RESUMEN DE LAS PUBLICACIONES MÁS IMPORTANTES SOBRE

TERAPIA ANTIRRETROVIRAL

Félix Gutiérrez Unidad de Enfermedades InfecciosasHospital General Universitario, Elche

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Criterios de selección • Artículos publicados en 2009

• Prioridad artículos españoles

Contenidos

• ¿Cuándo iniciar el TAR?• ¿Con qué fármacos?• Simplificación• Nuevas estrategias• Fármacos en desarrollo

Resumen de las publicaciones más importantes sobre TAR

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¿Cuándo empezar el TAR?

Kitahata MM, et al. N Engl J Med 2009;360:1815-26.

Lancet 2009; 373: 1352–63

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• NA-ACCORD, established in 2006, includes 22 HIV research cohorts– Inclusion criteria: Patients with HIV infection who had not

undergone previous therapy (1996-2006)– Stratified according to their CD4 + at baseline:

• 351-500 cells/mm3:8362 patients

• > 500 cells/mm3: 9155 patients

• Compared outcomes between patients who started ART within the given CD+ stratum with those who waited until after the CD4+ count fell below the stratum

• Primary outcome: death from any cause

Kitahata MM, et al. N Engl J Med 2009;360:1815-26.

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Kitahata MM, et al. N Engl J Med 2009;360:1815-26.

N=8362 N=9155

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Strengths WeaknessesRelatively large sample size Up to 45% of patients in each CD4+

stratum did not initiate ART or did

not have a CD4 decline.

These patients are not included in

the comparative analysis

Relative diversity of cohorts

Advanced statistical methods that attempted to analyze the data in a fashion similar to a RCT

Lead-time bias minimized (by having access to data for patients before ART was started)

Use of survival (death from any case) as end point

Causes of death available for only 16% of the patients

Lancet 2009; 373: 1352–63

Supports early initiation of ART

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• Analysis of 18 cohorts from Europe and US (ART Cohort Collaboration) N = 45,000

• Inclusion criteria: – ART-naive that had started cART (while AIDS-free,

with CD4< 550 c/μL) on or after Jan 1, 1998.– Data from patients followed up in 7 of the cohorts in

the era pre_HAART (1989–95) used to estimate distributions of lead times and unseen AIDS and death events in the absence of treatment.

Lancet 2009; 373: 1352–63

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• Analysis of 18 cohorts from Europe and US (ART Cohort Collaboration) N = 45,000

Lancet 2009; 373: 1352–63

Comparison HR* (95% CI)

1-100 vs 101-200 3.35 (2.99-3.75)

101-200 vs 201-300 2.21 (1.91-2.56)

201-300 vs 301-400 1.34 (1.12-1.61)

251-350 vs 351-450 1.28 (1.04-1.57)

351-450 vs 451-550 0.99 (0.76-1.29)

*Adjusted for lead-time and unobserved events.

Effects of deferring ART on mortality alone less pronounced, but patterns were consistent with those for rates of the combined endpoint of AIDS or death.

Adjusted hazard ratios for AIDS or death for initiation of cARTat a lower CD4 threshold (ie, deferred initiation) versus initiation in a range up to 100 cells per μL higher

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Strengths WeaknessesLarge sample size Patients were observed only

after they began ARTDiversity of cohorts

Adjustment for lead-time bias (events and deaths that occurred during deferral of therapy estimated with the use of historical data)

Ability to compare events frequencies between narrow overlapping CD4 strata

Analysis did not include non-fatal non-AIDS events that may be paramount at higher CD4

Lancet 2009; 373: 1352–63

Support a shift in recommendations towards initiation of ART at a minimum CD4 cell-count threshold of 350 cells/μL

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Kitahata MM, et al. N Engl J Med 2009;360:1815-26.

Both cohorts affected by major limitations of observational studies: Several potential unrecognized confounding factors, selection bias and indication bias (i.e. patients who delayed ART because of addiction, coexisting psychiatric conditions, illegal or underinsured status, or other socioeconomic problems or underlying diseases)

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¿Con qué fármacos iniciar el TAR?• Class-sparing regimens for initial treatment of HIV-1 infection (ACTG 5142). Riddler

S N Engl J Med. 2008 May 15;358(20):2095-106

• Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48 (ARTEMIS). Ortiz R et al. AIDS. 2008 Jul 31;22(12):1389-97.

• Once-daily atazanavir/ritonavir vs twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study.Molina JM et al. Lancet 2008 Aug

23;371: 604

• Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: prospective, randomized, noninferiority clinical trial, GESIDA 3903. Berenguer J, González J, Ribera E et al. Clin Infect Dis. 2008 Dec 15;47(12):1611

Resumen de las publicaciones más importantes sobre TAR

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¿Con qué fármacos iniciar el TAR?

• Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. Smith KY. AIDS 2009, Jul 31; 23:1547–1556.

• Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lennox JL. Lancet. 2009 Sep 5;374(9692):796-806

Resumen de las publicaciones más importantes sobre TAR

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AIDS 2009, 23:1547–1556

HEAT•Double-blind, placebo-matched, randomised trial, phase IV non-inferiority comparison of ABC/3TC vs TDF/FTC both with LPV/r•Primary endpoints: proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing=failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks•GSK

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HEAT: ABC/3TC vs TDF/FTC Each With LPV/RTV QD in Tx-Naive Patients

ABC/3TC 600/300 mg QD* + LPV/RTV 800/200 mg QD†

(n = 343)

TDF/FTC 300/200 mg QD +LPV/RTV 800/200 mg QD†

(n = 345)

HIV-infected patients with HIV-1 RNA

≥ 1000 copies/mL and any CD4+

cell count

(N = 688)

Stratification by HIV-1 RNA < or ≥ 100,000 copies/mL

*No HLA-B*5701 screening at BL.†LPV/RTV switched from soft-gel capsules to tablets at Week 48.

Regimen changes allowed in case of toxicityAbacavir → zidovudine; Tenofovir → alternative NRTI; LPV/r od to bid or FPV/r

Week 48 primary efficacy analysis Week 96

Smith KY. AIDS 2009, 23:1547–1556

15 HEAT: ABC/3TC Noninferior to TDF/FTC at Week 96

Smith KY. AIDS 2009, 23:1547–1556

•Week 48: VL<50 copies/ml (ITTE; M=F) 68% ABC/3TC vs. 67% TDF/FTC (95% CI 6.63-7.40), demonstrating noninferiority of ABC/3TC to TDF/FTC. •Noninferiority sustained at week 96 (60% vs. 58%, 95%CI 5.41 to 9.32). •Efficacy of both similar in patients with baseline VL>100 000 copies/ml or CD4<50 cells/ml. •Protocol-defined virologic failure: 14% in both groups.•Premature study discontinuation due to AE: 6% in both groups

Conclusion: Both ABC/3TC and TDF/FTC provided

comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in naive patients.

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• Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48• Secondary endpoints: CD4+ cell count, safety, and tolerability• 53% of patients had HIV-1 RNA > 105 copies/mL; 47% of patients had

CD4+ cell counts < 200 cells/mm3 at baseline

HIV-infected, treatment-naive patients with HIV-1 RNA > 5000 copies/mL and no resistance to EFV,

TDF, or FTC

(N = 563) EFV 600 mg QHS + TDF/FTC(n = 282)

RAL 400 mg BID + TDF/FTC(n = 281)

Week 96 planned follow-up

Week 48 current analysis

Lennox J, et al. Lancet 2009; 374: 796–806

STARTMRK (Merck)•Non-inferiority comparison.

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Δ: 4 (95% CI: -2 to 10)P < .001 for noninferiority

ITT, NC = F

• Significantly shorter time to virologic response with RAL vs EFV (P < .001)

• Significantly greater CD4+ cell count increase with RAL vs EFV

– +189 vs +163 cells/mm3; Δ: 26 cells/mm3 (95% CI: 4-47)

Lennox J, et al. Lancet 2009; 374: 796–806

log-rank test p<0·0001

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• Serious drug-related clinical adverse events in less than 2% in each drug group.

• Significantly fewer drug-related clinical AE on RAL vs EFV (difference –32·8%, 95% CI –40·2 to –25·0, p<0·0001).

• Fewer patients experienced CNS events by Week 8 with RAL vs EFV (10.3% vs 17.7%; P = .015)

Lennox J, et al. Lancet 2009; 374: 796–806

• Greater increases in all lipid parameters including HDL in EFV arm, no overall difference in TC:HDL ratio

• Fewer patients initiated lipid-lowering therapy with RAL vs EFV (3 vs 11)

19Resumen de las publicaciones más importantes sobre TAR: Simplificación

JAIDS 2009; August 15; 51:562–568)

JAIDS 2009 Jul 1;51(3):290-7.

JAIDS 2009 Apr 1;50(4):390.

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Nuevas Estrategias• Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir

and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. Arribas JR et al. JAIDS 2009 Jun 1;51(2):147-52

• Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-transcriptase inhibitor-sparing strategy: results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA). Negredo E, Clin Infect Dis. 2009 Sep 15;49(6):892-900.

• Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: a randomized trial. Gutiérrez-Valencia A et al. Ann Intern Med. 2009 Aug 4;151(3):149-56

Resumen de las publicaciones más importantes sobre TAR

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•At 96-week LPV/r monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. •Incidence of adverse events leading totreatment discontinuation was significantly lower with monotherapy.

JAIDS 2009 Jun 1;51(2):147-52

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The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; p=.039) and in the COX activity (26% and 32% at weeks 24 and 48).

Negredo E, Clin Infect Dis. 2009 Sep 15;49(6):892-900.

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Arms: EFV, 200 mg/d on days 1 through 6, 400 mg/d on days 7 through 13, and 600 mg/d on day 14 and after,or EFV 600 mg/d, from day 1.

Measurements: Neuropsychiatric symptoms and sleep quality assessed by questionnaires at 0, 7, 14, and 30 days.

Primary outcome: EFV-related NPAEs during the first 2 weeks, Secondary outcome: plasma HIV RNA level at 24 weeks.

Gutiérrez-Valencia A et al. Ann Intern Med. 2009 ;151:149

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Gutiérrez-Valencia A et al. Ann Intern Med. 2009 ;151:149

•Virologic and immunologic efficacy “similar” in both groups.

2525

Virus-CellFusion

gp41

gp120

V3 loop

CD4Binding

CD4

CellMembrane

CoreceptorBinding

CCR5/CXCR4(R5/X4)

CCR5 antagonistsMaravirocVicriviroc

CCR5mAb004PRO140

EnfuvirtideBMS-488043

TNX-355

CXCR4 antagonists AMD070

Resumen de las publicaciones más importantes sobre TAR

Nuevos Fármacos/Nuevas dianas

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• Anticuerpo murino humanizado IgG subtipo 4

• Inhibe la entrada actuando en un paso posterior a la unión de la gp120 y el receptor CD4

• Activo in vitro frente a virus R-5 y X4

• Administrado por infusión IV

• Estudio búsqueda dosis fase Ib de seguridad, farmacocinética y actividad antiviral:– TNX-355 en 3 dosis diferentes

• 15 mg/kg IV semanales

• 10 mg/kg IV carga y 6 mg/Kg cada 2 semanas

• 25 mg/Kg cada 2 semanas

Reducción sustantial de la carga viral (0.5 a 1.7 log10) en 20 de los 22 pacientes, seguro y bien tolerado

Jacobson et al. AAC. 2009 Feb;53(2):450-7

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Moyle G, Clin Infect Dis. 2009 Mar 15;48(6):798-805

•10 pacientes con virus X4 o dual•Monoterapia bid x 10 días. •En 4 de 10 reducción en la población X4, en 3 de ellos cambio de tropismo a R5 a los 10 días•No reacciones adversas>= G 2

Desarrollo clínico detenido en espera de más datos preclínicos (toxicidad hepática grave en ratones)

MUCHAS GRACIAS!!

Felicidades a los Presidentes del Congreso,

a la Junta y a GESIDA