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The document presents an overview of HIV/AIDS, highlighting statistics on its global prevalence, risk factors, and the role of antiretroviral therapy in reducing mortality rates. It details the mechanisms of action for various classes of antiretroviral drugs, their pharmacokinetics, dosages, and potential adverse effects. Additionally, it covers the HIV life cycle and the classification of drugs used in treatment, emphasizing the importance of understanding drug interactions and patient-specific considerations.

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SEMINAR PRESENTATION Moderator Dr. Saroj Purohit
• HIV infection/AIDS is a global problem. • At the end of 2009, an estimated 33.3 million PLWHA according to UNAIDS. • More than 95% of people living with HIV/AIDS reside in low- and middle-income countries; – 50% are female, and – 2.5 million are children <15 years.
• A significant proportion of people (25%) are unaware that they are HIV-positive • Racial and ethnic minorities continue to be disproportionately affected by HIV • Strongest risk factors for excess mortality is viral load greater than 400 copies/mL, CD4+ count less than 200 cells/mL and cytomegalovirus retinitis • Availability of antiretroviral therapy has resulted in decline in AIDS death rates
• HIV attacks and binds to specific cells of immune system, including – monocytes, macrophages, & T-cell lymphocytes • CD4 receptors (for binding) • coreceptor proteins (CCR-5, CXCR-4)(for fusion) • conformational changes to key HIV proteins (gp41 & gp120) • HIV fuses releases its contents
ss viral RNA is transcribed via RT into a ds proviral DNA that is subsequently incorporated into host cell's genetic material via integrase enzyme. HIV then uses the infected cell's machinery to translate, transcribe, and produce immature viral particles that bud and break from infected cell. For these immature virions to become infectious, the HIV protease enzyme must cleave large precursor polypeptides into functional proteins 5
HIV life cycle and antiretroviral drug targets
Classification of ART Drugs • Nucleo(t)side Reverse Transcriptase Inhibitors (NRTIs) • Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Protease Inhibitors (PIs) • Entry Inhibitors - Chemokine (CCR5) co-receptor antagonist • Fusion Inhibitors • Integrase Inhibitors (HIV integrase strand transfer inhibitors)
Nucleo(t)side Reverse Transcriptase Inhibitors (NRTIs) • First agents available for HIV Infection. • Less potent than NNRTIs) and pIs. • Have a central role in ART. • Have activity against HIV-1 and HIV-2. • Nucleoside and nucleotide an alogues • Differ from normal substrates only by a minor modification in sugar (ribose) molecule Drugs •Abacavir (ABC) •Didanosine (ddI) •Emtricitabine (FTC) •Lamivudine (3TC) •Stavudine (d4T) •Tenofovir (TDF) •Zidovudine (ZDV; formerly azidothymidine [AZT])
MOA • Interrupt HIV replication cycle via competitive inhibition of HIV reverse transcriptase and termination of the DNA chain • Reverse transcriptase. • An HIV-specific DNA polymerase • Allows HIV RNA to be transcribed into ss and ultimately ds proviral DNA and incorporated into host-cell genome. • Proviral DNA chain elongation is necessary before genome incorporation can occur RNA DNA • Acting as "false building blocks causes Chain termination, Nucleus • Once incorporated, work by preventing other nucleosides from Host absence of a 3’ OH group. also being incorporated b/c ofCell 10
MOA of NRTIs
Pharmacokinetics • NRTIs are prodrugs and undergoes phosphorylation by intracellular kinases to exert their activity. • Oral bioavailability ranges from 25%-93%, with tenofovir and didanosine on lower end of spectrum. • Food does not significantly affect absorption • Except didanosine, which must be taken on empty stomach • Renal elimination • Exception is abacavir, given at normal dose regardless of creatinine clearance. • Minimal drug-drug interactions occur. • Clinically significant Interactions involve didanosine. • With tenofovir, didanosine levels are higher than expected, • Didanosine and ribavirin combination should be avoided.
Name Dosage Form(s) Adult Dose Adverse Events Abacavir 300-mg tablet; 20-mg/mL oral solution 600 mg PO qd or 300 mg PO bid Hypersensitivity reaction (may include fever, rash, nausea, vomiting, diarrhea, malaise, shortness of breath, cough, pharyngitis); patients positive for HLA-B*5701 are at highest risk for hypersensitivity (perform HLA screening before initiating) Didanosine 125-mg, 200-mg, 250-mg, 400-mg enteric-coated capsule; 10-mg/mL suspension >60 kg: 400 mg PO qd Peripheral neuropathy, pancreatitis, nausea, < 60 kg: 250 mg PO qd lactic acidosis Take 30 min ac or 2 hr pc Oral solution: Divide daily dose bid Emtricitabine 200-mg capsule; 10-mg/mL oral solution 200 mg PO qd or 240 mg (24 mL) oral solution PO qd Minimal toxicity, hyperpigmentation
Name Dosage Form(s) Adult Dose Adverse Events Lamivudine 150-mg, 300-mg tablet; 10-mg/mL solution 300 mg PO qd or 150 mg PO bid Minimal toxicity, severe acute exacerbation of hepatitis may occur with HBV-coinfection upon discontinuation Stavudine 15-mg, 20-mg, 30-mg, 40-mg capsule; 1-mg/mL oral solution >60 kg: 40 mg PO bid < 60 kg: 30 mg PO bid Peripheral neuropathy, pancreatitis, lactic acidosis, lipoatrophy, hyperlipidemia Tenofovir 300-mg tablet 300 mg PO qd Nausea, vomiting, diarrhea, headache, asthenia, renal insufficiency Zidovudine 300-mg tablet; 100-mg 300 mg PO bid or capsule;10-mg/mL oral 200 mg PO tid solution;10-mg/mL intravenous solution Nausea, vomiting, headache, asthenia, Anemia, granulocytopenia, myopathy, lactic acidosis, hepatomegaly with steatosis, nail pigmentation, lipid abnormalities, lipoatrophy, hyperglycemia
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Were introduced in 1996 with approval of nevirapine. • Have potent activity against HIV-1 and are part of preferred initial regimens. • Efavirenz, confers most significant inhibition of viral infectivity • All exhibit same mechanism of action Drugs First-generation Delavirdine(DLV) Efavirenz (EFV) Nevirapine (NVP) Second-generation Etravirine (ETR) Rilpivirine (RPV)
MOA • HIV reverse transcriptase is a heterodimer composed of 2 subunits (p66 and p51). • NNRTIs bind p66 subunit at a hydrophobic pocket distant from active site of enzyme (allosteric site) • This noncompetitive binding induces a conformational change in enzyme • 1st generation NNRTIs are more rigid in structure • Resistance can quickly be developed . • 2nd generation NNRTIs have a more flexible structure, • Adjust readily and resist mutation more effectively
MOA of NNRTIs
Pharmacokinetics • All utilize cyt P450 for metabolism and exert varying induction and inhibition effects on specific isoenzymes (eg, CYP3A4, CYP2C9). • Results in a significant potential for drug-drug interactions • Delavirdine primarily uses the 3A4 isoenzyme for metabolism. • Nevirapine is metabolized mainly by 3A4 with some secondary metabolism through 2B6. • Efavirenz is primarily metabolized through 2B6 and secondarily through 3A4. • Etravirine is a substrate of 3A4, 2C9, and 2C19. • Highly protein-bound (98-99%), primarily to albumin and alpha1 acid glycoprotein except nevirapine • Serum half-lives are fairly extended, ranging (25-55 hours), • Except for delavirdine, (2-11 h)
Name Dosage Form(s) Adult Dose Adverse Events Delavirdine 100-mg, 200-mg tab. 400 mg PO tid Rash, headache Efavirenz 600-mg tab.; 50-mg, 200-mg caps 600 mg PO qd Take on empty stomach to decrease Adrs Rash, CNS (eg, somnolence, vivid dreams, confusion, visual hallucinations), hyperlipidemia Etravirine 100-mg, 200-mg tablets 200 mg PO bid Rash, nausea Nevirapine 200-mg tab; 400 mg XR tab; 10-mg/mL susp. 200 mg PO bid XR: 400 mg PO qd Rash, hepatitis Rilpivirine 25 mg PO qd with meal Depressive disorders, insomnia, headache, rash 25-mg tablet
Protease Inhibitors (PIs) • First introduced in 1995 • Are an integral part of treatment • Exhibit activity against clinical isolates of both HIV-1 and HIV-2. Drugs • Atazanavir sulfate, ATV • Darunavir • Fosamprenavir Calcium, FOS-APV • Indinavir, IDV, • lopinavir / ritonavir, LPV/RTV • Nelfinavir mesylate, NFV • Saquinavir mesylate, SQV • Tipranavir, TPV
MOA • HIV protease is a 99-amino-acid, aspartic acid protein • Responsible for maturation of virus particles late in viral life cycle. • Systematically cleaves individual proteins from gag and gag -pol polypeptide precursors into functional subunits for viral capsid formation during or shortly after viral budding from an infected cell. • Competitive inhibitors • Directly bind to HIV protease and prevent subsequent cleavage of polypeptides.
MOA of PIs
Pharmacokinetics • Significant first-pass metabolism by cytochrome P450 (CYP) 3A4 and 3A5 and intestinal efflux by p-glycoprotein is observed. • Highly protein-bound (97-99%), primarily to albumin and alpha1 acid glycoprotein except indinavir, • Short serum half-lives, ranging from 1.5-2 hours for indinavir and 7 hours for atazanavir. • Significant Interactions with medications cleared through CYP450 isoenzymes • Low-dose ritonavir (100-200 mg) is frequently coadministered with other protease inhibitors to block intestinal and hepatic 3A metabolism.
Name Dosage Form(s) Atazanavir 100-mg, 150-mg, 200- 400 mg PO qd or mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia Darunavir 75-mg, 150-mg, 300- 800 mg qd + ritonavir 100 mg PO mg, 400-mg, 600-mg qd or 600 mg bid + ritonavir 100 tablets mg PO bid Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia Fosamprenavir 700-mg tab; 50-mg/mL oral sus. Indinavir Adult Dose Adverse Events 700 mg bid + ritonavir 100 mg PO Rash, nausea, vomiting, bid or 1400 mg PO bid or 1400 mg diarrhea, hyperlipidemia, + ritonavir 100-200 mg PO qd hyperglycemia Sus.: Take without food with RTV: Take with food 100-mg, 200-mg, 400- 800 mg PO q8h Nephrolithiasis, nausea, indirect mg capsules 800 mg PO bid + ritonavir 100-200 hyperbilirubinemia, mg PO bid hyperlipidemia, hyperglycemia Take 1 h ac or 2 h pc;
Name Dosage Form(s) Adult Dose Adverse Events Lopinavir / ritonavir 100-mg/25-mg, 200mg/50-mg tablets; 80-mg/20-mg per mL oral solution 400 mg/100 mg PO bid or 800 mg/200 mg PO qd Oral solution: Take with meals Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, hyperglycemia Nelfinavir 250-mg, 625-mg tablets, 50 mg/g oral powder 1250 mg PO bid or 750 mg PO tid (cannot be boosted) Take with food Diarrhea, hyperlipidemia, hyperglycemia Ritonavir 100-mg tablet; 100-mg soft gelatin capsule; 80-mg/mL oral solution Boosting dose for other PIs: 100-400 mg/d Nausea, vomiting, diarrhea, asthenia, Nonboosting dose 600 mg bid hyperlipidemia, oral paresthesias, hyperglycemia Saquinavir 500-mg tablet; 200-mg hard gelatin capsule 1000 mg + ritonavir 100 mg PO bid Unboosted not recommended Take with food, or within 2 h pc Nausea, diarrhea, headache, hyperlipidemia, hyperglycemia, PR and QT interval prolongation Tipranavir 250-mg soft gelatin capsule 100-mg/mL oral solution 500 mg + ritonavir 200 mg PO bid Unboosted not recommended Hepatotoxicity, rash, hyperlipidemia, hyperglycemia, intracranial hemorrhage
Entry Inhibitors - Chemokine (CCR5) co-receptor antagonist • Maraviroc • Binding of gp120 HIV surface protein to CD4 receptor induces a structural change that reveals V3 loop of the protein. • V3 loop then binds with a chemokine coreceptor (principally either CCR5 or CXCR4), allowing gp41 to insert itself into the host cell and leading to fusion of the cell membranes. • Maraviroc selectively and reversibly binds CCR5 coreceptor, blocking V3 loop interaction and inhibiting fusion of cellular membranes. – As some viral strains may use an alternate co-receptor CXCR4 for entry, – a tropism assay is necessary to confirm that patient’s virus only uses CCR5 for entry.
• Pharmacokinetics • 75% protein-bound, primarily to albumin and alpha1acid glycoprotein. • Terminal half-life is 15-30 hours. • Metabolized through CYP3A4 and is a substrate for efflux pump p-glycoprotein. • Dosage adjustment is required when administered in combination with potent inhibitors or inducers of CYP3A4300 mg PO bid • Dose 150 mg PO bid (CYP3A4 inhibitors ± inducers) 600 mg PO bid (CYP3A4 inducers) • ADRs – Constipation, dizziness, cough, Pyrexia, Upper respiratory tract infections, Rash, Musculoskeletal symptoms, Abdominal pain, Hepatotoxicity, nasopharyngitis
Fusion Inhibitors • Enfuvirtide, • Act extracellularly to prevent fusion of HIV to CD4 or other target cell. • Blocks second step in fusion pathway by binding to HR1 region of gp41. • Does not allow HR1 and HR2 to fold properly, • Thus preventing conformational change of gp41 required to complete final step in fusion process • Dose 90 mg SC bid • Dose adjustments are not required in patients with renal insufficiency or mild-to-moderate hepatic insufficiency • ADRs Injection-site reactions (eg, pain, erythema, induration, nodules) diarrhea, nausea, fatigue, hypersensitivity reactions, increased rate of bacterial pneumonia
Integrase Inhibitors (HIV integrase strand transfer inhibitors) • 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. • Proviral integration involves 2 catalytic reactions: • 3'-processing in host-cell cytoplasm to prepare proviral strands for attachment • Strand transfer whereby proviral DNA is covalently linked to cellular DNA • IIs Competitively inhibit strand transfer reaction by binding metallic ions in active site. • Raltegravir & Elvitegravir • Dolutegravir – Newest integrase inhibitor, is now in very advanced clinical trials, with approval expected towards the end of 2013. – once-a-day medication, can be taken separately. – doesn't require a booster – appears to work against virus that is resistant to raltegravir and/or elvitegravir.
Pharmacokinetics Raltegravir • Rapid absorption, taken with or without food. half-life of 10-12 hours • Longer half-life in women, • 83% bound to plasma proteins • Metabolized by uridine diphosphate glucuronyl transferase • Other antiretroviral agents may alter metabolism • Antacids may decrease absorption by divalent cation binding, Elvitegravir • administered with low-dose ritonavir (100 mg) to reduce its first-pass metabolism and systemic clearance. • Coadministration results in a 20-fold increase in systemic exposure and a terminal half-life of 10-13 hours. • metabolized through CYP3A4 and UGT1A1/UGT1A3. • Drug-drug interactions with other medications are likely because of ritonavir • Antacids may decrease absorption
Name Dosage Form(s) Adult Dose Adverse Events Raltegravir 400-mg tablet 400 mg PO bid Nausea, diarrhea, headache, CK elevations, myopathy/rhabdomy olysis (rare) With rifampin: 800 mg PO bid Elvitegravir Available in ‘quad’ pill, elvitegravir/cob icistat/emtricitabine /tenofovir (Stribild). _ nausea, diarrhea, fatigue, and headache
Commercial Fixed-dose combinations Combination Name Zidovudine + lamivudine Combivir Zidovudine + abacavir Epzicom Zidovudine + lamivudine + abacavir Trizivir (combivir +ABC) Tenofovir + emtricitabine Truvada Tenofovir + emtricitabine + efavirenz Atripla (Truvada +EFV) Stavudine + lamivudine + nevirapine Triomunea Lopinavir + ritonavir Kaletra Rilpivirine + tenofovir/emtricitabine Complera Elvitegravir+ cobicistat+ tenofovir + emtricitabine Stribild
Anti HIV agents under trials • Nucleosides- DAPD, DOTC, GW-42086, D-D4FC • Non-nucleosides- DPC 961, DPC 083, Capravirine, Calanolide A, TMC 120 • PI’s- BMS 232632, AG 1776, DMP 450, CGP61755, DPC 681, DPC 684, TMC 126 • Fusion Inhibitors - T- 1249 • Interleukin-2 • Vaccine development- vCP1452, gp-160 • Integrase Inhibitors- DCQA/DCTA, Zintevir • Hydroxyurea-like Compounds- BCX-34,
Drugs with Potential to Interact with PIs or NNRTIs • Statins (simvistatin & lovastatin) • Azole antifungals • Anticonvulsants • Anti-TB (Rifampicin) • Warfarin 36 • • • • Midazolam, trizolam Clarithromycin Oral contraceptives Amitriptyline
Goals of Antiretroviral Therapy Control of viral replication Prevention or delay of progressive immunodeficiency Delayed progression to AIDS Prolonged Survival Decreased selection of resistant virus
DHHS ART Guidelines Therapy should be initiated in following patient : • ART should be initiated in all patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm3 (AI). • ART should also be initiated, regardless of CD4 count, in patients with the following conditions: – – – – Pregnancy (AI), to prevent perinatal transmission HIV- associated nephropathy (AII), Active TB Hepatitis B virus (HBV) coinfection when treatment of HBV is indicated (AIII).
Therapy options Standard ART consists of 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor. • Preferred regimen NNRTI – Based regimen • EFV/TDF/FTC PI – Based regimen • ATV/r + TDF/FTC • DRV/r (OD) + TDF/FTC INSTI – Based regimen • RAL + TDF/FTC Alternative Regimens NNRTI-Based Regimens EFV + ABC/3TC RPV/TDF/FTC RPV + ABC/3TC PI-Based Regimens ATV/r + ABC/3TC DRV/r + ABC/3TC FPV/r (once or twice daily) +ABC/3TC or TDF/FTC LPV/r (once or twice daily) +ABC/3TC or TDF/FTC INSTI-Based Regimen RAL + ABC/3TC
Patient selection • Patients initiating ART should be willing and able to commit to lifelong treatment • Should understand benefits and risks of therapy and importance of adherence • Patients may choose to postpone therapy, and providers, on a case-by-case basis, • May elect to defer therapy based on clinical and/or psychosocial factors.
Dosing of Antiretroviral Agents in Hepatic Failure
Dosing of Antiretroviral Agents in Renal Failure
Types of Treatment Failure: • Virologic Failure: if viral load is not <400 copies/mL after 3mo • Immunologic Failure: – The CD4 cell count persistently falls below the baseline CD4 cell count – The CD4 cell count fails to increase by more than 25-50 cells/μL after one year of treatment – There is a > 50% decline in CD4 cell count from its highest level on ART • Clinical Failure: – when the patient has a new AIDS-defining illness—i.e., a new WHO stage 3 or 4 condition--after initiation of ART
Clinical Indications to Change ART Due to Toxicity Symptom Clinical Indication Nausea Severe discomfort or minimal intake for > 3 days Vomiting Severe vomiting of all foods/fluids in 24 hrs, orthostatic hypotension or need of IV fluids Diarrhea Bloody diarrhea, orthostatic hypotension or need of IV fluids Fever Unexplained fever of > 39.6 C Headache Severe or requires narcotics Allergic Reaction Generalized urticaria, angioedema or anaphylaxis Peripheral Severe discomfort, objective weakness, loss of 2-3 Neuropathy previously present reflexes or sensory dermatomes 45 Fatigue Normal activity reduced > 50%
Lab Indications to Change ART Due to Toxicity Parameter Grade 3 Toxicity Normal Reference Values Hemoglobin (Hgb) < 7.0 g/dL M: 13.8 – 17.2 g/dL F: 12 – 15.6 g/dL *ANC < 750/mm3 1500 to 7000/mm3 Platelet count < 49 x 103/µL 130-400 x 103/µL Total Bilirubin > 3-7.5 x ULN*= 3.9-9.75mg/dL ≤ 1.3 mg/dL SCr > 1.7-2.0 (adult) ≤ 1.2 mg/dL AST / ALT 5-10 x ULN* = 210-420 U/L, 240-480 U/L ≤ 42 U/L , ≤ 48U/L Amylase, Lipase > 2-3 x ULN* 23-85 U/L, 0-160 U/L Triglyceride (TG) 8.49- 13.56 mmol/L < 200 mg/dL 1.6-2.0 X ULN < 200 mg/dL Hematology Chemistries LFTs Pancreatic Enzymes Lipids Cholesterol 46 * ULN = Upper Limit of Normal *ANC= Absolute neutrophil count
Serious Adverse Effects of NRTIs • All NRTIs** – Lactic acidosis/fatty liver* – Lipoatrophy (loss of subcutaneous fat) *Potentially life-threatening • Anemia – Zidovudine (AZT, ZDV) • Pancreatitis* – didanosine (ddI) • Neuropathy – didanosine (ddI) – stavudine (d4T) **d4T > ddI, AZT > ABC, TDF, 3TC 47
Serious Adverse Effects of NNRTIs • All NNRTIs – Hepatitis* – Skin rash • CNS symptoms – efavirenz • Stevens-Johnson syndrome* – nevirapine *Potentially life-threatening 48
Serious Adverse Effects of PIs • All PIs – Insulin resistance hyperglycemia and diabetes – Elevated serum lipids – Abnormal fat accumulation – Liver toxicity* *Potentially life-threatening 49
LIPODYSTROPHY SYNDROME • Main clinical features are peripheral fat loss, central fat accumulation, gyneacomastia, buffalo hump and other peripheral lipomatosis. • Incidence: 20-80% of pts in ARV drugs • Presumed Mechanism: inhibition of DNA polymerase gamma resulting in depletion of mitochondrial DNA
Lipodystrophy Syndrome: NRTIs versus PIs PIs NRTIs d4T>ZDV Lactic acid SC fat wasting TG Buffalo hump Intra-abdominal fat Cholesterol TG Insulin resistance John M, et al. Antiviral Ther. 2001;6:9-20.
• Rx – Low fat diet and aerobic exercise – Testosterone replacement therapy (in hypogonadal men) or anabolic steroids (eugonadal men) – Growth hormone (6mg/kg) may reduce fat accumulation – Metformin (500mg bid) • improves insulin sensitivity, results in weight loss and decreased intra- abdominal fat – Restorative surgery – Regimen change: PIs to NNRTIs or ABC
Lactic Acidosis/Hepatic Steatosis • Hyperlactemia is defined as venous lactate >2mmol/L • Mortality rate: up to 55% • Presumed Mechanism of toxicity: inhibition of DNA polymerase gamma resulting in depletion of mitochondrial DNA
• Dx – Clinical: N & V, myalgia, abd. Pain & distention, diarrhea, wt loss – Lab. • Elevated venous lactic acid • Surrogate markers include elevated creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), amylase or aspartate aminotransferase (AST), increase anion gap (>16), CT, US, biopsy showing liver steatosis
• Rx – Lactic acid <5mmol/L may not require – Therapeutic switch : D4T, ddl, or AZT to ABC,3TC or TDF may be reasonable – Supportive measures: hydration, mitochondrial ventilation and dialysis – Anecdotal case reports show possible benefit of thiamine, L-carnitine, vit-C and antioxidants – Riboflavin 50mg/kg - most extensive & favourable
Insulin Resistance • Incidence: – 30-90% pts on PIs and overt DM occurs in 1-11% with a mean of 7% in 5yr • Screening: – RBG, FBG and HbA1c after 2-3 mo of the start of PI base regimen • Risk: – Risk of atherosclerosis
Insulin Resistance • Rx – STD RX of type II DM and exercise – The two major classes of agents are insulin secretagogues (sulunylureas ) and insulin sensitizing agents ( metformin and thiazolidinediones / glitazones) – Metformin and glitazones have the potential advantage of improving insulin resistance and decreasing visceral fat accumulation – Therapeutic switch to non PI base ARV agents
Hyperlipidemia • All PIs appears to have this effect with possible exception of atazanavir; • Observed within 2 to 3 month of initiating PI based regimen • Risk: – Possible risk of atherogenesis • DX & Rx: – ^LDL and TG--PI based ART esp.with retonavir – ^TC and HDL—EFV & NVP
Rx of hyperlipidemia Lipid problem Preferred alternative comment Isolated high LDL Statin niacin High cholesterol Statin or fibrate and TG Start one and add other Start low dose and titrate upward, watch for myopathy with PIs Combination may increase risk of myopathy Isolated high TG statin fibrate Combination may increase risk of myopathy
Hepatotoxicity • NRTIs can cause hepatic steatosis, generally after more than 6 months of therapy, probably via mitochondrial toxicity.(D4T!) • NNRTIs can cause hepatitis in first 2-3 months of therapy, sometimes as a part of hypersensitivity reaction (NVP>EFV, DLV)-fluminant hepatic necrosis (NVP) • PIs can also cause hepatitis by an unknown mechanism, particularly in patients co-infected with hepatitis B or C, raised hepatic aminotransferase concentrations and alcoholism (RTV-the most common, among PIs) • Most hepatotoxic appears to be NVP followed by full dose RTV
HYPERSENSITIVITY • Is about 100 times more common in HIV Pts than in general population. • Erythematous maculopapular, pruritic and confluent rash, most ly on body and arms and begins after 1-2 weeks of therapy. • SJS or TEN develops in less than 0.3% of patients. • All NNRTI (Nevirapine,Delavirdine,Efavirenz, Etravirine), NRTI (Abacavir) and PI (Amprenavir) are common
• About 50% of ARV hypersensitivity resolves spontaneously despite continuation of therapy. • Therapy should be stopped if there is mucosal involvement, blistering, exfoliation, clinically significant hepatic dysfunction • Glucocorticosteroids are ineffective for prevention of nevirapine hypersensitivity. • Rechallenge is possible for mild to moderate NNRTI hypersensitivity but not for abacavir,
Laboratory monitoring of patients on ART: – CD4 cell count %: 3 and 6 months post-initiation, then every 6 months (all ages) – Viral load: 3 and 6 months post-initiation, then as follows: (Every 6 months for adults) – FBC: • AZT-based ART: at 4 and 12 weeks post-initiation, then annually only, and as clinically indicated • If not on AZT-based ART: annually only, and as clinically indicated
• AST/ALT: – NVP-based ART: 2, 4, and 12 weeks post-initiation, thereafter only as clinically indicated – EFV-based ART: 4 and 12 weeks post-initiation, thereafter only as clinically indicated – PI-based ART: only as clinically indicated • Glucose and total cholesterol/triglycerides annually only if on PI- based ART • Creatinine and creatinine clearance : 3 and 6 months post-initiation and then, if stable, every 6 months (TDF only) • RPR (rapid plasma reagin )or VDRL test: after baseline, only as indicated
Principles of HIV Drug Resistance • Results from changes (mutations) in genetic information in virus • These changes occur whenever HIV is replicating • Partial HIV suppression promotes resistance • Resistance can be delayed by suppressing virus completely • RT and protease are flexible (highly mutable) • Resistance may fade but not disappear when a drug is stopped • Some mutations allow certain viruses to resist effects of one or more antiretroviral drugs • Drug resistant virus usually grows faster and better than drug susceptible virus • Drug resistant virus replaces drug susceptible virus in patient 66
Resistance Testing • Two types: – Genotyping Detects drug resistance mutations on virus genome that may make it resistant to certain antiretrovirals • Less expensive • Can usually be completed in 1-2 weeks – Phenotyping Measure ability of viruses to grow in presence of various concentrations of antiretroviral drugs • More expensive • Generally takes 2-3 weeks to complete 67
Resistance Mutations • For some drugs (NNRTIs and 3TC), a single mutation causes high-level resistance. – Resistance to these drugs occurs very quickly • For other drugs (most NRTIs and PIs), many mutations must occur before high-level resistance is observed. – Resistance to these drugs occurs more slowly Cross-Resistance • Resistance to one drug can cause resistance to others of the same class – NNRTI: complete cross-class resistance – NRTI: partial cross-class resistance – PI: partial cross-class resistance • Partly overcome by ritonavir boosting 68
Minimize Emergence of Viral Resistance • Never prescribe ARVs in absence of adherence counseling and support • Never prescribe monotherapy or dual therapy • Ensure optimal serum drug concentrations – Avoid drug interactions – Diagnose and manage malabsorption • If ARV medications are to be discontinued, stop all drugs at same time – Possible exception: NNRTI-based regimen 69
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ART drugs ppt

  • 1.
  • 2.
    • HIV infection/AIDSis a global problem. • At the end of 2009, an estimated 33.3 million PLWHA according to UNAIDS. • More than 95% of people living with HIV/AIDS reside in low- and middle-income countries; – 50% are female, and – 2.5 million are children <15 years.
  • 3.
    • A significantproportion of people (25%) are unaware that they are HIV-positive • Racial and ethnic minorities continue to be disproportionately affected by HIV • Strongest risk factors for excess mortality is viral load greater than 400 copies/mL, CD4+ count less than 200 cells/mL and cytomegalovirus retinitis • Availability of antiretroviral therapy has resulted in decline in AIDS death rates
  • 4.
    • HIV attacksand binds to specific cells of immune system, including – monocytes, macrophages, & T-cell lymphocytes • CD4 receptors (for binding) • coreceptor proteins (CCR-5, CXCR-4)(for fusion) • conformational changes to key HIV proteins (gp41 & gp120) • HIV fuses releases its contents
  • 5.
    ss viral RNAis transcribed via RT into a ds proviral DNA that is subsequently incorporated into host cell's genetic material via integrase enzyme. HIV then uses the infected cell's machinery to translate, transcribe, and produce immature viral particles that bud and break from infected cell. For these immature virions to become infectious, the HIV protease enzyme must cleave large precursor polypeptides into functional proteins 5
  • 6.
    HIV life cycleand antiretroviral drug targets
  • 8.
    Classification of ARTDrugs • Nucleo(t)side Reverse Transcriptase Inhibitors (NRTIs) • Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Protease Inhibitors (PIs) • Entry Inhibitors - Chemokine (CCR5) co-receptor antagonist • Fusion Inhibitors • Integrase Inhibitors (HIV integrase strand transfer inhibitors)
  • 9.
    Nucleo(t)side Reverse TranscriptaseInhibitors (NRTIs) • First agents available for HIV Infection. • Less potent than NNRTIs) and pIs. • Have a central role in ART. • Have activity against HIV-1 and HIV-2. • Nucleoside and nucleotide an alogues • Differ from normal substrates only by a minor modification in sugar (ribose) molecule Drugs •Abacavir (ABC) •Didanosine (ddI) •Emtricitabine (FTC) •Lamivudine (3TC) •Stavudine (d4T) •Tenofovir (TDF) •Zidovudine (ZDV; formerly azidothymidine [AZT])
  • 10.
    MOA • Interrupt HIVreplication cycle via competitive inhibition of HIV reverse transcriptase and termination of the DNA chain • Reverse transcriptase. • An HIV-specific DNA polymerase • Allows HIV RNA to be transcribed into ss and ultimately ds proviral DNA and incorporated into host-cell genome. • Proviral DNA chain elongation is necessary before genome incorporation can occur RNA DNA • Acting as "false building blocks causes Chain termination, Nucleus • Once incorporated, work by preventing other nucleosides from Host absence of a 3’ OH group. also being incorporated b/c ofCell 10
  • 11.
  • 12.
    Pharmacokinetics • NRTIs areprodrugs and undergoes phosphorylation by intracellular kinases to exert their activity. • Oral bioavailability ranges from 25%-93%, with tenofovir and didanosine on lower end of spectrum. • Food does not significantly affect absorption • Except didanosine, which must be taken on empty stomach • Renal elimination • Exception is abacavir, given at normal dose regardless of creatinine clearance. • Minimal drug-drug interactions occur. • Clinically significant Interactions involve didanosine. • With tenofovir, didanosine levels are higher than expected, • Didanosine and ribavirin combination should be avoided.
  • 13.
    Name Dosage Form(s) Adult Dose AdverseEvents Abacavir 300-mg tablet; 20-mg/mL oral solution 600 mg PO qd or 300 mg PO bid Hypersensitivity reaction (may include fever, rash, nausea, vomiting, diarrhea, malaise, shortness of breath, cough, pharyngitis); patients positive for HLA-B*5701 are at highest risk for hypersensitivity (perform HLA screening before initiating) Didanosine 125-mg, 200-mg, 250-mg, 400-mg enteric-coated capsule; 10-mg/mL suspension >60 kg: 400 mg PO qd Peripheral neuropathy, pancreatitis, nausea, < 60 kg: 250 mg PO qd lactic acidosis Take 30 min ac or 2 hr pc Oral solution: Divide daily dose bid Emtricitabine 200-mg capsule; 10-mg/mL oral solution 200 mg PO qd or 240 mg (24 mL) oral solution PO qd Minimal toxicity, hyperpigmentation
  • 14.
    Name Dosage Form(s) Adult Dose AdverseEvents Lamivudine 150-mg, 300-mg tablet; 10-mg/mL solution 300 mg PO qd or 150 mg PO bid Minimal toxicity, severe acute exacerbation of hepatitis may occur with HBV-coinfection upon discontinuation Stavudine 15-mg, 20-mg, 30-mg, 40-mg capsule; 1-mg/mL oral solution >60 kg: 40 mg PO bid < 60 kg: 30 mg PO bid Peripheral neuropathy, pancreatitis, lactic acidosis, lipoatrophy, hyperlipidemia Tenofovir 300-mg tablet 300 mg PO qd Nausea, vomiting, diarrhea, headache, asthenia, renal insufficiency Zidovudine 300-mg tablet; 100-mg 300 mg PO bid or capsule;10-mg/mL oral 200 mg PO tid solution;10-mg/mL intravenous solution Nausea, vomiting, headache, asthenia, Anemia, granulocytopenia, myopathy, lactic acidosis, hepatomegaly with steatosis, nail pigmentation, lipid abnormalities, lipoatrophy, hyperglycemia
  • 15.
    Nonnucleoside Reverse TranscriptaseInhibitors (NNRTIs) • Were introduced in 1996 with approval of nevirapine. • Have potent activity against HIV-1 and are part of preferred initial regimens. • Efavirenz, confers most significant inhibition of viral infectivity • All exhibit same mechanism of action Drugs First-generation Delavirdine(DLV) Efavirenz (EFV) Nevirapine (NVP) Second-generation Etravirine (ETR) Rilpivirine (RPV)
  • 16.
    MOA • HIV reversetranscriptase is a heterodimer composed of 2 subunits (p66 and p51). • NNRTIs bind p66 subunit at a hydrophobic pocket distant from active site of enzyme (allosteric site) • This noncompetitive binding induces a conformational change in enzyme • 1st generation NNRTIs are more rigid in structure • Resistance can quickly be developed . • 2nd generation NNRTIs have a more flexible structure, • Adjust readily and resist mutation more effectively
  • 17.
  • 18.
    Pharmacokinetics • All utilizecyt P450 for metabolism and exert varying induction and inhibition effects on specific isoenzymes (eg, CYP3A4, CYP2C9). • Results in a significant potential for drug-drug interactions • Delavirdine primarily uses the 3A4 isoenzyme for metabolism. • Nevirapine is metabolized mainly by 3A4 with some secondary metabolism through 2B6. • Efavirenz is primarily metabolized through 2B6 and secondarily through 3A4. • Etravirine is a substrate of 3A4, 2C9, and 2C19. • Highly protein-bound (98-99%), primarily to albumin and alpha1 acid glycoprotein except nevirapine • Serum half-lives are fairly extended, ranging (25-55 hours), • Except for delavirdine, (2-11 h)
  • 19.
    Name Dosage Form(s) Adult Dose AdverseEvents Delavirdine 100-mg, 200-mg tab. 400 mg PO tid Rash, headache Efavirenz 600-mg tab.; 50-mg, 200-mg caps 600 mg PO qd Take on empty stomach to decrease Adrs Rash, CNS (eg, somnolence, vivid dreams, confusion, visual hallucinations), hyperlipidemia Etravirine 100-mg, 200-mg tablets 200 mg PO bid Rash, nausea Nevirapine 200-mg tab; 400 mg XR tab; 10-mg/mL susp. 200 mg PO bid XR: 400 mg PO qd Rash, hepatitis Rilpivirine 25 mg PO qd with meal Depressive disorders, insomnia, headache, rash 25-mg tablet
  • 20.
    Protease Inhibitors (PIs) •First introduced in 1995 • Are an integral part of treatment • Exhibit activity against clinical isolates of both HIV-1 and HIV-2. Drugs • Atazanavir sulfate, ATV • Darunavir • Fosamprenavir Calcium, FOS-APV • Indinavir, IDV, • lopinavir / ritonavir, LPV/RTV • Nelfinavir mesylate, NFV • Saquinavir mesylate, SQV • Tipranavir, TPV
  • 21.
    MOA • HIV proteaseis a 99-amino-acid, aspartic acid protein • Responsible for maturation of virus particles late in viral life cycle. • Systematically cleaves individual proteins from gag and gag -pol polypeptide precursors into functional subunits for viral capsid formation during or shortly after viral budding from an infected cell. • Competitive inhibitors • Directly bind to HIV protease and prevent subsequent cleavage of polypeptides.
  • 22.
  • 23.
    Pharmacokinetics • Significant first-passmetabolism by cytochrome P450 (CYP) 3A4 and 3A5 and intestinal efflux by p-glycoprotein is observed. • Highly protein-bound (97-99%), primarily to albumin and alpha1 acid glycoprotein except indinavir, • Short serum half-lives, ranging from 1.5-2 hours for indinavir and 7 hours for atazanavir. • Significant Interactions with medications cleared through CYP450 isoenzymes • Low-dose ritonavir (100-200 mg) is frequently coadministered with other protease inhibitors to block intestinal and hepatic 3A metabolism.
  • 24.
    Name Dosage Form(s) Atazanavir 100-mg, 150-mg,200- 400 mg PO qd or mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia Darunavir 75-mg, 150-mg, 300- 800 mg qd + ritonavir 100 mg PO mg, 400-mg, 600-mg qd or 600 mg bid + ritonavir 100 tablets mg PO bid Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia Fosamprenavir 700-mg tab; 50-mg/mL oral sus. Indinavir Adult Dose Adverse Events 700 mg bid + ritonavir 100 mg PO Rash, nausea, vomiting, bid or 1400 mg PO bid or 1400 mg diarrhea, hyperlipidemia, + ritonavir 100-200 mg PO qd hyperglycemia Sus.: Take without food with RTV: Take with food 100-mg, 200-mg, 400- 800 mg PO q8h Nephrolithiasis, nausea, indirect mg capsules 800 mg PO bid + ritonavir 100-200 hyperbilirubinemia, mg PO bid hyperlipidemia, hyperglycemia Take 1 h ac or 2 h pc;
  • 25.
    Name Dosage Form(s) Adult Dose AdverseEvents Lopinavir / ritonavir 100-mg/25-mg, 200mg/50-mg tablets; 80-mg/20-mg per mL oral solution 400 mg/100 mg PO bid or 800 mg/200 mg PO qd Oral solution: Take with meals Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, hyperglycemia Nelfinavir 250-mg, 625-mg tablets, 50 mg/g oral powder 1250 mg PO bid or 750 mg PO tid (cannot be boosted) Take with food Diarrhea, hyperlipidemia, hyperglycemia Ritonavir 100-mg tablet; 100-mg soft gelatin capsule; 80-mg/mL oral solution Boosting dose for other PIs: 100-400 mg/d Nausea, vomiting, diarrhea, asthenia, Nonboosting dose 600 mg bid hyperlipidemia, oral paresthesias, hyperglycemia Saquinavir 500-mg tablet; 200-mg hard gelatin capsule 1000 mg + ritonavir 100 mg PO bid Unboosted not recommended Take with food, or within 2 h pc Nausea, diarrhea, headache, hyperlipidemia, hyperglycemia, PR and QT interval prolongation Tipranavir 250-mg soft gelatin capsule 100-mg/mL oral solution 500 mg + ritonavir 200 mg PO bid Unboosted not recommended Hepatotoxicity, rash, hyperlipidemia, hyperglycemia, intracranial hemorrhage
  • 26.
    Entry Inhibitors -Chemokine (CCR5) co-receptor antagonist • Maraviroc • Binding of gp120 HIV surface protein to CD4 receptor induces a structural change that reveals V3 loop of the protein. • V3 loop then binds with a chemokine coreceptor (principally either CCR5 or CXCR4), allowing gp41 to insert itself into the host cell and leading to fusion of the cell membranes. • Maraviroc selectively and reversibly binds CCR5 coreceptor, blocking V3 loop interaction and inhibiting fusion of cellular membranes. – As some viral strains may use an alternate co-receptor CXCR4 for entry, – a tropism assay is necessary to confirm that patient’s virus only uses CCR5 for entry.
  • 28.
    • Pharmacokinetics • 75%protein-bound, primarily to albumin and alpha1acid glycoprotein. • Terminal half-life is 15-30 hours. • Metabolized through CYP3A4 and is a substrate for efflux pump p-glycoprotein. • Dosage adjustment is required when administered in combination with potent inhibitors or inducers of CYP3A4300 mg PO bid • Dose 150 mg PO bid (CYP3A4 inhibitors ± inducers) 600 mg PO bid (CYP3A4 inducers) • ADRs – Constipation, dizziness, cough, Pyrexia, Upper respiratory tract infections, Rash, Musculoskeletal symptoms, Abdominal pain, Hepatotoxicity, nasopharyngitis
  • 29.
    Fusion Inhibitors • Enfuvirtide, •Act extracellularly to prevent fusion of HIV to CD4 or other target cell. • Blocks second step in fusion pathway by binding to HR1 region of gp41. • Does not allow HR1 and HR2 to fold properly, • Thus preventing conformational change of gp41 required to complete final step in fusion process • Dose 90 mg SC bid • Dose adjustments are not required in patients with renal insufficiency or mild-to-moderate hepatic insufficiency • ADRs Injection-site reactions (eg, pain, erythema, induration, nodules) diarrhea, nausea, fatigue, hypersensitivity reactions, increased rate of bacterial pneumonia
  • 31.
    Integrase Inhibitors (HIVintegrase strand transfer inhibitors) • 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. • Proviral integration involves 2 catalytic reactions: • 3'-processing in host-cell cytoplasm to prepare proviral strands for attachment • Strand transfer whereby proviral DNA is covalently linked to cellular DNA • IIs Competitively inhibit strand transfer reaction by binding metallic ions in active site. • Raltegravir & Elvitegravir • Dolutegravir – Newest integrase inhibitor, is now in very advanced clinical trials, with approval expected towards the end of 2013. – once-a-day medication, can be taken separately. – doesn't require a booster – appears to work against virus that is resistant to raltegravir and/or elvitegravir.
  • 32.
    Pharmacokinetics Raltegravir • Rapid absorption,taken with or without food. half-life of 10-12 hours • Longer half-life in women, • 83% bound to plasma proteins • Metabolized by uridine diphosphate glucuronyl transferase • Other antiretroviral agents may alter metabolism • Antacids may decrease absorption by divalent cation binding, Elvitegravir • administered with low-dose ritonavir (100 mg) to reduce its first-pass metabolism and systemic clearance. • Coadministration results in a 20-fold increase in systemic exposure and a terminal half-life of 10-13 hours. • metabolized through CYP3A4 and UGT1A1/UGT1A3. • Drug-drug interactions with other medications are likely because of ritonavir • Antacids may decrease absorption
  • 33.
    Name Dosage Form(s) Adult Dose AdverseEvents Raltegravir 400-mg tablet 400 mg PO bid Nausea, diarrhea, headache, CK elevations, myopathy/rhabdomy olysis (rare) With rifampin: 800 mg PO bid Elvitegravir Available in ‘quad’ pill, elvitegravir/cob icistat/emtricitabine /tenofovir (Stribild). _ nausea, diarrhea, fatigue, and headache
  • 34.
    Commercial Fixed-dose combinations Combination Name Zidovudine+ lamivudine Combivir Zidovudine + abacavir Epzicom Zidovudine + lamivudine + abacavir Trizivir (combivir +ABC) Tenofovir + emtricitabine Truvada Tenofovir + emtricitabine + efavirenz Atripla (Truvada +EFV) Stavudine + lamivudine + nevirapine Triomunea Lopinavir + ritonavir Kaletra Rilpivirine + tenofovir/emtricitabine Complera Elvitegravir+ cobicistat+ tenofovir + emtricitabine Stribild
  • 35.
    Anti HIV agentsunder trials • Nucleosides- DAPD, DOTC, GW-42086, D-D4FC • Non-nucleosides- DPC 961, DPC 083, Capravirine, Calanolide A, TMC 120 • PI’s- BMS 232632, AG 1776, DMP 450, CGP61755, DPC 681, DPC 684, TMC 126 • Fusion Inhibitors - T- 1249 • Interleukin-2 • Vaccine development- vCP1452, gp-160 • Integrase Inhibitors- DCQA/DCTA, Zintevir • Hydroxyurea-like Compounds- BCX-34,
  • 36.
    Drugs with Potentialto Interact with PIs or NNRTIs • Statins (simvistatin & lovastatin) • Azole antifungals • Anticonvulsants • Anti-TB (Rifampicin) • Warfarin 36 • • • • Midazolam, trizolam Clarithromycin Oral contraceptives Amitriptyline
  • 37.
    Goals of AntiretroviralTherapy Control of viral replication Prevention or delay of progressive immunodeficiency Delayed progression to AIDS Prolonged Survival Decreased selection of resistant virus
  • 38.
    DHHS ART Guidelines Therapyshould be initiated in following patient : • ART should be initiated in all patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm3 (AI). • ART should also be initiated, regardless of CD4 count, in patients with the following conditions: – – – – Pregnancy (AI), to prevent perinatal transmission HIV- associated nephropathy (AII), Active TB Hepatitis B virus (HBV) coinfection when treatment of HBV is indicated (AIII).
  • 39.
    Therapy options Standard ARTconsists of 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor. • Preferred regimen NNRTI – Based regimen • EFV/TDF/FTC PI – Based regimen • ATV/r + TDF/FTC • DRV/r (OD) + TDF/FTC INSTI – Based regimen • RAL + TDF/FTC Alternative Regimens NNRTI-Based Regimens EFV + ABC/3TC RPV/TDF/FTC RPV + ABC/3TC PI-Based Regimens ATV/r + ABC/3TC DRV/r + ABC/3TC FPV/r (once or twice daily) +ABC/3TC or TDF/FTC LPV/r (once or twice daily) +ABC/3TC or TDF/FTC INSTI-Based Regimen RAL + ABC/3TC
  • 41.
    Patient selection • Patientsinitiating ART should be willing and able to commit to lifelong treatment • Should understand benefits and risks of therapy and importance of adherence • Patients may choose to postpone therapy, and providers, on a case-by-case basis, • May elect to defer therapy based on clinical and/or psychosocial factors.
  • 42.
    Dosing of AntiretroviralAgents in Hepatic Failure
  • 43.
    Dosing of AntiretroviralAgents in Renal Failure
  • 44.
    Types of TreatmentFailure: • Virologic Failure: if viral load is not <400 copies/mL after 3mo • Immunologic Failure: – The CD4 cell count persistently falls below the baseline CD4 cell count – The CD4 cell count fails to increase by more than 25-50 cells/μL after one year of treatment – There is a > 50% decline in CD4 cell count from its highest level on ART • Clinical Failure: – when the patient has a new AIDS-defining illness—i.e., a new WHO stage 3 or 4 condition--after initiation of ART
  • 45.
    Clinical Indications toChange ART Due to Toxicity Symptom Clinical Indication Nausea Severe discomfort or minimal intake for > 3 days Vomiting Severe vomiting of all foods/fluids in 24 hrs, orthostatic hypotension or need of IV fluids Diarrhea Bloody diarrhea, orthostatic hypotension or need of IV fluids Fever Unexplained fever of > 39.6 C Headache Severe or requires narcotics Allergic Reaction Generalized urticaria, angioedema or anaphylaxis Peripheral Severe discomfort, objective weakness, loss of 2-3 Neuropathy previously present reflexes or sensory dermatomes 45 Fatigue Normal activity reduced > 50%
  • 46.
    Lab Indications toChange ART Due to Toxicity Parameter Grade 3 Toxicity Normal Reference Values Hemoglobin (Hgb) < 7.0 g/dL M: 13.8 – 17.2 g/dL F: 12 – 15.6 g/dL *ANC < 750/mm3 1500 to 7000/mm3 Platelet count < 49 x 103/µL 130-400 x 103/µL Total Bilirubin > 3-7.5 x ULN*= 3.9-9.75mg/dL ≤ 1.3 mg/dL SCr > 1.7-2.0 (adult) ≤ 1.2 mg/dL AST / ALT 5-10 x ULN* = 210-420 U/L, 240-480 U/L ≤ 42 U/L , ≤ 48U/L Amylase, Lipase > 2-3 x ULN* 23-85 U/L, 0-160 U/L Triglyceride (TG) 8.49- 13.56 mmol/L < 200 mg/dL 1.6-2.0 X ULN < 200 mg/dL Hematology Chemistries LFTs Pancreatic Enzymes Lipids Cholesterol 46 * ULN = Upper Limit of Normal *ANC= Absolute neutrophil count
  • 47.
    Serious Adverse Effectsof NRTIs • All NRTIs** – Lactic acidosis/fatty liver* – Lipoatrophy (loss of subcutaneous fat) *Potentially life-threatening • Anemia – Zidovudine (AZT, ZDV) • Pancreatitis* – didanosine (ddI) • Neuropathy – didanosine (ddI) – stavudine (d4T) **d4T > ddI, AZT > ABC, TDF, 3TC 47
  • 48.
    Serious Adverse Effectsof NNRTIs • All NNRTIs – Hepatitis* – Skin rash • CNS symptoms – efavirenz • Stevens-Johnson syndrome* – nevirapine *Potentially life-threatening 48
  • 49.
    Serious Adverse Effectsof PIs • All PIs – Insulin resistance hyperglycemia and diabetes – Elevated serum lipids – Abnormal fat accumulation – Liver toxicity* *Potentially life-threatening 49
  • 50.
    LIPODYSTROPHY SYNDROME • Mainclinical features are peripheral fat loss, central fat accumulation, gyneacomastia, buffalo hump and other peripheral lipomatosis. • Incidence: 20-80% of pts in ARV drugs • Presumed Mechanism: inhibition of DNA polymerase gamma resulting in depletion of mitochondrial DNA
  • 51.
    Lipodystrophy Syndrome: NRTIs versusPIs PIs NRTIs d4T>ZDV Lactic acid SC fat wasting TG Buffalo hump Intra-abdominal fat Cholesterol TG Insulin resistance John M, et al. Antiviral Ther. 2001;6:9-20.
  • 52.
    • Rx – Lowfat diet and aerobic exercise – Testosterone replacement therapy (in hypogonadal men) or anabolic steroids (eugonadal men) – Growth hormone (6mg/kg) may reduce fat accumulation – Metformin (500mg bid) • improves insulin sensitivity, results in weight loss and decreased intra- abdominal fat – Restorative surgery – Regimen change: PIs to NNRTIs or ABC
  • 54.
    Lactic Acidosis/Hepatic Steatosis •Hyperlactemia is defined as venous lactate >2mmol/L • Mortality rate: up to 55% • Presumed Mechanism of toxicity: inhibition of DNA polymerase gamma resulting in depletion of mitochondrial DNA
  • 55.
    • Dx – Clinical:N & V, myalgia, abd. Pain & distention, diarrhea, wt loss – Lab. • Elevated venous lactic acid • Surrogate markers include elevated creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), amylase or aspartate aminotransferase (AST), increase anion gap (>16), CT, US, biopsy showing liver steatosis
  • 56.
    • Rx – Lacticacid <5mmol/L may not require – Therapeutic switch : D4T, ddl, or AZT to ABC,3TC or TDF may be reasonable – Supportive measures: hydration, mitochondrial ventilation and dialysis – Anecdotal case reports show possible benefit of thiamine, L-carnitine, vit-C and antioxidants – Riboflavin 50mg/kg - most extensive & favourable
  • 57.
    Insulin Resistance • Incidence: –30-90% pts on PIs and overt DM occurs in 1-11% with a mean of 7% in 5yr • Screening: – RBG, FBG and HbA1c after 2-3 mo of the start of PI base regimen • Risk: – Risk of atherosclerosis
  • 58.
    Insulin Resistance • Rx –STD RX of type II DM and exercise – The two major classes of agents are insulin secretagogues (sulunylureas ) and insulin sensitizing agents ( metformin and thiazolidinediones / glitazones) – Metformin and glitazones have the potential advantage of improving insulin resistance and decreasing visceral fat accumulation – Therapeutic switch to non PI base ARV agents
  • 59.
    Hyperlipidemia • All PIsappears to have this effect with possible exception of atazanavir; • Observed within 2 to 3 month of initiating PI based regimen • Risk: – Possible risk of atherogenesis • DX & Rx: – ^LDL and TG--PI based ART esp.with retonavir – ^TC and HDL—EFV & NVP
  • 60.
    Rx of hyperlipidemia Lipidproblem Preferred alternative comment Isolated high LDL Statin niacin High cholesterol Statin or fibrate and TG Start one and add other Start low dose and titrate upward, watch for myopathy with PIs Combination may increase risk of myopathy Isolated high TG statin fibrate Combination may increase risk of myopathy
  • 61.
    Hepatotoxicity • NRTIs cancause hepatic steatosis, generally after more than 6 months of therapy, probably via mitochondrial toxicity.(D4T!) • NNRTIs can cause hepatitis in first 2-3 months of therapy, sometimes as a part of hypersensitivity reaction (NVP>EFV, DLV)-fluminant hepatic necrosis (NVP) • PIs can also cause hepatitis by an unknown mechanism, particularly in patients co-infected with hepatitis B or C, raised hepatic aminotransferase concentrations and alcoholism (RTV-the most common, among PIs) • Most hepatotoxic appears to be NVP followed by full dose RTV
  • 62.
    HYPERSENSITIVITY • Is about100 times more common in HIV Pts than in general population. • Erythematous maculopapular, pruritic and confluent rash, most ly on body and arms and begins after 1-2 weeks of therapy. • SJS or TEN develops in less than 0.3% of patients. • All NNRTI (Nevirapine,Delavirdine,Efavirenz, Etravirine), NRTI (Abacavir) and PI (Amprenavir) are common
  • 63.
    • About 50%of ARV hypersensitivity resolves spontaneously despite continuation of therapy. • Therapy should be stopped if there is mucosal involvement, blistering, exfoliation, clinically significant hepatic dysfunction • Glucocorticosteroids are ineffective for prevention of nevirapine hypersensitivity. • Rechallenge is possible for mild to moderate NNRTI hypersensitivity but not for abacavir,
  • 64.
    Laboratory monitoring ofpatients on ART: – CD4 cell count %: 3 and 6 months post-initiation, then every 6 months (all ages) – Viral load: 3 and 6 months post-initiation, then as follows: (Every 6 months for adults) – FBC: • AZT-based ART: at 4 and 12 weeks post-initiation, then annually only, and as clinically indicated • If not on AZT-based ART: annually only, and as clinically indicated
  • 65.
    • AST/ALT: – NVP-basedART: 2, 4, and 12 weeks post-initiation, thereafter only as clinically indicated – EFV-based ART: 4 and 12 weeks post-initiation, thereafter only as clinically indicated – PI-based ART: only as clinically indicated • Glucose and total cholesterol/triglycerides annually only if on PI- based ART • Creatinine and creatinine clearance : 3 and 6 months post-initiation and then, if stable, every 6 months (TDF only) • RPR (rapid plasma reagin )or VDRL test: after baseline, only as indicated
  • 66.
    Principles of HIVDrug Resistance • Results from changes (mutations) in genetic information in virus • These changes occur whenever HIV is replicating • Partial HIV suppression promotes resistance • Resistance can be delayed by suppressing virus completely • RT and protease are flexible (highly mutable) • Resistance may fade but not disappear when a drug is stopped • Some mutations allow certain viruses to resist effects of one or more antiretroviral drugs • Drug resistant virus usually grows faster and better than drug susceptible virus • Drug resistant virus replaces drug susceptible virus in patient 66
  • 67.
    Resistance Testing • Twotypes: – Genotyping Detects drug resistance mutations on virus genome that may make it resistant to certain antiretrovirals • Less expensive • Can usually be completed in 1-2 weeks – Phenotyping Measure ability of viruses to grow in presence of various concentrations of antiretroviral drugs • More expensive • Generally takes 2-3 weeks to complete 67
  • 68.
    Resistance Mutations • Forsome drugs (NNRTIs and 3TC), a single mutation causes high-level resistance. – Resistance to these drugs occurs very quickly • For other drugs (most NRTIs and PIs), many mutations must occur before high-level resistance is observed. – Resistance to these drugs occurs more slowly Cross-Resistance • Resistance to one drug can cause resistance to others of the same class – NNRTI: complete cross-class resistance – NRTI: partial cross-class resistance – PI: partial cross-class resistance • Partly overcome by ritonavir boosting 68
  • 69.
    Minimize Emergence ofViral Resistance • Never prescribe ARVs in absence of adherence counseling and support • Never prescribe monotherapy or dual therapy • Ensure optimal serum drug concentrations – Avoid drug interactions – Diagnose and manage malabsorption • If ARV medications are to be discontinued, stop all drugs at same time – Possible exception: NNRTI-based regimen 69
  • 70.

Editor's Notes

  • #44 ddC=zalcitabine
  • #57 Anecdotal =low account of incidents