feedback from 15th ias conference 13-18 august 2006 simon collins hiv i-base

Simon Collins: Toronto feedback: HIV I-Base UK-CAB September 2006

Feedback from 15th IAS Conference13-18 August 2006

Simon CollinsHIV i-Base


Feedback from 15th IAS Conference

1.Treatment access

2. New drugs

3. New strategies: boosted-PI monotherapy

4. Other issues



1.Treatment access

• many smaller studies including long-term data

• working in all countries, access for women and

children, TB coinfection, late diagnosis, adherence,

side effects

• funding - now 1.6 million on treatment, but dependent

on funding increasing every year, if this is to expand


North Africa and the Middle East

Europe and Central Asia

East, South and South-East Asia

Latin America and the Caribbean

Sub-Saharan Africa

0

200

400

600

800

1000

1200

1400

End 2002

Mid-2003

End 2003

Mid-2004

End 2004

Mid-2005

End 2005

People receiving therapy

(thousands)

2006 Report on the global AIDS epidemic (UNAIDS, 2006) Piot WESS0102

Number of people on antiretroviral therapy in low- and middle-income countries, 2002‒2005


0

10

20

30

40

50

60

70

80

90

100

Q1-04 Q2-04 Q3-04 Q4-04 Q1-05 Q2-05 Q3-05 Q4-05 Q1-06 Q2-06

Quarters

Number of Sites

Cote d'Ivoire

South Africa

Tanzania

Zambia

Total

Côte d’Ivoire: 57 sites

South Africa: 3 sites

Scale up of treatment in the Elizabeth Glaser Pediatric AIDS Foundation “Project HEART”

Initiating Care and ARV Treatment for over 68,000 people in 28 months at 95 sites in four African countries

Marlink THAB0201


Women's access to HIV treatment, June 2006 - Piot

United Republic of Tanzania

Mozambique

Malawi

Zimbabwe

Zambia

Central African Republic Botswan

a Kenya

Côte d'IvoireNamibia

Rwanda

BurundiSouth Africa

Uganda

Nigeria

10% 40% 50% 60% 70%20% 30%

Percentage of adults on ART who are women Percentage of HIV-infected persons who are women


• Adherence to ART is better in African programmes than in North America

• A meta-analysis of 27 studies in sub-Saharan African countries

and 31 North American studies showed that adequate adherence was observed in 77% of patients in Africa and 55% of patients in North America.

• It is important to ensure that these reassuring initial rates of adherence will be sustained over time.

• Data from Senegal suggest that the involvement of communities may be the key to maintaining adherence in the long term.

“Refuting the Afro-pessimists”


“... we are on the cusp of a huge financial crisis... and have been lulled into a damaging false security (we jumped from $300 million a year… in the late 1990's, to $8.3 billion in 2005. It sounds impressive. But we need $15 billion in 2006, and $18 billion in 2007, and $22 billion in 2008. This will take us to $30 billion in 2010 … the moment of universal access to treatment, prevention and care.”

“We're billions and billions short of those targets. If these circumstances continue, universal access is doomed. The financial promises made at the G8 Summit in Gleneagles one year ago, are already unraveling. We will never accumulate the extra $25 billion for Africa by 2010 as was committed.”

“PEPFAR has not yet announced its extension beyond 2008; when it does (as it surely will), the annual contribution, given the other demands on the US Treasury, will probably remain at $3 billion a year. That large amount was a very significant percentage of the total expenditure on AIDS back in 2003/2004. But as a percentage of what is needed for global AIDS programmes in 2008 - $22 billion - $3 billion seems pretty paltry from the world's superpower.”

Stephen Lewis: closing ceremony



2. New drugs

• MK-0518

• maraviroc

• etravirine

• TNX-355

• atripla, T-1144, T-999, PL-100 etc


• MK-0518 is a strand transfer inhibitor of HIV integrase (integrase is 3-step process and K-0518 block the final step, where the viral DNA is spliced into the CD4-cell DNA)

• In treatment naïve patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm3, MK-0518 studied at four dose levels for 24 weeks:

• had potent antiretroviral activity• 85-95% with HIV RNA < 50 copies/mL• achieved viral suppression faster than EFV • was generally well tolerated

MK-0518 Merck’s integrase inhibitor: great promise

Markowitz THLB0214


Part I: 40 Rx-naïve ptsrandomised to 100, 200,

400, or 600mg 0518 twice daily, or placebo.

8 patients in each arm

Protocol 004: Study DesignPart I

Integrase Monotherapy

for 10 days

Part II

Combination Therapy

4 doses 0518 vs EFV,

All plus TDF/FTC

*TDF = tenofovir

Part II: 150 Rx-naïve pts randomised to 100, 200,

400, or 600mg 0518 twice daily, or efavirenz, all

+TDF/FTCfor 48 weeks

30 new patients in each arm HIV RNA of 1.7 – 2.2 log10 copies/mL

Morales-Ramirez et al, EACS 2005 IAC 2006 Abs# THLB0214


Protocol 004: Baseline Characteristics

MK-0518 mg bid*Efavirenz * 600mg qd

N=38100

N=39

200

N=40

400

N=41

600

N=40

Age-mean (yrs) 37 34 36 37 36

%Male 85 73 90 73 76

%Non-White 82 65 66 65 68

HIV RNA

copies/ml** (log10cp/ml)

58206

(4.8)

64715

(4.8)

43083

(4.6)

57919

(4.8)

67554

(4.8)

CD4 – mean (cells/ul)

314 296 338 271 280

% with AIDS 31 33 29 43 37

* With TFV/3TC ** = geometric mean


IAC 2006 Abs# THLB0214

Protocol 004: HIV RNA Change from Baseline*(log10 copies/mL) (95% CI)

0 2 4 8 12 16 24Week

-3

-2

-1

0

Change From Baseline in HIV RNA (Log

10

Copies/mL)

m518p4rna6 Aug. 10, 2006

MK-0518 100mg 38 39 39 39 39 39 25MK-0518 200mg 40 40 40 40 40 40 27MK-0518 400mg 40 41 41 41 41 41 27MK-0518 600mg 39 38 38 38 38 38 28Efavirenz 37 38 38 37 38 37 26

*assay LoQ 400 copies/ mL

Markowitz THLB0214


IAC 2006 Abs# THLB0214

Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 copies/mL (NC=F)

0 2 4 8 12 16 24Week

0

20

40

60

80

100

Percent of Patients withHIV RNA <50 copies/mL

*

*

m518p4.r50.5 Aug. 3, 2006

MK-0518 100mg 39 39 39 39 39 39MK-0518 200mg 40 40 40 40 40 40MK-0518 400mg 41 41 41 41 41 41MK-0518 600mg 40 40 40 40 40 40Efavirenz 38 38 38 38 38 37

* P < 0.001 for MK -0518 at each dose vs. EFV

Markowitz THLB0214


Common (≥5%) drug related side effects

MK 0518 (all doses) +TDF/FTC

N=160 (%)

Efavirenz

+TDF/FTC

N=38 (%)

Nausea 11 13

Headache 9 24

Dizziness 8 26

Diarrhea 7 11

Insomnia 7 11

Abnormal dreams

6 18

Flatulence 6 -

Additional AEs seen at ≥ 5% in efavirenz group:Nightmare (11%)Vomiting (8%)Malaise (8%)

Fatigue (5%)Disturbance in attention (5%)Lethargy (5%)Anxiety (5%)

* With TFV/3TC


Maraviroc

• Double-blind placebo controlled study in 190 mixed/dual

tropic patients

• Randomised to optimised background regimen (OBT) including

at least one sensitive drug, plus either maraviroc once-daily

(n=63), vs maraviroc twice daily (n-61) or placebo (n-60).

[1]

• Over 90% patients were PI-experienced

• 50-60% currently using T-20

• Baseline CD4 count <100 cells/mm3

• Baseline viral load > 5logs respectively

• >95% patients had dual/mixed tropism.


Maraviroc

Table 1: Virologic and immunologic responses at week 24

All treated patients with D/M-tropic HIV-1

Placebo + OBT

n = 58

MVC QD + OBT

n = 57

MVC BID + OBT

n = 52

Mean decrease in HIV-1 RNA (log10c/mL)*

-0.97 -0.91 -1.20

Treatment diff (MVC-OBT) in HIV-1 RNA decrease (log10c/mL) (97.5% CI

+0.06 (-0.53, +0.64)

-0.23(-0.83, +0.36)

HIV RNA < 400 c/mL (%)

HIV RNA < 50 c/mL (%)

24.1

15.5

24.6

21.1

30.8

26.9

Mean decrease in HIV-1 RNA in pts using T-20

-0.89 -1.26 -1.44

Mean CD4 change (cells/mm3, mean)

All treated patients with D/M-tropic HIV-1

+36 (n=58) +60 (n=57) +62 (n=52)

Mean CD4 change (cells/mm3, mean)

Pts with only X4-tropic HIV-1 detectable at time of virologic failure

-104 (n=2) +48 (n=12) +33 (n=12)

As no progression of HIV, questions importance of tropism test???


Etravirine (TMC-125)

Phase II study in 199 treatment experienced patients with documented NNRTI resistance and 3 or more primary PI mutations.

Randomised to TMC125 (400 mg or 800 mg bid) with an investigator selected background, or standard-of-care control regimen.

Median baseline CD4 - 100 cells/mm3; viral load 4.7 log copies/mL

Table 1: Results of etravirine (TMC-125) at 48-weeks400mg 800mg control

Mean VL change (log) -0.88 * -1.01 * -0.14

Mean CD4 change +58 +61 +13

VL failure 9% 9% 78%

Med. duration of Rx (wks) 48 wks 48 wks18 wks

* P <0.05 compared to control


TNX-355

Table 1: Baseline characteristics and ITT responses to TNX-355

15mg/kg +OBR 10mg/kg+OBR placebo+OBR

N 28 27 27

Age 47 44 46

% male/female 78/22 93/7 89/11

Baseline CD4 (%<200) 299 (26%) 223 (51%) 245 (43%)

Baseline VL (%>5log) 4.8 (26%) 5.0 (57%)4.8 (33%)

Mean change in CD4+ +51 (p=0.016) +48 (p=0.031) +1

Mean VL change wk-48 -0.71 (p<0.010) -0.96 (p<0.001) -0.14

N (%) >/= 1.0 log 9 (32) 10 (37) 3 (11)

N (%) >/= 0.5 log 11 (39) (p=0.029) 12 (44) (p=0.014) 3 (11)

% <400 (%<50) c/mL 7 (4) 4 (0) 0 (0)

Median TLVR (days) 253 (p=0.003) 230 (p=0.003) 0Ref: Norris D, Morales J, Godofsky E et al. TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 Weeks. Late breaker abstract THLB0218.


* Selected regimens

1996: d4T/3TC/IDV 10 pills, TID

2002: ZDV/3TC/EFV 3 pills, BID

1998: ZDV/3TC/EFZ 5 pills, BID

2004: TVD or EPZ /EFV 2 pills, QD

2006: ATRIPLA 1 pill, QD

Treatment Simplification* - 1996 - 2006

Montaner WEPL0101


0.01

0.1

1

10

100

0 1 2 3 4 5 6 7

Time (days)

Plasma Concentration

(μ/ )g mL

Early data on long-release entry Early data on long-release entry inhibitors - ‘2nd generation T-20’inhibitors - ‘2nd generation T-20’

TRI-1144TRI-1144

TRI-999TRI-999

Subcutaneous DoseCynomolgus monkey

Normalized to 3 mg/Kg

ENFENF



3. New strategies:

• Kaletra monotherapy

• Fosamprenavir/r vs Lopinavir/r

• tenofovir/FTC vs AZT/3TC


Kaletra monotherapy

Three randomised trials using different study designs came to similar conclusions:

“For the majority of patients who have never failed on a Protease Inhibitor containing regimen, including naïve patients, Kaletra (LPV/r) monotherapy may be an effective, virologically suppressive and well tolerated regimen characterised by a high genetic barrier and by very low incidences of viral resistance.” - J. McIntyre, lead rapporteur


92 67 4843 36 31

No. at riskLPV/r Arm EFV Arm

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72

% Maintaining ResponseLPV/r ArmEFV Arm

Weeks since switch to maintenance (LPV/r arm) or 3rd consecutive HIV-1 RNA value <50 copies/mL (EFV arm)

90%

62%

P<0.001 (log-rank test)

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72



90%

62%



90%

62%


Time from LPV/r monotherapy to 1st of 2 VL > 50 c/mLLPV/r maintenance versus corresponding EFV subjects

Cameron THLB0201


92 83 6343 36 31

No. at riskLPV/r Arm EFV Arm

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72



95%84%

p=0.18 (log-rank test)

0%

20%

40%

60%

80%

100%

0 8 16 24 32 40 48 56 64 72



95%84%

p=0.18 (log-rank test)

Time from LPV/r monotherapy to 1st of 2 VL > 500 c/mL LPV/r maintenance versus corresponding EFV subjects

Cameron THLB0201


Kaletra monotherapy

3 posters including 2 from UK

Examples of individual cases: tolerability, adherence etc

• In developed countries: treatment naïve, reduction NOT treatment experienced, or individualised:

Higher viral load rebound, viral failure, resistance

• In access countries: as second-line therapy


Fosamprenavir/r vs lopinavir/r

Median baseline CD4 ~ 200 cells/mm3 (with 15-18% < 50 cells/mm3) and viral load 5.1 log copies/mL (with 50% over 100,000 copies/mL). Median age was 37 years; 78% were male; 58% were white/Caucasian; and 11% were CDC Class C.

Fosamprenavir/r vs lopinavir/r in treatment-naive patients: 48-week results

FPV/r LPV/r

N 434 444

% VL <400 c/mL, (%) * 73% 71%

% VL <50 c/mL (%) 66% 65%

Median CD4 change c/mm3 (IQR) +176 (106-281) +191 (124-287)

Virological failure; n (%) 16 (4%) 24 (5%)

Drug-related Grade 2-4 AEs; n (%) 55 (13%) 46 (10%)

Discontinuations due to AEs; n (%) 53 (12%) 43 (10%)

• (95% CI -3.26, 5.47)

•very high adherence rates (calculated by percentage of returned pills) of >/= 98% for the protease inhibitors and 99.4% for abacavir/3TC.


TDF/FTC/EFV vs AZT/3TC/EFV

Baseline median age 37, 14% female, 59% white, median viral load 5.0 copies/mL, median CD4 237 cells/mm3

ITT, n=509, (n=22) with baseline NNRTI mutations

Week 96 results

TDF+FTC arm (n=244) CBV arm (n=243)

HIV RNA<400 c/mL 76% 64% (p=0.004)

HIV RNA<50 c/mL 69% 63% (p=0.15)

CD4 cell incease 270 237 (p=0.036)

A/e discont. 5% 11% (p<0.001)

(most common: anemia, nausea, fatigue, vomiting, rash)

Renal safety profile was also similar (serum creatinine, Cockcroft-Gault GFR (p=0.05).

Weight increase 2.7kg 0.5kg (p<0.001)

DEXA, median limb fat 7.7 kg, n=144 5.5 kg, n=136 (p<0.001)

No patient developed the K65R mutation.

Significantly more patients on AZT/3TC developed M184V/I (9 vs 2, p=0.037).



4.Other issues

• Prevention: circumcision, PrEP, ARV treatment, HSV treatment

• European resistance data

• UK studies: late diagnosis, use of STARHS, complementary medicine and ARV interactions, UAI behavioural 5 cities study

• Global: TB, HCV coinfection, children



• Circumcision studies 3-4 oral presentations, 5+ posters

• PrEP

• European resistance - SPREAD - 1083 newly diagnosed individuals from 17 countries (20% recent infections <1 year): 44% gay/bi, 42% heterosexual. 9% IVDU; 34% outside Western Europe. From 13 sub-types, ~9% had IAS-defined resistance - slightly higher in recent infections vs undefined infections. RTI -5-5% (30% >1 mutation); PI - 3%, NNRTI 2.6%; <1% dual-class resistance. TUAB 0101.



• Use of complementary alternative medicine - 10% - Cross sectional multiple choice questionnaire of ~250 patients: 154 (60%) using herbal remedies, 88 (34%) using physical treatment and 67 (25%) using both. 25 pts (10%) were asked to stop CAM because of potential interaction with ARVs, and slightly higher proportion (n=30) asked to be cautious - but little details in abstract. Only 50% had discussed CAM with their HIV doctor. - MOPE 0219

• UK late diagnosis and mortality - MOPE 0067, MOPE0296;

• STARHS use - Brighton - 80/665 diagnoses identified as recent infections increasing from 20% in 1996 to 50% in 2004 - MOPE 0504

• UK UAI and behaviour of gay men in 5 UK cities ~ 4380 questionnaires and 3660 swabs. HIV prevalence - 12-14% in London and Brighton, 9% in Manchester, 3% in Glasgow and 5% in Edinburgh. 41% (range 33/48%, Manchester/Glasgow) HIV+ men were undiagnosed, and 50% (n=70) reported most recent result as HIV-negative (therefore believing they were HIV-negative). MOPE 0517 A second behaviour study reported higher rates of serosorting in heterosexual African HIV+ individuals - WEPDC05


• TB is a leading cause of death in Africa and, in some settings, the leading cause of death among people with HIV

• First 3-6 months after starting HAART may even have increase in TB followed by decline

• Early diagnosis is required to further decrease this risk

The overlapping challenges of two epidemics: HIV and TB


Days since Sputum Collected

2402101801501209060300

Proportion Surviving

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

-.1

Survival from time of Sputum Collection

High prevalence and mortality from extensively-drug resistant (XDR) TB in TB/HIV co-infected patients in rural South Africa

Gandhi THLB0210


2%

<20%

20-40%

40-60%

60-80%

6%

6%

12%

9%

>80%

79%

25.5%

11%

8%

95%

57%

83%

29%

66%

69%

59%

16%

5%

20%

7%

15%

16%

<1%

22%

87%

61%68%

15%

68%

5%

6%

0%11%

17%

20%

5%

81%

1%

49%

3%14%

16%

2%16%

32%

29%

16%

34%

82%

80%

86%

71%

82%

49%

IDU as % of all HIV/AIDS cases with known transmission routeNOTE: % of AIDS cases in countries not reporting HIV Sources: EuroHIV; national reports;

Hepatitis C/HIV co-infection in IDUs is a major issue in Europe

Kruk WEAX0101


Children make up –

• 14% of new global infections,

• 18% of HIV related deaths

• 5.6% of persons living with HIVKLINE WESY0104

UNICEF estimates that 660,000 children urgently require antiretroviral treatment, most of them in sub-Saharan Africa

“Care of the infected and uninfected child must include treatment of their mothers and families”

Ruth Nduati

Children need to be on the global agenda


• The issue of nursing staff needs was a common theme through many presentations in Track B.

• In sub Saharan Africa alone, more than 600,000 nurses are needed to deliver HIV care and other services

• Nurses staff need to be supported and appropriately utilised

“If I’d wanted to be an undertaker, I wouldn’t have trained as a nurse”South African nurse, quoted by Alta Van Dyke

“Open your purses, we need more nurses”,


Thanks

Slides:

• Rapporteur summary of Track B: James McIntyre

• New drugs from Late Breaker abstracts online

http://www.ias.se

(Follow link to conference, then conference programme, then related session link)

feedback from 15th ias conference 13-18 august 2006 simon collins hiv i-base

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