events (< 2%): hepatic failure, viral meningitis, osteonecrosis, rhabdomyelitis ◦ Lab abnormalities: ↑ bilirubin, amylase/lipase, AST/ALT 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 31 Entry inhibitors
  • 32. Integrase inhibitors Raltegravir (RAL) -- 2011 ◦ Blocks catalytic activity of integrase  prevent insertion of HIV genetic material into host genome ◦ Biphasic elimination, Glucuroidation (UGT1A1) ◦ 83% plasma protein bound ◦ Antacids & iron bind to integrase (2 hrs dose interval) ◦ Adverse Events: GI intolerance, fever, headache, creatine kinase elevation (myopathy, rhabdomyolysis), exacerbation of depression ◦ Treatment experienced patients 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 32
  • 33. Elvitegravir (2012) ◦ Available only as FDC (cobicistat, emtricitabine, tenofovir)  requires boosting cobicistat (PK enhancer, inhibits CYP3A4 & intestinal transport proteins) or ritonavir ◦ C/I in renal disorder Dolutegravir (2013) ◦ Retains activity against virus resistant to raltegravir & elvitegravir for HIV-1 ◦ UGT1A1 & CYP3A ◦ Inhibits renal organic cation transporter (OCT2) ◦ > 12yrs 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 33
  • 34. Maturation Inhibitors Bevirimat (Phase III) ◦ Semisynthetic derivative of Chinese herb (syzigium claviflorum) ◦ Inhibits viral maturation – released viruses cannot infect other host cells ◦ Well tolerated (nausea, headache) ◦ Glucuronidation ◦ Cross resistance with PI 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 35
  • 35. Azithromycin “Off-label” ◦ Prevent: Disseminated MAC  primary & secondary prophylaxis, syphilis ◦ Treat: toxoplasmosis, MAC, bacterial enteric infections (campylobacteriosis, shigellosis), bacteremia, osteomyelitis, syphilis Foscarnet ◦ Inhibits HIV reverse transcriptase ◦ In resistant cases, markedly ↓ plasma HIV load & improves immunological status ◦ Foscarnet induction therapy – 5 g iv BD for 6 weeks + antiretroviral regimen Hydroxyurea ◦ 1st ART targeting cellular factor (novel, inexpensive HIV combination therapy) ◦ Resistance resistant (impedes resistance to NRTIs) ◦ Cytostatic, immunomodulatory effects -- reduce activated HIV target cells (long-term treatment) ◦ Hydroxyurea-based regimens  Effective, potent (sustained viral suppresion), well tolerated in primary & chronic HIV 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 36
  • 36. Post Exposure Prophylaxis (PEP) ◦ Initiate as soon as possible ◦ 2 drug regime (low risk): 3TC (150 mg) + AZT (300 mg) BD for 4 weeks ◦ Expanded 3 drug regime (high risk): Above + IDV/r 800 mg TDS* 4 weeks ◦ Serology: 0, 6, 12 weeks, 6, 12 months 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 37
  • 37. Pregnancy ◦ 2nd trimester ◦ AZT (300 mg) + 3TC (150 mg) + NFV (1250 mg) BD ◦ Efavirenz – teratogenic ◦ Nevirapine - ↑ hepatotoxicity in CD4 > 250 Perinatal prophylaxis ◦ Intra-partum: AZT 2 mg/kg; 1 mg/kg/hr until delivery ◦ Post-partum: (Infant) AZT syrup 2 mg/kg QID or 1.5 mg/kg IV QID for 6 weeks ◦ Single dose of NVP (200 mg) --- onset of delivery + neonate within 1st 3 days (2 mg/kg) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 38 Pocket Guide Adult HIV/AIDS Treatment January 2006
  • 38. Hepatitis Co-infection HBV ◦ Tenofovir, Lamivudine (LMV), Emtricitabine (FTC) ◦ Hepatocellular inflammation “Flares”  LMV or FTC + entecavir ◦ In early HIV, treat HBV only: adefovir/entecavir HCV ◦ ART excluding didanosine with ribavirin 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 39
  • 39. Opportunistic infections 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 40 TB (latent) > 5mm INH 300 mg//day + pyridoxine 50 mg/day PCP CD4 < 200/mm3 or CD4% <14, oral thrush TMP-SMX 1 tab/day Toxoplasmosis CD4 < 100/mm3 + anti-Tox IgG TMP-SMX 1 tab/day MAC CD4 < 50/mm3 Azithromycin 1200 mg/wk Clarithromycin 500 mg BD Varicella Exposure to chickenpox/zoster VZIG 6.25 mL IM < 96 hr
  • 40. 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 41
  • 41. Pneumocystis carinii pneumonia Acute therapy ◦ TMP-SMX 15-20 mg/kg/day IV for 21 days Chronic maintenance therapy ◦ TMP-SMX ◦ Alternative: Dapsone 100 mg/day ◦ Dapsone 50 mg/day + pyrimethamine 50 mg + leucovorin 25 mg/wk ◦ Dapsone 200 mg + pyremethamine 75 mg + leucovorin 25 mg/wk ◦ Pentamidine aerosol 300 mg/month ◦ Atovaquone 1500 mg/day 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 42 Toxoplasma gondii Encephalitis Acute therapy: Pyrimethamine 200 mg, then 50 mg (< 60 kg)/day + sulfadiazine 1,000 (<60 kg) QID + leucovorin 10-20 mg/day
  • 42. Disseminated Mycobacterium Avium Complex Disease (MAC) At least 2 drugs as initial therapy ◦ Clarithromycin 500 mg BD + Ethionamide 15 mg/kg/day ◦ Consider adding a 3rd agent (CD4 < 50, high mycobacterial load, absence of ART); Rifabutin 300 mg/day ◦ Chronic maintenance therapy ◦ Clarithromycin 500 mg BD + Ethionamide 15 mg/kg/day +/- Rifabutin 300 mg/day lifelong until sustained immunity Cryptosporidiosis Acute therapy ◦ Amphotericin B 0.7 mg/kg/day IV + Flucytosine 25 mg/kg QID for 2 weeks followed by fluconazole 400 mg/day for 8 weeks/until CSF sterile ◦ Chronic maintenance therapy ◦ Fluconazole 200 mg/day 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 43
  • 43. Immune Reconstitution Inflammatory Syndrome (IRIS) ◦ Initiation therapy with low CD4 or advancing disease ◦ Associated with better virological response to therapy Paradoxical worsening ◦ Onset: <1 week to years ◦ Incidence: 10-25% ◦ Implicating pathogens: TB, other mycobacterial diseases, cryptococcosis, HBV, HCV, Pneumocystis pneumonia ◦ Symptomatic relief ◦ Defer ART 1-3 weeks (depending on CD4 count) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 44 CID 2004;38:1159-66
  • 44. Salvage Therapy ◦ Treatment interruptions ◦ Multi-drug Rescue ◦ Drug selection based on past exposure & resistance, treatment failure ◦ Foscarnet induction ◦ Mega-HAART ◦ Typically 5-9 drugs ◦ Boosted PI ◦ 1-2 NNRTIs ◦ Several NRTIs ◦ Hydroxyurea ◦ Adherence > 95% required 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 45 3rd International Workshop on Salvage Therapy for HIV infection HIV/AIDS eJournal 6(3),2000
  • 45. Investigational Agents NRTIs ◦ Apricitabine ◦ KP-1461 ◦ Stampidine ◦ Racivir ◦ Fozivudine tidoxil NNRTIs ◦ Elvucitabine (Phase III) ◦ Capravirine (Phase II) ◦ Lersivirine 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 46 aidsinfo.nih.gov Entry Inhibitors ◦ Vicriviroc (Phase III) ◦ Cicriviroc ◦ Apraviroc (Banned) ◦ AMDO70 ◦ PRO 140 ◦ Peptide T ◦ Ibalizumab ◦ BMS-488043 ◦ PRO 542 Integrase Inhibitors – GS 9137
  • 46. Recent advances ◦ Gene modification ◦ Tesamorelin (INN) -- synthetic GHRH, used in HIV-associated lipodystrophy (↓ excess abdominal fat) ◦ Portmanteau inhibitor -- combination of 2 drugs, each being type of inhibitor (reverse transcriptase inhibitor + integrase inhibitor) & (integrase inhibitor + CCR5 entry inhibitor– 2011) ◦ Vaccines -- Viral gp120--RV 144 (Phase I/II), Live vector viruses– Adeno V520 (Phase II), pure gp120 protein + killed canary pox (Phase II) ◦ Vaginal rings (contraception + anti- HIV property) ◦ 1% Tenofovir vaginal gels (↓ risk of HSV-2 -----↓ risk of HIV) ◦ Pre-exposure prophylaxis (PrEP) -- FDC tenofovir disoproxil fumarate 300 mg + emtricitabine 200 mg (High risk) ◦ Combination pills Tenof-EM -- FTC + TDF (1 tablet OD) Trustiva -- EFV + FTC + TDF (1st 3-drug combination – July 2006) (1 tablet OD) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 48
  • 47. Crofelemer - Oral proanthocyanidine oligomer  relieves symptoms of diarrhea in HIV/AIDS in patients on ART. - It acts by voltage independently blocking 2 structurally unrelated chloride channels in the gut (CFTR – cystic fibrosis transmembrane conductance regulator) and calcium activated channel anoctamin 1. - Inhibition  few chloride ions excreted in gut  ↓ Na & H2O  improve stool consistency  ↓ duration of diarrhoea - Not absorbed in the gut……excreted with stool. Somatrem and Somatropin - Recombinant growth hormone for AIDS related wasting 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 49
  • 48. India’s AIDS programme disintegrating? ◦ NACP-IV (2012-17)--- World Bank funded $250 million ◦ Supply of antiretroviral drugs, erratic since December 2013. Without replenishments, stocks depleted rapidly in 2014, eventually resulting in empty shelves from January. Over last 9 months, every ART centre in country has run out of at least 1 drug for several weeks. (Feb 2015) http://www.livemint.com/Politics/n2svOmWwLqMsZuViMKwHmJ/IsIndiasAIDSprogrammedisintegrating 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 51
  • 49. Is HIV curable? ◦ Homozygous CCR5 allele  inactive CCR5 gene product --- high resistance against HIV1 ◦ In 40 year patient with AML (1998), allogeneic stem cell transplantation from HLA matched donor --- complete chimerism -- non–CCR5tropic variant ---- discontinuation of HAART ≥ 20 months, HIV1 virus remained undetected ◦ Central role of CCR5 receptor during HIV1 infection & disease progression 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 52 Long Term Control of HIV by CCR5 Delta32/Delta32 Stem Cell Transplantation — NEJM
  • 50. ◦ Mississippi baby (2010) – HIV at birth from HIV-positive mother, In 2013 thought to be cured of HIV -------- July 10, 2014 ◦ Timothy Ray Brown, The Berlin patient, first and only person 'cured' of HIV- --stem cell transplant from a donor naturally resistant, off antiretroviral therapy since 1st day of his stem cell transplant (2008) 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 53 nejm.org february 13, 2014
  • 51. 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 54
  • 52. References ◦ Goodman Gillman 12th edition ◦ Katzung 13th edition ◦ Rang and Dale 7th edition ◦ KD Tripathi 7th editon ◦ KK Sharma 2nd edition ◦ NACO Annual Report 2014-15 (www.naco.gov.in) ◦ WHO-UNAIDS Report 2014-15. (www.unaids.org) ◦ Interim who clinical staging of hiv/aids and hiv/aids case definitions for surveillance. ◦ http://aidsinfo.nih.gov/guidelines on 9/14/2015 16-09-2015 MIMER Medical College Talegaon Department of Pharmacology 55

Hinweis der Redaktion

  1. Each virion expresses 72 glycoprotein projections composed of gp120 and gp41-----viral envelope derives from host cell and contains some host-cell membrane proteins, including class I and class II MHC molecules Within envelope is viral core, or nucleocapsid, which includes a layer of a protein called p17 and an inner layer of a protein called p24. Genome consists of two copies of single-stranded RNA, which are associated with two molecules of reverse transcriptase (p64) and nucleoid proteins p10, a protease, and p32, an integrase.
  2. M-tropic, binds to CD4 T helper cells & CCR5 of macrophage T-tropic viruses infect T cells by binding with CD4 & CXCR4 Genes essential for viral replication: tat: activates transcription, rev: export of unspliced & singly spliced mRNAs from nucleus LTR sequence: promoter & enhancer elements Genes not essential for viral replication: vif: promotes maturation & infectivity nef (negative factor): Downregulates host-cell class I MHC & CD4 vpr, vpx & vpu
  3. Robert Gallo, co-discoverer of HIV
  4. no. 1 in Africa…….has become chronic disease like DM, HTN Women  51% (leading cause of death in reproductive age) Global prevalence rate (% of people ages 15-49 who are infected) was 0.8% in 2014 New infections, increase life expectancy with HIV, population growth HIV has led to a resurgence of TB
  5. World’s 3rd highest population with HIV (Maharashtra is 40%) 1959…..first case in Congo to have AIDS. National health policies…..National AIDS Control Programme  The four high prevalence states of South India (Andhra Pradesh – 500,000, Maharashtra – 420,000, Karnataka – 250,000, Tamil Nadu – 150,000) account for 55% of all HIV infections in the country. West Bengal, Gujarat, Bihar and Uttar Pradesh are estimated to have more than 100,000 PLHA each and together account for another 22% of HIV infections in India.
  6. Treatment naïve  3 drugs Treatment failure  4 or more drugs The increased cost of earlier ART would be partly offset by subsequent reduced costs (such as decreased hospitalization and increased productivity) and preventing new HIV infections.
  7. Do not eradicate virus from cells that already harbour integrated proviral DNA. Renal excretion (except AZT & ABC-----hepatic glucuronidation) Intracellular T1/2 – 2-50 hrs----active anabolites----less frequent dosing
  8. 1st two compete for the same metabolic pathway of virus…..never combine (Thymidine analogue) purple  peripheral neuropathy + pancreatitis Blue  used in HBV infection 1. prototype. Competitively inhibits viral reverse transcriptase and terminates chain prolongation (ziduvodine triphosphate) Active against HIV1, HIV2, HTLV1 & 2 Prevents infection of new cells. 65% bioavailabilty, hepatic glucoridation, plasma protein binding 30% and in CSF conc. is 50%. Toxicity due to partial inhibition of cellular mitochondrial DNA polymerase gamma…..has high affinity for zidovudine triphosphate. 3. Adenosine analogue….enteric coated capsules……as acid liable…..not routinely used due to toxicity Conversion to didanosine triphosphate….. Competes with ATP incorporation into viral DNA, inhibit viral reverse transcriptase & terminates proviral DNA. Ganciclovir, tenofovir & allopurinol increases whereas methadone decreases its AUC. The combination of didanosine and hydroxyurea was used to exploit a beneficial interaction that creates a favorable intracellular ratio of concentrations of dideoxyadenosine 5'-triphosphate to deoxythymidine 5'-triphosphate. Although this combination may boost didanosine antiviral activity modestly, it also increases toxicity, producing peripheral neuropathy and fatal pancreatitis, and should be avoided. 4. Cytidine analogue 5. Deoxycytidine analogue…..inhibits reverse transcriptase & HBV DNA polymerase…..chain termination High bioavailability (80%), cotrimoxazole inhibits its renal elimination……..First line drug for HBV and HIV Stavudine & ziduovudine & ribavirin…. Mutual anatagonism (inhibit phosphorylation). DI with paracetamol…glucuronidation……..Nelfinavir decrease plasma levels…..Probenecid, fluconazole & lamivudine increase plasma levels 6. hyperpigmentation of skin 7. Only nucleoside….relatively newer….active against HBV…bioavailability 25% Hydrolysed followed by phosphorylation to tenofovir diphosphate…..which is active unlike others (active form is triphosphate) First line 3 drug regime as an alternative Avoid combination: ddI…….increases ddI conc. 8. Guanosine analogue Carbovir triphosphate…..resistance develops slowly, low cross resistance 80% bioavailability….well tolerated genetic…..one of the strongest pharmacogenetic associations ever described Metabolised by alcohol dehydrogenase partly…..alcohol increases its plasma levels
  9. Causes conformational change-----decreases activity…..binding site specific…..virus strain specific…HIV-1 Potent & highly effective agents PI & NNRTI  inducers/inhibitors of CYPs/other enzymes/transport protein
  10. 1. 200 mg OD x 14 days then 200 mg BD….autoinduction Bioavailability 95% Hepatitis within first 6 weeks…regular LFT 2. CNS disorder  vivid dreams, dizziness, headache, loss of concentration……. Bioavailability 50%....self inducer……high fat meal ↑ by 39 & 79% …..> 90% protein bound----Rash….discontinuation not required unless blistering and desquamation present (1.7%). Onset ~ 11 days, duration ~ 14 days. CNS……usually subside 2-4 weeks following initiation) 3. 100 mg tabs in > 3oz water to make slurry…bioavailability 85%....should not be given with antacid Usual duration = 2 weeks, discontinuation not required unless accompanied by fever, swelling, mucous membrane involvement or arthralgias. 4. False-positive cannabinoid test
  11. Cleavage site---- N-terminal of proline residues….between phenylalanine & proline….prevents proteolytic cleavage of HIV Gag & pol precursors essential for structural & functional components of virus….. Fails to mature Lemon stick apprearance
  12. 1st three  older Ritonavir + lopinavir combination common Last three  sulfa containing ---- skin rashes 7. amprenavir---C/I in pregnant women, children < 4 years old (oral solution contains propylene glycol & vitamin E --- ↑ bioavailability)  lactic acidosis, seizures & respiratory depression. (Withdrawn in 2007)
  13. T-20……..Dose: 90 mg (1mL) s.c. BD (use within 24 hrs) MVC…..Only ART which binds to host protein……HIV can develop resistance to this drug through two distinct pathways. A patient starting maraviroc therapy with HIV that is predominantly CCR5-tropic may experience a shift in tropism to CXCR4- or dual/mixed-tropism predominance. This is especially likely in patients harboring low-level but undetected CXCR4- or dual/mixed-tropic virus prior to initiation of maraviroc. Alternatively, HIV can retain its CCR5-tropism but gain resistance to the drug through specific mutations in the V3 loop of gp 120 that allow virus binding in the presence of inhibitor. plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist ofCXCR7
  14. LTR….long terminal repeat`…….HIV-1, HIV-2……Chromosomal integration is a defining characteristic of retrovirus life cycles and allows viral DNA to remain in the host cell nucleus for a prolonged period of inactivity or latency. Because human DNA is not known to undergo excision and reintegration, this is an excellent target for antiviral intervention.
  15. OCT2…. dofetilide and metformin.
  16.  Foscarnet has been administered intravitreally for the treatment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are incomplete. Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2. Cytostatic-----suppressing growth and multiplication of cells.
  17. 3TC----lamivudine
  18. AZT….80% decrease NVP-----50-60% decrease
  19.  Pegylated interferon with ribavirin is approved for treatment but results are suboptimal and tolerability poor. Ribavirin is a nucleoside analogue used in combination with interferon alfa to treat hepatitis C. Because of similar mechanisms of action, the combination of these 2 drugs could potentially increase such toxicity. A case of fatal lactic acidosis and pancreatitis is described in an HIV-infected patient coinfected with hepatitis C on a didanosine-containing antiretroviral regimen after treatment of hepatitis C was initiated with ribavirin and pegylated interferon alfa-2b. Extreme caution should be exercised when didanosine and ribavirin are used concomitantly because of the increased risk of mitochondrial toxicity and the syndrome of severe metabolic acidosis with elevated lactic acid levels.
  20. An increasingly recognized complication of initiating antiretroviral therapy is accelerated inflammatory reaction to overt or subclinical opportunistic infections or malignancies. This is thought to reflect reversal of immunodeficiency, resulting in new antimicrobial host defenses.
  21. 1% Tenofovir vaginal gels (↓ risk of HSV-2 ----- indirectly ↓ risk of HIV)------ 3 times higher risk Portmanteau inhibitor "It's one drug that does the same thing as two independent drugs would do. 3TC---Lamivudine……FTC----emtricitabine……TDF---tenofovir…..EFV---efavirenz
  22. 1. there are no recovered AIDS patients. 2. HIV infection may remain latent for long periods before causing AIDS 3. HIV-1 mutates at a rapid rate and efficiently selects mutant forms that evade immunity. 4. killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues. 5. HIV may be encountered daily by individuals at high risk. 6. the great majority of HIV infection is through the genital tract. 7. there is no suitable animal model for HIV/AIDS at present.
  23. 50% concession …….HIV/AIDS (Prevention & control) Bill 2014------Bill to end stigma & discrimation (long awaited legislation)
  24. Shift from hetero to homozygous. Done in Germany
  25. Thirty hours after the baby was born, she was treated with intense antiretroviral therapy. When the baby was about 18 months old, the mother did not bring the child in for scheduled examinations for the next five months. When the mother returned with the child, doctors expected to find high levels of HIV, but instead the HIV levels were undetectable Congo free of mother to child transmission No sexual transmission seen in compliant patients