Human immunodeficiency virus (HIV) infection
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Human immunodeficiency virus (HIV) infection
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HIV therapeutics is a specialised field so only those doctors with experience in HIV management should prescribe antiretroviral therapy.
Rather than acting as a detailed guide, this chapter aims to provide general information that will enable the practitioner or student to understand the principles of antiretroviral therapy, to recognise common adverse effects of the drugs, and to appreciate the importance of drug interactions with antiretrovirals. Prophylaxis and treatment of opportunistic infections in HIV-infected adults are also detailed.
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Treatment with highly active combination antiretroviral therapy has led to substantial reductions in HIV infection-related morbidity and mortality. However, indications for initiation of antiretroviral treatment are now more conservative than they were in the past. This is because of i) difficulties with long-term adherence to many treatment regimens, ii) emerging information about toxicities of antiretroviral drugs, and iii) the potential for development of resistance to antiretroviral drugs (with subsequent narrowing of therapeutic options) if treatment does not completely suppress viral replication.
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Indications for antiretroviral therapy
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Indications for treatment according to current guidelines:
·           symptomatic patients including those with HIV-associated opportunistic infections, malignancies, central nervous system disease, thrombocytopenia
·           asymptomatic adults with CD4 cell counts <350/microlitre or HIV viral load >55 000 copies/mL (by reverse transcriptase polymerase chain reaction assay). [Note]
In seroconversion illness, treatment is appropriate on theoretical grounds but is of unproven clinical benefit based on current published evidence.
For further information refer to:
·           Australian antiretroviral guidelines [draft at time of writing], Australasian Society for HIV Medicine, 2001. www.ashm.org.au/index.php?PageCode=23.
For treatment of HIV-infected children, refer to US guidelines:
·           Guidelines for the use of antiretroviral agents in pediatric HIV infection; Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, 2001. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=51.
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For prevention of maternal-fetal transmission by treating the mother prepartum and peripartum and treating the infant postpartum, refer to US guidelines:
·           Recommendations for the use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States, US Public Health Service Taskforce, 2002. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=66.
For postexposure prophylaxis after significant exposure to a known HIV-infected source, refer to Postoccupational exposure prophylaxis (PEP) against blood borne viruses (BBV) and Postsexual assault prophylaxis.
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·           UK guidelines: British HIV Association (BHIVA) guidelines for the treatment of HIV disease with anti-retroviral therapy, 2001. www.aidsmap.com/about/bhiva/bhivagd.asp
·           US guidelines: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [regularly updated]. Recommendations of the panel on clinical practices for treatment of HIV infection, 2002. www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=50.
Antiretroviral drugs
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The 3 major classes of antiretrovirals are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors , see Table 1 (Antiretroviral drugs and oral dosing).
For initial antiretroviral therapy at least 3 drugs are used in combination [Note 1]
 |
Two NRTIs: zidovudine plus lamivudine [Note 2], or zidovudine plus didanosine, or stavudine plus lamivudine |
 |
PLUS EITHER |
1 |
a NNRTI: nevirapine or efavirenz |
 |
OR |
1 |
a protease inhibitor: nelfinavir or indinavir |
 |
OR |
1 |
a protease inhibitor in combination with low dose ritonavir [Note 3]: lopinavir+ritonavir [Note 2] or indinavir plus ritonavir or saquinavir plus ritonavir |
 |
OR if HIV viral load <100Â 000 copies/mL |
2 |
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[For specific contraindications and neonatal doses, consult the product information. The drug name and not the abbreviation should be used when these drugs are prescribed.]
Antiretroviral |
Usual adult doses |
Paediatric doses |
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) |
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300Â mg 12-hourly |
>3 months: 8Â mg/kg up to 300Â mg 12-hourly |
|
didanosine (ddI) |
<60Â kg: 250Â mg daily |
120Â mg/m2 12-hourly (up to 150Â mg/m2 in neurological disease) |
>60Â kg: 400Â mg daily or 250mg if co-administered with tenofovir |
  |
|
lamivudine (3TC) |
150Â mg 12-hourly |
4Â mg/kg (up to 150Â mg) 12-hourly |
stavudine (d4T) |
<60Â kg: 30Â mg 12-hourly |
1Â mg/kg (up to 30Â mg) 12-hourly |
>60Â kg: 40Â mg 12-hourly |
  |
|
300Â mg daily |
not available in paediatric formulation |
|
zalcitabine (ddC) |
0.75Â mg 8-hourly |
0.01Â mg/kg 8-hourly |
zidovudine (ZDV) |
250Â mg 12-hourly or 200Â mg 8-hourly |
160Â mg/m2 (up to 200Â mg) 8-hourly |
300+150Â mg 12-hourly |
not available in paediatric formulation |
|
300+150+300Â mg 12-hourly |
not available in paediatric formulation |
|
Non-nucleoside reverse transcriptase inhibitors (NNRTI) |
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400Â mg 8-hourly |
not recommended under 12 years |
|
600Â mg daily |
<40Â kg: 200 to 400Â mg daily, see product information |
|
200Â mg daily for 2 weeks, then 200Â mg 12-hourly |
see product information |
|
Protease inhibitors (PI) |
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>50Â kg: 1200Â mg 12-hourly OR 600Â mg 12-hourly when combined with low-dose ritonavir (100Â mg 12-hourly) <50Â kg: 20Â mg/kg 12-hourly |
4Â years or older, and <50Â kg: 20Â mg/kg 12-hourly (capsules) |
|
800Â mg 8-hourly OR 800Â mg 12-hourly when combined with low-dose ritonavir (100Â mg 12-hourly) |
3 years or older: 500Â mg/m2 (up to 800Â mg) 8-hourly |
|
400+100Â mg 12-hourly |
2 years or older: 230+57.5Â mg/m2 12-hourly |
|
750Â mg 8-hourly or 1250Â mg 12-hourly |
25 to 45Â mg/kg 8-hourly |
|
600Â mg 12-hourly (Poorly tolerated when used alone at this dose usually combined at low dose with another protease inhibitor.) |
250Â mg/m2 12-hourly, increase to 400Â mg/m2 12-hourly over 5 days |
|
saquinavir  |
1200Â mg 8-hourly OR 1000Â mg 12-hourly when combined with low-dose ritonavir (100Â mg 12-hourly) |
under study |
saquinavir |
1000Â mg 12-hourly when combined with low-dose ritonavir (100Â mg 12-hourly) |
under study |
Before starting antiretroviral therapy
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Successful therapy is dependent upon a high level of adherence to the treatment regimen. Patients should be advised about strategies to improve adherence (for example, use of diaries, pill containers or alarms) and provided with detailed information about medication dosing and side effects.
Some antiretroviral drugs cause hyperlipidaemia and/or glucose intolerance. Cardiovascular risk factors should be assessed, and modified if possible.
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 Monitoring antiretroviral therapy
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Patients require close and regular (1- to 3-monthly) follow-up. The best indicator of antiretroviral activity is the HIV viral load, which should fall to below 50 copies/mL after 3 to 6 months in most patients not previously treated with antiretrovirals. The CD4 cell count generally increases when viral replication is suppressed. Monitoring of serum chemistries, blood lipids and haematology is also important.
Prophylaxis and treatment of opportunistic infections in HIV-infected adults (Table 2)
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Pathogen |
Primary treatment |
Maintenance therapy |
Primary prophylaxis [Note 1] |
 |
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fluconazole 50Â mg orally daily for 10 to 14 days OR itraconazole 100Â mg orally daily for 10 to 14 days OR miconazole 2% gel 3Â mL orally 6-hourly for 10 to 14 days OR nystatin liquid 1Â mL orally 6-hourly for 10 to 14 days |
If frequent recurrences, fluconazole 50Â mg orally daily or 150Â mg weekly |
- not established. |
 |
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  |
fluconazole 200Â mg orally initially, then 100Â mg daily for 14 days OR itraconazole 200Â mg orally daily for 14 days OR ketoconazole 200Â mg orally daily for 14 days |
For repeated episodes fluconazole 100Â mg orally daily OR itraconazole 200Â mg orally daily OR ketoconazole 200Â mg orally daily |
- not established. |
 |
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amphotericin 0.75Â mg/kg IV daily for 2 to 4 weeks WITH OR WITHOUT flucytosine 25Â mg/kg IV/orally 6-hourly for 14 days [Note 2] OR (mild disease) as a single drug, fluconazole 800Â mg orally/IV initially, then 400Â mg daily |
fluconazole 200Â mg orally daily |
- not indicated - maintenance therapy for Candida with fluconazole would be effective prophylaxis for cryptococcosis |
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valganciclovir 900Â mg orally 12-hourly for 14 to 21 days [Note 3] OR ganciclovir 5Â mg/kg IV 12-hourly for 14 to 21 days OR foscarnet 90Â mg/kg IV 12-hourly for 14 to 21 days (actual dose based on creatinine clearance, see product information) OR cidofovir 5Â mg/kg IV weekly for 2 weeks CO-ADMINISTER WITH probenecid (contraindicated if proteinuria >2+ or creatinine clearance <55Â mL/minute) |
valganciclovir 900Â mg orally daily OR ganciclovir 10Â mg/kg IV 3 times weekly or 5Â mg/kg IV 5 times weekly OR foscarnet 90 to 120Â mg/kg/day IV 5 times weekly (actual dose based on creatinine clearance, see product information) OR
cidofovir 5Â mg/kg IV every 2 weeks |
- not established. |
 |
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famciclovir 500Â mg orally 12-hourly for 7 to 10 days OR valaciclovir 500Â mg orally 12-hourly for 7 to 10 days OR aciclovir 200Â mg orally 5 times daily for 7 to 10 days |
For frequent, severe recurrences famciclovir 500Â mg orally 12-hourly OR valaciclovir 500Â mg orally 12-hourly OR aciclovir 200Â mg orally 8-hourly or 400Â mg orally 12-hourly |
- not established |
 |
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  |
ethambutol 15 to 25 mg/kg orally daily PLUS EITHER clarithromycin 500 mg orally 12-hourly OR azithromycin 600 mg orally daily WITH OR WITHOUT rifabutin 300 mg orally daily [Note 4] |
- as for primary treatment - 2 to 3 drugs used according to tolerance and drug interactions   |
- commenced when CD4 cell count <75/microlitre -Â azithromycin 1.2Â g orally weekly or clarithromycin 500Â mg orally 12-hourly or rifabutin 300Â mg orally daily [Note 4] |
Mycobacterium tuberculosis [Note 5] |
 |
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- management only by specialists with HIV and TB expertise - complex drug interactions between HIV and TB drugs usually preclude standard TB regimens |
- not established |
- if positive Mantoux test (>5mm in patient who has not had BCG) isoniazid 300Â mg orally daily for 9 months |
 |
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trimethoprim+sulfamethoxazole 5+25Â mg/kg orally/IV 6 to 8 hourly for 21 days OR pentamidine 4Â mg/kg up to 300Â mg IV daily for 21 days OR (mild to moderate disease only) dapsone 100Â mg orally daily PLUS trimethoprim 5 to 7.5Â mg/kg orally 12-hourly for 21 days OR (mild to moderate disease only) as a single drug atovaquone 750Â mg orally 12-hourly for 21 days |
trimethoprim+sulfamethoxazole 80+400 to 160+800Â mg orally daily or 160+800Â mg orally 3 or 4 times weekly or 12-hourly 2 times weekly OR pentamidine 300Â mg IV/aerosolised every 2 to 4 weeks [Note 6] OR dapsone 100Â mg orally 3 times weekly |
- commenced when CD4 cell count <200/microlitre - regimens as for maintenance therapy |
 |
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sulfadiazine 1 to 1.5Â g orally/IV 6-hourly for 3 to 6 weeks PLUS pyrimethamine 50 to 100Â mg orally initially, THEN 25 to 50Â mg daily for 3 to 6 weeks [Note 7] If hypersensitive to sulfadiazine, substitute clindamycin 600Â mg orally/IV 6-hourly for 3 to 6 weeks |
sulfadiazine 500Â mg orally 6-hourly or 1Â g orally 12-hourly PLUS pyrimethamine 25 to 50Â mg orally daily [Note 7 ] If hypersensitive to sulfadiazine, substitute clindamycin 600Â mg orally 8-hourly |
- prophylaxis for P. carinii with trimethoprim+sulfamethoxazole is effective prophylaxis for toxoplasmosis |
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famciclovir 500Â mg orally 8-hourly for 7 to 14 days OR valaciclovir 1Â g orally 8-hourly for 7 to 14 days OR aciclovir 800Â mg orally 5 times daily for 7 to 14 days OR aciclovir 10Â mg/kg IV 8-hourly for 7 to 14 days |
normally not necessary except after second episode of varicella-zostervirus   |
- not established. |
For patients on highly active antiretroviral therapy, indications for cessation of either primary prophylaxis or maintenance therapy are: ·           CMV maintenance therapy: CD4 cell count >100–150/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load ·           Cryptococcus neoformans maintenance therapy: CD4 cell count >100–200/microlitre for >=6 months with nondetectable or stable low HIV viral load ·           MAC: CD4 cell count >100/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load (primary prophylaxis) or CD4 cell count >100/microlitre for >=6 months with nondetectable or stable low HIV viral load AND after 12 months of MAC treatment with no signs or symptoms of MAC (maintenance therapy) ·           Pneumocystis carinii: CD4 cell count >200/microlitre for 3 to 6 months with nondetectable or stable low HIV viral load ·           Toxoplasma gondii: as for Pneumocystis carinii. |
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Note 2: |
Bone marrow suppression may occur with flucytosine; monitor levels (see Flucytosine monitoring). |
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Note 3: |
At the time of publication, valganciclovir is available on the Section 100 Highly Specialised Drugs Program for cytomegalovirus retinitis only. |
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Note 4: |
Significant drug interactions occur between protease inhibitors and rifabutin, see Interactions with antimicrobials. |
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Note 5: |
Multidrug-resistant TB needs specialist advice, 5 to 6 drugs and longer duration of treatment, often 2 years. |
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Note 6: |
Administer aerosolised pentamidine via a jet nebuliser producing a droplet size of 1 to 2 microns. |
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Note 7: |
Calcium folinate 15Â mg orally daily may reduce the incidence of neutropenia. |
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Reasons for changing antiretroviral therapy and recommended modifications (Table 3)
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Reason |
Regimen modification |
Toxicity or intolerance of individual drugs in the regimen |
         Use another drug from the same or different class |
Antiretroviral failure (initial failure to decrease viral load, or viral load rebound after suppression): |
 |
a) due to poor adherence |
         Review adherence, reinforce adherence strategies, consider regimen simplification.          Monitoring of protease inhibitor and non-nucleoside reverse transcriptase inhibitor blood levels may be considered. |
b) due to antiretroviral resistance  |
         Use at least 2 new drugs, preferably belonging to a different class or with a low probability of cross-resistance to drugs in the previous regimen.          Use results of resistance testing if available. |
c) due to altered pharmacokinetics (eg. drug-drug interaction, severe liver dysfunction, malabsorption) |
         Review other medications and adjust accordingly.          Monitoring of protease inhibitor and non-nucleoside reverse transcriptase inhibitor blood levels may be considered. |
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Some important adverse reactions of antiretroviral drugs (Table 3)
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Antiretroviral |
Adverse reactions |
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) |
|
class effects |
hyperlactataemia, lactic acidosis, hepatic steatosis, lipodystrophy [Note 1] |
abacavir |
hypersensitivity reaction [Note 2] (fever, headache, myalgia, gastrointestinal symptoms, respiratory symptoms, with or without rash) |
didanosine |
pancreatitis, diarrhoea, nausea, peripheral neuropathy |
lamivudine |
abnormal liver function, anaemia and neutropenia (advanced disease), pancreatitis (rare) |
stavudine |
peripheral neuropathy, pancreatitis (rare) |
tenofovir |
asthenia, headache, diarrhoea, nausea, vomiting (class effects above less likely) |
zalcitabine |
peripheral neuropathy, mouth ulcers, pancreatitis (rare) |
zidovudine |
nausea, headaches (soon after starting), anaemia, neutropenia (advanced disease), myalgia, myopathy |
Non-nucleoside reverse transcriptase inhibitors (NNRTI) |
|
delavirdine |
rash, abnormal liver function, fever |
efavirenz |
rash, abnormal liver function, neuropsychological reactions (disturbed sleep, altered dreams, light headedness [on starting, usually resolves after days to weeks]) |
nevirapine |
rash, hepatitis, fever |
Protease inhibitors (PI) |
|
class effects |
lipodystrophy [Note 1], hyperglycaemia, hyperlipidaemia (most common with ritonavir), abnormal liver function |
amprenavir |
nausea, vomiting, diarrhoea, rash, perioral paraesthesia |
indinavir |
nephrolithiasis, nausea, hyperbilirubinaemia |
lopinavir+ritonavir |
nausea, vomiting, diarrhoea |
nelfinavir |
diarrhoea |
ritonavir |
nausea, vomiting, diarrhoea, perioral paraesthesia |
saquinavir |
diarrhoea, nausea, abdominal discomfort |
Note 1: Abnormal fat accumulation (central obesity, breast enlargement, buffalo hump) or fat wasting in limbs and face (lipoatrophy); the relative contribution of PIs and NRTIs varies, but lipoatrophy is associated with use of thymidine analogues (stavudine, zidovudine) |
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Note 2: Rechallenge contraindicated in all patients, potentially fatal; presence of HLA-B57 highly predictive of hypersensitivity but reactions can occur in absence of HLA-B57. |
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Antiretroviral interactions
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The protease inhibitors and non-nucleoside reverse transcriptase inhibitors inhibit or induce the cytochrome P450 enzymes and interact with many other drugs.
Some important contraindications are listed below (Table 2.10), see also Interactions with antimicrobials for more detail. Comprehensive, up-to-date information can be found at www.hiv-druginteractions.org/.
Prescribers should consult specialised up-to-date treatment guidelines, or drug information services if there is any doubt about the possibility of a significant interaction.
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Some medications that are contraindicated with antiretroviral drugs (Table 5)
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Protease inhibitors |
NNRTI [Note] |
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amprenavir |
indinavir |
lopinavir+ |
nelfinavir |
ritonavir |
saquinavir |
delavirdine |
efavirenz |
nevirapine |
|
amiodarone |
 |
 |
 |
X |
X |
 |
 |
 |
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cisapride |
X |
X |
X |
X |
X |
X |
X |
X |
 |
diazepam |
X |
 |
 |
 |
 |
 |
 |
 |
 |
dihydroergotamine |
X |
X |
X |
X |
X |
X |
X |
X |
 |
ergotamine |
X |
X |
X |
X |
X |
X |
X |
X |
 |
flecainide |
 |
 |
X |
 |
X |
 |
 |
 |
 |
H2-receptor antagonists |
 |
 |
 |
 |
 |
 |
X |
 |
 |
ketoconazole |
 |
 |
 |
 |
 |
 |
 |
 |
X |
midazolam |
X |
X |
X |
X |
X |
X |
X |
X |
 |
pethidine |
 |
 |
 |
 |
X |
 |
 |
 |
 |
pimozide |
X |
X |
X |
X |
X |
X |
 |
 |
 |
proton pump inhibitors |
 |
 |
 |
 |
 |
 |
X |
 |
 |
quinidine |
 |
 |
 |
X |
X |
 |
 |
 |
 |
rifabutin |
 |
 |
 |
 |
 |
X |
X |
 |
 |
rifampicin |
X |
X |
X |
X |
 |
X |
X |
 |
X |
simvastatin |
X |
X |
X |
X |
X |
X |
X |
 |
 |
St John's wort |
X |
X |
X |
X |
X |
X |
X |
X |
X |
triazolam |
X |
X |
X |
X |
X |
X |
X |
X |
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X = contraindicated combination |
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Note: Non-nucleoside reverse transcriptase inhibitors |
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