Actualizacion de Tratamiento Antiretroviral

Dra. Elsa Palou Medicina Interna Infectologia I.N.T./UNAH

08/08/2012

Ciclo VIH
CD4
TR

Dinmica Viral
Produccin diaria de nuevo virus : 10 billones 50% cleared in 6 oras 1 mutacin asociada a la R cada da

Integrase

VIH

CCR5 CXCR4
Protease Rev

Tat

Eventos de los CD4

Eventos de la Carga Viral

184V (3tC), 74V (ddI), K65R, 15 Mecanismos de resistencias A los NRTIs TAMs [AZT,D4T]

Clavel, F. et al. N Engl J Med 2004;350:10231035

Mecanismos de resistencias A los NNRTIs RT101,103,106,181,190, [Nevirapina, delavirdina), RT: 103, 188, 190, produce resistencia a Enfavirenz.

Clavel, F. et al. N Engl J Med 2004;350:10231035

Protease inhibitors

Tx. Antiretroviral, gralidades, Clasificacin CDC

CELULAS CD4 Ms de 500
500-200 Menos de 200

GRUPO A
A1 A2

GRUPO B
B1 B2

GRUPO C
C1 C2

A3

B3

C3

Mejorar la calidad de vida Reduccin de morbilidad VIH-relacionada y mortalidad La restauracin y/o preservacin de funcin inmunolgica Supresin mxima y durable de carga viral

Metas de Terapia & las Herramientas para Lograr Metas

Seleccin de rgimen de ARV Preservacin de opciones del tratamiento futuras Secuencia racional de terapia Adicin aumentando al mximo la eficacia Uso de pruebas de resistencia en escenas clnicas seleccionadas

Terapia Antiretrovial: Perspectiva historica

1987: AZT en monoterapia HIV RNA change (log10 c/mL)
0 -0.5 -1 -1.5 -2 -2.5 -3 24-week response
Fischl, NEJM, 1987 Hamilton, NEJM, 1992

1994: Dos farmacos

0 -0.5 -1 -1.5 -2 -2.5 -3 24-week response
Eron, NEJM, 1995; Hammer, NEJM, 1996

1997: HAART
0 -0.5 -1 -1.5 -2 -2.5 -3 24-week response
Gulick, NEJM, 1997; Cameron, Lancet, 1998

Indicaciones de Inicio de Tratamiento

Sida ( Estadio 3 y 4 OMS) Pte asintomtico con CD4 < 200 Pte asintomtico CD4 >200 y < 350 Pte asintomtico CD4 >350, pero Carga Viral >100,000-PCR. Pte asintomatico, CD4> 350 y C.V. <100,000 segn el mtodo. OBSERVACIN.

Tipos de Medicamentos ARV.

Inhibidores Nucleosidos de Transcriptasa Reversa.( NTR ) Inhibidores No Nucleosidos de Transcriptasa Reversa ( NNTR ) Inhibidores de Proteasas Inhibidores de Fusin Inhibidores de Integrasa.

08/08/2012

Tipos de Drogas, NRT

Zidovudina ( AZT, Retrovir). Didanosina ( ddi, Videx), Zalcitabine ( ddc, Hivid ), Lamivudina ( 3TC, Epivir) Stavudina ( D4T, Zerit). Abacavir (Ziagen) AZT + 3TC ( Combivir) AZT+3TC+Abacavir ( Trizivir) Tenofovir Emtricitabina

Tipos de Drogas NNRT

Nevirapine: ( Viramune)

Delavirdine : ( Rescriptor),

Efavirenz: ( Sustiva, Stocrim)

Tipos de Drogas, IP.

Indinavir (Crixivan):. Ritonavir: ( Norvir), Nelfinavir: (Viracept), Amprenavir: ( Agenerase). Lopinavir / Ritonavir: ( Kaletra) Atazanavir/ Ritonavir Darunavir/ Ritonavir Fosamprenavir/ Ritonavir Tripanavir/ritonavir

Esquemas mas Utilizados

Nunca utilizar una sola droga Siempre utilizar al menos 3 drogas No descontinuar Tratamiento a menos que exista intolerancia o resistencia 2NRT + 1 NNRT 2NRT + 1 IP 2NNRT + 1 IP

Actualizacin TARV

Esquemas Primera Lnea en Honduras:

AZT+3TC ( Combivir) +EFV D4T+3TC+NVP ( Triomune) 2 INTR+1 INNTR

TARV, OMS/OPS, Borrador 2006, Recursos Limitados

Esquema de Eleccin: AZT+3TC

Esquema Alternativo: Tenofovir + 3Tc ABC+3TC DDI+3TC Esq. Alt. 1 Linea: 3 INTR

EFV o NVP

ACTUALIZACION TARV

Se Recomienda NO utilizar D4T por toxicidad mitocondrial ( Lipodistrofia, acidosis lctica, hiperlipidemia) En caso necesario solo utilizar D4T de 30 Mg ( Triomune 30), independiente del peso del Pte. 3 INTR en: TB, Embarazadas con > 250 CD4, coinfeccin con hepatitis viral, hepatotoxicidad.
OMS/Ops Guias en entornos Rec. Limitados, 2006, Borrador

Initial Treatment: Preferred Components

NNRTI Option
Efavirenz*

NRTI Options
Tenofovir + emtricitabine**

OR
PI Options
Atazanavir

+ ritonavir Fosamprenavir + ritonavir (BID) Lopinavir/ritonavir (BID)

Zidovudine + lamivudine**

*Avoid in pregnant women and women with significant

pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa.

Initial Treatment: Alternative Components

NNRTI Option
Nevirapine*

NRTI Options
Abacavir + lamivudine Didanosine + (emtricitabine or lamivudine)

OR

PI Options
Atazanavir** Fosamprenavir Fosamprenavir

(1x/day) Lopinavir/ritonavir (1x/day)

*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm3 **Atazanavir must be boosted with ritonavir if used in combination with tenofovir

+ ritonavir

Regimens not recommended:

prevent perinatal HIV transmission)

Antiretroviral Medications: Should not be offered at any time

Monotherapy (except possibly zidovudine used to

Dual NRTI therapy 3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir NRTI-sparing regimens

Antiretroviral components not recommended: Didanosine + stavudine Stavudine + zidovudine Emtricitabine + lamivudine

Antiretroviral Medications: Should not be offered at any time

Antiretroviral components not recommended:

Efavirenz in pregnancy and in women with significant potential for pregnancy* Nevirapine initiation in women with CD4 >250 cells/mm3 or men with CD4 >400 cells/mm3
* Women who are trying to conceive or who are not using effective and consistent contraception.

Antiretroviral Medications: Should not be offered at any time

Antiretroviral Components in Initial Therapy: NRTIs

ADVANTAGES Established backbone of combination therapy Minimal drug interactions PI and NNRTI preserved for future use

DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) Triple NRTI regimens show inferior virologic response compared with efavirenz- and indinavirbased regimens*

* Triple NRTI regimen of abacavir + lamivudine + zidovudine to be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.

Antiretroviral Components in Initial Therapy: NNRTIs

ADVANTAGES DISADVANTAGES Less dyslipidemia and Resistance - single fat maldistribution mutation than in PI-based Cross-resistance regimens among NNRTIs PI options preserved Rash; hepatotoxicity for future use Potential drug interactions (CYP450)

Antiretroviral Components in Initial Therapy: PIs

ADVANTAGES Longest prospective data NNRTI options preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) Greater potential for drug interactions (CYP450), especially with ritonavir

Adverse Effects: NRTIs

All NRTIs: Lactic acidosis and hepatic steatosis (higher incidence with stavudine) Lipodystrophy (higher incidence with stavudine)

Adverse Effects: NNRTIs

All NNRTIs: Rash Drug-drug interactions Nevirapine hepatotoxicity (may be severe and life-threatening), rash including StevensJohnson syndrome Efavirenz - neuropsychiatric, teratogenic in nonhuman primates (FDA Pregnancy Category D)

Adverse Effects: PIs

All PIs: Hyperlipidemia Insulin resistance and diabetes Lipodystrophy Elevated liver function tests Possible increased bleeding risk in hemophiliacs Drug-drug interactions

Virologic failure:

Treatment-Experienced Patients: ARV Treatment Failure

HIV RNA >400 copies/mL after 24 wks, >50 after 48 wks, or >400 copies/mL after viral suppression

Immunologic failure:
CD4 increase of <25-50 cells/L in first year of therapy, or decline in CD4 count to below baseline

Clinical progression:
Occurrence of HIV-related events (after >3 months on therapy; excludes immune reconstitution syndromes)

Treatment Regimen Failure: Assessment

Possible causes:
Suboptimal adherence Medication intolerance Pharmacokinetic issues Suboptimal drug potency Viral resistance

Approach depends on cause of regimen failure and remaining antiretroviral options

Virologic Failure: Changing an ARV Regimen (2)

General principles (2): In general, 1 active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. In some patients with advanced HIV and few treatment options, this may be considered to reduce the risk of immediate clinical progression. Consult with experts

Limited prior treatment:

Treatment-Experienced Patients: Goals of Therapy

Maximum viral suppression Consider early change to prevent further resistance mutations

Extensive prior treatment:

Preservation of immune function Prevention of clinical progression Balance benefits of partial viral suppression with risk of additional resistance mutations

Drug Resistance Testing

Clinical Setting/ Recommendation Recommended: Acute HIV infection, if treatment is to be started Rationale
Determine

if resistant virus was transmitted; guide treatment decisions. Consider resistance testing if treatment is deferred
Transmitted

Chronic

HIV infection before starting ART

drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection; consider resistance testing earlier in the course of infection

Drug Resistance Testing

Clinical Setting/ Recommendation Recommended: Pregnancy
Virologic

Rationale

Maximize

drugs.

the number of active

failure during ART

Determine

role of resistance in drug failure and maximize the number of active drugs in the new regimen
To

Suboptimal

suppression of VL after starting ART

guide treatment decisions.

Drug Resistance Testing

Clinical Setting/ Recommendation
USUALLY NOT RECOMMENDED:
After

Rationale

drugs

discontinuation of

Resistance

mutations may become minor species in the absence of selective drug pressure
Resistance

Plasma

VL <1,000 HIV RNA copies/mL

assays unreliable if HIV RNA is low

ACTUALIZACION TARV. OMS-OPS/ 2003-2006

Esquema 1 lnea en Fallo Teraputico Esquema 2 lnea Recomendado

AZT+3TC

ABC+DDI TDF+DDI + IP/r

+
NVP o EFV

Treatment for Pregnant Women*

To reduce risk of perinatal transmission:

Antiretroviral (ARV) therapy recommended in all pregnant women Reduction of HIV viral load to <1000 copies/mL

* See also the US Public Health Services Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States.

Antiretroviral Drug Use in Pregnant Women: NRTIs

Recommende d agents Zidovudine
Efficacy

studies and extensive experience Should be included in the regimen unless significant toxicity or other contraindication
Zidovudine

Lamivudine

+ lamivudine is the recommended dual NRTI backbone

Alternate agents

Antiretroviral Drug Use in Pregnant Women: NRTIs

Didanosine Emtricitabine Stavudine Abacavir Tenofovir
Cases

of lactic acidosis with didanosine + stavudine; use only if no other alternatives

Insufficient data to recommend

No

studies in human pregnancy; bone toxicity in monkey studies and some pediatric studies
Teratogenic

Not recommended

Zalcitabine

in animals

Recommended Nevirapine agent

Antiretroviral Drug Use in Pregnant Women: NNRTIs No evidence of teratogenicity

Increased

risk of liver toxicity in women who start nevirapine with CD4>250; in these women, use

nevirapine-based regimens only if benefit outweighs risk

Not recommended

Efavirenz

FDA

pregnancy category D

Teratogenic

in monkeys Avoid in first trimester; consider after second trimester only if no other alternatives

Delavirdine

Teratogenic

in rodent studies

ART in Pregnant Women: PIs

Recommende d Agents Lopinavir/ ritonavir
Dosing

recommendations not established; may require increased dose during pregnancy No PK data on tablet formulation Limited clinical experience; study underway

Nelfinavir

PK

data and extensive clinical experience in pregnancy Preferred PI for use in pregnant women

Web Sites to Access the Guidelines

http://www.aidsetc.org http://aidsinfo.nih.gov

Web Sites to Access the Guidelines

http://www.aidsetc.org http://aidsinfo.nih.gov www.uptodate.com. www.idsa.org www.cdc.gov OPS/OMS: TARV en ALAC, version 2003, borrador 2006

Tratamiento ARV