Characteristics of Successful ARV Programs

1
Characteristics of Successful ARV Programs

• Use potent durable ART regimens
• Ensure patient adherence continuity of care
• Attention to patient education, social support,
  family treatment
• Uninterrupted drug supply
• Effective training of health care providers
• Prevention as integral part of treatment

Attention to systems of HIV/AIDS care, not just
ART
2
The Life Cycle of HIV-1 and Major Antiviral
Targets
Hammer, S. M. N Engl J Med 20023462022-2023
3
Currently Available Antiretroviral Drugs
Fusion Inhibitor Enfuvirtide (T-20)
4
Initial ART Regimen

• 2NN Study
• ACTG 384
• DP-006 Study

5
The 2NN study

• Comparison of first-line antiretroviral therapy
  with regimens including nevirapine, efavirenz, or
  both drugs, plus stavudine and lamivudine a
  randomised open-label trial, the 2NN Study

F. van Leth et. al. Lancet. 20041253-63
6
Trial Design
Nucleoside backbone d4T and 3TC

• Inclusion criteria
• pVL gt 5000 copies/mL
• any CD4 cell count
• any stage of CDC classification

7
Outcome Measures

• Primary of patients with treatment failure at
  week 48
• lt 1log10 decline in pVL in first 12 weeks
• 2 consecutive pVL gt 50 copies/mL from week 24
  onwards
• new CDC-C event or death
• change of allocated treatment
• Secondary outcomes
• of patients with pVL lt 50 copies/mL at each
  study week
• change in CD4 cells
• incidence of adverse events
• change in lipid concentrations

8
Baseline Characteristics
9
Primary Outcomes
Success only significant difference EFV vs
NVPEFV, plt 0.001
10
Virologic Success
No significant differences in any of the pairwise
comparisons
11
pVL lt 50 copies/mLITT
12
Increase in CD4 cellsOT
13
Summary
14
Conclusions

• NVP and EFV have comparable potency in
  suppressing HIV-1 replication
• NVP-od and NVP-bd show comparable efficacy
• Co-administration of NVP and EFV results in
  higher treatment failure due to increased
  toxicity

15
Comparison of Sequential Three-Drug and
Four-Drug Regimens as Initial Treatment for HIV
Infection (ACTG 384)

• GK Robbins, et. al.
• N Engl J Med. 2003 3492293-2303.
• RW Shafer, et. al.
• N Engl J Med. 2003 3492304-2315.

16
Objectives

• To compare the initiation of therapy with
• EFV vs. NFV (both in combination with two NRTI)
• AZT 3TC vs. d4T ddI (in combination with
  either NFV or EFV)
• To compare the use of a four-drug regimen
  including two nucleoside analogues, EFV, and NFV
  with the use of two sequential three-drug
  regimens

17
Overall Study Design

• Randomized, partially-blinded, multicenter study
  in treatment-naïve subjects (n980)
• pVL ?500 copies/mL
• Followed for 24 - 36 months
• No CD4 cell count entry criteria
• 6 treatment groups (2 x 3 factorial design)
• d4T ddI EFV
• d4T ddI NFV
• AZT 3TC EFV
• AZT 3TC NFV
• d4T ddI EFV NFV
• AZT 3TC EFV NFV

18
Study Arms (n155 for each arm)

• STEP 1 STEP 2 STEP 3
• A d4TddIEFV ? AZT3TCNFV ? salvage
• B d4TddINFV ? AZT3TCEFV ? salvage
• C AZT3TCEFV ? d4TddINFV ? salvage
• D AZT3TCNFV ? d4TddIEFV ? salvage
• E d4TddINFVEFV ? (no step 2) ? salvage
• F AZT3TCNFVEFV ? (no step 2) ? salvage
• Criteria for (STEP 1 to STEP 2) or (STEP 1 to
  STEP 3)
• Virologic failure
• Regimen intolerance / toxicity
• Premature treatment discontinuation (for any
  reason)

19
Endpoints

• Primary endpoint time to failure of two
  sequential three-drug regimens (virologic
  failure, toxicity, or premature discontinuation
  for any reason)
• Time to step 3
• Secondary endpoints time to first virologic
  failure, first regimen failure, and toxicity
• Time to step 2

20
Primary Endpoint(Three-Drug Regimens)
21
Secondary Endpoint Failure of 1st Regimen
(Three-drug regimens)
22
Time to First Virologic Failure (Three-Drug
Regimens)
Initial regimen
ddId4TEFV ddId4TNFV COMEFV COMNFV
23
Toxicity (Three-Drug Regimens)
Severe/dose-modifying toxic effect
Peripheral neuropathy
Plt0.001 Initial regimen
Plt0.001 Initial regimen
ddId4TEFV or ddId4TNFV COMEFV or COMNFV
ddId4TEFV or ddId4TNFV COMEFV or COMNFV
Severe / dose-modifying toxicity
Peripheral neuropathy
24
Summary(Three-Drug Regimens)

• Significant interaction between the choice of
  NRTI backbone and the choice of EFV or NFV
• Comparisons for each primary end point showed a
  trend that favored initiation of treatment with
  EFV over initiation with NFV when AZT 3TC were
  used as the NRTI (HR for failure of second
  regimen, 0.71 95 CI, 0.48 to 1.06) but not when
  ddI d4T were used
• Similar trend favoring initiation of therapy with
  AZT 3TC when EFV was used (HR, 0.68 95 CI,
  0.46 to 1.01) but not when NFV was used
• No additional benefit from adding NFV to
  AZT3TCEFV

25
EFV AZT and 3TC, EFV IDV, and IDV AZT and
3TC in the Treatment of HIV-1 Infection in Adults

• RCT
• Open-label
• N450
• Subjects HIV-1 infected ART naïve CD4 gt50
  cells HIV RNA gt10,000 copies
• ITT MissingFailed

NEJM 1999 3411865-1873
26
DP-006 Study Week 168 Follow-up Suppression lt
400 Copies/mL
100
80
60
Proportion With VL lt 400 ()
40
20
P lt .0001 EFV vs IDV triple-drug arms at Week 168
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
B/L
Weeks
ITT, MF analysis Proportion of subjects with
response according to TLOVR definition of
treatment success.
Tashima et al. Abstract TuPeB4547.
27
New Drugs

• Emtricitabine
• Tenofovir DF
• Lopinavir-Ritonavir
• Atazanavir
• Enfuvirtide

28
Efficacy and safety of emtricitabine (FTC) vs d4T
in combination therapy in ART-naive patients a
randomized trial
Saag MS. JAMA 2004292180-90
29
Primary Outcome Persistent Virologic Response
30
CD4 Cell Count Change
31
Efficacy and safety of tenofovir DF vs d4T in
combination therapy in ART-naive patients a
3-year randomized trial
Gallant JE. JAMA 2004292191-201
32
Week-144 Virologic Outcomes
N600 ITT (Missing Failure)
100
80
73 69
60
Patients with HIV-1 RNA lt 50 copies/mL ()
40
TDF 3TC EFV
20
d4T 3TC EFV
0
0
24
48
72
96
120
144
Weeks
Gallant et al. Abstract TuPeB4538.
33
Week 144 Total Limb Fat
12
10
8.6
9
P lt .001
7.9
8
7
6
Kilograms
5.0
5
4.5
4
3
2
1
Weeks
0
48
96
144
TDF3TCEFV 128 115
d4T3TCEFV 134 117
Gallant et al. Abstract TuPeB4538.
34
Greater Effect of Stavudine on Triglycerides
234 200 184 183
177 175 171
250 211 194 182
179 170 162
Gallant et al. Abstract TuPeB4538.
35
LPV-RTV vs NFV for the initial treatment of HIV
infection
75 t vs. 63, Plt0.001
HR, 2.0 95 CI, 1.5 to 2.7 Plt0.001
67 vs. 52, Plt0.001
HIV protease resistance mutations demonstrated in
viral isolates from 25 of 76 NFV-treated patients
(33) and none of 37 patients treated with
LPV-RTV (Plt0.001)
Walmsley S. N Engl J Med. 20023462039-46
36
RCT of atazanavir with 3TC and d4T in ART-naive
subjects
48-week results N476 ITT, non-completionfailur
e

• Mean changes in pVL
• ATV 400 mg -2.51
• ATV 600 mg -2.58
• NFV -2.31
• CD4 cell count increased comparably
• Adverse events were similar across treatments
  except diarrhea (gt with NFV) and jaundice (gt with
  ATV)
• Lipid changes with ATV were significantly less
  than with NFV

Virological Efficacy
Murphy RL. AIDS. 2003172603-14.
37
Enfuvirtide TORO 1 2 Trials

• Week 48 data
• patients achieving lt 400 copies/mL at 48 weeks
  30.4 vs 12 (P lt .0001)
• Median time (weeks) to virologic failure 32 vs
  11 (P lt .0001)
• Local injection-site reactions were observed in gt
  90 of ENF patients
• Cause of discontinuation in 4.4
• Increased incidence of bacterial pneumonia
  observed in the ENF arm (6.6 vs 0.6 events per
  100 person-years)

58.3
35.8
P lt0.001
Time to Protocol-Defined Virologic Failure, as of
Week 24
Lalezari J. NEJM. 20033482175-85 Abstract LB2.
IAS 2003
38
Structured Treatment Interruptions

• Still considered experimental NOT recommended
  in clinical practice
• Goals
• ? total time on therapy
• Decrease drug toxicity
• Decrease cost
• Induce HIV-specific T-cell stimulation
• Improve QOL

• No short- and long-term benefit in acute or
  chronic infection
• STI as pre-salvage approach
• Associated with greater risk of disease
  progression
• No immunologic or virologic benefits
• No improvement in QOL

• May be considered in
• Patients who began ART when treatment was
  recommended at higher CD4 count cut-offs
• Patients who have immunologic reserve (based on
  CD4 counts gt350) and who are experiencing
  ART-related toxicity

J Infect Dis. 2002186634-643 Arch Intern Med.
20031631220-1226 N Engl J Med.
2003349837-846
39
Effect of Adherence on Survival

• 1422 HIV-infected adults were followed for 2 to 6
  years after starting HAART
• Adherent patients who started treatment with
  lower (0.200 to 0.349 x 109 cells/L) and higher
  (0.350 x 109 cells/L) CD4 cell counts had
  statistically similar mortality rates
• Non-adherent patients had higher mortality rates
  than adherent patients, regardless of baseline
  CD4 cell count of 0.200 to 0.349 x 109 cells/L
  or 0.350 x 109 cells/L
• In HIV-infected patients adherence may be the
  most important determinant of survival (rather
  than when therapy is initiated before a CD4 cell
  count of 0.200 x 109 cells/L)

Wood E. Ann Intern Med. 2003139810-6.
40
Association Between WHO 3x5 Regimens and
Survival in San Francisco
First-line Regimen

• Case-control study
• 310 cases all died before 2003
• 1161 controls all alive through 2002
• 4 regimens recommended by WHO 3x5 associated
  with best survival
• However, analysis does not account for subsequent
  switches may not be available in developing
  countries

d4T-3TC-EFV
AZT-3TC-EFV
d4T-3TC-NVP
AZT-3TC-NVP
d4T-3TC-NFV
AZT-3TC-NFV
d4T-3TC-IDV
AZT-3TC-IDV
d4T-3TC-SQV
AZT-3TC-SQV
1 3 5 7 9 11
28
0
Adjusted Odds Ratio for Death Compared With
d4T-3TC-EFV
Chen et al. Abstract MoOrC1082.
41
Generic Antiretroviral Drugs

• Antiretroviral drug content in products from
  developing countries
• The active ingredient in tested drug products was
  within 15 of the labeled amount (range, -12 to
  15) for drugs that were properly stored
• Clin Infect Dis. 2004381317-9
• Effectiveness and safety of a generic fixed-dose
  combination of NVP, d4T 3TC in HIV-1-infected
  adults in Cameroon open-label multicentre trial
• The proportion of patients with undetectable pVL
  (lt400 copies per mL) after 24 weeks of treatment
  was 80 (95 CI 68-89)
• Lancet. 200436429-34
• Effectiveness of Generic Fixed-Dose Combinations
  of Highly Active Antiretroviral Therapy for
  Treatment of HIV Infection in India
• Fixed-dose formulations of NVP-based combination
  therapy are safe and produced durable clinical
  and immunologic benefit
• J Acquir Immune Defic Syndr. 2004371566-1569

42
Conclusions

• Initial HAART regimen EFVAZT3TC
• Newer drugs
• FTC once-daily dosing FTCgtd4T
• TDF better lipid profiles less lipodystrophy
• LPV-RTV potent, durable, resistance unlikely
• ATV comparable potency to NFV once-daily
  dosing no effect on lipids
• T-20 salvage
• Generic drugs good enough
• STI still remains experimental