Pharmacology

Unit 7

HIV Care and ART:

A Course for Physicians

2

Learning Objectives

Describe the mechanism of action of antiretroviral (ARV) drugs

List the common side effects of ARVs List the standard ARV doses Identify the ARVs that require dose adjustment

for patients with renal or hepatic disease List the ARVs that have food requirements

3

Learning Objectives (2)

Describe the mechanisms of drug interactions relevant to ARVs

Identify commonly used drugs that may have important interactions with ARVs

Describe the principles and mechanisms of drug resistance

Antiretroviral Drugs

5

Ethiopian ART Guideline

First Line Second Line

AZT or d4T

and

3TC

and

NVP or EFV

ABC, TDF, or AZT

and

ddI

and

Lop/r, SQV/r, NFV, IND/r

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2003 vs. 2005 WHO Guidelines

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Classes of Antiretrovirals

NRTIs Nucleoside reverse transcriptase inhibitorsNucleotide reverse transcriptase inhibitors (NtRTI)

NNRTIs – non-nucleoside reverse transcriptase inhibitors

PIs – protease inhibitors Fusion Inhibitors

8

ARVs and the HIV Lifecycle

9

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

RNA DNANucleus

Host Cell

10

Types of NRTIs

Zidovudine (AZT) Stavudine (d4T) Lamivudine (3TC) Didanosine (ddI) Abacavir (ABC) Zalcitabine (ddC) Emtricitabine (FTC) Tenofovir (TDF)-Nucleotide RTI

11

Zidovudine (AZT, ZDV)

Dosing: 300mg BID Food Interactions

None – can take with or without food Food decreases AZT-related nausea

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ZDV: Toxicity

Nausea Bone Marrow

SuppressionAnemia Neutropenia

Headache

Myalgia Myopathy Insomnia Pigmentation of nail

beds Lactic acidosis, fatty

liver

13

ZDV: Bone Marrow Suppression

Correlates with drug dose & duration, marrow reserve, and stage of disease

Anemia occurs after 4-6 weeks Neutropenia occurs after 12-24 weeks Marrow histology shows normal or reduced RBC

precursors Management

Stop AZT if Hgb <8 gm/dl Hgb typically recovers in 1 to 2 weeks

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ZDV-Related Fingernail Discoloration

Nail Hyperpigmentation Can be seen on hands and feet after 2-6 weeksUsually dark bluish-black vertical-line discoloration More common among African populationThis is NOT an indication to stop ZDV

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Lamivudine (3TC)

Dosing: 150mg BID or 300mg QD Food Interactions: none Toxicity: very rare Component of all first-line regimens Also active against Hepatitis B Main disadvantage: rapid development of

resistance

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Emtricitabine (FTC)

Dosing: 1 x 200mg capsule QD Food Interactions: no food interactions Toxicity

Mild abdominal discomfortOccasional nausea

Emtricitabine is the fluorinated version of lamivudine

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Hepatitis B Co-infection

Drugs active against both HBV & HIV: 3TC, FTC, TDF HBV develops rapid resistance to 3TC and FTC TDF + (3TC or FTC) is the optimal NRTI backbone Differential diagnosis of exacerbation of hepatic disease

in these patients: Development of 3TC or FTC resistance “HBV flair” secondary to stopping 3TC or FTC ART related hepatoxocity (AZT, d4T, ddI, EFV, NVP, All PIs) Immune reconstitution syndrome

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Lamivudine + Zidovudine

Dosing: 1 tablet (150 / 300mg) BID Food Interactions

None – with or without food is okFood decreases ZDV-related nausea

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Stavudine (d4T)

Dosing40 mg BID for weight > 60 kg30 mg BID for weight < 60 kg

Food Interactions: None Toxicity (use lower dose to reduce risk of S/E

development for patients < 60kg)Peripheral Neuropathy (5-15%, pain, tingling, and numbness in

extremities)Lactic acidosis, fatty liverLipoatrophyPancreatitisHypertriglyceridemia

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d4T: Dose-related Side Effects

Peripheral Neuropathy: Onset usually after 2-6 months of therapy. If develops: discontinue d4T at onset (or reduce dose

to 20mg Q12H if weight > 60kg, or 15mg Q12H if < 60kg)

Lipoatrophy: loss of fat tissue on arms, legs, and face

Pancreatitis:If develops, discontinue therapy. When symptoms resolve, do not re-challenge with

stavudine

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Facial Lipoatrophy

© ITECH, 2006

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Abacavir (ABC)

Dosing: 1 x 300mg tablet BID Food Interactions: no food interactions Generally well tolerated Toxicity

Hypersensitivity reaction • Occurs within first 6 weeks of therapy

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Hypersensitivity to Abacavir

Observed in approximately 5% of all patients receiving abacavir

Multi-organ system involvement Most common signs and symptoms:

Fever (>80%)Rash (maculopapular or urticarial) (70%)Fatigue (>70%)Flu-like symptoms (50%)GI (nausea, vomiting, diarrhea, abdominal pain)

(50%)

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Hypersensitivity to Abacavir (2)

Counsel and prepare patient for hypersensitivity symptoms and to contact provider/pharmacist immediatelyEspecially during first month of therapy

Provider/pharmacist determines cause of symptoms: abacavir or not

Hypersensitivity may be fatal (19 deaths) NEVER rechallenge Genetic predisposition Similar to life-threatening reaction to NVP

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Abacavir Re-challenge

20% risk of anaphylactic-like reaction upon re-challenge Death can occur with hours of restarting Symptoms may include include:

hypotensionbronchoconstriction renal failure

Laboratory changes may include Increased CPKElevated liver function testsReduced lymphocyte count

Abacavir should never be re-challenged!

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Tenofovir Disoproxil Fumarate (TDF)

Dosing: 1 x 300mg tablet QD Food Interactions: None Very well tolerated, side effects are minimal Toxicity

Renal insufficiency (rare)• Must dose adjust with renal failure

Also has activity against Hepatitis BDosed 300mg QDActive against Lamivudine resistant HBV strainsHBV resistance 1% at 1 year If TDF is stopped, may have HBV hepatitis flare

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Didanosine (ddI)

Requires a basic environment Food Interactions: take on empty stomach Dosing (one of the following)

1 x 400mg enteric coated capsule QD (if <60kg: 250mg QD)2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg: 125 mg

BID or 250mg QD)• NOTE: If use buffered tablets, 2 or more tablets must be

used at each dose to provide adequate buffer250mg of reconstituted buffered powder BID (if <60kg: 167mg

BID)• Mix pediatric powder with liquid antacid

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Didanosine (ddl) (2)

If taken with TDF must reduce ddI dose:> 60 kg < 60 kg250 mg/d 200 mg/d

Without dose adjustment – blunted CD4 response

ToxicityPeripheral NeuropathyGI intolerancePancreatitis (7%2%)Lactic acidosis, fatty liver

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NRTI Class Side Effects

As with all antiretrovirals, side effects are worst during the first 1 to 2 weeks of therapy.

Counsel patients Potential for side effects How to handle side effectsDon’t give up

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NRTI Class Side Effects (2)

Peripheral Neuropathy: ddl + d4TWith continued treatment may be irreversible

Lactic Acidosis, fatty liver: d4T > ddl > AZT Lipoatrophy: d4T > AZT Pancreatitis: ddl > d4T Marrow Suppression: AZT

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NRTI Mitochondrial Toxicity

Inhibition of mitochondrial DNA polymerase- oxidative metabolism, ATP generation

Implicated in lactic acidosis with hepatic steatosis

Other possible manifestations:Neuropathy (d4T, ddI) Lipoatrophy (d4T)Pancreatitis (ddI)Myopathy (AZT)Cardiomyopathy (AZT)

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Hyperlactatemia/Lactic Acidosis

Rare but potentially fatal syndrome (1/1000 pt/yrs) Linked to prolonged use of NRTIs, especially ddI and

d4T Acute or subacute onset Symptoms: nausea, vomiting, weight loss, fatigue Lab: increased anion gap (or lactate level) Ultrasound: fatty liver Management: discontinue NRTI – may take months to

reverse. No specific treatment

33

Neucloside Pairings

YES NO

AZT + 3TC * AZT + d4T

d4T + 3TC * d4T + ddI

TDF + 3TC * (TDF + ddI)

ddI + 3TC * (AZT + ddI)

* Can use FTC same as 3TC

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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

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Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIsNevirapine (NVP)Efavirenz (EFV)

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Nevirapine (NVP)

Dosing: 200 mg QD x 2 weeks, then 200 mg BID Food Interactions: None Toxicity

Rash (17%)Nausea & vomitingHepatitis (8-18%)

• Risk is greatest in first 6 weeks of therapy• Could be benign or fatal

Black Box warning by FDA (USA): Do not use NVP in women w/ starting CD4>250Do not use NVP in men w/ starting CD4> 400

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Hepatotoxicity: NVP & PIs

NVP:Hepatic necrosis 1st 6-16 weeks after starting RxThose at higher risk for hepatitis include:

• Patients with a history of alcohol abuse, coinfection with hepatitis B or C and in patients who are older or are women.

• Persons with higher CD4 cell counts or elevated LFTs at baseline

PI & NNRTIs: All cause ↑ ALT/AST in 10-15%

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Hepatotoxicity: NVP & PI (2)

NVP Others

When First 6-16 weeks Late

Sxs Rash, GI Sxs No Sxs

Long term consequence

Serious Unknown

When to d/c drug

Promptly ALT> 5-10 x ULN

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NVP: Hepatotoxicity “Symptomatic Hepatitis”

CD4 count Rate

Women CD4 > 250 11%

CD4 < 250 0.9%

Men CD4 > 400 6.4%

CD4 < 400 2.3%

Analysis of 607 treatment naïve patients (2NN)

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NVP for PMTCT

Issue is RESISTANCE and EFFICACY No SAFETY concerns

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Nevirapine-Induced Rash

Courtesy of HIV Web Study, www.hivwebstudy.org

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Nevirapine-Induced Rash (2)

To reduce the riskThe dose should be escalated over the first 2 weeks

• Starting at 200mg QD for 2 weeks and then increasing to 200mg BID

This dosing makes sense because nevirapine autoinduces hepatic cytochrome P450 enzymes (CYP3A4)

• Which reduces its own half-life over 2 to 4 weeks from 45 to 25 hours.

43

Efavirenz (EFV)

Dosing: 3 x 200mg capsules or 600mg tab QHS Food Interactions

Take on an empty stomach or with low-fat meal• High-fat meals increase absorption by 50%

increases side effects

Consistent results: persistent activity after >5 years

Never surpassed in clinical trial

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Efavirenz Toxicity

CNS Changes (52%) Rash (15-27%) usually does not require

discontinuation Hepatotoxicity (2-8% experience increase in

LFTs > 5 ULN) Contraindicated during pregnancy

Teratogenic—Class D

45

Efavirenz CNS Toxicity

Symptoms: confusion, Insomnia, nightmares, poor concentration, mood change, dizziness, dysequilibrium, depression, psychosis, “disconnected”

Onset: first dose Course: usually resolves in 2-3 weeks Cause: Unknown Management: warn patient

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Which Third Drug to Use?

Advantage Disadvantage

NNRTI ↓ pill burden

Potency

Rifampin

Low barrier to resistance

Rash

EFV & pregnancy

PI Potency

Less resistance

Boost with RTV

Metabolic effects

Drug intolerance

GI intolerance

47

EFV vs. NVP

NVP EFV

Daily doses 2 1

Efficacy Similar Similar

Pregnancy Yes No

TB (Rifampin) No (?) Yes

Side Effects Liver *; Rash * CNS

Resistance Low barrier Low barrier

* May be lethal

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NNRTI Class Effects

Side effectsRashHepatotoxicity

Cross resistance:A single mutation, the K103N, causes high-level

resistance to all 3 drugs in this class: EFV, NVP, and DLV

Latent pool foreverImportance of adherence

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NNRTI Rash

Often diffuse, slightly raised, itchy

Vary in redness and distribution

Can be severe - Steven’s Johnson Syndrome

Courtesy of the Public Health Image Library/CDC/ J. Pledger, BSS/VD

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DNA

Host Cell

Protease Inhibitors (PIs)

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Protease Inhibitors (2)

Lopinavir + Ritonavir Nelfinavir Saquinavir-HGC Indinavir Fosamprenavir Atazanavir Ritonavir

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Ritonavir (RTV)

Substantial GI intolerance prevents use at full, original dose

Now used to boost other PIs Doses < 400 mg/day – no anti-HIV activity Nomenclature: /r (LPV/r, SQV/r) Requires refrigeration Hard to make

53

Ritonavir Boosting

AUC

Saquinavir 30 – 74 x

Lopinavir 15 – 20 x

Indinavir 3 – 6 x

Nelfinavir 1.5 x

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Clinical Pharmacology of ART 54

Pharmacokinetic Rationale for Dual PI Therapy

Single PI is used: Peaks may reach well above the desired

concentration for effectiveness • This may lead to drug toxicity

Levels of the drug may become too low• Permitting viral replication

PIs are used together Lower peak levels achieved

• Reduces the chance of side effects Higher trough levels acheived

• Increases potency and reduces the chance of viral replication

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Lopinavir/ritonavir (LPV/r)

Dosing: 3 caps (400 mg lopinavir/100 mg ritonavir) BIDEach capsule contains LPV 133mg / RTV 33mg

Food Interactions: take with food Toxicity

NauseaWeaknessDiarrhea (mild to moderate)LipodystrophyALT/AST increase

Refrigeration recommendedStable at room temperature for up to 2 monthsHot temperatures should be avoided

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Nelfinavir (NFV)

Dosing: 1250 mg PO BID Food Interactions: take with meal Toxicity

Diarrhea (10%-30%)Abdominal painFlatulenceNauseaRashLipodystrophyALT/AST increase

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Saquinavir-Hard Gel Capsules (SQV) Invirase

Dosing: Must take with Ritonavir 1000 mg /100 mg bid with food

ToxicityDiarrheaNauseaAbdominal painHeadacheLipodystrophyALT /AST increase

Refrigeration recommended, but OK at room temperature for up to 3 monthsHot temperatures should be avoided

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Indinavir (IDV)

Dosing: 2 x 400mg q 8 hours ORWith RTV 800 / 100 mg bid

Food Interactions: take on empty stomach, or with low fat snack (e.g. non-fat milk)

Capsules are sensitive to moisture

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Indinavir (IDV): Toxicity

Nausea Diarrhea Nephrolithiasis (flank pain, ↑ SrCr, hematuria, pyuria)

(2%) Dry lips, dry skin Bald patches in hair Ingrown toe or finger nails Acid reflux (3%) Hyperbilirubinemia (10-15%) Lipodystrophy ALT /AST increase

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PI Class Side Effects

Metabolic Disorders Hepatotoxicity Hyperglycemia, insulin

resistance Lipid abnormalities Fat redistribution

Bone Disorders

GI Intolerance Drug Interactions

CYP450 3A4 Inhibition: RTV, LPV > IDV = NFV = APV >SQV

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Hepatotoxicity

Increased LFT’s observed with all PI’s. More common in pts with chronic viral hepatitis

(HBV, HCV). Data do not support withholding PI’s from pts co-

infected with HBV or HCV. Increased ALT/AST is common (10-20%),

asymptomatic and unclear consequence

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HIV Lipodystrophy Syndrome

DefinitionA complex medical condition Including abnormal fat redistribution and metabolic disturbances Seen in HIV patients receiving ART

Metabolic complications (primarily PI therapy) Hepatic insulin resistance Impaired glucose toleranceType 2 diabetesHypertriglyceridemiaHypercholesterolemiaDecreased high density lipoprotein (HDL)

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Fat Redistribution

Fat accumulation (lipohypertrophy) --PIsDorsocervical fatVisceral adiposityBreast enlargement

Fat loss (lipoatrophy) – d4TFacial fat lossSubcutaneous fat loss of extremities

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Fat Redistribution Syndromes

Fonte: Dominic C. Chow, MD, University of Hawaii; Larry J. Day, MD, University of Michigan; Cecilia M. Shikuma, MD, University of Hawaii

65

HIV Lipodystrophy Syndrome (2)

Abnormality Assoc. agent

Monitoring Conse - quence

Rx

Fat re-distribution

All ARVs

Appearance Cosmetic None;

d/c drug

Insulin resistance

All PIs Blood glucose

Diabetes Standard

Lipid Increase All PIs, except ATV

Lipids Cardio-vascular disease

Standard

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Management of Hyperlipidemia

LDL Goal Life Style Drug Rx

Cardiovascular Disease or Diabetes

< 70 < 100 > 130

> 2 risks * < 100 – 130 < 130 > 130

0-1 risk * < 160 < 190 > 190

* Risk = HBP, Age > 45-55 yrs, smoking, genetics

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Fusion Inhibitor: Enfuvirtide (T-20)

First fusion inhibitor Binds to gp41 and prevents HIV entry into host cellUsed as part of salvage regimen for ART experienced

patients

Dosing: 90 mg BID by subcutaneous injection Food interaction: None Toxicity

Injection site reactions (98%)Nausea, diarrhea, fatigue, hypersensitivity (< 1%)

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Dosing Considerations in Patients with Liver Disease

Drug Hepatic impairment

NRTIs No dosage recommendation

NVP No data available; avoid use in patients with moderate to severe hepatic impairment

EFV No recommendation; use with caution in patients with hepatic impairment

LPV/r

SQV

NFV

No recommendation; use with caution in patients with hepatic impairment

IND Reduce dose from 800mg to 600mg in moderate cirrhosis

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Dosing Considerations in Patients with Renal Failure

CrCl

>60

CrCl

30-59

CrCl

10-29

CrCl

<10

AZT 300mg bid 300mg bid 300mg bid 100mg tid

3TC 150mg bid 150mg qd 100mg qd 50mg qd

d4T* 40mg bid 20mg bid 20mg qd 20mg qd

ddI* 400mg qd 200mg qd 125mg qd 125mg qd

TDF 300mg qd 300mg q48 300mg twice/wk

300mg qwk

*dosing for patients > 60kg

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Significant Drug Interactions with ART

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Mechanisms for Drug Interactions

Altered intracellular activationD4T combined with ZDV

Altered drug absorption and tissue distributionFlouroquinolones combined with antacids form

insoluble complex

Altered drug metabolismRifampicin combined with NVP

Reduced renal excretion

72

First Pass Effect

Orally administered drugs Absorbed in the gastrointestinal tract Pass through the portal venous system to the liver Subject to first pass effect in the liver

• May limit systemic circulationOnce in the systemic circulation, drugs interact with

receptors in target tissues

73

Drug Metabolism/Elimination

Goal of metabolism: To change the active part of the medication, making

them more water-soluble and more readily excreted by the kidney

Metabolism occurs via two types of reactions: 1. Phase I reactions involve:

Oxidation, hydrolysis, and reduction, take place primarily in the liver CYP450

2. Phase II reactions involve: Conj (adding another compound) to form glucuronides

74

Cytochrome (CYP450)

Present in liver, small intestines, lungs, and brain Primary function is to alter toxins (drugs) to speed

excretion Isoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily

responsible for drug metabolism Also metabolize steroid hormones, vitamins, toxins,

prostaglandins, fatty acids Knowledge of substrates, inhibitors and inducers helps

predict drug interactions important as PIs are metabolized 80-95% by the CYP450

isoenzymes in liver and small intestine

75

Cytochrome P450 Enzymes

Outcome of Drug

Interaction

Variability

Patient Factors Drug Factors

•Genetics

•Diseases

•Diet/Nutrition

•Environment

•Smoking

•Alcohol

•Dose

•Duration

•Dosing Times

•Sequence

•Route

•Dosage Form

Adapted from Philip D. Hansten, Science & Medicine 1998

76

P450 Drug Interactions

SubstrateAny drug that is metabolized by one or more of the P450

enzymes It is the object drug which is affected by inducer or inhibitor

InducerSpeeds up metabolismDecreases substrate level (lack of efficacy is concern)Onset/offset is gradual

InhibitorSlows metabolism of substrate drug Increases level of drug in blood (toxicity is concern)Quick onsetThis process is almost always competitive and reversible

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CYP P450 Drug-Drug Interactions

Pharmacologic action of drug is altered by coadministration of second drug

Co-administration may:

Drug B

Drug A

No Consequences

effect (e.g. ritonavir + saquinavir; ritonavir + simvastatin)

effect (e.g.,rifampin + protease inhibitors, indinavir + coumadin)

New effect (e.g., ritonavir + amitriptyline;)

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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 Alternative medicine Clarithromycin Oral contraceptives Amitriptyline

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Drug interactions - Key Points

A drug interaction may occur when A new medication is startedA medication is discontinuedA dose is changed

Use reference manuals when starting / changing therapy

Beware of food requirements with certain ARVs

Drug Resistance

81

Case Study: Berhan

A 50 year old male patient completed 9 months of TB therapy (with rifampicin and isoniazid along with pyridoxine) 3 weeks ago and is continuing with ARV (EFV 800 mg qhs, 3TC 150 mg bid and ZDV 300 mg bid) therapy

He presents to the ER with a bloody nose and bruises on his arm.

Other current medications include:coumadin for atrial fibrillationatenolol for blood pressure

What do you suspect has happened?

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Principles of HIV Drug Resistance

Not all drug failure is due to resistance Partial HIV suppression promotes resistance Resistance can be delayed by suppressing the

virus completely RT and protease are flexible (highly mutable) Resistance may fade but not disappear when

a drug is stopped

83

Principles of Resistance (2)

Some mutations allow certain viruses to resist the effects of one or more antiretroviral drugs

Each infected person has a mixture of viruses, some of which are resistant to some medications

The drug resistant virus usually grows faster and better than the drug susceptible virus

The drug resistant virus replaces the drug susceptible virus in the patient

84

Resistance Testing

Two types:Genotyping

• Less expensive

• Can usually be completed in 1-2 weeksPhenotyping

• More expensive

• Generally takes 2-3 weeks to complete

85

Suspect Resistance in the Setting of Treatment Failure

Due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated

These variants often contain mutations that confer variable levels of resistance to antiretroviral agents

Poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’

86

How Does Resistance Develop?

Results from changes (mutations) in the genetic information in the virus

These changes occur whenever HIV is replicating

Every possible mutation occurs tens of thousands of times each day

87

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

88

Cross-Resistance

Resistance to one drug can cause resistance to others of the same classNNRTI: complete cross-class resistanceNRTI: partial cross-class resistancePI: partial cross-class resistance

• Partly overcome by ritonavir boosting

89

Minimize Emergence of Viral Resistance

Never prescribe ARVs in the 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 the same timePossible exception: NNRTI-based regimen

Case Studies

91

Case Study: Mulu

48 yo woman has received NVP/3TC/d4T. The pharmacy has no NVP in stock

What should she do?Continue 3TC/d4T until the NVP becomes available,

then add NVPStop all drugsStop NVP for 7 days then stop 3TC/d4T

92

Case Study: Mengistu

A 50 year old man has taken EFV/AZT/3TC for 1 year. He now presents with thrush.

What should he take now?1. NVP / 3TC / ddI

2. NFV / 3TC / d4T

3. NVP / 3TC / AZT / ABC

4. LPV/r / d4T / AZT

5. NFV / TDF / ddI

93

Case Study: Senait

20 year old woman has received EFV/AZT/3TC and has done well with a CD4 increase from 180 280 /mm3. She becomes pregnant.

What should she take?1. NVP / AZT / 3TC

2. NFV / AZT / 3TC

3. NVP / d4T / ddI

4. NVP / TDF / ABC

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Case Study

Which of the following is the best regimen for a patient with HIV who failed EFV/3TC/AZT and now has active TB?1. LPV/r / d4T / ddI

2. NFV / ddI / TDF

3. NVP / ddI / TDF

4. NFV / d4T / TDF

5. Stop ART; resume after completion of Rifampicin

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Key Points

Goals of ART include: Suppression of viral replicationRestoration of immunologic function

Effective ART requires strict adherence, proper monitoring of side effects and disease

progression, recognition and treatment of co-morbidities.

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Key Points (2)

ART involves a combination of at least 3 drugs, usually 2 NRTIs + 1 NNRTI or 1 PI.

First line regimen for Ethiopia is d4T/3TC/NVP. A drug interaction can occur whenever a

medication is started or discontinued, or whenever a dose is changed.

97

Key Points (3)

Physicians must be knowledgeable about potential drug-drug and drug-food interactions.

Physicians should question a patient about their current medications whenever filling a prescription that is new for them, when a dose is changing or when a medication is being discontinued.

Patients should be educated that drug interactions can also occur if they stop or receive a change in dose of their medications.

98

Key Points (4)

Drug resistance occurs when HIV continues to grow in the presence of medications.

A patient with HIV will develop drug resistance if treated with only 1-2 drugs or if they regularly miss doses.

Drug resistance limits activity of current drug regimen and limits future options.