art and drug resistance
TRANSCRIPT
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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,
hyperglycemia, fat -redistribution,
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,
hyperglycemia, fat -redistribution,
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,
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,
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
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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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