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
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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 building DNA Acting as "false blocks causes Chain termination, Nucleus Once incorporated, work by preventing other nucleosides from Host also being incorporated b/c ofCell absence of a 3 OH group.

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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
Lamivudine

Dosage Form(s)
150-mg, 300-mg tablet; 10-mg/mL solution

Adult Dose
300 mg PO qd or 150 mg PO bid

Adverse Events
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 Nausea, vomiting, headache, asthenia, Anemia, granulocytopenia, myopathy, lactic acidosis, hepatomegaly with steatosis, nail pigmentation, lipid abnormalities, lipoatrophy, hyperglycemia

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

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 400 mg PO tid 600 mg PO qd Take on empty stomach to decrease Adrs

Adverse Events Rash, headache Rash, CNS (eg, somnolence, vivid dreams, confusion, visual hallucinations), hyperlipidemia

Delavirdine 100-mg, 200-mg tab. Efavirenz 600-mg tab.; 50-mg, 200-mg caps

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 tablet

25 mg PO qd with meal

Depressive disorders, insomnia, headache, rash

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
Atazanavir

Dosage Form(s)

Adult Dose

Adverse Events
Indirect hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%), hyperlipidemia Rash, nausea, diarrhea, hyperlipidemia, hyperglycemia

100-mg, 150-mg, 200- 400 mg PO qd or mg, 300-mg capsules 300 mg + ritonavir 100 mg PO qd

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 700-mg tab; 50-mg/mL oral sus.

Fosamprenavir

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

Indinavir

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 Lopinavir / ritonavir

Dosage Form(s)

Adult Dose

Adverse Events Nausea, vomiting, diarrhea, asthenia, hyperlipidemia, hyperglycemia

100-mg/25-mg, 200400 mg/100 mg PO bid or mg/50-mg tablets; 800 mg/200 mg PO qd 80-mg/20-mg per mL oral Oral solution: Take with meals solution

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

 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 Inhibitors - Chemokine (CCR5) co-receptor antagonist

entry,
a tropism assay is necessary to confirm that patients 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/rhabdomy olysis (rare)

Elvitegravir

Available in quad pill, elvitegravir/cob icistat/emtricitabine /tenofovir (Stribild).

nausea, diarrhea, fatigue, and headache

Commercial Fixed-dose combinations

Combination
Zidovudine + lamivudine Zidovudine + abacavir

Name
Combivir Epzicom

Zidovudine + lamivudine + abacavir

Tenofovir + emtricitabine Tenofovir + emtricitabine + efavirenz Stavudine + lamivudine + nevirapine

Trizivir (combivir +ABC)

Truvada Atripla (Truvada +EFV) Triomunea

Lopinavir + ritonavir
Rilpivirine + tenofovir/emtricitabine Elvitegravir+ cobicistat+ tenofovir + emtricitabine

Kaletra
Complera Stribild

Anti HIV agents under trials

Nucleosides- DAPD, DOTC, GW-42086, D-D4FC Non-nucleosides- DPC 961, DPC 083, Capravirine, Calanolide A, TMC 120 PIs- 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 Midazolam, trizolam Clarithromycin Oral contraceptives Amitriptyline

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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

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

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

INSTI Based regimen

RAL + TDF/FTC

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/L 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 illnessi.e., a new WHO stage 3 or 4 condition--after initiation of ART

Clinical Indications to Change ART Due to Toxicity

Symptom Nausea Vomiting Diarrhea Fever Clinical Indication Severe discomfort or minimal intake for > 3 days Severe vomiting of all foods/fluids in 24 hrs, orthostatic hypotension or need of IV fluids Bloody diarrhea, orthostatic hypotension or need of IV fluids 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
Fatigue
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Normal activity reduced > 50%

Lab Indications to Change ART Due to Toxicity

Parameter Hemoglobin (Hgb) Hematology *ANC Grade 3 Toxicity < 7.0 g/dL < 750/mm3 Normal Reference Values M: 13.8 17.2 g/dL F: 12 15.6 g/dL 1500 to 7000/mm3

Platelet count
Total Bilirubin Chemistries SCr AST / ALT LFTs Pancreatic Enzymes Lipids Cholesterol * ULN = Upper Limit of Normal
46

< 49 x 103/L
> 3-7.5 x ULN*= 3.9-9.75mg/dL > 1.7-2.0 (adult) 5-10 x ULN* = 210-420 U/L, 240-480 U/L > 2-3 x ULN* 8.49- 13.56 mmol/L 1.6-2.0 X ULN

130-400 x 103/L
1.3 mg/dL 1.2 mg/dL 42 U/L , 48U/L

Amylase, Lipase Triglyceride (TG)

23-85 U/L, 0-160 U/L < 200 mg/dL < 200 mg/dL

*ANC= Absolute neutrophil count

Serious Adverse Effects of NRTIs

All NRTIs** Lactic acidosis/fatty
Anemia Zidovudine (AZT, ZDV) Pancreatitis* didanosine (ddI) Neuropathy

liver*
Lipoatrophy (loss of

subcutaneous fat)
*Potentially life-threatening **d4T > ddI, AZT > ABC, TDF, 3TC

didanosine (ddI)
stavudine (d4T)

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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

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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

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.

PIs

 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 HDLEFV & NVP

Rx of hyperlipidemia
Lipid problem Preferred alternative niacin comment Start low dose and titrate upward, watch for myopathy with PIs Combination may increase risk of myopathy Combination may increase risk of myopathy Isolated high LDL Statin

High cholesterol Statin or fibrate and TG Isolated high TG fibrate

Start one and add other statin

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 PIbased 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

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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
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THANK YOU