Pharmacology

Unit 7HIV Care and ART: A Course for Physicians

This Unit should take approximately 3 hours, 5 minutes to implement.Step 1: Unit Overview and Learning Objectives (Slides 1 3) 5 minutesStep 2: Antiretroviral Drugs (Slides 4 69) 2 hoursStep 3: Significant Drug Interactions with ART (Slides 70 79) 20 minutesStep 4: Drug Resistance (Slides 80 89) 20 minutesStep 5: Case Studies (Slides 90 94) 10 minutesStep 6: Summary of Key Points (Slides 95 98) 10 minutes

*Learning ObjectivesDescribe the mechanism of action of antiretroviral (ARV) drugsList the common side effects of ARVs List the standard ARV dosesIdentify the ARVs that require dose adjustment for patients with renal or hepatic disease List the ARVs that have food requirements

Step 1: Unit Overview and Learning Objectives (Slides 1 3) 5 minutes

*Learning Objectives (2)Describe the mechanisms of drug interactions relevant to ARVs Identify commonly used drugs that may have important interactions with ARVsDescribe the principles and mechanisms of drug resistance

Antiretroviral Drugs

Step 2: Antiretroviral Drugs (Slides 4 69) 2 hours

*Ethiopian ART Guideline

First LineSecond LineAZT or d4Tand3TCandNVP or EFVABC, TDF, or AZTandddIandLop/r, SQV/r, NFV, IND/r

Effective ART requires use of three-drug combinations. This slide shows the combinations available in Ethiopia, and reflects the WHO guideline. The individual drugs will be reviewed in this unit, and the principles of combining therapy will be reviewed in subsequent units.

*2003 vs. 2005 WHO Guidelines

This picture shows both the 2003 and 2005 (preliminary report) WHO guidelines on antiretroviral therapy in developing settings. FTC, TDF, and ABC have been included in the first line options.

*Classes of AntiretroviralsNRTIs Nucleoside reverse transcriptase inhibitorsNucleotide reverse transcriptase inhibitors (NtRTI)NNRTIs non-nucleoside reverse transcriptase inhibitors PIs protease inhibitorsFusion Inhibitors

There are two different classes of anti-HIV drugs that target the reverse transcriptase enzyme, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Protease Inhibitors will be discussed later in the session. Fusion Inhibitors: Fusion inhibitors bind to the HR1 site in the gp41 subunit of the viral envelope glycoprotein and prevent the conformational change that is needed to allow virus to enter the cell.

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*ARVs and the HIV Lifecycle

Use this slide as a brief review of the HIV lifecycle and to point out where each of the four classes of ARVs workThe following slides contain more detail about how each class of ARVs work, the different drugs in each class, and their side effects

The first step in the HIV lifecycle is viral attachment and fusion at the cell membrane. This can be blocked by fusion inhibitors, which are extremely expensive ARVs that are used primarily for salvage therapy in the US and Europe.Once HIV has invaded the host cell, reverse transcriptase (RT) translates HIVs genetic material (single stranded RNA) into double stranded DNA - the building block of all human cells. NRTIs and NNRTIs inhibit this step. This viral DNA then integrates into the host cell DNA. This is another potential site for therapy (still experimental)When the cell is activated, the viral DNA undergoes translation and creates complex HIV proteins. These new HIV proteins are not infectious until the viral protease enzyme cuts each complex protein chain into smaller functional proteins that can be used to build the new virus (e.g., the core, the envelope). This is the step that protease inhibitors block.

*Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

RNADNA

NucleusHost Cell

1

NRTIs compete with the normal physiological nucleosides used for DNA synthesis. They differ from the normal substrates only by a minor modification in the sugar (ribose) molecule. Acting as "false building blocks, nucleoside analogs incorporate themselves, preventing DNA synthesis, because normal bridges can no longer be built to build the double strand. Thus they prevent the development of functional viral DNA

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

Please refer to the Ethiopian DACA for current availability of drugs.

*Zidovudine (AZT, ZDV)Dosing: 300mg BIDFood InteractionsNone can take with or without food Food decreases AZT-related nausea

The first ARV approved in 1987 15 years have passed, and AZT is still a common component of ARV regimens. Early ZDV was dosed 5 times daily and the toxicities were much greater. Now, the drug is better tolerated, though it does still have significant side effects (nausea, anemia).Zidovudine is available in Ethiopia as combination Zidovudine/Lamivudine

Reference Notes:Nucleoside Analog: Thymidine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite, zidovudine 5-triphosphate.Bioavailability (F): 60%CSF Levels: 60% of serum levelsT1/2: 1 hourIntracellular T1/2 (NRTIs exert their effect intracellulary, duration of action is based on intracellular half-life): 3 hours

*ZDV: ToxicityNauseaBone Marrow SuppressionAnemia NeutropeniaHeadache

MyalgiaMyopathy InsomniaPigmentation of nail bedsLactic acidosis, fatty liver

Nausea Most common side effect for AZTEating prior to dose helps reduce nauseaMacrocytosis is common and not associated with anemia, see increase in MCV of 25-40 units after 6-24 weeks, serves as crude indicator of adherence.

*ZDV: Bone Marrow SuppressionCorrelates with drug dose & duration, marrow reserve, and stage of diseaseAnemia occurs after 4-6 weeksNeutropenia occurs after 12-24 weeksMarrow histology shows normal or reduced RBC precursorsManagementStop AZT if Hgb

*ZDV-Related Fingernail DiscolorationNail 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

*Lamivudine (3TC)Dosing: 150mg BID or 300mg QDFood Interactions: noneToxicity: very rareComponent of all first-line regimens Also active against Hepatitis BMain disadvantage: rapid development of resistance

Minimal Side Effects: Best tolerated of all antiretrovirals.ResistanceLow barrier to resistance: a single point mutation (M184V) is sufficient for loss of effectiveness Advantages of the M184V mutation include:Improves the susceptibility of certain ZDV-resistant viruses in some patientsImpairs viral fitnessKeeping 3TC as part of a combination despite proven resistance is therefore sensible because this drug will continue reduce the replicative capacity of HIV

Nucleoside Analog: Cytosine analogueMechanism of Action: It is phosphorylated 3 times by thymidine kinase to the active metabolite, 3TC-triphosphate Bioavailability (F): 86%CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA from CSF)T1/2: 3-6 hoursIntracellular T1/2: 12 hours

*Emtricitabine (FTC)Dosing: 1 x 200mg capsule QDFood Interactions: no food interactionsToxicityMild abdominal discomfortOccasional nauseaEmtricitabine is the fluorinated version of lamivudine

The flourinated version was designed to reduce toxicity and prolong drug half-life, but clinically there does not appear to be any difference between the 2 drugs. FTC has demonstrated activity against Hepatitis B, but it is not FDA approved for this indication.

Nucleoside Analog: Cytosine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite, emtricitabine 5-triphosphateBioavailability (F): Good oral bioavailability.CSF Levels: Estimated to be low (in monkeys, CSF level was 4% of serum levels)T1/2: 8-9 hoursIntracellular T1/2: > 20 hours

* Hepatitis B Co-infectionDrugs active against both HBV & HIV: 3TC, FTC, TDFHBV develops rapid resistance to 3TC and FTCTDF + (3TC or FTC) is the optimal NRTI backbone Differential diagnosis of exacerbation of hepatic disease in these patients: Development of 3TC or FTC resistanceHBV flair secondary to stopping 3TC or FTC ART related hepatoxocity (AZT, d4T, ddI, EFV, NVP, All PIs)Immune reconstitution syndrome

*Lamivudine + Zidovudine Dosing: 1 tablet (150 / 300mg) BIDFood InteractionsNone with or without food is okFood decreases ZDV-related nausea

This drug combination is available in Ethiopia.

*Stavudine (d4T)Dosing40 mg BID for weight > 60 kg30 mg BID for weight < 60 kgFood Interactions: NoneToxicity (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

Less gastrointestinal side effects and limited myelotoxicity compared to ZDV, and just as effective. However, long term toxicities are substantial.

Nucleoside Analog: Thymidine analogueMechanism of Action: It is phosphorylated 3 times, first by thymidine kinase, 2nd by thymidylate kinase, and 3rd by pyrimidine diphosphate kinase to the active metabolite, stavudine triphosphate.Bioavailability (F): 86%CSF Levels: 30% - 40% of serum levels

*d4T: Dose-related Side EffectsPeripheral 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 facePancreatitis:If develops, discontinue therapy. When symptoms resolve, do not re-challenge with stavudine

Peripheral Neuropathy: Symptoms will dissipate slowly after stopping d4T or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating.Lipoatrophy: It may take years for lipoatrophy to visibly improve following discontinuation of d4Td4T should be replaced ideally with abacavir or tenofovir.

*Facial Lipoatrophy ITECH, 2006

Characterized by thinning of the buccal fat pad. May result or exacerbate stigma associated with HIV.Appears to be most common with long-term stavudine use.Usually not reversible, but changing medications may prevent progression.

*Abacavir (ABC)Dosing: 1 x 300mg tablet BIDFood Interactions: no food interactionsGenerally well toleratedToxicityHypersensitivity reaction

Occurs within first 6 weeks of therapy

Patients should be counseled about abacavir hypersensitivity reaction (see next slides).

Reference NotesNucleoside Analog: Guanine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite.Bioavailability (F): 83%CSF Levels: 27%-33% of serum levelsT1/2: 1.5 hoursIntracellular T1/2: > 12 hoursElimination: 81% metabolized by alcohol dehydrogenase and glucouronyl transferase with renal excretion of metabolites; 16% recovered in stool, and 1% unchanged in urine. Dose does not need to be adjusted for compromised renal function. No data on hepatic failure, use usual dose.Pediatric Dose: 8mg/kg BID Pregnancy: (Category C) Crosses placenta.Drug Interaction: Alcohol increases ABC levels by 41%. Abacavir does not impact alcohol levels. Clinically, moderate alcohol use appears to be fine, do not need to adjust dose.Resistance: ABC selects for the following mutations: 65, 74, 115, and 184. The 184 mutation leads to complete cross-resistance with 3TC, but by itself does not significantly decrease ABC susceptibility. Mutations at codons 65 and 74 lead to cross-resistance to ddI and ddC. Significant resistance requires multiple mutations, usually in addition to the 184 mutation. If have M184V + at least 3 NAMS, expect ABC failure.

*Hypersensitivity to AbacavirObserved in approximately 5% of all patients receiving abacavirMulti-organ system involvementMost common signs and symptoms:Fever (>80%)Rash (maculopapular or urticarial) (70%)Fatigue (>70%)Flu-like symptoms (50%)GI (nausea, vomiting, diarrhea, abdominal pain) (50%)

Symptoms Appear 1-2 weeks after initiation of ABC (up to 6 weeks). Onset of the symptoms is felt after a dose. Symptoms improve between doses and then worsen again after next dose. The symptoms appear to worsen with each dose. In contrast to other allergic reactions (e.g., nevirapine or TMP/SMX), where onset of rash or other symptoms occur immediately and do not worsen with each dose.If the provider does not feel that the patient could be adherent to their medications during the first 2-4 weeks of therapy, they should not be given abacavir.

*Hypersensitivity to Abacavir (2)Counsel and prepare patient for hypersensitivity symptoms and to contact provider/pharmacist immediatelyEspecially during first month of therapyProvider/pharmacist determines cause of symptoms: abacavir or notHypersensitivity may be fatal (19 deaths)NEVER rechallengeGenetic predisposition Similar to life-threatening reaction to NVP

If the symptoms are felt to be related to abacavir, the patient should be told that they do in fact have an allergy and they should NEVER be given abacavir again. If the symptoms are felt to result from another cause or it is unclear, continue administration of doses under observation to see if symptoms worsen with each dose. Patients should NOT be counseled to stop abacavir on their own if symptoms occur because symptoms may not actually be related to abacavirIf they stop medication, the real cause cannot be determined and subsequently must be assumed to be abacavir, consequently, abacavir can never be used again for this patient (i.e., an NRTI has been wasted for this patient).

*Abacavir Re-challenge20% risk of anaphylactic-like reaction upon re-challengeDeath can occur with hours of restartingSymptoms may include include:hypotensionbronchoconstrictionrenal failureLaboratory changes may includeIncreased CPKElevated liver function testsReduced lymphocyte count

Abacavir should never be re-challenged!

Re-challenge among persons with the abacavir hypersensitivity has been associated with death in at least 3 patients.If anaphylactic reaction develops, treatment is supportive with IV fluids, dialysis, etc. Steroids and histamines are not usually effective.

*Tenofovir Disoproxil Fumarate (TDF)Dosing: 1 x 300mg tablet QDFood Interactions: NoneVery well tolerated, side effects are minimalToxicityRenal insufficiency (rare)

Must dose adjust with renal failureAlso has activity against Hepatitis BDosed 300mg QDActive against Lamivudine resistant HBV strainsHBV resistance 1% at 1 yearIf TDF is stopped, may have HBV hepatitis flare

Monitor for renal impairment monthly: decreasing CrCl; glucose, phosphate, or protein in urine, low serum phosphate or potassium. Renal compromise is rare, but TDF should be stopped if patient develops renal compromise

Nucleotide Analog: TDF is different from nucleosides in that it has already been phosphorilated once.Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of tenofovir. After oral administration, TDF is rapidly cleaved by nonspecific extracellular carboxyesterases into tenofovir. Once inside cells tenofovir is metabolized by adenylate cyclase and nucleoside diphosphate kinase to the active moiety, tenofovir diphosphate (PMPApp). Bioavailability (F): 25% (fasting) to 40% (with food). Bioavailability improves with food, especially high-fat meals.CSF Levels: unknown % of serum levelsT1/2: 12 to 18hoursIntracellular T1/2: 10 to 50 hours

*Didanosine (ddI)Requires a basic environmentFood Interactions: take on empty stomachDosing (one of the following)1 x 400mg enteric coated capsule QD (if

*Didanosine (ddl) (2)If taken with TDF must reduce ddI dose:> 60 kg< 60 kg250 mg/d 200 mg/dWithout dose adjustment blunted CD4 responseToxicityPeripheral NeuropathyGI intolerancePancreatitis (7%2%)Lactic acidosis, fatty liver

ddI is a D drugUse lower dose to reduce risk of S/E development for patients < 60kg. Dose-related side effectsPeripheral Neuropathy: Frequency: 5%-12%. Onset usually after 2-6 months of therapy. If patient develops peripheral neuropathy discontinue ddI at onset (or reduce dose to 250mg QD). Symptoms will dissipate slowly after stopping ddI or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating.Pancreatitis: Reported in 1%-9%, fatal in 6%. Risk factors include: renal failure, alcohol abuse, morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and concurrent use of d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue therapy. When symptoms resolve, do not re-challenge with didanosine.

*NRTI Class Side EffectsAs 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 effectsDont give up

As therapy continues, patients are better able to tolerate the medications.Counsel patients Present the potential for side effects with a regimen so that they know what to expect Provide them with advice about how to handle side effects (whether they can manage the side effect at home, should call to touch base, or need to come to the clinic to be seen). Reassure them that side effects do improve over time, so its important not to give up too quickly on the medications unless having severe side effects.

*NRTI Class Side Effects (2) Peripheral Neuropathy: ddl + d4TWith continued treatment may be irreversibleLactic Acidosis, fatty liver: d4T > ddl > AZTLipoatrophy: d4T > AZTPancreatitis: ddl > d4TMarrow Suppression: AZT

Peripheral neuropathy and pancreatitis Most noted with the D drugs ddC, d4T, ddI. Rates of occurrence differ by drug (see slide). Note: peripheral neuropathy can develop as a result of HIV infection alone.Peripheral neuropathy Damage to the peripheral nervous system. Onset usually occurs after 2-6 months of therapy. Symptoms range from tingling, numbness, aching, or burning sensations to severe pain usually in the feet, legs and sometime in the arms and hands. It often begins in the toes and/or fingers bilaterally and evolves on hands in a glove pattern or on feet in a sock pattern. Numbness and muscle weakness can also occur.

*NRTI Mitochondrial Toxicity Inhibition of mitochondrial DNA polymerase- oxidative metabolism, ATP generationImplicated in lactic acidosis with hepatic steatosis Other possible manifestations:Neuropathy (d4T, ddI) Lipoatrophy (d4T)Pancreatitis (ddI)Myopathy (AZT)Cardiomyopathy (AZT)

In vitro, d4T/ddi/ddc worse than azt/3tc/abc

*Hyperlactatemia/Lactic AcidosisRare but potentially fatal syndrome (1/1000 pt/yrs)Linked to prolonged use of NRTIs, especially ddI and d4TAcute or subacute onsetSymptoms: nausea, vomiting, weight loss, fatigueLab: increased anion gap (or lactate level)Ultrasound: fatty liver Management: discontinue NRTI may take months to reverse. No specific treatment

High chance of death even if it is treated immediately. May occur in conjunction with a severely enlarged liver. Mitochondrial processLactate or lactic acid is a by-product of sugar (glucose) processing by cells. Little organs inside each human cell called mitochondria process glucose to provide energy for the cell. Lactate is a by-product of this process. Lactic acidosis occurs when there is an over-accumulation of lactate in the body that the liver is unable to clear. Nucleoside analogues Disrupt mitochondria function inside the cell. This could cause excessive lactate production, which could lead to lactic acidosis if the liver is not functioning properly. Many of the other side-effects of nucleoside analogues may also be associated with damage to mitochondria including peripheral neuropathy (numbness or pain in the feet and hands); bone marrow suppression; pancreatitis (inflammation of the pancreas); hepatic steatosis (accumulation of fat in the liver); and myopathy (muscle damage).

*Neucloside Pairings

YESNOAZT + 3TC *AZT + d4Td4T + 3TC *d4T + ddITDF + 3TC *(TDF + ddI)ddI + 3TC *(AZT + ddI)* Can use FTC same as 3TC

*Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

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NNRTIS also work at the beginning, inhibiting Reverse Transcriptase, but they work in a different way than NRTIs. They hook on to the actual enzyme (reverse transcriptase) and stop it from working. The result is the same as the NRTIs: the DNA copy of viral RNA cannot be made and therefore cannot be integrated into the nucleus. Again, the life cycle breaks down.

*Non-Nucleoside Reverse Transcriptase InhibitorsNNRTIsNevirapine (NVP)Efavirenz (EFV)

*Nevirapine (NVP)Dosing: 200 mg QD x 2 weeks, then 200 mg BID Food Interactions: NoneToxicityRash (17%)Nausea & vomitingHepatitis (8-18%)

Risk is greatest in first 6 weeks of therapyCould be benign or fatalBlack Box warning by FDA (USA): Do not use NVP in women w/ starting CD4>250Do not use NVP in men w/ starting CD4> 400

Hepatotoxicity If occurs in first 8 weeks: appears to be a hypersensitivity reaction and may be accompanied by drug rash, eosinophilia, and systemic symptoms. Some patients have presented with nonspecific symptoms of hepatitis and progressed to hepatic failure.Some patients on NVP develop hepatotoxicity later in the course of treatment. This form of hepatitis is more benign and similar to hepatitis seen with other anti-HIV drugs.

*Hepatotoxicity: NVP & PIsNVP: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 baselinePI & NNRTIs: All cause ALT/AST in 10-15%

Occurrence of increase in LFTsAsymptomatic: 9% of persons (> 5 times the upper limit of normal ULN) Symptomatic: 4% of persons (Half of these cases were associated with rash)

*Hepatotoxicity: NVP & PI (2)

NVPOthersWhenFirst 6-16 weeksLateSxsRash, GI SxsNo SxsLong term consequenceSeriousUnknownWhen to d/c drugPromptlyALT> 5-10 x ULN

*NVP: Hepatotoxicity Symptomatic Hepatitis

CD4 countRateWomenCD4 > 250 11%CD4 < 2500.9%MenCD4 > 4006.4%CD4 < 4002.3%Analysis of 607 treatment nave patients (2NN)

*NVP for PMTCTIssue is RESISTANCE and EFFICACYNo SAFETY concerns

*Nevirapine-Induced RashCourtesy of HIV Web Study, www.hivwebstudy.org

Most commonly appears on the body and armsTwo forms Milder form erythematous, maculopapular rashcontinue medication with close observationantihistamines may be administeredSevere form with mucous membrane involvement, SJS & TENDRESS: Drug rash, eosinophilia, systemic symptomsD/C if fever, blisters mucous membrane, conjunctivitis, edema, arthalgiasUsually appears within the first month of therapy, although occasionally it may start a few weeks later.Patients that do experience a rash during the 2-week lead-in should not increase the dose until the rash has resolved (mean duration of rash is 14 days). If the patient experiences rash and stops nevirapine on their own, provider would not reintroduce nevirapine with the dose escalation until the rash has resolved.Patients should call their provider or pharmacist or return to clinic if they develop a rash or have any blistering in the mouth, and if they develop fever, arthralgias, or myalgias.

*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 BIDThis 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.

Patients that stop their medications for > 7 days should restart their regimen with the dose escalation: Daily dosing for 2-weeks, then increase to 200mg BID.It is suggested that nevirapine and other medications that often cause rash (e.g., abacavir and SMX/TMP) should not be started simultaneously so that the offending agent can more easily be identified if a rash develops. For example, for a new patient arriving in clinic that meets criteria for ART and PCP prophylaxis, start SMX/TMP at first visit and monitor for side effects, then start nevirapine at least 1 month later as part of ART regimen.Prednisone and antihistamines are not effective in preventing nevirapine rash. In fact, prednisone administration during the first 2 weeks of nevirapine therapy appears to increase the incidence of rash.

*Efavirenz (EFV)Dosing: 3 x 200mg capsules or 600mg tab QHSFood InteractionsTake on an empty stomach or with low-fat meal

High-fat meals increase absorption by 50% increases side effectsConsistent results: persistent activity after >5 yearsNever surpassed in clinical trial

*Efavirenz ToxicityCNS Changes (52%) Rash (15-27%) usually does not require discontinuationHepatotoxicity (2-8% experience increase in LFTs > 5 ULN)Contraindicated during pregnancyTeratogenicClass D

RashUsually morbiliform Symptoms can be treated as needed (e.g., hydrocortisone cream and antihistamines for itching). If patient develops a more serious rash (blistering of mucous membranes or skin, seen in about 1%-2% of cases; or SJS) EFV should be discontinued. Median time of onset of the rash is 11 days and the duration is 14 days.HepatotoxicityRate is less frequent and less severe than seen with NVP. Increase risk of occurrence if co-infected with HCV or also taking other hepatotoxic medications

Bioavailability (F): 40%-45% with or without food. CSF Levels: .25%-1.2% of serum levels (these levels are above the IC95 for wild-type HIV)T1/2: 40-55 hoursElimination: Metabolized by CYP450 3A4. 14% to 34% excreted in urine as glucuronide metabolites and 16% to 61% in stool. Do not need to adjust dose for renal or hepatic compromis.

* Efavirenz CNS ToxicitySymptoms: confusion, Insomnia, nightmares, poor concentration, mood change, dizziness, dysequilibrium, depression, psychosis, disconnectedOnset: first doseCourse: usually resolves in 2-3 weeksCause: UnknownManagement: warn patient

*Which Third Drug to Use?

AdvantageDisadvantageNNRTI pill burdenPotencyRifampinLow barrier to resistanceRashEFV & pregnancyPIPotencyLess resistanceBoost with RTVMetabolic effectsDrug intoleranceGI intolerance

*EFV vs. NVP

NVPEFVDaily doses21EfficacySimilarSimilarPregnancyYesNoTB (Rifampin)No (?)YesSide EffectsLiver *; Rash *CNSResistanceLow barrierLow barrier* May be lethal

*NNRTI Class EffectsSide effectsRashHepatotoxicityCross resistance:A single mutation, the K103N, causes high-level resistance to all 3 drugs in this class: EFV, NVP, and DLVLatent pool foreverImportance of adherence

Do not appear to cause rash and hepatitis in the same manner. Nevirapine: if onset of rash or liver toxicity occur, can probably be safely switched to efavirenz (and vice versa), unless the toxicity on nevirapine was very severe. Just because a patient gets a rash to one medication does not mean they will develop rash to the other agent.Rate of Rash: EFV (15%-27%) > DLV (18%) > NVP (17%)Rate of rash that requires discontinuation of the offending agent: NVP (7%) > DLV (4.3%) > EFV (1.7%).ResistanceNVP: Induction of resistance with single doseCounsel patients about the importance of adherence related to this class of medications, only a single mutation is needed to make a person resistant to all NNRTIs. Location of mutation: Distant from replication site; confers no reduction in viral fitness

*NNRTI RashOften diffuse, slightly raised, itchyVary in redness and distributionCan be severe - Stevens Johnson Syndrome

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

*

DNA

Host Cell Protease Inhibitors (PIs)

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Protease is essential for assembly of new viral particles. Without it, new viruses cannot be assembled.PIs prevent protease from assembling new virus in the final stages of the life cycle.

*Protease Inhibitors (2)Lopinavir + RitonavirNelfinavir Saquinavir-HGC Indinavir FosamprenavirAtazanavirRitonavir

* The top 4 protease inhibitors (PIs) are recommended as second-line treatment agents.

*Ritonavir (RTV)Substantial GI intolerance prevents use at full, original doseNow used to boost other PIsDoses < 400 mg/day no anti-HIV activityNomenclature: /r (LPV/r, SQV/r)Requires refrigerationHard to make

This drug is used only at a dose that alone has virtually no antiretroviral effect (that is why boosted protease combination e.g. LPV/r - is considered one of the three drugs in a PI-based regimen). However, combined with other PIs, it has a powerful effect on the other PIs metabolism boosting the other PIs effect.

*Ritonavir Boosting

AUCSaquinavir30 74 xLopinavir15 20 xIndinavir3 6 xNelfinavir1.5 x

AUC = area under the curve: Basically represents the drug concentration. Boosting with Ritonivir increases the other PI drug concentration by 1.5 to 70 fold.

*Clinical Pharmacology of ART*Pharmacokinetic Rationale for Dual PI TherapySingle PI is used: Peaks may reach well above the desired concentration for effectiveness

This may lead to drug toxicityLevels of the drug may become too low

Permitting viral replicationPIs 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

*Lopinavir/ritonavir (LPV/r)Dosing: 3 caps (400 mg lopinavir/100 mg ritonavir) BIDEach capsule contains LPV 133mg / RTV 33mgFood Interactions: take with foodToxicityNauseaWeaknessDiarrhea (mild to moderate)LipodystrophyALT/AST increaseRefrigeration recommendedStable at room temperature for up to 2 monthsHot temperatures should be avoided

Lopinavir/r Approximately 10 times more potent than RTV alone against wild-type HIV.Generally well tolerated. Pancreatitis has been reported in adults, possibly due to high triglyceride levels.

Reference NotesBioavailability (F): ~80% with food and 48% on an empty stomach, but by combining LPV with ritonavir (in the capsule), LPV levels are increased significantly.CSF Levels: unknown %, likely low because LPV is 98-99% protein boundT1/2: 5 to 6 hours (for LPV when combined with RTV)Elimination: Metabolized primarily by CYP450 3A4 enzymes. Less than 3% is excreted unchanged in urine. Do not need to adjust doses for renal compromise. Use with caution in patients with hepatic impairmentPediatric Dose: 230mg/m2 LPV / 57.5mg/m2 RTV BID Pregnancy: (Category C) Crosses placenta. Drug Interaction: The major effect is due to inhibition of CYP3A4. This effect is less than seen with full doses of RTV.

*Nelfinavir (NFV)Dosing: 1250 mg PO BID Food Interactions: take with mealToxicityDiarrhea (10%-30%)Abdominal painFlatulenceNauseaRashLipodystrophyALT/AST increase

Patients should be given a prescription for an antidiarrheal at the time they are prescribed nelfinavir and taught how to mange the diarrhea if it should occurTake 1 to 2 doses of loperamide at onset of diarrhea and then take 1 loperamide for each loose stool after that, up to a maximum of 8 loperamide per day. If patients find that 1 loperamide 3 times daily [or any other regimen] controls their diarrhea, they can follow that regimen regularly to prevent diarrhea before it occursOther options for diarrhea control include calcium 500mg BID, psyllium 1 tablespoon once or twice daily mixed in water once or twice daily with the water volume (120ml), oat bran 1500mg BID, or pancreatic enzymes at 1 to 2 tablets with each meal. If diarrhea cannot be controlled with antidiarrheals, patients should consult with their provider or pharmacist, it may be necessary to change to another PI or NNRTI. If constipation develops from antidiarrheal use, the patient should reduce their loperamide dose or other agents.

Reference NotesBioavailability (F): 20% to 80% with meals. Food increases absorption by 2 to 3-fold. Fatty meals improve absorption further.CSF Levels: No detectable levels in CSFT1/2: 3.5 to 5 hoursElimination: Primarily metabolized by CYP450 3A4. Only 1% to 2% is found in urine. Up to 90% is found in stool, primarily as a hydroxylated metabolite designated M8, which is as active as nelfinavir against HIV. No dosage adjustments needed with renal compromise. Use with caution in patients with hepatic impairment.Pediatric Dose: 20-45mg/5kg TID Pregnancy: (Category B) Present in breast milk and minimal concentration crosses placenta.

*Saquinavir-Hard Gel Capsules (SQV) InviraseDosing: Must take with Ritonavir 1000 mg /100 mg bid with foodToxicityDiarrheaNauseaAbdominal painHeadacheLipodystrophyALT /AST increaseRefrigeration recommended, but OK at room temperature for up to 3 monthsHot temperatures should be avoided

Nausea and diarrhea are more common with the soft-gel formulation than with the hard-gel formulation as a result of:Better bioavailability (i.e., more drug is absorbed so potential for more side effects)A component of the soft-gel capsules which causes diarrheaDosing:SQV is rarely used alone, it is commonly combined with RTV.Standard dose for soft-gel capsule with RTV: SQV 400mg BID + RTV 400mg BID; or 1000mg SQV BID + 100mg RTV BID; or SQV 1600mg QD + RTV 100mg QDThe hard-gel capsule should ALWAYS be dosed with RTV, dosing same as for soft-gel capsules.

*Indinavir (IDV)Dosing: 2 x 400mg q 8 hours ORWith RTV 800 / 100 mg bidFood Interactions: take on empty stomach, or with low fat snack (e.g. non-fat milk)Capsules are sensitive to moisture

If taken with a low fat snack (such as dry toast with jelly, juice, coffee with skim milk, or cereal with skim milk), as opposed to an empty stomach (defined as 1 hour before or 2 hours after a meal), patients are more able to tolerate the gastrointestinal side effects. Coordinating 3 doses every 8 hours on an empty stomach can be very difficult for most patients. If this dosing is chosen, patients should be counselled about adherence.Currently indinavir is commonly combined with RTV in order to improve dosing schedule (can change to BID dosing) and food requirements as well as reduce gastrointestinal and lipid abnormalities. 1.5 litres of water are still required to prevent kidney stones even when combined with RTV.

*Indinavir (IDV): Toxicity NauseaDiarrheaNephrolithiasis (flank pain, SrCr, hematuria, pyuria) (2%)Dry lips, dry skinBald patches in hairIngrown toe or finger nailsAcid reflux (3%)Hyperbilirubinemia (10-15%)LipodystrophyALT /AST increase

Kidney stonesMost serious side effect in both adults and childrenSeen in about 10%-28% of patients (depending on duration of treatment, age, and fluid prophylaxis); it may be more frequent in hot climates. Temporary abnormal kidney function, including acute kidney failure and inflammation has been observed in some patients with nephrolithiasis. The condition may be signalled by severe pain beneath the ribs with or without blood in the urine. Indinavir may need to be interrupted for a few days. The condition may recur in half of the patients if indinavir is restarted. Patients taking indinavir must drink plenty of fluids to prevent the development of kidney stonesAt least 1.5 litres of water daily and more in hot weather. Caffeinated or alcoholic beverages do not promote hydration and should not be counted in the 1.5 litre daily fluid requirement.In most cases the maximum bilirubin elevation was observed after one or more weeks of treatmentJaundice (yellowing of the skin) and elevations in liver enzymes have been reported only rarely. In most cases patients with elevated bilirubin are asymptomatic.

*PI Class Side EffectsMetabolic DisordersHepatotoxicityHyperglycemia, insulin resistanceLipid abnormalitiesFat redistributionBone Disorders

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

Whilst many side effects develop in the first few weeks on new medication, some do not emerge until the medication has been used over the longer term. As more information becomes available about the mechanisms that cause long-term side effects, it will be more possible to develop effective interventions to prevent and treat these side effects. Metabolism A general term for the breakdown of food and production of energy within the body. Sugar and fat are sources of energy. Abnormalities in sugar and fat levels or abnormalities in the processing of fats and sugars may indicate metabolic disorders and cause physical symptoms. Metabolic disordersHave caused the greatest concern in developed countries.A number of metabolic disorders have been reported among people taking anti-HIV therapy. These include hyperlipidemia (high levels of fat in the blood); diabetes, high blood sugar (hyperglycemia), and insulin resistance; and high levels of lactate (a by-product of sugar metabolism in the body); elevated ALT (a liver enzyme); and lipodystrophy (fat redistribution).Drug interactions: In addition, PIs are known to interact with multiple other medications. The role of the pharmacist is critical for recognizing and identifying and preventing potential drug interactions through dosage adjustment or preventing co-administration of contraindicated medications.

*HepatotoxicityIncreased LFTs observed with all PIs.More common in pts with chronic viral hepatitis (HBV, HCV).Data do not support withholding PIs from pts co-infected with HBV or HCV.Increased ALT/AST is common (10-20%), asymptomatic and unclear consequence

Ritonavir has been more frequently associated with severe liver toxicity. Elevated liver enzymes in the blood can occur at any time during PI treatment. Symptoms of liver toxicity include: weight loss, loss of appetite, nausea and vomiting, fever, abdominal pain, itchy skin, an enlarged or tender liver, and jaundice. Liver toxicity is more common in patients who: drink too much alcohol; had high liver enzymes on blood tests when treatment started; use other medication that can cause toxicity to the liver such as d4T; or are coinfected with hepatitis B or C.

*HIV Lipodystrophy SyndromeDefinitionA complex medical condition Including abnormal fat redistribution and metabolic disturbances Seen in HIV patients receiving ARTMetabolic complications (primarily PI therapy) Hepatic insulin resistanceImpaired glucose toleranceType 2 diabetesHypertriglyceridemiaHypercholesterolemiaDecreased high density lipoprotein (HDL)

Little is known about the pathogenesis, its prevention, diagnosis and treatment. Current data indicate that its pathogenesis is multifactorial, including direct effects of HIV infection, its therapy, and patient-related factors.This fat redistribution and disturbances in glucose and fat metabolism resemble the "metabolic syndrome" in HIV-negative patients.

*Fat RedistributionFat accumulation (lipohypertrophy) --PIsDorsocervical fatVisceral adiposityBreast enlargementFat loss (lipoatrophy) d4TFacial fat lossSubcutaneous fat loss of extremities

Lipodystrophy can be very distressing for patients. They can feel as though people on the street will now be able to recognize that they are HIV-positive. It is important to explain the risk of lipodystrophy to patients and to also convey that the benefits of therapy outweigh the risks. Counsel patients about how lipodystrophy will present so that they can recognize it and bring it to the attention of their provider or pharmacist as soon as possible

*

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

Lipoaccumulation: dorsocervical Fat Pad

*HIV Lipodystrophy Syndrome (2)

AbnormalityAssoc. agentMonitoringConse - quenceRxFat re-distributionAll ARVsAppearanceCosmeticNone;d/c drugInsulin resistanceAll PIsBlood glucoseDiabetesStandardLipid IncreaseAll PIs, except ATVLipidsCardio-vascular diseaseStandard

*Management of Hyperlipidemia

LDL GoalLife StyleDrug RxCardiovascular Disease or Diabetes< 70< 100> 130> 2 risks *< 100 130< 130> 1300-1 risk *< 160< 190> 190* Risk = HBP, Age > 45-55 yrs, smoking, genetics

Statins such as pravastatin, fluvastatin, and atorvastatin can be used safely with PIs to reduce LDL. Fibric acid analogues such as gemfibrozil or fenofibrate are also effective, as is metformin.Metformin can theoretically precipitate lactic acidosis but this adverse interaction has not been described.

*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 patientsDosing: 90 mg BID by subcutaneous injectionFood interaction: NoneToxicityInjection site reactions (98%)Nausea, diarrhea, fatigue, hypersensitivity (< 1%)

Newest class of ARV and is very expensive. (costing approximately 20,000 USD per year)The T-20 molecule is very large. T-20 is available as a kit containing 60 doses w/ syringes, diluent & alcohol pads. The medication needs to be reconstituted at time of or within 24 hours of dose administration (108mg vial diluted with 1.1 mL sterile water for injection giving a volume of 1.2ml). Once reconstituted, the vial must be used or placed in the refrigerator within 30 minutes. SQ injections can be given in the upper arm, anterior thigh, or abdomen. Injection site reactions are very common (98%), but only require discontinuation of therapy for 3%.

*Dosing Considerations in Patients with Liver Disease

DrugHepatic impairmentNRTIsNo dosage recommendationNVPNo data available; avoid use in patients with moderate to severe hepatic impairmentEFVNo recommendation; use with caution in patients with hepatic impairmentLPV/rSQVNFVNo recommendation; use with caution in patients with hepatic impairmentINDReduce dose from 800mg to 600mg in moderate cirrhosis

These recommendations are from the DHHS guidelines, 2005

*Dosing Considerations in Patients with Renal Failure*dosing for patients > 60kg

CrCl >60CrCl 30-59CrCl10-29CrCl

*Significant Drug Interactions with ART

Step 3: Significant Drug Interactions with ART (Slides 70 79) 20 minutes

*Mechanisms for Drug InteractionsAltered intracellular activationD4T combined with ZDV Altered drug absorption and tissue distributionFlouroquinolones combined with antacids form insoluble complexAltered drug metabolismRifampicin combined with NVP Reduced renal excretion

Pharmacokinetic drug interactions may involve:Fluctuation in intracellular drug concentrations of active drug (D4T, DV) due to impairment of phosphorylation (which is needed to change the drug to its active state). D4T and ZDV should NEVER be used together because they are antagonistic.Changes in gastric pH and drug absorptionAbsorption is sometime dependent upon acidity of the gut eg. ketoconazole requires an aciditic pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption)Other examples of changes in GI absorption: Binding interactions divalent or trivalent cations such as aluminum, magnesium or calcium bind to quinolones and inhibit absorption.

*First Pass EffectOrally 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

This is a diagram to help visualize where various drug interactions occurDrugs that are extensively metabolized result in minimal delivery to systemic circulation.Absorption of drugs from the GI tract depends on the drug's ability to pass across intestinal cell membranes, withstand the highly acidic environment of the stomach, and resist destruction in the liver (first-pass effect).In most cases drugs pass through cell membranes of intestines by simple diffusion, from an area of high concentration (inside the lumen of the intestines) to an area of lower concentration (bloodstream). Active transport across the GI mucosa, very much like a shuttle system, is another way some substances are absorbed (i.e. Vitamin B12). Other factors that may affect absorption of drugs include food and other medications that may inactivate the drug.Metabolism can occur in the intestine, blood or liver. Extensive first pass metabolism of PIs through gut wall and liver may account for poor and variable bioavailability of this class.

*Drug Metabolism/EliminationGoal of metabolism:To change the active part of the medication, making them more water-soluble and more readily excreted by the kidneyMetabolism occurs via two types of reactions:

Phase I reactions involve: Oxidation, hydrolysis, and reduction, take place primarily in the liver CYP450Phase II reactions involve:Conj (adding another compound) to form glucuronides

Fecal excretion is seen with drugs that are not absorbed from the intestines or have been secreted in the bileChanging the molecular structure of drugs increases water solubility and decreases their fat solubility, which speeds up the excretion of the drug in the urine. Oxidative and reduction processes make a molecule's charge more positive or negative than the original drug. Regardless of the positivety or negativity, a charged molecule is dissolvable in water. (blood serum is primarily water) These reactions take place primarily in the liver CYP450. Oxidative metabolism may result in formation of an active metabolite or inactive compound, acetates, or sulfates. These reactions make it more prone to elimination by the kidney.

*Cytochrome (CYP450) Present in liver, small intestines, lungs, and brainPrimary function is to alter toxins (drugs) to speed excretionIsoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily responsible for drug metabolismAlso metabolize steroid hormones, vitamins, toxins, prostaglandins, fatty acidsKnowledge of substrates, inhibitors and inducers helps predict drug interactionsimportant as PIs are metabolized 80-95% by the CYP450 isoenzymes in liver and small intestine

Enzymes are categorized into families (by a number ), which are further subdivided into subfamilies denoted by a capital letter. Individual proteins within a subfamily called isoenzymes are identified again by a numberFor example: 3A4 (3 =family, A= subfamily, 4= Individual protein called isoenzyme) Isoenzymes:1A2, 2C9/19, 2D6, 3A4 are primarily responsible for drug metabolismExample: The 20 fold increase in plasma concentraion of saquinavir caused by ritonavir is probabaly produced by inhibition of CYP3A4 at both sites.

*Cytochrome P450 EnzymesOutcome of Drug Interaction

Variability

Patient Factors

Drug FactorsGeneticsDiseasesDiet/NutritionEnvironmentSmokingAlcohol

DoseDurationDosing TimesSequenceRouteDosage Form

Adapted from Philip D. Hansten, Science & Medicine 1998

There is variability in the outcomes of drug interactions involving CYP450.Outcomes are affected by patient factors as well as drug factors. Patient Factors:Genetic polymorphisms are associated with certain ethnic groups.5-10% Caucasians are poor metabolizers of 2D6 substrates.Whereas 1-2% of the Asian population are poor metabolizers.Diseases: Liver disease: decreased enzyme activity, may affect 1st pass effect= increased bioavailabilityCardiac failure results in decreased blood flow to the liver.Diet/nutrition: grapefruit juice inhibits isoenzyme 3A4 in the intestinal wallFoods: charbroiled meats (due to hydrocarbons) and brussel sprouts can induce 1A2 isoenzymeSmoking: induces CYP 1A1, 1A2, 2E1Alcohol: chronic drinking induces 2E1Drug Factors:Dose: Fluconazole at doses over 200-400 mg daily, it becomes a potent inhibitor of 3A4.Duration: inhibition of CYP450 has a quick onset and a quick offset, whereas induction effects have a long onset and offsetRoute: the intravenous or intramuscular routes bypass the oral 1st pass effect

*P450 Drug InteractionsSubstrateAny drug that is metabolized by one or more of the P450 enzymes It is the object drug which is affected by inducer or inhibitorInducerSpeeds up metabolismDecreases substrate level (lack of efficacy is concern)Onset/offset is gradualInhibitorSlows metabolism of substrate drugIncreases level of drug in blood (toxicity is concern)Quick onsetThis process is almost always competitive and reversible

Ask participants, What is the difference between a substrate, and inducer and an inhibitor?

*CYP P450 Drug-Drug InteractionsPharmacologic action of drug is altered by coadministration of second drugCo-administration may:

Drug ANo Consequenceseffect (e.g. ritonavir + saquinavir; ritonavir + simvastatin)

effect (e.g.,rifampin + protease inhibitors, indinavir + coumadin)New effect (e.g., ritonavir + amitriptyline;)

Drug-drug interactions can result in therapeutically desired effecta negative drug-interactiona new side effect of a drugOr no consequence at allAdverse reactions may occur:For example, lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4. Combined with an inhibitor of 3A4 (eg ritonavir), the concentration of these drugs increase substantially and increase the risk of myopathy, in some cases leading to rhabdomyolysis and acute renal failure.

*Drugs with Potential to Interact with PIs or NNRTIsStatins (simvistatin & lovastatin)Azole antifungalsAnticonvulsantsAnti-TB (Rifampicin)Warfarin

Midazolam, trizolamAlternative medicine ClarithromycinOral contraceptivesAmitriptyline

Pharmacists play a critical role in detecting drug interactions, before they happen.Pharmacists need to ask patients what other medications they are currently taking whenever dispensing a new medication to avoid potential interactions. Be aware that changing or discontinuing medications may result in altered drug levels and potential adverse outcomes.

*Drug interactions - Key Points A drug interaction may occur when A new medication is startedA medication is discontinuedA dose is changedUse reference manuals when starting / changing therapyBeware of food requirements with certain ARVs

If an inducing drug is discontinued, the level of the substrate drug may now be increased and could lead to toxicity.

Drug Resistance

Step 4: Drug Resistance (Slides 80 89) 20 minutes

*Case Study: BerhanA 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) therapyHe presents to the ER with a bloody nose and bruises on his arm. Other current medications include:coumadin for atrial fibrillationatenolol for blood pressureWhat do you suspect has happened?

Ask a participant to read the case aloud. Solicit participant response to the question at the bottom of the slide and discuss the answer as a group. Answer:This patient is over-anticoagulated. This probably occurred as a result of an increased dose of coumadin to adjust for the affect of rifampin (which increases the metabolism of coumadin and thereby necessitates an increased dose to maintain a therapeutic level), and then forgetting to change the dose back to the original dose after completion of Rifampin containing TB therapy.

*

Principles of HIV Drug ResistanceNot all drug failure is due to resistance Partial HIV suppression promotes resistance Resistance can be delayed by suppressing the virus completelyRT and protease are flexible (highly mutable)Resistance may fade but not disappear when a drug is stopped

3

HIV mutations occur quickly and easily during viral replication. It is expected and not unusual. Some mutations are undesirable but some are favorable and may slow the replicative capacity of HIV.

*Principles of Resistance (2)Some mutations allow certain viruses to resist the effects of one or more antiretroviral drugsEach infected person has a mixture of viruses, some of which are resistant to some medicationsThe drug resistant virus usually grows faster and better than the drug susceptible virusThe drug resistant virus replaces the drug susceptible virus in the patient

Although much of drug failure is caused by drug resistance there are immune system factors, patient genetic factors and virologic factors that can cause ARV to be less effective. In the patient genetic factors like a class I haplotype , chemokine receptors, levels of chemokines can have an effect on drug therapy. The immunologic factors including the primary immune response deletion of cytotoxic T cells, and chronic immune activation can affect ARV treatment. The virus itself can affect ARV treatment by its rate of replication, formation of syncytial inducing virus, the size of the inoculum (think blood transfusion), or the state of viral latency. When ARVs are stopped the wild type virus proliferates outgrowing the resistant strains leaving them undeliverable (NESM 2001:344;472) back to wild type virus. This resistant virus may be achieved in the reservoirs or sequestered havens in the CNS, latent CD4 cells, genital tract, etc. and will usually return within 6 to 12 months upon retreatment with ARV.

*Resistance TestingTwo types:Genotyping

Less expensiveCan usually be completed in 1-2 weeksPhenotyping

More expensiveGenerally takes 2-3 weeks to complete

Genotyping detects drug resistance mutations on the virus genome that may make it resistant to certain antiretrovirals. Phenotyping Measure the ability of viruses to grow in the presence of various concentrations of antiretroviral drugs

*Suspect Resistance in the Setting of Treatment FailureDue to HIVs high transcription error rate and high level of replication, mutant HIV variants constantly generatedThese variants often contain mutations that confer variable levels of resistance to antiretroviral agentsPoor adherence or suboptimal regimens can lead to resistance and viral breakthrough

Resistance will occur over time due to the nature of the HIV virus however the first regimen is usually the best and the longest lasting.There is some clinical indication to think that resistant virus may not be as virulent as wild type virus. So even in the setting of non-virologic suppression if you have no further regimens to consider, staying on ART has still been found to decrease death, and morbidity from opportunistic infections. There is a large pool of virus and even partial suppression of the viral load affords some albeit imperfect protection of the immune system. It is in salvage cases such as this that clinicians in developed nations may take advantage of phenotype viral studies to determine which ARV are most likely to have the best chance to have effect on lowering viral load.

*How Does Resistance Develop?Results from changes (mutations) in the genetic information in the virusThese changes occur whenever HIV is replicatingEvery possible mutation occurs tens of thousands of times each day

Some HIV variants will still be stopped with HAART, but other HIV variants will continue replicating. In many resistant viruses, the wild type virus will usually be suppressed but other variants are not. When a resistant virus assumes the role of predominate viral type it will cause the viral load to increase. An increased viral load may be the first indication of resistance. (While the resistant virus is predominating the ARV continues to control the drug susceptible population which in over time becomes smaller and smaller).Ultimate aim of anti-HIV treatment: to prevent the virus population from finding an evolutionary escape route by using an appropriate combination of anti-HIV agents and to halt virus replication completely. The future will tell if the patient can be fully cured by keeping this inhibition up for years...With sufficient pressure on the virus via ARV it is hoped that both wild type and resistant type will be controlled keeping the viral load in circulation undetectable.

*Resistance MutationsFor some drugs (NNRTIs and 3TC), a single mutation causes high-level resistance. Resistance to these drugs occurs very quicklyFor other drugs (most NRTIs and PIs), many mutations must occur before high-level resistance is observed. Resistance to these drugs occurs more slowly

*Cross-ResistanceResistance 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

*Minimize Emergence of Viral ResistanceNever prescribe ARVs in the absence of adherence counseling and supportNever prescribe monotherapy or dual therapyEnsure optimal serum drug concentrationsAvoid drug interactions Diagnose and manage malabsorption If ARV medications are to be discontinued, stop all drugs at the same timePossible exception: NNRTI-based regimen

Providers can play an important role in delaying the occurrence of HIV resistance through good prescribing practices and assisting patients in achieving adherence. Monotherapy or dual therapy may be used for PMTCT or for post-exposure prophylaxis only but should not be used as HAART therapy.Adherence is the responsibility of the provider. Irresponsible prescriptive practice results in non-adherence and resistance. Factors that will contribute to adherence and decrease resistance:Pre-prescribingPatient educationPsychosocial supportDemonstration of likely success by adherence to careVerbalized understanding of HIV, ARV and adherence Non-chaotic lifestyle*MOST EXPERTS RECOMMEND STAGGERING DISCONTINUATION OF NNRTI BASED REGIMEN (STOP NRTI BACKBONE 7-14 DAYS AFTER STOPPING NNRTI)

Case Studies

Step 5: Case Studies (Slides 90 94) 10 minutes

*Case Study: Mulu48 yo woman has received NVP/3TC/d4T. The pharmacy has no NVP in stockWhat should she do?Continue 3TC/d4T until the NVP becomes available, then add NVPStop all drugsStop NVP for 7 days then stop 3TC/d4T

Answer 2 and 3 are both options. Many experts would prefer option 3 to reduce the chance of developing resistance to NVP. Stopping all meds together at the same time may result in NVP resistance because the drugs long half-life basically would basically result in monotherapy.

*Case Study: MengistuA 50 year old man has taken EFV/AZT/3TC for 1 year. He now presents with thrush.What should he take now?

NVP / 3TC / ddINFV / 3TC / d4TNVP / 3TC / AZT / ABCLPV/r / d4T / AZTNFV / TDF / ddI

May have NNRTI resistance, making NVP poor choice; Also likely developed M183V mutation for 3TC; may have mutation for AZT and d4T resistanceBest Answer: 5NVP / 3TC / ddI (essentially only 1 active drug)NFV / 3TC / d4T (essentially only 2 active drugs)NVP / 3TC / AZT / ABC (adding 1 drug)LPV/r / d4T / AZT (do not use AZT/d4T together) NFV / TDF / ddI (must dose adjust ddI)

*Case Study: Senait20 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?

NVP / AZT / 3TCNFV / AZT / 3TCNVP / d4T / ddINVP / TDF / ABC

Best answer: 1 or 2

1. NVP / AZT / 3TC (WHO recs)2. NFV / AZT / 3TC (USA most experience)3. NVP / d4T / ddI (not rec. due liver toxicity)4. NVP / TDF / ABC (little data)It ok to give NVP to pregnant women with CD>250 ONLY IF this CD4 count reflects immune restoration from ART. In other words, the CD4>250 cut off is only relevant to treatment nave patients.

*Case StudyWhich of the following is the best regimen for a patient with HIV who failed EFV/3TC/AZT and now has active TB?

LPV/r / d4T / ddINFV / ddI / TDFNVP / ddI / TDFNFV / d4T / TDFStop ART; resume after completion of Rifampicin

Answer: 5

1. do not combine d4T/ddI2. ddI/TDF not best regimen3. avoid NVP + Rif because Rif reduces levels of NVP signficantly4. Might be OK but substituting D4T for AZT which may have same mutation5. Correct answer

*Key PointsGoals of ART include: Suppression of viral replicationRestoration of immunologic functionEffective ART requires strict adherence, proper monitoring of side effects and disease progression, recognition and treatment of co-morbidities.

Step 6: Summary of Key Points (Slides 95 98) 10 minutes

*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.

*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.

*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.

This Unit should take approximately 3 hours, 5 minutes to implement.Step 1: Unit Overview and Learning Objectives (Slides 1 3) 5 minutesStep 2: Antiretroviral Drugs (Slides 4 69) 2 hoursStep 3: Significant Drug Interactions with ART (Slides 70 79) 20 minutesStep 4: Drug Resistance (Slides 80 89) 20 minutesStep 5: Case Studies (Slides 90 94) 10 minutesStep 6: Summary of Key Points (Slides 95 98) 10 minutes

Step 1: Unit Overview and Learning Objectives (Slides 1 3) 5 minutes

Step 2: Antiretroviral Drugs (Slides 4 69) 2 hoursEffective ART requires use of three-drug combinations. This slide shows the combinations available in Ethiopia, and reflects the WHO guideline. The individual drugs will be reviewed in this unit, and the principles of combining therapy will be reviewed in subsequent units.

This picture shows both the 2003 and 2005 (preliminary report) WHO guidelines on antiretroviral therapy in developing settings. FTC, TDF, and ABC have been included in the first line options.

There are two different classes of anti-HIV drugs that target the reverse transcriptase enzyme, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Protease Inhibitors will be discussed later in the session. Fusion Inhibitors: Fusion inhibitors bind to the HR1 site in the gp41 subunit of the viral envelope glycoprotein and prevent the conformational change that is needed to allow virus to enter the cell.

.

Use this slide as a brief review of the HIV lifecycle and to point out where each of the four classes of ARVs workThe following slides contain more detail about how each class of ARVs work, the different drugs in each class, and their side effects

The first step in the HIV lifecycle is viral attachment and fusion at the cell membrane. This can be blocked by fusion inhibitors, which are extremely expensive ARVs that are used primarily for salvage therapy in the US and Europe.Once HIV has invaded the host cell, reverse transcriptase (RT) translates HIVs genetic material (single stranded RNA) into double stranded DNA - the building block of all human cells. NRTIs and NNRTIs inhibit this step. This viral DNA then integrates into the host cell DNA. This is another potential site for therapy (still experimental)When the cell is activated, the viral DNA undergoes translation and creates complex HIV proteins. These new HIV proteins are not infectious until the viral protease enzyme cuts each complex protein chain into smaller functional proteins that can be used to build the new virus (e.g., the core, the envelope). This is the step that protease inhibitors block.

1

NRTIs compete with the normal physiological nucleosides used for DNA synthesis. They differ from the normal substrates only by a minor modification in the sugar (ribose) molecule. Acting as "false building blocks, nucleoside analogs incorporate themselves, preventing DNA synthesis, because normal bridges can no longer be built to build the double strand. Thus they prevent the development of functional viral DNA

Please refer to the Ethiopian DACA for current availability of drugs.

The first ARV approved in 1987 15 years have passed, and AZT is still a common component of ARV regimens. Early ZDV was dosed 5 times daily and the toxicities were much greater. Now, the drug is better tolerated, though it does still have significant side effects (nausea, anemia).Zidovudine is available in Ethiopia as combination Zidovudine/Lamivudine

Reference Notes:Nucleoside Analog: Thymidine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite, zidovudine 5-triphosphate.Bioavailability (F): 60%CSF Levels: 60% of serum levelsT1/2: 1 hourIntracellular T1/2 (NRTIs exert their effect intracellulary, duration of action is based on intracellular half-life): 3 hours

Nausea Most common side effect for AZTEating prior to dose helps reduce nauseaMacrocytosis is common and not associated with anemia, see increase in MCV of 25-40 units after 6-24 weeks, serves as crude indicator of adherence.

AnemiaLaboratory monitoring of patients should include haemoglobin counts where possible, to assess for the development of thisMore common in advanced disease (7%), than early disease (1%).In severe cases, blood transfusion may be needed. If anemia returns when a full dose of AZT is restored, it is best to switch to another drug.

Minimal Side Effects: Best tolerated of all antiretrovirals.ResistanceLow barrier to resistance: a single point mutation (M184V) is sufficient for loss of effectiveness Advantages of the M184V mutation include:Improves the susceptibility of certain ZDV-resistant viruses in some patientsImpairs viral fitnessKeeping 3TC as part of a combination despite proven resistance is therefore sensible because this drug will continue reduce the replicative capacity of HIV

Nucleoside Analog: Cytosine analogueMechanism of Action: It is phosphorylated 3 times by thymidine kinase to the active metabolite, 3TC-triphosphate Bioavailability (F): 86%CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA from CSF)T1/2: 3-6 hoursIntracellular T1/2: 12 hours

The flourinated version was designed to reduce toxicity and prolong drug half-life, but clinically there does not appear to be any difference between the 2 drugs. FTC has demonstrated activity against Hepatitis B, but it is not FDA approved for this indication.

Nucleoside Analog: Cytosine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite, emtricitabine 5-triphosphateBioavailability (F): Good oral bioavailability.CSF Levels: Estimated to be low (in monkeys, CSF level was 4% of serum levels)T1/2: 8-9 hoursIntracellular T1/2: > 20 hours

This drug combination is available in Ethiopia.Less gastrointestinal side effects and limited myelotoxicity compared to ZDV, and just as effective. However, long term toxicities are substantial.

Nucleoside Analog: Thymidine analogueMechanism of Action: It is phosphorylated 3 times, first by thymidine kinase, 2nd by thymidylate kinase, and 3rd by pyrimidine diphosphate kinase to the active metabolite, stavudine triphosphate.Bioavailability (F): 86%CSF Levels: 30% - 40% of serum levels

Peripheral Neuropathy: Symptoms will dissipate slowly after stopping d4T or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating.Lipoatrophy: It may take years for lipoatrophy to visibly improve following discontinuation of d4Td4T should be replaced ideally with abacavir or tenofovir.

Characterized by thinning of the buccal fat pad. May result or exacerbate stigma associated with HIV.Appears to be most common with long-term stavudine use.Usually not reversible, but changing medications may prevent progression.

Patients should be counseled about abacavir hypersensitivity reaction (see next slides).

Reference NotesNucleoside Analog: Guanine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite.Bioavailability (F): 83%CSF Levels: 27%-33% of serum levelsT1/2: 1.5 hoursIntracellular T1/2: > 12 hoursElimination: 81% metabolized by alcohol dehydrogenase and glucouronyl transferase with renal excretion of metabolites; 16% recovered in stool, and 1% unchanged in urine. Dose does not need to be adjusted for compromised renal function. No data on hepatic failure, use usual dose.Pediatric Dose: 8mg/kg BID Pregnancy: (Category C) Crosses placenta.Drug Interaction: Alcohol increases ABC levels by 41%. Abacavir does not impact alcohol levels. Clinically, moderate alcohol use appears to be fine, do not need to adjust dose.Resistance: ABC selects for the following mutations: 65, 74, 115, and 184. The 184 mutation leads to complete cross-resistance with 3TC, but by itself does not significantly decrease ABC susceptibility. Mutations at codons 65 and 74 lead to cross-resistance to ddI and ddC. Significant resistance requires multiple mutations, usually in addition to the 184 mutation. If have M184V + at least 3 NAMS, expect ABC failure.

Symptoms Appear 1-2 weeks after initiation of ABC (up to 6 weeks). Onset of the symptoms is felt after a dose. Symptoms improve between doses and then worsen again after next dose. The symptoms appear to worsen with each dose. In contrast to other allergic reactions (e.g., nevirapine or TMP/SMX), where onset of rash or other symptoms occur immediately and do not worsen with each dose.If the provider does not feel that the patient could be adherent to their medications during the first 2-4 weeks of therapy, they should not be given abacavir.

If the symptoms are felt to be related to abacavir, the patient should be told that they do in fact have an allergy and they should NEVER be given abacavir again. If the symptoms are felt to result from another cause or it is unclear, continue administration of doses under observation to see if symptoms worsen with each dose. Patients should NOT be counseled to stop abacavir on their own if symptoms occur because symptoms may not actually be related to abacavirIf they stop medication, the real cause cannot be determined and subsequently must be assumed to be abacavir, consequently, abacavir can never be used again for this patient (i.e., an NRTI has been wasted for this patient).

Re-challenge among persons with the abacavir hypersensitivity has been associated with death in at least 3 patients.If anaphylactic reaction develops, treatment is supportive with IV fluids, dialysis, etc. Steroids and histamines are not usually effective.

Monitor for renal impairment monthly: decreasing CrCl; glucose, phosphate, or protein in urine, low serum phosphate or potassium. Renal compromise is rare, but TDF should be stopped if patient develops renal compromise

Nucleotide Analog: TDF is different from nucleosides in that it has already been phosphorilated once.Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of tenofovir. After oral administration, TDF is rapidly cleaved by nonspecific extracellular carboxyesterases into tenofovir. Once inside cells tenofovir is metabolized by adenylate cyclase and nucleoside diphosphate kinase to the active moiety, tenofovir diphosphate (PMPApp). Bioavailability (F): 25% (fasting) to 40% (with food). Bioavailability improves with food, especially high-fat meals.CSF Levels: unknown % of serum levelsT1/2: 12 to 18hoursIntracellular T1/2: 10 to 50 hours

Having to take this drug on an empty stomach can be more difficult on patients from an adherence standpoint.

Nucleoside Analog: Inosine analogueMechanism of Action: It is phosphorylated 3 times to the active metabolite, 2, 3-dideoxyadenosine 5-triphosphate (ddATP)Bioavailability (F): 30-40%. Food decreases bioavailability by 55% - doses should be taken on an empty stomach. ddI is degraded by gastric acid. Consequently it is dosed with buffer (buffered chewable tablets) or enteric coated for delayed release (Videx-EC). CSF Levels: 20% of serum levelsT1/2: 1.5 hoursIntracellular T1/2: 25-40 hoursElimination: 40% renally excreted unchanged in urine. Reduce dose with renal compromise

ddI is a D drugUse lower dose to reduce risk of S/E development for patients < 60kg. Dose-related side effectsPeripheral Neuropathy: Frequency: 5%-12%. Onset usually after 2-6 months of therapy. If patient develops peripheral neuropathy discontinue ddI at onset (or reduce dose to 250mg QD). Symptoms will dissipate slowly after stopping ddI or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating.Pancreatitis: Reported in 1%-9%, fatal in 6%. Risk factors include: renal failure, alcohol abuse, morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and concurrent use of d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue therapy. When symptoms resolve, do not re-challenge with didanosine.

As therapy continues, patients are better able to tolerate the medications.Counsel patients Present the potential for side effects with a regimen so that they know what to expect Provide them with advice about how to handle side effects (whether they can manage the side effect at home, should call to touch base, or need to come to the clinic to be seen). Reassure them that side effects do improve over time, so its important not to give up too quickly on the medications unless having severe side effects.

Peripheral neuropathy and pancreatitis Most noted with the D drugs ddC, d4T, ddI. Rates of occurrence differ by drug (see slide). Note: peripheral neuropathy can develop as a result of HIV infection alone.Peripheral neuropathy Damage to the peripheral nervous system. Onset usually occurs after 2-6 months of therapy. Symptoms range from tingling, numbness, aching, or burning sensations to severe pain usually in the feet, legs and sometime in the arms and hands. It often begins in the toes and/or fingers bilaterally and evolves on hands in a glove pattern or on feet in a sock pattern. Numbness and muscle weakness can also occur.

In vitro, d4T/ddi/ddc worse than azt/3tc/abc

High chance of death even if it is treated immediately. May occur in conjunction with a severely enlarged liver. Mitochondrial processLactate or lactic acid is a by-product of sugar (glucose) processing by cells. Little organs inside each human cell called mitochondria process glucose to provide energy for the cell. Lactate is a by-product of this process. Lactic acidosis occurs when there is an over-accumulation of lactate in the body that the liver is unable to clear. Nucleoside analogues Disrupt mitochondria function inside the cell. This could cause excessive lactate production, which could lead to lactic acidosis if the liver is not functioning properly. Many of the other side-effects of nucleoside analogues may also be associated with damage to mitochondria including peripheral neuropathy (numbness or pain in the feet and hands); bone marrow suppression; pancreatitis (inflammation of the pancreas); hepatic steatosis (accumulation of fat in the liver); and myopathy (muscle damage).

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NNRTIS also work at the beginning, inhibiting Reverse Transcriptase, but they work in a different way than NRTIs. They hook on to the actual enzyme (reverse transcriptase) and stop it from working. The result is the same as the NRTIs: the DNA copy of viral RNA cannot be made and therefore cannot be integrated into the nucleus. Again, the life cycle breaks down.

Hepatotoxicity If occurs in first 8 weeks: appears to be a hypersensitivity reaction and may be accompanied by drug rash, eosinophilia, and systemic symptoms. Some patients have presented with nonspecific symptoms of hepatitis and progressed to hepatic failure.Some patients on NVP develop hepatotoxicity later in the course of treatment. This form of hepatitis is more benign and similar to hepatitis seen with other anti-HIV drugs.

Occurrence of increase in LFTsAsymptomatic: 9% of persons (> 5 times the upper limit of normal ULN) Symptomatic: 4% of persons (Half of these cases were associated with rash)

Most commonly appears on the body and armsTwo forms Milder form erythematous, maculopapular rashcontinue medication with close observationantihistamines may be administeredSevere form with mucous membrane involvement, SJS & TENDRESS: Drug rash, eosinophilia, systemic symptomsD/C if fever, blisters mucous membrane, conjunctivitis, edema, arthalgiasUsually appears within the first month of therapy, although occasionally it may start a few weeks later.Patients that do experience a rash during the 2-week lead-in should not increase the dose until the rash has resolved (mean duration of rash is 14 days). If the patient experiences rash and stops nevirapine on their own, provider would not reintroduce nevirapine with the dose escalation until the rash has resolved.Patients should call their provider or pharmacist or return to clinic if they develop a rash or have any blistering in the mouth, and if they develop fever, arthralgias, or myalgias.

Patients that stop their medications for > 7 days should restart their regimen with the dose escalation: Daily dosing for 2-weeks, then increase to 200mg BID.It is suggested that nevirapine and other medications that often cause rash (e.g., abacavir and SMX/TMP) should not be started simultaneously so that the offending agent can more easily be identified if a rash develops. For example, for a new patient arriving in clinic that meets criteria for ART and PCP prophylaxis, start SMX/TMP at first visit and monitor for side effects, then start nevirapine at least 1 month later as part of ART regimen.Prednisone and antihistamines are not effective in preventing nevirapine rash. In fact, prednisone administration during the first 2 weeks of nevirapine therapy appears to increase the incidence of rash.

RashUsually morbiliform Symptoms can be treated as needed (e.g., hydrocortisone cream and antihistamines for itching). If patient develops a more serious rash (blistering of mucous membranes or skin, seen in about 1%-2% of cases; or SJS) EFV should be discontinued. Median time of onset of the rash is 11 days and the duration is 14 days.HepatotoxicityRate is less frequent and less severe than seen with NVP. Increase risk of occurrence if co-infected with HCV or also taking other hepatotoxic medications

Bioavailability (F): 40%-45% with or without food. CSF Levels: .25%-1.2% of serum levels (these levels are above the IC95 for wild-type HIV)T1/2: 40-55 hoursElimination: Metabolized by CYP450 3A4. 14% to 34% excreted in urine as glucuronide metabolites and 16% to 61% in stool. Do not need to adjust dose for renal or hepatic compromis.

Do not appear to cause rash and hepatitis in the same manner. Nevirapine: if onset of rash or liver toxicity occur, can probably be safely switched to efavirenz (and vice versa), unless the toxicity on nevirapine was very severe. Just because a patient gets a rash to one medication does not mean they will develop rash to the other agent.Rate of Rash: EFV (15%-27%) > DLV (18%) > NVP (17%)Rate of rash that requires discontinuation of the offending agent: NVP (7%) > DLV (4.3%) > EFV (1.7%).ResistanceNVP: Induction of resistance with single doseCounsel patients about the importance of adherence related to this class of medications, only a single mutation is needed to make a person resistant to all NNRTIs. Location of mutation: Distant from replication site; confers no reduction in viral fitness

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Protease is essential for assembly of new viral particles. Without it, new viruses cannot be assembled.PIs prevent protease from assembling new virus in the final stages of the life cycle.

* The top 4 protease inhibitors (PIs) are recommended as second-line treatment agents.

This drug is used only at a dose that alone has virtually no antiretroviral effect (that is why boosted protease combination e.g. LPV/r - is considered one of the three drugs in a PI-based regimen). However, combined with other PIs, it has a powerful effect on the other PIs metabolism boosting the other PIs effect.

AUC = area under the curve: Basically represents the drug concentration. Boosting with Ritonivir increases the other PI drug concentration by 1.5 to 70 fold.

Lopinavir/r Approximately 10 times more potent than RTV alone against wild-type HIV.Generally well tolerated. Pancreatitis has been reported in adults, possibly due to high triglyceride levels.

Reference NotesBioavailability (F): ~80% with food and 48% on an empty stomach, but by combining LPV with ritonavir (in the capsule), LPV levels are increased significantly.CSF Levels: unknown %, likely low because LPV is 98-99% protein boundT1/2: 5 to 6 hours (for LPV when combined with RTV)Elimination: Metabolized primarily by CYP450 3A4 enzymes. Less than 3% is excreted unchanged in urine. Do not need to adjust doses for renal compromise. Use with caution in patients with hepatic impairmentPediatric Dose: 230mg/m2 LPV / 57.5mg/m2 RTV BID Pregnancy: (Category C) Crosses placenta. Drug Interaction: The major effect is due to inhibition of CYP3A4. This effect is less than seen with full doses of RTV.

Patients should be given a prescription for an antidiarrheal at the time they are prescribed nelfinavir and taught how to mange the diarrhea if it should occurTake 1 to 2 doses of loperamide at onset of diarrhea and then take 1 loperamide for each loose stool after that, up to a maximum of 8 loperamide per day. If patients find that 1 loperamide 3 times daily [or any other regimen] controls their diarrhea, they can follow that regimen regularly to prevent diarrhea before it occursOther options for diarrhea control include calcium 500mg BID, psyllium 1 tablespoon once or twice daily mixed in water once or twice daily with the water volume (120ml), oat bran 1500mg BID, or pancreatic enzymes at 1 to 2 tablets with each meal. If diarrhea cannot be controlled with antidiarrheals, patients should consult with their provider or pharmacist, it may be necessary to change to another PI or NNRTI. If constipation develops from antidiarrheal use, the patient should reduce their loperamide dose or other agents.

Reference NotesBioavailability (F): 20% to 80% with meals. Food increases absorption by 2 to 3-fold. Fatty meals improve absorption further.CSF Levels: No detectable levels in CSFT1/2: 3.5 to 5 hoursElimination: Primarily metabolized by CYP450 3A4. Only 1% to 2% is found in urine. Up to 90% is found in stool, primarily as a hydroxylated metabolite designated M8, which is as active as nelfinavir against HIV. No dosage adjustments needed with renal compromise. Use with caution in patients with hepatic impairment.Pediatric Dose: 20-45mg/5kg TID Pregnancy: (Category B) Present in breast milk and minimal concentration crosses placenta.

Nausea and diarrhea are more common with the soft-gel formulation than with the hard-gel formulation as a result of:Better bioavailability (i.e., more drug is absorbed so potential for more side effects)A component of the soft-gel capsules which causes diarrheaDosing:SQV is rarely used alone, it is commonly combined with RTV.Standard dose for soft-gel capsule with RTV: SQV 400mg BID + RTV 400mg BID; or 1000mg SQV BID + 100mg RTV BID; or SQV 1600mg QD + RTV 100mg QDThe hard-gel capsule should ALWAYS be dosed with RTV, dosing same as for soft-gel capsules.

If taken with a low fat snack (such as dry toast with jelly, juice, coffee with skim milk, or cereal with skim milk), as opposed to an empty stomach (defined as 1 hour before or 2 hours after a meal), patients are more able to tolerate the gastrointestinal side effects. Coordinating 3 doses every 8 hours on an empty stomach can be very difficult for most patients. If this dosing is chosen, patients should be counselled about adherence.Currently indinavir is commonly combined with RTV in order to improve dosing schedule (can change to BID dosing) and food requirements as well as reduce gastrointestinal and lipid abnormalities. 1.5 litres of water are still required to prevent kidney stones even when combined with RTV.

Kidney stonesMost serious side effect in both adults and childrenSeen in about 10%-28% of patients (depending on duration of treatment, age, and fluid prophylaxis); it may be more frequent in hot climates. Temporary abnormal kidney function, including acute kidney failure and inflammation has been observed in some patients with nephrolithiasis. The condition may be signalled by severe pain beneath the ribs with or without blood in the urine. Indinavir may need to be interrupted for a few days. The condition may recur in half of the patients if indinavir is restarted. Patients taking indinavir must drink plenty of fluids to prevent the development of kidney stonesAt least 1.5 litres of water daily and more in hot weather. Caffeinated or alcoholic beverages do not promote hydration and should not be counted in the 1.5 litre daily fluid requirement.In most cases the maximum bilirubin elevation was observed after one or more weeks of treatmentJaundice (yellowing of the skin) and elevations in liver enzymes have been reported only rarely. In most cases patients with elevated bilirubin are asymptomatic.

Whilst many side effects develop in the first few weeks on new medication, some do not emerge until the medication has been used over the longer term. As more information becomes available about the mechanisms that cause long-term side effects, it will be more possible to develop effective interventions to prevent and treat these side effects. Metabolism A general term for the breakdown of food and production of energy within the body. Sugar and fat are sources of energy. Abnormalities in sugar and fat levels or abnormalities in the processing of fats and sugars may indicate metabolic disorders and cause physical symptoms. Metabolic disordersHave caused the greatest concern in developed countries.A number of metabolic disorders have been reported among people taking anti-HIV therapy. These include hyperlipidemia (high levels of fat in the blood); diabetes, high blood sugar (hyperglycemia), and insulin resistance; and high levels of lactate (a by-product of sugar metabolism in the body); elevated ALT (a liver enzyme); and lipodystrophy (fat redistribution).Drug interactions: In addition, PIs are known to interact with multiple other medications. The role of the pharmacist is critical for recognizing and identifying and preventing potential drug interactions through dosage adjustment or preventing co-administration of contraindicated medications.

Ritonavir has been more frequently associated with severe liver toxicity. Elevated liver enzymes in the blood can occur at any time during PI treatment. Symptoms of liver toxicity include: weight loss, loss of appetite, nausea and vomiting, fever, abdominal pain, itchy skin