ModeratorDr. Saroj Purohit

ART DRUGS

SEMINAR PRESENTATION

• 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

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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

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

analogues• 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])

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RNA DNANucleus

Host Cell

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• Acting as "false building blocks causes Chain termination, • Once incorporated, work by preventing other nucleosides from

also being incorporated b/c of absence of a 3’ OH group.

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 or300 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< 60 kg: 250 mg PO qdTake 30 min ac or 2 hr pc Oral solution: Divide daily dose bid

Peripheral neuropathy, pancreatitis, nausea, lactic acidosis

Emtricitabine 200-mg capsule;10-mg/mL oral solution

200 mg PO qd or240 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 or150 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 capsule;10-mg/mL oral solution;10-mg/mL intravenous solution

300 mg PO bid or 200 mg PO tid

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

DrugsFirst-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 EventsDelavirdine 100-mg, 200-mg tab. 400 mg PO tid Rash, headache

Efavirenz 600-mg tab.;50-mg, 200-mg caps

600 mg PO qdTake 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 bidXR: 400 mg PO qd

Rash, hepatitis

Rilpivirine 25-mg tablet 25 mg PO qd with meal Depressive disorders, insomnia, headache, rash

Protease Inhibitors (PIs)

Drugs• Atazanavir sulfate, ATV• Darunavir• Fosamprenavir Calcium,

FOS-APV• Indinavir, IDV,• lopinavir / ritonavir,

LPV/RTV• Nelfinavir mesylate, NFV• Saquinavir mesylate, SQV• Tipranavir, TPV

• First introduced in 1995 • Are an integral part of

treatment• Exhibit activity against

clinical isolates of both HIV-1 and HIV-2.

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) Adult Dose Adverse EventsAtazanavir 100-mg, 150-mg, 200-

mg, 300-mg capsules400 mg PO qd or300 mg + ritonavir 100 mg PO qd

Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia

Darunavir 75-mg, 150-mg, 300-mg, 400-mg, 600-mg tablets

800 mg qd + ritonavir 100 mg PO qd or 600 mg bid + ritonavir 100 mg PO bid

Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia

Fosamprenavir 700-mg tab;

50-mg/mL oral sus.

700 mg bid + ritonavir 100 mg PO bid or 1400 mg PO bid or 1400 mg + ritonavir 100-200 mg PO qdSus.: Take without foodwith RTV: Take with food

Rash, nausea, vomiting, diarrhea, hyperlipidemia, hyperglycemia

Indinavir 100-mg, 200-mg, 400-mg capsules

800 mg PO q8h800 mg PO bid + ritonavir 100-200 mg PO bidTake 1 h ac or 2 h pc;

Nephrolithiasis, nausea, indirect hyperbilirubinemia, hyperlipidemia, hyperglycemia

Name Dosage Form(s) Adult Dose Adverse Events

Lopinavir / ritonavir

100-mg/25-mg, 200-mg/50-mg tablets;80-mg/20-mg per mL oral solution

400 mg/100 mg PO bid or800 mg/200 mg PO qdOral 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 Nonboosting dose 600 mg bid

Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, oral paresthesias, hyperglycemia

Saquinavir 500-mg tablet;200-mg hard gelatin capsule

1000 mg + ritonavir 100 mg PO bidUnboosted not recommendedTake with food, or within 2 h pc

Nausea, diarrhea, headache, hyperlipidemia, hyperglycemia, PR and QT interval prolongation

Tipranavir 250-mg soft gelatin capsule100-mg/mL oral solution

500 mg + ritonavir 200 mg PO bidUnboosted 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

With rifampin: 800 mg PO bid

Nausea, diarrhea, headache, CK elevations, myopathy/rhabdomyolysis (rare)

Elvitegravir Available in ‘quad’ pill, elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild).

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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,

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Drugs with Potential to Interact with PIs or NNRTIs

• Statins (simvistatin & lovastatin)• Azole antifungals• Anticonvulsants• Anti-TB (Rifampicin)• Warfarin

• 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

• Preferred regimenNNRTI – Based regimen

• EFV/TDF/FTC

PI – Based regimen• ATV/r + TDF/FTC• DRV/r (OD) + TDF/FTC

INSTI – Based regimen• RAL + TDF/FTC

Standard ART consists of 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor.

Alternative RegimensNNRTI-Based Regimens EFV + ABC/3TC

RPV/TDF/FTCRPV + ABC/3TC

PI-Based Regimens ATV/r + ABC/3TCDRV/r + ABC/3TCFPV/r (once or twice daily)+ABC/3TC or TDF/FTCLPV/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

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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 Neuropathy

Severe discomfort, objective weakness, loss of 2-3 previously present reflexes or sensory dermatomes

Fatigue Normal activity reduced > 50%

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Lab Indications to Change ART Due to Toxicity

Parameter Grade 3 Toxicity

Normal Reference Values

Hematology

Hemoglobin (Hgb) < 7.0 g/dL M: 13.8 – 17.2 g/dLF: 12 – 15.6 g/dL

*ANC < 750/mm3 1500 to 7000/mm3

Platelet count < 49 x 103/µL 130-400 x 103/µL

Chemistries

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

LFTs

AST / ALT 5-10 x ULN* = 210-420 U/L, 240-480 U/L

≤ 42 U/L , ≤ 48U/L

Pancreatic Enzymes

Amylase, Lipase > 2-3 x ULN* 23-85 U/L, 0-160 U/L

Lipids

Triglyceride (TG) 8.49- 13.56 mmol/L

< 200 mg/dL

Cholesterol 1.6-2.0 X ULN < 200 mg/dL

* ULN = Upper Limit of Normal *ANC= Absolute neutrophil count

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• All NRTIs**

– Lactic acidosis/fatty

liver*

– Lipoatrophy (loss of

subcutaneous fat)

• Anemia

– Zidovudine (AZT, ZDV)

• Pancreatitis*

– didanosine (ddI)

• Neuropathy

– didanosine (ddI)

– stavudine (d4T)*Potentially life-threatening

**d4T > ddI, AZT > ABC, TDF, 3TC

Serious Adverse Effects of NRTIs

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Serious Adverse Effects of NNRTIs

• All NNRTIs

– Hepatitis*

– Skin rash

• CNS symptoms

– efavirenz

• Stevens-Johnson

syndrome*

– nevirapine

*Potentially life-threatening

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Serious Adverse Effects of PIs

• All PIs

– Insulin resistance hyperglycemia and diabetes

– Elevated serum lipids

– Abnormal fat accumulation

– Liver toxicity*

*Potentially life-threatening

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

NRTIsd4T>ZDV

Lactic acid SC fat wasting TGBuffalo hump

Intra-abdominal fat Cholesterol TGInsulin resistance

PIs

Lipodystrophy Syndrome: NRTIs versus PIs

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

• 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

Insulin Resistance

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 hyperlipidemiaLipid problem Preferred alternative comment

Isolated high LDL Statin niacin Start low dose and titrate upward, watch for myopathy with PIs

High cholesterol and TG

Statin or fibrate Start one and add other

Combination may increase risk of myopathy

Isolated high TG fibrate statin 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,

– 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

Laboratory monitoring of patients on ART:

• 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

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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

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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

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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

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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

THANK YOU