Art and Drug Resistance

8/8/2019 Art and Drug Resistance

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ANTI RETRO VIRALANTI RETRO VIRALTHERAPYTHERAPY

ANDANDDRUG RESISTANCEDRUG RESISTANCE


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ANTI RETRO VIRAL DRUGS

REVERSE TRANSCRIPTASE INHIBITOR

NON NUCLEOSIDE DERRIVATIVE

NUCLEOTIDE DERRIVATIVE

NUCLEOSIDE DERRIVATIVE

PROTEASE INHIBITOR

ENTRY INHIBITOR

FUSION INHIBITOR INTEGRASE INHIBITOR

MATURATION INHIBITOR


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Celsentri binds with a receptor on whiteblood cells and prevents HIV from enteringthe cell in that way.But it cannot prevent

HIV from using a second receptor thatoften shows up often late in the diseaseprogression. That means the drug willwork in only about half of HIV patients.Those who use Celsentri will need anexpensive test to determine if they will behelped.


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Isentress inhibits the integrase enzyme, which is criticalfor HIV's replication. Nearly two-thirds of those with drugresistance had their virus levels fall to undetectablelevels while using Isentress and two other agents,

according to a pair of studies released in February. Thatcompares with about one-third whose virus levelsbecame undetectable while solely on the other agents.

So far, the drug appears low on side effects, . A fewpatients in the clinical trials developed cancers related to

HIV, but the data do not show they were caused by thedrug, said Robin Isaacs, Merck's executive director ofclinical research.


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NON NUCLEOSIDEREVERSE

TRANSCRIPTASE INHIBITOR

NON COMPITITIVE INHIBITORS

SPECIFIC FOR HIV1 NOT USEFUL FOR HIV 2

NOT REQUIRE INTRACELLULAR PHOSPHORYLATION FORACTIVITY

SINGLE CODON MUTATION LEADS TO RESISTANCE. CROSS RESISTANCE IS VERY COMMON.

NO ACTIVTY AGAINEST CELLULAR DNA POLMERASE.

MOST COMMON SIDE EFFECT IS RASH, INCIDENCE

IS 15-20%.


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NEVIRAPINE

FDA-approved for the treatment of HIV-1 infection inadults and children FDA-approved for the treatment ofHIV-1 infection in adults and children

FDA-approved for the treatment of HIV-1 infection inadults and children

Elevated hepatic transaminases, severe and fatalhepatitis has been associated with nevirapine use; thismay be more common in women, especially duringpregnancy.

Drug should not be initiated in women with CD4 cellcounts >250 per mm3 or men with CD4 counts >400 permm3 unless benefits clearly outweigh the risks.


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EFAVIRENZ

Cleared predominantly by CYP2B6 with a prolonged t1/2that permits once-daily dosing.

Predominant adverse effects of efavirenz involve theCNS ( dizziness, impaired concentration, dysphoria,

frank psychosis, depression, or hallucinations). CNSside effects generally lessen or resolve within the first 4weeks of therapy.

Efavirenz is the only antiretroviral drug that isunequivocally teratogenic, causing neural tube defects;thus, women of childbearing potential should use twomethods of birth control and avoid pregnancy whiletaking this drug.


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DELAVIRDINE

Due to its shorter t1/2 and rapid emergence ofresistance, delavirdine is the least used of theNNRTIs.

Absorption is best at acid pH and may bedecreased by histamine H2 receptor antagonistsor proton pump inhibitors.

It should be avoided with CYP3A4 substrateswith a narrow therapeutic index and not

combined with potent inducers of CYP3A4 (e.g.,carbamazepine, phenobarbital, phenytoin,rifabutin, and rifampin).

Not available in India


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ETAVIRENE

Etravirine is a diarylpyrimidine derivative that is

currently available on expanded access for

treatment of HIV infection in combination with

other agents. In contrast to the othernonnucleoside reverse transcriptase inhibitors,

which all exhibit cross-resistance, etravirine may

be active against strains of HIV that are resistant

to other nonnucleoside reverse transcriptaseinhibitors. its side effects are rash, headache,

nausea, and diarrhea.


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NUCLEOSIDE AND NUCLEOTIDE

REVERSE TRANSCRIPTASE INHIBITOR

Nucleoside and Nonnucleoside reverse transcriptaseinhibitors prevent infection of susceptible cells but haveno impact on cells that already harbor HIV.

After entering in the cell and undergoing

phosphorylation, they block replication of the viralgenome both by competitively inhibiting incorporation ofnative nucleotide and by terminating elongation ofnascent proviral DNA because they lack a 3-hydroxylgroup.

These compounds inhibit both HIV-1 and HIV-2 andseveral have broad-spectrum activity against otherretroviruses; some are also active against hepatitis Bvirus (HBV) or the herpesviruses.


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Important toxicities common to this class of drugs result frominhibition of mDNA synthesis.

Toxicities include anemia, granulocytopenia, myopathy, peripheralneuropathy, and pancreatitis.

Lactic acidosis with or without hepatomegaly and hepatic steatosis

is a rare but potentially fatal complication seen with stavudine,zidovudine, didanosine, and zalcitabine.

Phosphorylated emtricitabine, lamivudine, and tenofovir have lowaffinity for DNA polymerase gand are largely devoid ofmitochondrial toxicity.

Drugs that are subject to mitochondrial toxicities generally should

not be coadministered with otther agents that can cause neuropathy(e.g.,ethambutol, isoniazid, vincristine,cisplatin,and pentamidine)or pancreatitis.


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Saquinavir 600 mg q8h Diarrhea, nausea,

headach,hyperglycemia, fat

redistribution, lipid abnormality

Ritonavir 600 mg bid

100 mg bd

Nausea, abdominal pain,

hyperglycemia, fat -redistribution,

lipid abnormality

Indinavir sulphate 800 mg q8h300 mg bid

Nephrolethiasis,indirectHyper bilirubenemia,


lipid abnormality

Amprenavir \ fos

amprenavir

1200 mg bid

600 mg bid+ ritonavir

100 mg bid

1200 mg qd +ritonavir

200 mg qd

Nausea, vomitng ,dirrhoea,

rash,oral parasthesias,


lipid abnormality


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Stavudine (D4T) 60 kg 40 mg bid

Pancreatitis,perip-heral

neuropathy, hepatic

steatosis ,Lactic acidosis

Lipodystrophy,ascending

neuromuscularweakness

Lamivudine (3TC) 150 mg bid

Emtricitabine (FTC) 200 mg qd

Abacavir 300mg bid Hyper sensitivity reaction

(can be severe),fever,

rash,nasea,vomiting,

fatigue,loss of appetite

Tenofovir 300 mg qd Potential for renal toxicity


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Drug Dose Side effect

Zidovudine 300 mg bd Anemia,granulocytopennia,myopa>thy,lactic

acidosis, hepatic

steatosis ,nausea

Didanosine 60 kg 200mg bd

Pancreatitis,perip-heral

neuropathy,hepatic steatosis

Lactic acidosis

Zalsitabine 0.75 mg tid Pancreatitis,perip-heral

neuropathy, hepatic

steatosis ,Lactic acidosisOral ulcer,hepatomegaly


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Nelfinavir 750 mg tid

1250 mg bid

Dirrhoea,,loose stools,

hyperglycemia, fat -

redistribution, lipid

abnormality

Lopinavir\ritonavir 400 mg\100 mg bid Dirrhoea,,loose stools,

hyperglycemia, fat -

redistribution, lipid

abnormality

Atazanavir 400 mg qd

300 mg qd +100 mg qdritonavir

Hyper bilirubenemia,PR

prolongation,nausea

,vomiting,dirrhoea,,loose

stools, hyperglycemia, fat

-redistribution, lipid

abnormality


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EFV + (3TC or FTC) + (AZT or TDF)

PI-based LPV/r + (3TC or FTC) + AZT


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MARAVIROCSELZENTRY

Licensed In combination with other antiretroviral

agents in treatment experienced adults infected

with only CCR5-tropic HIV-1 that is resistant to

multiple antiretroviral agents. Dose is 150-400 mg depending upon

concomittent drug.

Side effects are hepatotoxicity, nasopharyngitis,

fever, cough, rash, abdominal pain, dizziness,

fever, musculoskeletal symptoms


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RALTEGRAVIR

(Isentress)

Integrase inhibitorLicensed In combination with other antiretroviral agents

in treatment experienced patients with evidence of

ongoing HIV-1 replcationDose-400 mg bid


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ENFUVERTIDE

((FUZEON) Entry\Fusion Inhibitor

a 36-amino-acid synthetic peptide

This prevents formation of a six-helix bundle critical for membrane

fusion and viral entry into the host cel

Because of its unique mechanism of action, enfuvirtide retainsactivity against viruses that have become resistant to antiretroviral

agents of other classes.

Enfuvirtide must be givenparentally.

The most prominent adverse effects of enfuvirtide are injection site

reactions, including pain, erythema, induration, and nodules orcysts. These cause drug discontinuation in ~5% of patients. Use of

enfuvirtide has been associated with increased lymphadenopathy

and pneumonia.


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CDC Classification System forHIV-

Infected Adults and Adolescents

CD 4 CELL

CATEGORY

CLINICAL CATEGIRIES

A

Asymptomatic, Acute

HIV, or PGL

B

Symptomatic but not A

or C

C

AIDSindicator

conditions

>500 cells A1 B1 C1

200-499

cells

A2 B2 C2


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. CDC Classification System: Category B symptomatic conditions aredefined as symptomatic conditions occurring in an HIV-infected adolescentor adult that meet at least 1 of the following criteria:a) They are attributed toHIV infection or indicate a defect in cell-mediated immunity. b) They areconsidered to have a clinical course or management that is complicated byHIV infection. Examples include, but are not limited to, the following:

Bacillary angiomatosis Oropharyngeal candidiasis (thrush)

Vulvovaginal candidiasis, persistent or resistant

Pelvic inflammatory disease (PID)

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Hairy leukoplakia, oral

Idiopathic thrombocytopenic purpura Constitutional symptoms, such as fever (>38.5C) or diarrhea lasting >1

month

Peripheral neuropathy

Herpes zoster (shingles), involving 2 episodes or 1 dermatome


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Category C AIDS-Indicator Conditions

Bacterial pneumonia, recurrent (2 episodes in 12months)

Candidiasis of the bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical carcinoma, invasive, confirmed by biopsy

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary


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Cryptosporidiosis, chronic intestinal (>1-month duration)

Cytomegalovirus disease (other than liver, spleen, ornodes)

Encephalopathy, HIV-related

Herpes simplex: chronic ulcers (>1-month duration), orbronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1-month duration)


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Pneumocystis jiroveci(formerly carinii) pneumonia(PCP)

Progressive multifocal leukoencephalopathy (PML)

Salmonella septicemia, recurrent (nontyphoid)

Toxoplasmosis of brain Wasting syndrome due to HIV (involuntary weight loss

>10% of baseline body weight) associated with eitherchronic diarrhea (2 loose stools per day 1 month) orchronic weakness and documented fever 1 month


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Kaposi sarcoma

Lymphoma, Burkitt, immunoblastic, or primary centralnervous system

Mycobacteriumavium complex (MAC) orMkansasii,disseminated or extrapulmonary

Mycobacteriumtuberculosis, pulmonary orextrapulmonary

Mycobacterium, other species or unidentified species,disseminated or extrapulmonary


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RESISTANCE TESTING

Genotypic assay-:detect drug resistance mutations

present in the relevant viral genes. genotypic assays

involve sequencing of the entire reverse transcriptase

and protease genes, where as others use probes to

detect selected mutations that are known to confer drug

resistance. Genotypic assays can be performed rapidly,

and results can be reported within 1-2 weeks of sample

collection.

Phenotypic assay:-Phenotypic assays measure a virus'sability to grow in different concentrations of antiretroviral

drugs. Automated, recombinant phenotypic assays are

commercially available with results available in 2-3

weeks.


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WHEN TO START ARTWHEN TO START ART

Antiretroviraltherapyis recommended forallpatients withhistoryofan AIDS-definingillness or severe symptoms of HIVinfection regardless of CD4+ T cellcount (AI).

Antiretroviraltherapyis also recommended for

Asymptomaticpatients with 350 cells/mm3andplasma HIV RNA >100,000 copies/mL mostexperienced clinicians defer therapybut some clinicians may

considerinitiating treatment (CII).Therapyshould be deferred forpatients with

CD4+T cellcounts of >350 cells /mm3and

plasma HIV RNA


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WHAT TO START

2 most clinical experience with combination therapy in treatment-naveindividuals is based on two different types combination regimens,namely:

NNRTI-based (1NNRTI +2 NRTI)

PI-based (1-2 PI + NRTI) regimens

Preferred NNRTI (AII):

Efavirenz (except during first trimesterofpregnancyorin womenwith high pregnancypotential*)

Alternative NNRTI (BII):

Nevirapine maybe usedas an alternative in adult females with CD4+Tcellcounts


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Alternative PIs (BII):

atazanavir**

fosamprenavir

fosamprenavir+ ritonavir* once-dai

lopinavir/ritonavir (co-formulated) once-daily

Other Possible Options (CII):

nelfinavir

saquinavir+ ritonavir*

*Ritonavirat dailydoses of 100-400mgusedas apharmacokinetic booster

**Ritonavir 100mgper dayis recommended when tenofovir


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Antiretroviral Regimens Not

Recommended

Monotherapy (EII). Single NRTI therapy Dual nuTriple-NRTI regimens (EII): Except for

abacavir/ lamivudine/zidovudine (CII) and

possibly zidovudine/lamivudine + tenofovir (DII),

triple-NRTI regimens should NOT be used routinely

because of suboptimal virologic activity [90, 135-139]

or lack of data.

NRTI-sparing regimens (DII): Because of

pharmacokinetic interactions, drug toxicities, and drug

resistance issues, these regimens (e.g., efavirenz

together with indinavir or lopinavir/ritonavir) are not

cleoside regimens


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Amprenavir oral solution in pregnant women;

treatment-nave men with CD4+ T cell counts

>400 cells/mm3 (DI) Greater risk of symptomatic,

including serious and life-threatening, hepatic events

stavudine (EII). The combined use of

didanosine and stavudine as a dual-NRTI backbone can

result in a high incidence of toxicities, particularly

peripheral neuropathy, pancreatitis,

Saquinavir as a single PI (i.e., unboosted) (EII).

Saquinavir mesylate is contraindicated as a single PI

because of poor bioavailability that averages only 4%, Stavudine + zidovudine (EII). These two NRTIs

should not be used in combination because of the

demonstration of antagonism in vitro[149]and in viv


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LIMITATIONS TO TREATMENT

SAFETY AND EFFICACY

Adverse Effects of Antiretroviral

Agents

Drug Interactions


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Drug Interactions

PI and NNRTI Drug Interactions.

All PIs are substrates of CYP3A4, wheretheir metabolicrate may be altered in thepresence of CYP inducers or

inhibitors. Some PIs may also be inducers

or inhibitorsrate may be altered in thepresence of CYP inducers or

inhibitors.


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The NNRTIs are also substrates of

CYP3A4 and can act

as an inducer (nevirapine), an inhibitor

(delavirdine), or amixed inducer and inhibitor (efavirenz).

Thus, these

antiretroviral agents can interact with each

other in multiple ways and with other drugs

commonly prescribed

for other concomitant diseases.


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MANAGEMENT OF THE TREATMENT

EXPERIENCED PATIENT

Panels Recommendations:

Virologic failure on treatment can be definedas a

confirmed HIV RNAlevel>400 copies/mL after 24

weeks, >50 copies/mL after 48 weeks, ora repeated

HIV RNAlevel>400 copies/mL afterprior

suppression ofviremia to


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children 250 cells/mm3 or in


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In managingvirologic failure, the provider shouldmake a distinction between limited, intermediate,

and extensive prior treatment exposure and

resistance.

The goalof treatment forpatients with prior drug

exposure and drug resistance is to re-establish

maximalvirologic suppression. For some patients with extensive prior drug

exposure and drug resistance where viral

suppression is difficultorimpossible toachieve with

currentlyavailable drugs, the goalof treatmentis

preservation ofimmune function andprevention of

clinicalprogression. Assessingandmanagingapatient with extensive

priorantiretroviralexperience and drug resistance

whois experiencing treatment failure is complex

and expertadvice is critical.


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In managingvirologic failure, the provider should

make a distinction between limited, intermediate,


resistance.


exposure and drug resistance is to re-establish

maximalvirologic suppression. For some patients with extensive prior drug




preservation ofimmune function andprevention of

clinicalprogression.

Assessingandmanagingapatient with extensive priorantiretroviralexperience and drug resistance


and expertadvice is critical.


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In managingvirologic failure, the provider should

make a distinction between limited, intermediate,


resistance.


exposure and drug resistance is to re-establish maximalvirologic suppression.

For some patients with extensive prior drug




preservation ofimmune function andprevention of clinicalprogression.

Assessingandmanagingapatient with extensive

priorantiretroviralexperience and drug resistance



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Definitions and Causes of Antiretroviral

Treatment Failure

Antiretroviral treatment failure can be defined as a

suboptimal response to therapy. Treatment failure is

often associated with virologic failure, immunologic failure, and/or clinical progression (See below.)

Virologic Failure can be defined as incomplete or

lack of HIV RNA response to antiretroviral therapy:

Incomplete virologic response: This can be defined

as repeated HIV RNA >400 copies/mL after 24

weeks or >50 copies/mL by 48 weeks in a treatmentnave

patient initiating therapy. Baseline HIV RNA may impact the time course of response and some

patients will take longer than others to suppress HIV

RNA levels. The timing, pattern, and/or slope of

HIV RNA decrease may predict ultimate virologic

response [193]. Immunologic Failure can be defined as failure to

increase the CD4 cell count by 25-50 cells/mm3 above

the baseline count over the first year of therapy, or a decrease to below the baseline CD4 cell count on

therapy. Mean increases in CD4 cell counts in

treatment-nave patients with initial antiretroviral

regimens are approximately 150 cells/mm3 over the


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first year [197]. A lower baseline CD4 cell count may

be associated with less of a response to therapy. For

reasons not fully understood, some patients may have

initial CD4 cell increases, but then minimal

subsequent increases.

Immunologic failure (i.e., return to baseline CD4 cell count) occurred an average of 3 years following

virologic failure in patients remaining on the same PIcontaining

antiretroviral regimen [198].

Clinical Progression can be defined as the occurrence

or recurrence of HIV-related events (after at least 3

months on an antiretroviral regimen), excluding immune

reconstitution syndromes [199, 200]. In one study,

clinical progression (a new AIDS event or death) occurred in 7% of treated patients with virologic

suppression, 9% of treated patients with virologic

rebound, and 20% of treated patients who never achieved

virologic suppression over 2.5 years [190].

Relationship Across Virologic Failure,

Immunologic Failure, and Clinical Progression.

Some patients demonstrate discordant responses in

virologic, immunologic and clinical parameters [201]. In addition, virologic failure, immunologic failure,

and clinical progression have distinct time courses and

may occur independently or simultaneously. In

general, virologic failure occurs first, followed by

Page 23

Guidelines forthe Useof AntiretroviralAgents in HIV-1-Infected Adults and Adolescents


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Changing an Antiretroviral Therapy

Regimen for Virologic Failure

Panels Recommendations: For the patient with virologic failure,perform

resistance testing while the patient stillis taking the drug regimen or within 4 weeks after regimen

discontinuation (A

II). Use the treatment historyandpastand current resistance test results toidentifyactive agents (preferablyatleast two fullyactive agents) to design a new regimen (AII). A fullyactive agentis one likelyto demonstrate antiretroviralactivityon the basis of both the treatment historyand susceptibility

on drug-resistance testing. Ifatleast two fullyactive agents cannot be identified, considerpharmacokinetic enhancementofprotease

inhibitors (with the exception of nelfinavir) with ritonavir (BII) and/or re-usingotherprior antiretroviralagents toprovidepartialantiretroviral

activity(CIII). Addinga drug with activityagainst drug-resistant virus (e.g., apotent ritonavir-boostedPI) anda drug with a newmechanismofaction (e.g., HIV entry

inhibitor) toan optimized backgroundantiretroviral

regimen can provide significantantiretroviral

activity(BII). In general, one active drug should not be added toa

failing regimen because drug resistance is likelyto

develop quickly(DII). However, in patients with advanced HIV disease (e.g., CD4


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Tipranavir and darunavir are two new protease

inhibitors approved for patients who are highly

treatment-experienced or have HIV-1 strains resistant

to multiple PIs based on its demonstrated activity

against PI-resistant viruses [224, 225]. However,

New Agents. Investigational reverse transcriptase

inhibitors (e.g., TMC-125) with distinct resistance

patterns and activity against drug-resistant viruses are

currently under investigation in clinical trials [226].

scon nua on or n errup on o


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scon nua on or n errup on o

Antiretroviral Therapy Short-term therapy interruptions

When all regimen components have similar halflives

and do not require food for proper absorption all drugs should be stopped

simultaneously or may be given with a sip of water,

if allowed. All discontinued regimen components

should be restarted simultaneously.

When all regimen components have similar halflives

and require food for adequate absorption,

and the patient is required to take nothing by

mouth for a sustained period of time temporary discontinuation of all drug components is indicated.

The regimen should be restarted as soon as the

patient can resume oral intake.

When the antiretroviral regimen contains drugs

with differing half-lives stopping all drugs

simultaneously may result in functional

monotherapy with the drug with the longest half-life

(typically an NNRTI). Options in this circumstance

are discussed below. (See Discontinuation of

efavirenz or nevirapine.)

When a patient experiences a severe or lifethreatening

toxicity all components of the drug

regimen should be stopped simultaneously,

regardless of drug half-life.


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Planned long-term therapy

interruptions

In patients who initiated therapyduring acute HIV

infection and achieved virologic

suppression -


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In patients who have had exposure to multiple

antiretroviral agents, have experienced

antiretroviral treatment failure, and have few

treatment options available because of extensive

resistance mutations - interruption is generally In patients on antiretroviral therapy who have

maintained a CD4+ cell count above the level

currently recommended for treatment initiation

and whose baseline CD4+ was either above or

below that recommended threshold interruption

is also not recommended unless it is done in a

clinical trial setting .


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CONSIDERATIONS FOR

ANTIRETROVIRAL USE IN

SPECIAL PATIENT POPULATIONS

Acute HIV Infection

Panels Recommendations: Whether treatmentofacute HIVinfection results in

long-termvirologic, immunologic, or clinical benefitis unknown; treatment should be considered optionalat this time (CIII). Therapyshouldalso be consideredoptional for patients in whom HIV seroconversion has occurred within the previous 6months (CIII). If the clinician andpatient elect to treatacute HIV infection with antiretroviraltherapy, treatment should be implemented with the goalof suppressing

plasma HIV RNAlevels to below detectable levels (AIII). Forpatients with acute HIVinfection in whom

therapyis initiated, testing forplasma HIV RNA

levels and CD4+ T cellcountand toxicity

monitoring should beperformedas described for patients with established, chronic HIVinfection (AII). If the decision is made toinitiate therapyin a

p

erso

n with

acu

te HIVinfect

ion, gen

otypi

c resistance testingat baseline willlikelyoptimize virologic response; this strategyis therefore recommended (BIII). If therapyis deferred, genotypic resistance testing should stillbe considered, because the resultmaybe usefulin optimizing the virologic response when therapyis ultimatelyinitiated


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Lactic acidosis


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NEVIRAPINE


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Art and Drug Resistance

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