Overview of treatment guidelines

1
Overview of treatment guidelines

• Papa Salif Sow MD, MSc
• Department of Infectious DiseasesUniversity of
  Dakar, Senegal

2
Treatment Responses in First Year of
HAARTImproving Over Time

• 4143 subjects from 5 clinic cohorts in Europe and
  Canada
• Treatment-naive started HAART from 1996-2002
• ? risk of virologic failure, ? median CD4
  increase in later years
• In recent years, most failure due to loss to
  follow-up or treatment discontinuation

with gt 500 copies/mL
100
90
80
70
60
With VL gt 500 on ART
50
40
30
24.8
23.0
17.3
20
12.4
10
8.4
8
10
0
1996
1997
1998
1999
2000
2001
2002
Lampe S, et al. CROI 2005 - Abstract 593
3
Antiretroviral Therapyand Management, 2008

• The Drugs
• When to Start Them
• Choosing a Regimen
• Monitoring Response
• Adherence
• Failure
• Drug Resistance
• Adverse Drug Effects

4
Retrovirus life cycle
Coreceptor inhibitors
5
Antiretroviral Therapy

• Six Drug Classes-FDA Approved
• Nucleoside/Nucleotide Reverse Transcriptase
  Inhibitors (NRTI)
• Non-Nucleoside Reverse Transcriptase Inhibitors
  (NNRTI)
• Protease Inhibitors (PI)
• Fusion Inhibitors
• CCR5 Co-receptor blockers
• Integrase Inhibitors

6
Antiretroviral Therapy

• NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE
  INHIBITORS (NRTIs)
• AZT (zidovudine (ZDV) Retrovir)
• 3TC (lamivudine Epivir)
• d4T (stavudine Zerit)
• ddI (didanosine Videx)
• Abacavir (ABC, Ziagen)
• Emtricitabine (FTC, Emtriva)
• Tenofovir (TDF, Viread)

7
Antiretroviral Therapy

• NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  (NRTIs)
• Fixed Combinations
• Combivir (AZT and 3TC)
• Epzicom (3TC and ABC)
• Trizivir (AZT, 3TC and ABC)
• Truvada (FTC and TDF)

8
Antiretroviral Therapy

• One Pill-Once-a-day
• ATRIPLA
• Tenofovir/Emtricitabine/Efavirenz

9
Antiretroviral Therapy

• NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  (NNRTIs)
• Efavirenz (Sustiva)
• Nevirapine (Viramune)
• Delavirdine (Rescriptor)
• 2nd Generation
• Etravirine (Intelence, TMC125)

10
Antiretroviral Therapy

• PROTEASE INHIBITORS
• Ritonavir (Norvir)
• Saquinavir (Invirase)
• Nelfinavir (Viracept)
• Indinavir (Crixivan)
• Fosamprenavir (Lexiva)
• Lopinavir/ritonavir (Kaletra)
• Atazanavir (Reyataz)
• Tipranavir (Aptivus)
• Darunavir (Prezista)

11
Antiretroviral Therapy

• FUSION INHIBITORS
• Enfuvirtide (T-20, Fuzeon)
• Synthetic peptide blocks gp41 mediated fusion
• Subcutaneous injection twice/day
• Indicated for salvage therapy (use with at
  least one other active drug or in patients with
  high risk of disease progression/death)

12
Antiretroviral Therapy

• New in 2007
• CCR5 Blockers
• Maraviroc (Selzentry)
• Integrase Inhibitors
• Raltegravir (Isentress, MK-0518)
• 2nd Generation NNRTI
• Etravirine (Intelence, TMC125)

13
Goals of HIV Therapy Tools to Achieve Goals

• TOOLS
• Maximize adherence
• Rational sequencing of therapy
• Preservation of future treatment options
• Use of resistance testing in selected clinical
  settings

• GOALS
• Maximal and durable suppression of viral load
• Restoration and/or preservation of immune
  function
• Improvement of quality of life
• Reduction of HIV-related morbidity and mortality

Available at http//aidsinfo.nih.gov/guidelines
14
Goals of ARV Therapy
Treatment start
Viralload
50 copies/mL
Years
Time
15
Antiretroviral Therapyand Management, 2007

• When to Start

16
When to Start?

• Prevent Immune system destruction
• More effective when started early
• Preserve HIV directed CTL

• Toxicities of treatment
• Increased risk of resistance
• Low rate of disease progression
• Cost

Early
Later
17
(No Transcript)
18
(No Transcript)
19
Pregnant women with HIV infection in need of
HAART should receive it
20
Recommendations for initiating antiretroviral
therapy in HIV-infected pregnant women
(1) Treatment is recommended if TLC lt 1200/mm3.
(2) The precise CD4 cell level above this value
at which ARV treatment should be started has not
been established. (3) Treatment can be
considered t if CD4 counts lt 350 cells/mm3,
particularly for women with CD4 values nearing
the threshold of 200/mm3.
21
CD4 count at start of ART, 20035

• Comparison of the regional variation of CD4
  counts at the time ART therapy initiated
• Review of data from 42 countries, 176 sites
  n33,008

Median CD4 counts at the start of therapy, by
region/country
North America US 187 Canada 164 South
America Brazil 159 Argentina 181 Sub-Saharan
Africa South Africa 87 Botswana 97 Malawi
97 Australasia India 103 Vietnam 53 Japan
192 China 163 Australia 239
We are starting too late!
Egger M, et al. 14th CROI, Los Angeles 2007, 62
22
MORTALITY ON HAART BY INITIAL CD4 AND VIRAL LOAD
Probablity of Survival ()
n1219
Time from Start of ARVs (mths)
Hogg JAMA 2001286 2568
23
Antiretroviral TherapyChoosing a Regimen

• Potency
• Tolerability
• Drug interactions
• Social issues
• Convenience

• Availability
• Cost
• Prior therapy
• Resistance and cross resistance

24
Anti-retroviral TherapyNNRTI based

• Advantages
• Effective
• Low pill count
• Easier adherence
• Defer PIs

• Disadvantages
• Toxicities
• Low genetic barrier
• Cross resistance

25
First Line ARV Drugs in Adults and Adolescents
(WHO 2006)
Preferential 2 NRTI/NNRTI approach
AZT or d4T
EFV
3TC or FTC
NVP
TDF or ABC
Alternative triple NRTI approach
Preferential NRTI to be combined with 3TC or
FTC. Triple NRTI should be considered as an
alternative strategy for first-line in situations
where NNRTI options provide additional
complications and to preserve the PI class for
second line(e.g., pregnancy, viral hepatitis
co-infection, TB confection, women who wish to
fall pregnant or who have CD4 count gt 250 cells
/mm3 severe reactions to NVP or EFV and HIV-2
infection).
26
IMPORTANT Addendum to WHO 2006 Guidelines on
Antiretroviral Therapy for HIV Infection in
Adults and Adolescents. NEW DOSAGE
RECOMMENDATIONS FOR STAVUDINE (d4T) Stavudine
(d4T) is now recommended at the dose of 30 mg
twice daily for all adult and adolescent patients
regardless of body weight.(A-III)
27
The Choice of the NRTI Backbone

• The choice of dual-NRTI backbones for initial
  therapy should now consist of 1 of 3 fixed-dose
  coformulations

AZT/3TC ABC/3TC TDF/ FTC
28
AZT/3TC
29
Study 934 TDF FTC vs. AZT/3TC with EFV 24
week data
100
80
60
Responders,
40
Genotypes at Wk 24 (n 18) Wild-type (n
8) EFV-R M184V (n 10) No TAMs No K65R
20
0
4
8
12
16
20
24
B/L
Wks
TLOVR, time to loss of virologic response
Gazzard B, et al. ICAAC 2004. Abstract 1137c.
30
Study 934 Reasons for Study Discontinuation
P lt .01
Gazzard B, et al. ICAAC 2004. Abstract 1137c.
31
GS 934 Study 48 Weeks

• Study population HIV-infected, treatment-naïve
  patients, VL gt10K (N487)
• Study treatment (ZDV/3TC vs TDF/FTC) EFV

Press release, Gilead, 3-Feb-05
32
ABC/3TC
33
ABC 3TC EFV vs AZT 3TC EFV CNA30024
Double-blind trial in naïve patients
Virologic response (VL ?50 c/mL) ITT Exposed
CD4 change from BL ITT Exposed
95 CI (6.3, 7.9)
p0.0039
More nausea, vomiting, fatigue, anemia in AZT
arm. More HSR in ABC arm.
DeJesus E, et al. 43rd ICAAC, Chicago, September
2003, H-446
34
TDF/FTC
35
TDF EFV 3TC vs. d4T EFV 3TC Gilead 903
144 week data
ITT MissingFailure
73 69
Patients with VL lt 50 c/mL
Weeks
Gallant JE. JAMA. 2004292135
36
GS 903 Patients () with Lipodystrophy
19
20
TDF3TCEFV d4T3TCEFV

18
16
14
12
12

Patients with Selected Toxicities ()
10
8
6
4
3
4

1
1
2

0
Investigator-defined p value lt 0.001
Week 48
Week 96
Week 144
Preliminary Data on File, Gilead Sciences, Inc.
37
GS 903Mean Change in Fasting Triglycerides
Wk 48, 96, 144, p lt 0.001
134
103
90
Change from Baseline (mg/dL)
8
1
5
Weeks
Gallant JE. JAMA. 2004292135
38
Choice of NRTI Backbone

• TDF/FTC
• Longest intracellular half-lives
• Well tolerated
• 1 QD no food restrictions
• No mitochondrial toxicity
• M184V ?? susceptibility to TDF
• TDF nephrotoxicity?
• FTC hyperpigmentation
• K65R cross-resistance to ABC, ddI

• AZT/3TC
• Years of clinical experience
• Prevention of K65R or L74V
• Gradual and sequential emergence of TAMs
• BID dosing, 2 pills/day
• TAMs ?broad cross-resistance
• GI side effects
• Hematologic toxicity
• Mitochondrial toxicity

• ABC/3TC
• Well tolerated
• 1 QD no food restrictions
• L74VgtK65R no TDF cross-resistance
• Better CD4 response than AZT/3TC
• ABC HSR, with potential confusion when combined
  with NNRTI
• More patient education required
• Failure with M184V? ? susceptibility
  ABC 3TC

39
Initiating Antiretroviral Therapy Never use
these combinations

• As components of a regimen
• ddI/d4T (toxicity)
• d4T/AZT (compete for activation)
• FTC/3TC (same drug)
• Efavirenz if pregnant or potentially pregnant
  (category D)
• Nevirapine women with CD4 gt 250 or men with CD4
  gt 400
• As a regimen
• Mono, dual
• ddI/TDF NNRTI

40
(No Transcript)
41
Poor adherence is the main cause of treatment
failure
42
When to Switch from 1st Line to 2nd Line ARV
Regimens for Treatment Failure
Clinical failure is defined as a occurrence of
new or recurrent WHO clinical stage 3 or 4 event
(excluding IRIS). CD4 failure is defined as a
fall to (or below) the pre-treatment baseline or
a 50 drop from the on-treatment peak level or
persistent levels lt 100 cells/mm3. Virological
failure is provisionally defined as a plasma
HIV-1 RNA level gt10,000 copies/ml after a minimum
of 6 months on therapy.
43
Treatment Failure and Drug Resistance in
Resource Limited Settings
Virologic failure
Immunologic failure
Clinical failure
CD4 Count
Drug Resistance
Viral Load
CARE5. Kumarasamy P Salif Sow 2008
44
Anti-retroviral TherapyPI based

• Advantages
• Effective
• Higher genetic barrier to resistance
• Defer NNRTIs

• Disadvantages
• Toxicities
• Pill number
• Cross resistance
• Drug interactions

45
Second line ARV drugs in adults and adolescents
(WHO 2006)
Standard second-line option if NRTI/NNRTI
approach were used in first-line therapy
PI/r
ddI or TDF
EFV or NVP
NRTI sparing option if the triple NRTI approach
were used in first-line therapy
ABC or 3TC (AZT)
Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r,
LPV/r and SQV/r) are considered as the key
component in second-line regimens and its use
should be reserved for this situation. LPV/r is
the only PI currently available as a FDC and a
new formulation that doesn't need refrigeration
was recently launched. In the absence of a cold
chain and where the new LPV/r formulation is not
available, NFV can be employed as the PI
component but it is considered less potent than a
RTV-boosted PI. The use of 3TC (AZT) are
listed for strategic use as resistance to both
drugs is predicted to be present following
failure on the respective first-line regimen
listed. 3TC will maintain the M184V mutation
which may potentially decrease viral replicative
capacity as well as induce some degree of viral
resensitization to AZT or TDF AZT may prevent or
delay the emergence of the K65R mutation.
However, it must be stressed that the clinical
efficacy of this strategy in this situation has
not been proven.
46
Current Status of 2nd Line ART in Resources
Limited Settings

• Limited availability
• Switching often not done or done late
• Incomplete formularies limit options
• Often used without supporting CD4 and VL data
• Regimens more complex than current 1st line
• Lack of pediatric formulations
• High cost relative to 1st line
• PI drug interactions, especially with rifampicin
• Whats next after 2nd line fails?

Hammer, S
47
Treatment Failurein Resource Limited Settings

• Lack of widespread availability of CD4 and VL
  testing implies that completeness of response to
  any line of therapy may not be fully assessed and
  treatment failure will be picked up later
• Greater degree of drug resistance will occur

• Goal of therapy should remain maximal virologic
  suppression

48
HAART Not Without Complications
Dyslipidemia / CHD
Hepatic toxicity
Adherence
Gastrointestinal
Resistance
Lipodystrophy
49
Estimated number of people receiving
antiretroviral therapy December 2006
72 still excluded
50
What about 3rd line treatment?...