Antiretroviral update spring 2008
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Antiretroviral Update Spring 2008. Lisa M. Chirch, M.D. Stony Brook University - CPHE NY/NJ AIDS Education and Training Center. Objectives. Review DHHS guidelines and most recent changes / additions Overview of recent significant clinical trial results

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Antiretroviral update spring 2008

Antiretroviral UpdateSpring 2008

Lisa M. Chirch, M.D.

Stony Brook University - CPHE

NY/NJ AIDS Education and Training Center


Objectives

Objectives

  • Review DHHS guidelines and most recent changes / additions

  • Overview of recent significant clinical trial results

  • Review currently approved, available antiretroviral (ARV) medications and known toxicities, idiosyncrasies

  • Report on new agents in the pipeline, or under ongoing investigation in Phase II and III trials

  • Case vignettes and discussion


Indications for initiating arv therapy for the chronically hiv 1 infected patient

Indications for initiating ARV therapy for the chronically HIV-1 infected patient

* Initiation of ARV also recommended for individuals co-infected with Hepatitis B, HIV-associated nephropathy, and pregnant women;Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008.


Predicted 6 month risk of aids according to age cd4 and viral load

Predicted 6 month risk of AIDS according to age, CD4, and viral load

  • Based on Poisson regression model: Phillips A, et al. AIDS 2004 (CASCADE Collaboration- Concerted Action on SeroConversion to AIDS and Death in Europe: www.ctu.mrc.ac.uk/cascade

  • Examples:

    • 35 year old with CD4 100, has 6 month risk of progression to AIDS of 4.7% if viral load is 3,000; 9.3% if VL is 30,000; 18% if 300,000.

    • 55 year old with CD4 of 150 has 4.7% risk if VL 3,000; 18.2% if VL 300,000.

    • 55 year old with CD4 of 350 has 1.2% risk if VL 3,000, 3.6% if VL 100,000, 5% if VL 300,000.


Antiretroviral update spring 2008

20

Which of the following fixed dose combinations (FDCs) are designated as preferred initial NRTI options according to the most recent DHHS guidelines?

A) TDF/FTC and ZDV/3TC

B) ABC/3TC and TDF/FTC

C) ZDV/ABC/3TC and TDF/FTC

D) ABC/3TC and ZDV/3TC


Which of the following arvs is contraindicated in women with cd4 cell counts above 250

20

Which of the following ARVs is contraindicated in women with CD4 cell counts above 250?

A) Efavirenz

B) Nelfinavir

C) Nevirapine

D) Didanosine


Which of the following regimens is not recommended in women who are or may become pregnant

20

Which of the following regimens is not recommended in women who are or may become pregnant?

A) EFV/TDF/FTC

B) FPV/r plus ABC/3TC

C) LPV/RTV plus ZDV/3TC

D) All of the above


Preferred and alternative arvs in updated dhhs guidelines

Preferred and Alternative ARVs in updated DHHS Guidelines

Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008.


Rationale recent data klean

Rationale: recent data (KLEAN)

  • Inclusion of boosted fosamprenavir in the “preferred” list:

  • KLEAN: phase 3, open-label, multi-center, non-inferiority study comparing the safety and efficacy of ritonavir-boosted fosamprenavir to lopinavir/ritonavir, both in combination with abacavir/lamivudine

  • 878 treatment-naïve patients

  • At week 48, no significant differences between arms in terms of virologic, immunologic, or metabolic response; few adverse events in similar numbers among 2 groups

Eron J et al. The Lancet. August 5, 2006; 368(9534):476-482.


Bms 089

BMS-089

  • 96-week randomized, open-label study comparing the efficacy and safety of 400 mg atazanavir versus 300 mg of atazanavir boosted with 100 mg of ritonavir, both in combination with lamivudine and stavudine.

  • 199 naïve patients

  • Both arms had high rates of virologic response and were well-tolerated

Malan E. et al. 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abstract 107LB


Bms 0891

BMS-089

  • There were 10 virologic failures in the unboosted arm, compared to only 3 in the ritonavir-boosted arm; 7 people in the unboosted arm developed resistance mutations, primarily at the 184 codon, compared to only 1 in the boosted arm.

  • Patients on ritonavir had higher rate of hyperbilirubinemia

  • Changes in total cholesterol and triglyceride levels were significantly higher in the ritonavir-boosted arm; HDL also increased nearly identically in both arms.


Gilead 934

Gilead 934

  • Randomized, open-label, non-inferiority trial comparing tenofovir, emtricitabine to zidovudine, lamivudine, both in combination with Efavirenz.

  • 517 naïve patients

  • At week 96 significantly more patients in tenofovir / FTC arm achieved and maintained HIV RNA levels below 400 copies/mL, and had significantly greater limb fat by DEXA.

  • The groups were similar in terms of patients achieving HIV RNA < 50 copies/mL

  • Higher toxicity rates in zidovudine / lamivudine arm (esp. anemia), may have contributed

Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. Joel E. Gallant et al., for the Study 934 Group. The New England Journal of Medicine. January 19, 2006;354(3):251-260.


Acceptable but inferior options

Acceptable but inferior options

  • Nelfinavir

    • Inferior virologic efficacy

    • Pregnancy: good tolerability and adequate PK data

  • Stavudine / lamivudine

    • Significant toxicities: peripheral neuropathy, lipoatrophy, lactic acidosis and hepatic steatosis, pancreatitis

    • Use if preferred or alternative dual NRTI combination cannot be used


Arv components not recommended as initial therapy

ARV components NOT recommended as initial therapy


Arv regimens not recommended at any time

ARV Regimens not recommended at any time


May 2007 update

May 2007 update

  • For HIV/HBV co-infected patients, entecavir should not be used for the treatment of HBV infection without concomitant treatment for HIV.

  • Previous in vitro data showed no significant activity against HIV-1; but recent case-series of 3 patients reported decline in HIV-RNA and emergence of M184V mutations in one co-infected patient on entecavir monotherapy.

Supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents – October 2006.


Why do treatments fail

Why Do Treatments Fail

  • adherence

  • side effects – acute and longer-term

  • baseline resistance or cross-resistance

  • use of less potent antiretroviral regimens

  • sequential monotherapy

  • drug levels and drug interactions

  • tissue reservoir penetration

  • other, unknown reasons


M184v

M184V

  • Arises rapidly on 3TC or FTC therapy

  • Continued antiviral activity in presence of drug and mutation

  • decreased viral replication fitness

  • Presence of M184V slows the evolution of thymidine analogue mutations (TAMs)

  • Increased susceptibility to ZDV, d4T, TDF

  • Modest decreased susceptibility to ddI and ABC


Antiretroviral update spring 2008

TAMs

  • Emerge gradually with ongoing failure of ZDV or d4T

  • Rare with ddI, TDF, ABC in absence of thymidine analogue

  • Development of TAMs tends to follow distinct pathways of mutation at either codons 41 and 215, or at codons 67, 70, 219

McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.


Antiretroviral update spring 2008

K65R

  • Selected by TDF and less frequently ABC in the absence of thymidine analogue

  • Decreased susceptibility to TDF, ABC, and ddI

  • Activity of TDF may be partially retained with M184V present

  • Increases susceptibility to ZDV

McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.


Antiretroviral update spring 2008

L74V

  • Selected by ABC or ddI in the absence of a thymidine analogue

  • Decreases susceptibility to ABC and ddI

  • Does not decrease susceptibility to TDF or thymidine analogues

McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.


Nnrti mutations

NNRTI mutations

  • Long term virologic response to sequential NNRTI use is poor, particularly when 2 or more mutations are present

  • K103N, Y188L, or G190A mutations likely prevent the clinical utility of all NNRTI’s currently approved

  • Importance of most mutations depends on the presence of Y181C, which has an impact only in the presence of at least 1 other mutation (important for Etravirine)

Johnson VA et al. Topics in HIV Medicine 2007; 15(4): 119-125.


Nnrti hypersusceptibility

NNRTI hypersusceptibility

  • Longer duration of NRTI use, prior use of zidovudine, and abacavir or zidovudine resistance have been associated with enhanced susceptibility to NNRTIs (defined as IC50 of >2.5-fold less than that of wild-type reference strain)

  • Greater short term reductions in viral load in patients with hypersusceptibility to efavirenz, who received that drug as salvage therapy

Hirsch M. CID 2003;37:113-128.


Protease gene mutations

Protease gene mutations

  • Major mutations

    • Selected first in the presence of drug, or shown at the virologic or biochemical level to lead to an alteration in drug binding or an inhibition of viral replication

    • Effect on drug susceptibility phenotype

  • Minor mutations

    • Emerge later, by themselves do not have significant effect on phenotype, but may improve replicative fitness in the presence of major mutations

  • Presence of at least 2 key mutations (e.g., D30N, G48V, I50V, V82A/F/T/S, I84V, and L90M) generally confers broad cross-resistance to most currently available PIs

  • “boosting” with low dose ritonavir may result in higher and more prolonged drug concentrations and greater suppression of viral variants that contain a limited number of mutations

Hirsch M. CID 2003;37:113-128.


Envelope gene mutations

Envelope gene mutations

  • Entry of HIV-1 into cell involves attachment mediated by gp120 binding to CD4, chemokine coreceptor binding, and association of 2 trimeric helical coils (HR-1 and HR-2) located in the ectodomain of gp41 into a 6-helix bundle that brings virus and cell membranes closer together, allowing fusion

  • T-20 (enfuvirtide) binds HR-1 and blocks association with HR-2, inhibiting fusion and viral entry

Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.


Entry inhibitors

Entry inhibitors

  • Mutations at gp41 codons 36-45 are associated with an average 20-fold increase from baseline IC50

  • CCR5 inhibitors: Maraviroc activity is limited to patients with only R5-using virus detectable; some cases of failure during therapy are associated with outgrowth of X4 virus that pre-exists as a minority population below the level of detection

  • Mutations in the gp120 molecule that allow the virus to bind R5 receptors in the presence of drug have been described

Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.


Integrase mutations

Integrase mutations

  • Raltegravir failure was associated with integrase mutations in 2 distinct genetic pathways defined by 2 or more mutations including:

    • A major mutation at either Q148H/K/R or N155H, and

    • 1 or more minor mutations


The potential for nephrotoxicity with tenofovir is an important consideration in patients who have

20

The potential for nephrotoxicity with tenofovir is an important consideration in patients who have

A) hyperpigmentation

B) severe anemia

C) baseline renal insufficiency

D) none of the above


Tenofovir renal issues

Tenofovir – renal issues

  • Several case reports noting development of renal insufficiency in patients on tenofovir, some without prior history of renal dysfunction

  • Nephrotoxicity involving tubular dysfunction with Fanconi syndrome noted in toxicological studies, dose-limiting toxicity in animal studies


Tenofovir renal issues1

Tenofovir – renal issues

  • Two similar nucleotide analogues, cidofovir and adefovir, have been associated with dose-limiting, renal tubular cell toxicity in patients in infectious hepatitis or cytomegalovirus infection

  • Renal toxicity is mediated by proximal tube epithelial cells that express human renal organic anion transporter (hOAT1) and actively uptake these drugs


Antiretroviral update spring 2008

Figure 1.        Renal biopsy image by light microscopy showing acute tubular injury with loss and irregularity of tubular epithelial cells (hematoxylin and eosin strain; original magnification, ×100). Inset, prominent nuclear enlargement with hyperchromatic and smudged chromatin (hematoxylin and eosin stain; original magnification, ×400).


Tenofovir renal issues2

Tenofovir – renal issues

  • Package insert revision 2005: dose should be adjusted for patients with creatinine clearance of <50 mL/min.

    • Cockcroft-Gault equation:

      • (140-age) x (lean body weight in kg) x 0.85 (females) / 72 x plasma creatinine

  • CD4 and viral load seem not to be predictors of renal toxicity

  • Patients on tenofovir should be monitored closely for early signs of tubulopathy (glycosuria, proteinuria, acidosis, mild creatinine increases) every 2 weeks for the first 2 months; therapy should be stopped if any signs of tubulopathy develop

Karras et al. CID 2003; 36: 1070-1073; Zimmerman et al. CID 2006; 42: 283-90.


More important clinical trials

More important clinical trials

  • The SMART study

  • ACTG 5142

  • TITAN


Smart

SMART

  • Strategies for Management of AntiRetroviral Treatment

  • Randomized, prospective study: 33 countries, 80% in North America and Europe

    • Median CD4 597, 72% had viral load <400 copies/mL

    • 5,472 HIV-infected adults with CD4 >350

    • Control group took ART continuously “viral suppression group”

    • “drug conservation group” took therapy episodically (initiated when CD4 <250, stopped when >350)

El-Sadr W et al. N Engl J Med 2006; 355(22):2283-2296


Smart1

SMART

  • Results:

    • Trial halted by DSMB with a mean follow up time of only 16 months

    • Greater risk of clinical disease progression events and overall death in drug conservation group

    • Greater risk of serious renal, hepatic, and cardiovascular events

    • Rather than protect patients, the withdrawal of therapy increased risk of death from any cause, including that of opportunistic infections. Cardiovascular, hepatic, and renal disease, which are often associated with ART, were greater in the treatment interruption arm.


Actg 5142

ACTG 5142

  • Phase 3, randomized, open-label study comparing three regimens: lopinavir/ritonavir + 2 NRTI; Efavirenz vs. 2 NRTI; lopinavir/ritonavir + efavirenz

  • 753 ART-Naive patients with viral load >2,000

  • NRTIs were chosen by clinicians and patients; initially only one provided at no cost (extended-release stavudine…later tenofovir was added)


Actg 51421

ACTG 5142

  • Week 96

    • Proportion of patients with VL < 50 copies/mL statistically significantly greater in Efavirenz arm

    • Median increase in CD4 count was significantly higher in the lopinavir arm

    • Those patients in the NRTI-sparing arm had significantly higher fasting triglyceride levels (14% grade 3, compared to 6% in lopinavir arm, 3% in efavirenz arm); 45% moderate of severe laboratory abnormality

    • No resistance to lopinavir was observed; however, resistance to efavirenz was detected in nearly half of patients who failed this regimen; NRTI resistance was more common with virologic failure on efavirenz as well

Riddler S. et al. New England Journal of Medicine, May 15, 2008.


Antiretroviral update spring 2008

Riddler S, et al. 96 week data from ACTG 5142


Titan

TITAN

  • Phase 3 study comparing darunavir/r and lopinavir/r in patients with VL < 1000 copies/mL, on stable but failing regimen for at least 12 weeks

  • 604 patients randomized to open label lopinavir/r or darunavir/r, both with optimized background selected based on resistance testing (T-20 and investigational drugs excluded)

  • Previous lopinavir therapy exclusion criteria

  • Data from week 48 present at IDSA 2007, San Diego


Titan1

TITAN

  • Both PIs were well tolerated, only 7% discontinued due to toxicity

  • Lipid level elevation similar between the groups; higher incidence of diarrhea in lopinavir arm (42% vs. 32%), rash in darunavir arm (16% vs. 7%)

  • Significantly more patients in darunavir arm achieved VL <50; fewer patients in darunavir arm had virologic failure (10% vs 22%), and had primary PI mutations (21% vs. 36%)

  • **among patients with baseline lopinavir fold-change of greater than 10-fold, only 28% achieved VL <50 (greater virologic failure driven by baseline phenotypic resistance to lopinavir??)


Antiretroviral update spring 2008

TITAN – 48 weeks efficacy results

Adapted from Hardy WD et al. IDSA 2007; San Diego, CA. Abstract 1209.


Newly available arvs

Newly available ARVs

  • MERIT

  • MOTIVATE

  • BENCHMRK

  • MERCK 004

    • Integrase cross-resistance

    • Effects on lipid parameters

  • DUET


Antiretroviral update spring 2008

MERIT: Maraviroc vs Efavirenz in Treatment-Naive Patients

Stratified by HIV-1 RNA < or  100,000 copies/mL and by Northern or Southern Hemisphere

Week 48 primary endpoint

Week 96

MVC 300 mg twice daily + ZDV/3TC

(n = 360)

Antiretroviral-naive patients infected with CCR5-tropic HIV-1 and HIV-1 RNA  2000 copies/mL

(N = 740)

EFV 600 mg once daily + ZDV/3TC

(n = 361)

MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16)

  • Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI

Saag M, et al. IAS 2007. Abstract WESS104.


Antiretroviral update spring 2008

MERIT: Patients With VL < 50 Copies/mL by baseline VL

  • EFV patients more likely to discontinue due to AE

    • Overall : 25.2%

    • AE: 13.6%

    • Efficacy: 4.2%

  • MVC patients more likely to discontinue due to lack of efficacy

    • Overall: 26.9%

    • AE: 4.2%

    • Efficacy: 11.9%

EFV

MVC

100

90

80

71.6

69.6

66.6

70

59.6

60

50

Patients, %

40

30

20

10

0

n =

211

204

150

156

BL VL < 100,000 copies/mL

BL VL ≥ 100,000 copies/mL

Saag M, et al. IAS 2007. Abstract WESS104.


Antiretroviral update spring 2008

MOTIVATE: Maraviroc in Treatment-Experienced Patients With R5 Virus

  • Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies

  • 44% failed screening with X4 or dual/mixed virus detected

  • Primary endpoint: mean change in HIV-1 RNA at Week 24

  • Based on MOTIVATE data FDA approved MVC in August 2007 for use in treatment-experienced patients with R5-tropic virus only

2:2:1 randomization;

stratified by ENF use and VL

Week 24 planned interim analysis

Week 48

Patients infected with R5; HIV-1 RNA ≥ 5000 copies/mL; stable ART or no ART for ≥ 4 weeks; previous ART experience with ≥ 1 agent (≥ 2 for PIs) from 3 of the 4 antiretroviral drug classes for ≥ 6 months or documented resistance to members of 3 of 4 classes

(MOTIVATE 1: N = 601, Canada, US; MOTIVATE 2: N = 475,

Europe, Australia, US)

MVC 150 mg or 300 mg* twice daily + OBR†

MVC 150 mg or 300 mg* once daily + OBR†

Placebo + OBR†

*Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. †OBR: 3-6 ARVs.

Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.


Antiretroviral update spring 2008

MOTIVATE 1 and 2: Combined Virologic and Immunologic Efficacy

  • MVC + OBR associated with significantly greater virologic suppression than placebo plus OBR in treatment-experienced patients

    • Increased activity observed with de novo use of enfuvirtide, LPV/RTV

*HIV-1 RNA value imputed as baseline if patient discontinued before 24 weeks.†Patients with missing values were classified as failures unless they were responders at Weeks 20 and 32.‡P = .0001 vs placebo group.

Gulick RM, et al. IAS 2007. Abstract WEPEB116LB.


Maraviroc dosing

Maraviroc dosing

  • With CYP3A inhibitors: 150 mg po BID

    • PIs (except tipranavir)

    • Ketoconzale, itraconazole, clarithromycin

  • With NRTIs, nevirapine, tipranavir / ritonavir,enfuvirtide: 300 mg po BID (recommended dose)

  • With CYP3A inducers: 600 mg (2 tabs) po BID

    • Efavirenz

    • Rifampin

    • Carbamazepine

    • Phenytoin

    • phenobarbital


Tropism testing

“Trofile”: co-receptor tropism assay - detects R5 vs. X4 virus

Monogram biosciences

HIV RNA > 1000 copies/mL required

Tropism testing


Antiretroviral update spring 2008

Protocol 004: Raltegravir vs Efavirenz in Treatment-Naive Patients

  • Treatment-naive patients (n = 198) with VL > 5000 copies/mL and CD4+ > 100 cells/mm3 randomized to one of 4 doses of RAL (100, 200, 400, 600 mg BID) or EFV (600 mg QD) each with TDF + 3TC

  • Viral dynamics substudy: second-phase decay may be accelerated with RAL[2]

Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. Murray JM, et al. IAS 2007. Abstract TUAB103.


Antiretroviral update spring 2008

Protocol 004: RAL Associated With Fewer Lipid Effects vs EFV

  • RAL well tolerated with no dose-related toxicities

    • Dizziness, headache, and atypical dreams more frequent with EFV

  • Total cholesterol, LDL-cholesterol, triglycerides not increased by RAL

*All RAL dose groups combined.

Markowitz M, et al. IAS 2007. Abstract TUAB104.


Benchmrk

BENCHMRK

  • Double blind clinical trial: pts assigned to 200, 400 or 600 mg of MK-0518 BID along with OBT or placebo with OBT

  • 178 patients with at least one resistance mutation in each of 3 drug classes, VL > 5,000, CD4 above 50

  • 14% placebo group achieved VL<50 by week 24

  • 65, 57, 67% achieved VL<50 taking 3 doses of MK-0518

  • Co-administration of T-20 boosted responses by about 20% in the MK-0518 arms


Antiretroviral update spring 2008

BENCHMRK 1 and 2: Raltegravir (MK-0518) in Treatment-Experienced Pts

  • Randomized, double-blind, placebo-controlled, parallel phase III studies

  • Primary endpoints: HIV-1 RNA, CD4+ cell counts, and adverse events at Week 16

Planned duration:Week 48

Primary endpoints: Week 16

HIV-infected,

triple-class resistant,

HIV-1 RNA > 1000 copies/mL

BENCHMRK-1 (N = 350)

(Europe, Asia/Pacific, Peru)

BENCHMRK-2 (N = 349)

(North, South America)

Raltegravir 400 mg twice daily + OBR*

BENCHMRK-1 (n = 232)

BENCHMRK-2 (n = 230)

Placebo + OBR*

BENCHMRK-1 (n = 118)

BENCHMRK-2 (n = 119)

*Selected investigational antiretrovirals permitted in OBR.

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.


Antiretroviral update spring 2008

BENCHMRK 1 and 2: VL < 400 copies/mL (ITT, NC = F)

Raltegravir + OBR

Placebo + OBR

BENCHMRK-2

BENCHMRK-1

100

100

77%

77%

80

80

P < .001 at Week 16

P < .001 at Week 16

60

60

Patients With HIV-1 RNA < 400 copies/mL (%)

40

40

43%

41%

20

20

0

0

0

2

4

8

12

16

24

0

2

4

8

12

16

24

Weeks

Weeks

128

n =

232

230

158

n =

230

229

n =

118

118

81

n =

119

119

69

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.


Antiretroviral update spring 2008

BENCHMRK 1 and 2: VL < 50 copies/mL (ITT, NC = F)

Raltegravir + OBR

Placebo + OBR

BENCHMRK-2

BENCHMRK-1

100

100

80

80

61%

62%

60

60

Patients with HIV-1 RNA < 50 copies/mL (%)

P < .001 at Week 16

P < .001 at Week 16

40

40

36%

33%

20

20

0

0

0

2

4

8

12

16

24

0

2

4

8

12

16

24

Weeks

Weeks

n =

232

230

158

n =

230

229

128

n =

118

118

81

n =

119

119

69

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.


Antiretroviral update spring 2008

BENCHMRK 1 and 2: VL < 400 c/mL at Wk 16 by Specific Agents in OBR

Raltegravir + OBR

n

Placebo + OBR

Overall Efficacy Data

447

79

230

43

Efficacy by Agents in OBR

Enfuvirtide

Darunavir

44

98

+

+

23

87

42

90

+

24

63

80

+

90

47

55

191

74

90

29

+ : First use in OBR

– : No use in OBR

0

20

40

60

80

100

Patients (%)

Statistical analysis: virologic failure carried forward.

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.


Raltegravir and malignancies

Raltegravir and ?malignancies

  • Malignancy Conclusions• In the original application, an imbalance in rates of malignancies was noted. The malignancy types and rates in the raltegravir group are those anticipated in a severely immunodeficient HIV/AIDS population and are consistent with reported rates in the literature. A history of malignancy prior to enrollment was common and many of the malignancies in the raltegravir group were likely present at time of study entry or were recurrences of prior diagnosed malignancies.• Based on an updated analysis of the same study cohorts, the imbalance in rates of malignancies has not been sustained with additional follow-up. This is consistent with the possibility that the original imbalance was a function of small numbers of cases and relatively imprecise estimates of rates.• While the updated analysis is reassuring, the total amount of safety follow-up is limited and additional data are needed. Further follow-up is proposed in the Risk Management Plan.

Excerpted from Merck Briefing Document for FDA Hearing Sept 5, 2007


Raltegravir and malignancy

Raltegravir and malignancy

  • ".....Overall, the rates and kinds of malignancies seen in patients receiving raltegravir in the clinical development program approximate the rates and kinds of malignancies reported in the literature for patients with HIV/AIDS........It is also noteworthy that in the patients receiving raltegravir who ultimately developed a malignancy, the median CD4 cell count was 122 cells/mm3 and all patients with malignancy had a history of AIDS, a known independent risk factor for malignancy. Most of the malignancies encountered are associated with well known risk factors for malignancy such as AIDS, oncogenic viruses (papillomavirus infection, hepatitis B virus infection), and tobacco.


Antiretroviral update spring 2008

Figure 19 displays Kaplan-Meier estimates of time to malignancies for the double-blind phase of Protocols 004, 005, 018, and 019. Of note, no events occurred in the raltegravir arm after month 4 in this analysis.Figure 19Kaplan-Meier Plot of Time to Malignancy-Double-Blind PhasePhase II and III StudiesOriginal Application


Antiretroviral update spring 2008

Figure 20 displays Kaplan-Meier estimates of time to malignancies for the double blind phase of Protocols 004, 005, 018 and 019 cumulatively seen over 18 months of therapy in this updated malignancy analysis. Figure 20Kaplan-Meier Plot of Time to Malignancy-Double-Blind PhasePhase II and III StudiesCumulative Update as of 09-Jul-2007Note: These data have not been reviewed by the FDA.


Antiretroviral update spring 2008

Integrase Inhibitor Resistance and Cross-Resistance

  • Protocol 004: VF in 5 RAL recipients (3%)

    • 3 had no detected integrase mutations

    • 1 had N155H + M184M/I/V

    • 1 had N155H + other mutations (V151I, D232D/N, G163G/R)

  • Separate report of 2 patients with VF on elvitegravir (EVG)/RTV, with no VL response during first week after switch to RAL

    • Suggests high level of cross-resistance between first 2 integrase inhibitors

    • Patient 1 had N155H and 3 other integrase mutations at VF (VL: 840 copies/mL) on EVG/RTV

      • Regained viral suppression (< 50 copies/mL) after addition of DRV/RTV to RAL

    • Patient 2 had Q148R and 4 other integrase mutations at VF (VL: 10,700 copies/mL) on EVG/RTV

      • Failed to regain suppression after addition of DRV/RTV to RAL

Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. DeJesus E , et al. IAS 2007. Abstract TUPEB032 .


Antiretroviral update spring 2008

DUET-1 and -2: Etravirine + DRV/RTV-Containing OBR Phase III Trials

Week 24‡

Week 48

HIV-infected patients with virologic failure on current HAART regimen, history of ≥ 1 NNRTI resistance mutations, ≥ 3 PI mutations, HIV-1 RNA > 5000 copies/mL

(DUET-1: N = 612 DUET-2: N = 591)

ETR 200 mg BID*

+ DRV/RTV-containingOBR†

Placebo

+ DRV/RTV-containingOBR†

*New formulation equivalent to 800 mg BID with old formulation.

†Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ± enfuvirtide.

‡Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR)

Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1.


Antiretroviral update spring 2008

DUET-1 and -2: Virologic Response at Week 24 (TLOVR Analysis)

100

DUET-1

DUET-2

ETR

Placebo

P = .0003

80

P = .005

62%

60

56%

44%

VL < 50 copies/mL, %

39%

40

20

0

P

ETR

P

ETR

Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1.


Antiretroviral update spring 2008

DUET-1 and -2: BL ETR Mutations and Virologic Response at Week 24

  • 13 mutations associated with ETR resistance

    V90IA98G

    L100IK101E/P

    V106IV179D/F

    Y181C/I/VG190A/S

  • Presence of ≥ 3 ETR mutations associated with response similar to placebo + OBR

    • 70% of patients had 0 or 1 ETR resistance mutations at BL

    • 14% of patients had ≥ 3 ETR resistance mutations at BL

100

90

80

70

60

Patients With HIV-1 RNA < 50 copies/mL (%)

50

40

30

20

10

0

0

1

2

3

4

5

No. of BL ETR Mutations

Patients (%)

40

30

16

8

5

1

Katlama C, et al. IAS 2007. Abstract WESS204.2.


Investigational arvs

Investigational ARVs

Vicriviroc – ACTG 5211

Elvitegravir

CCR5 monoclonal antibody – PRO 140

others


Antiretroviral update spring 2008

ACTG 5211: Phase II Trial of Vicriviroc in Treatment-Experienced Patients

Stratified by enfuvirtide use and

baseline CD4+ count < or ≥ 50 cells/mm³

Day 14

Week 48

Placebo(n = 28)

Antiretroviral-experienced patients with HIV-1 RNA ≥ 5000 copies/mL and R5-only virus on ritonavir-containing regimen (N = 118)

Vicriviroc 5 mg once daily(n = 30)

Discontinued

Vicriviroc 10 mg once daily(n = 30)

Vicriviroc 15 mg once daily(n = 30)

Failing

regimen

OBR

(includes 100-800 mg Ritonavir)

Gulick R, et al. J Infect Dis 2007;196:304-312.


Antiretroviral update spring 2008

ACTG 5211: Patients with HIV-1 RNA < 50 copies/mL at 24 and 48 Weeks

  • VCV + RTV-containing OBR associated with sustained antiviral activity at Week 48

Placebo

Vicriviroc 10 mg

Vicriviroc 15 mg

100

90

80

70

60

Patients, %

50

40

37

40

27

27

30

20

11

7

10

0

Week 24

Week 48

Gulick R, et al. J Infect Dis 2007;196:304-312.


Antiretroviral update spring 2008

ACTG 5211: Safety, Tolerability, and Tropism on Failure

  • Incidence of grade 3/4 AEs comparable among arms (P ≥ .6)

  • 10 patients developed malignancies (4 additional patients since Week 24)

    • Vicriviroc: 8 patients

      • Non-Hodgkin’s lymphoma: n = 2–Hodgkin’s disease: n = 2

      • Gastric adenocarcinoma: n = 1–Squamous cell carcinoma: n = 1

      • Basal cell carcinoma: n = 1–Kaposi sarcoma recurrence: n = 1

    • Placebo: 2 patients

      • Squamous cell carcinoma: n = 2

  • 9 (35%) of 26 patients with VF on vicriviroc had dual/mixed or X4 virus detected

Gulick R, et al. J Infect Dis 2007;196:304-312.


Antiretroviral update spring 2008

Placebo

0.5 mg/kg

2 mg/kg

5 mg/kg

*

PRO 140 1302: Effects of a Single IV Humanized CCR5 Antibody Infusion

PRO 140 0.5 mg/kg single IV infusion

(n = 10)

Patients with asymptomatic R5-tropic HIV-1 infection, HIV-1 RNA > 5000 copies/mL, CD4+ cell count > 250 cells/mm3 (with nadir > 200), and no antiretroviral therapy for ≥ 3 months

(N = 39)

PRO 140 2.0 mg/kg single IV infusion

(n = 10)

59-day

follow-up

PRO 140 5.0 mg/kg single IV infusion

(n = 10)

Placebo

(n = 9)

0.5

0.0

-0.5

Mean Change in VL, log10 copies/mL

-1.0

*P ≤ .01

†P ≤ .001

‡P ≤ .0001

-1.5

-2.0

0

10

20

30

40

50

60

Study Day

Saag MS, et al. IAS 2007. Abstract WESS201.


The hla b 5701 genotype has been shown to be a predictive risk factor for

20

The HLA-B*5701 genotype has been shown to be a predictive risk factor for

A) poor CD4+ cell response

B) ABC hypersensitivity

C) insulin resistance

D) lipoatrophy


New testing available

New testing available

  • HLA-B*5701 testing for Abacavir hypersensitivity (HSR) – LabCorp, Quest; PCR on whole blood or buccal swab to determine presence of HLA-B5701 allele

    • HSR observed in about 5% of patients in clinical trials; 89% of cases occur in the first 6 weeks of therapy with ABC

    • Most have multiple symptoms (fever, rash, myalgias, arthralgias, etc…)

Ziagen package insert; GSK 2003; J Antimicrob Chemother. 2007; 59:591-593.


Antiretroviral update spring 2008

SHAPE: Retrospective Case-Control Study

CASES

CONTROLS

Black and white subjects with clinically suspectedABC HSR (CS-HSR)

Black and white subjects enrolled in KLEAN, ALOHA,CNA30027, CNA30032

ABCskin patch test and HLA-B*5701

Identify ABC-tolerantsubjects

White: n = 130

Black: n = 69

White: n = 202

Black: n = 206

Skin patch test positive

Skin patch test negative

White: n = 42

Black: n = 5

White: n = 85

Black: n = 63

Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008 .


Antiretroviral update spring 2008

SHAPE: Sensitivity and Specificity of HLA-B*5701

CS-HSR confirmed by HLA-B*5701

Sensitivity of HLA-B*5701

Specificity of HLA-B*5701

100%

99%

100%

96%

100

90

80

70

44%

60

Sensitivity/Specificity of HLA-B*5701, %

50

40

14%

30

20

10

57/130

42/42

194/202

10/69

5/5

204/206

0

Skin Test Positive

CS-HSR

Skin Test Positive

Control

CS-HSR

Control

White

Black

Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008


Case 1

Case 1

  • 46 year old male diagnosed in 2004; initial CD4 400 cells/mm3; VL 55,000 copies/mL

  • 2 years later CD4 decreased to 230, VL increased to 150,000, and the patient opts to begin ART:

    • Tenofovir / emtricitabine

    • Atazanavir 300mg + Ritonavir 100 mg

  • After 6 months his CD4 is 450, VL <50


Case 11

Case 1

  • The patient reports good tolerance of regimen and overall good health; he uses loratadine and pseudoephedrine for occasional bouts of seasonal rhinitis / sinusitis

  • He also reports occasional overeating and binge drinking, accompanied by rare episodes of heartburn


Case 12

Case 1

  • A few months later after having missed a regular quarterly visit, the patient’s CD4 is 290 and VL 27,500; repeat testing confirms

  • On questioning the patient reveals having missed occasional doses of ritonavir, in an attempt to reduce diarrhea and bloating, and having initiated over the counter omeprazole nearly daily, 20-40 mg


Antiretroviral update spring 2008

20

In addition to reinforcing the importance of adherance to ritonavir, as well as the other drugs in his ARV regimen, what next steps would you take?

A) advise the patient to avoid omeprazole within 12 hours of taking atazanavir

B) advise to discontinue atazanavir and intensify the regimen, increasing the dose to 400 mg /day

C) advise to discontinue omeprazole and order resistance testing


Antiretroviral update spring 2008

20

Genotype reveals the following mutations:RT: K65R, M184V, G190API: I50L, G73SWhich regimen would you choose at this juncture?

A) new boosted PI + NRTI

B) new boosted PI + NRTI plus enfuvirtide

C) NNRTI plus NRTIs


Case 13

Case 1

  • Genotype reveals likely lack of susceptibility to approved NNRTIs (G190A); although he has not been exposed to this class he may have acquired the mutation at initial infection or subsequent reinfection

  • Use of a fusion inhibitor is unnecessary in this case to construct a regimen with at least 2, ideally 3 active agents; reserving active agents for future use is an important strategy in HIV management


Based on resistance mutations which combination would you choose m184v k65r g190a

20

Based on resistance mutations, which combination would you choose? (M184V, K65R, G190A)

A) Tenofovir + emtricitabine

B) Zidovudine + lamivudine

C) Abacavir + lamivudine

D) Stavudine + lamivudine


Case 14

Case 1

  • Genotype pattern suggests susceptibility to abacavir, didanosine, and tenofovir would most likely be reduced

  • The M184V may increase susceptibility to zidovudine in the presence of 3TC or FTC

  • Stavudine likely remains phenotypically active


Antiretroviral update spring 2008

20

Cased on recent clinical trial data, treatment history, and genotype, which boosted PI would you choose?

A) Fosamprenavir / ritonavir

B) Lopinavir / ritonavir

C) Darunavir / ritonavir


Case 15

Case 1

  • All 3 choices are reasonable and have a good likelihood of achieving undetectable HIV-1 RNA; the patient has minimal PI resistance (I50L confers resistance to atazanavir, G73S confers broad PI resistance, but likely would have little impact unaccompanied by another major PI mutation)

  • Based on the results of TITAN, darunavir/ritonavir out-performed lopinavir/ritonavir at 48 weeks in less treatment-experienced patients (31% naïve, 38% had received 1 PI)


Case 16

Case 1

  • POWER-1 demonstrated the superiority of darunavir/ritonavir over investigator-selected comparator PIs in triple-class experienced patients (in combination with OBT)

  • KLEAN and CONTEXT demonstrated efficacy and noninferiority of boosted fosamprenavir in comparison with lopinavir/ritonavir, in both naïve and experienced patients, respectively


Case 2

Case 2

  • 50 year old male initially diagnosed in 1987, RF MSM; initial CD4 800, nadir about 150. + history of Kaposi’s sarcoma, recurrent molluscum, and esophageal candidiasis

  • ART regimens:

    • 1992-1995: zidovudine monotherapy; CD4 241

    • 1995-1996: zidovudine + lamivudine; CD4 327, VL 100K

    • 1996-1998: zidovudine + lamivudine + indinavir; CD4 708

    • 1998-2003: didanosine+ ritonavir + saquinavir; CD4 580, VL 236K

    • 2003-2004: lamivudine + didanosine + lopinavir / ritonavir; CD4 336, VL 111 K

      • Diagnosed with acute HBV infection, +sAg and eAg


Case 21

Case 2

  • In 2004, virtual phenotype/genotype shows:

    • RT: M184V, 41L, 210W, 215Y

    • PI: 54V, 71V, 82A

    • Data for atazanavir and fosamprenavir not yet available


Antiretroviral update spring 2008

20

Based on this resistance pattern and the patient’s history, what regimen would you choose at this juncture?

A) Zidovudine / lamivudine + lopinavir / ritonavir

B) Tenofovir / emtricitabine + nevirapine

C) Tenofovir / emtricitabine + stavudine + efavirenz

D) Tenofovir / emtricitabine + efavirenz + fosamprenavir + ritonavir


Case 22

Case 2

  • He begins new regimen of tenofovir and FTC, + boosted fosamprenavir, + efavirenz: CD4 >600; VL <400 consistently for > 1 year.

  • The patient requests regimen simplification in 1/07 due to pill burden and fatigue, GI side effects, and lipodystrophy. He attempts to enroll in a local clinial trial examining the role of rosiglitazone in HIV-related lipodystrophy.


What do you recommend now

20

What do you recommend now?

A) refuse a change in regimen, reinforce the importance of compliance

B) agree to give the patient a “drug holiday” (structured treatment interruption)

C) change the regimen to tenofovir / emtricitabine / efavirenz, which has just become available


Case 23

Case 2

  • The patient begins tenofovir / emtricitabine / efavirenz.

  • 3 months later he feels great, is tolerating the drug extremely well, and his CD4 count is still 708 (35%)…

  • BUT…his viral load has climbed to 6437…now what?


Antiretroviral update spring 2008

  • A) continue his current regimen…the viral load was probably a “blip” and will come back down.

  • B) restart fosamprenavir and ritonavir.

  • C) repeat the viral load and order resistance testing with plans to completely change his regimen.


Case 24

Case 2

  • Genotype/virtual phenotype performed in April 2007 reveals the same NRTI mutations as previously (M184V and multiple TAMs); he now has the K103N, and the same PI mutations as he had in 2003, with phenotypic sensitivity only to saquinavir, tipranavir, and darunavir.

  • What happened?


Antiretroviral update spring 2008

  • A) although he reported 100% compliance, he probably missed doses and developed resistance to the NNRTIs

  • B) the lack of three fully active drugs put more selection pressure on efavirenz, bringing out an archived virus with the K103N mutation, which he acquired either at initial infection or later by reinfection

  • C) the geno/pheno from 2003 used a different technique and was therefore probably wrong


Case 25

Case 2

  • The patient is concerned about his viral rebound, and is willing to begin a new regimen. Based on most recent geno/pheno the patient begins tenofovir/emtricitabine, stavudine, darunavir, and ritonavir. His regimen now contains 3 drugs active against HIV and 2 active against hepatitis B.

  • Although he is tolerating the regimen well, and his viral load became undetectable after 6 weeks (CD4 still about 700), he is now concerned about increasing abdominal girth and wasting of the extremities, which has been a chronic problem, but he’s noticed it even more since initiating the new regimen.


Antiretroviral update spring 2008

20

What might be a reasonable option for this patient in the near future, assuming his viral load remains undetectable?

A) add enfuvirtide to his current regimen

B) substitute maraviroc for darunavir / ritonavir

C) substitute raltegravir for stavudine, with the possibility of adding / substituting etravirine at a later date


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