Acute Infection: Pregnant Patients and Risk of Vertical Transmission

1
Acute Infection Pregnant Patients and Risk of
Vertical Transmission

• Transmission risk correlates with maternal HIV-1
  RNA level (P lt .001)
• Treatment should be considered to decrease
  mother-to-fetus transmission of virus

Garcia PM, et al. N Engl J Med. 1999341394-402.
2
When to Start Therapy

• What are the special considerations for
  initiating therapy in a patient who presents with
  a very low CD4 cell count and/or an acute
  AIDS-defining condition?

3
ACTG A5164 Immediate vs Deferred ART in Patients
With Acute OIs
Stratified by CD4 cell count lt or ? 50
cells/mm3, PCP, BI, or other OI
Immediate ART(initiation within 48 hours of
randomization and within 14 days of starting OI
treatment) (n 141)
HIV-infected patients receiving treatment for
presumed or confirmed acute OI/BI (N 282)
48 weeks
Deferred ART(initiation between Weeks 4 and
32) (n 141)
48 weeks
Patients with TB excluded.
Zolopa A, et al. CROI 2008. Abstract 142.
4
ACTG A5164 Improved Outcomes With Immediate ART
During Acute OI

• Median duration from start of OI treatment to
  initiation of HAART
• Immediate group 12 days
• Deferred group 45 days
• No significant difference between groups in
  composite primary endpoint (virologic response,
  clinical progression, and death P .215)
• Immediate treatment associated with significant
  reduction in clinical progression or death
  through Week 48 vs deferred treatment (P .035)
• 14.2 vs 24.1, respectively OR 0.51 (99 CI
  0.23-1.15)
• Week 48 virologic outcomes similar between groups
• Safety and incidence of immune reconstitution
  events similar between groups
• 62 of patients presented with PCP potential
  impact of steroids?

Zolopa A, et al. CROI 2008. Abstract 142.
5
SAPIT Optimal Timing of ART Relative to TB
Treatment in Coinfected Patients
Integrated TreatmentEarly initiate within first
2 months of starting TB treatment Late initiate
as soon as possible after 2 months of intensive
TB treatment phase completed (n 431)
HIV-infected patients with smear-positive TB (N
645)
18 months
Sequential TreatmentInitiate as soon as possible
after completing TB treatment (n 214)
ART once-daily ddI/3TC EFV

• Safety monitoring committee discontinued
  sequential treatment arm in September 2008 due to
  55 lower mortality in integrated vs sequential
  treatment arms (5.1 vs 11.6 deaths per 100
  patient-years P .0049)

Caprisa Web site. Available at
http//www.caprisa.org/joomla/index.php/memberacce
ss/95-pressrelease17092008. Accessed January 7,
2009.
6
Indications for Initiation of ART in Patients
with TB/HIV Co-Infection
7
Early ART Decreases Survival in HIV Patients
With Cryptococcal Meningitis

• HIV-infected African patients diagnosed with
  cryptococcal meningitis randomized to receive 10
  wks of fluconazole 800 mg QD ART (n 26) or
  fluconazole alone (n 28)
• After 10 wks, all patients received fluconazole
  200 mg QD ART

1.00
Delayed ART
0.75
Early ART
Survival
0.50
0.25
P .028
0.00
0
600
800
200
400
Time to Death (in Days)

• After 2 yrs of follow-up 23 deaths in early ART
  group (87 mortality rate) vs 9 deaths in delayed
  ART group (37 mortality rate) (P .002)
• Median survival, early ART vs delayed ART 35 vs
  274 days (P .028)

Makadzange AT, et al. CROI 2009. Abstract 36cLB.
Graphic reproduced with permission.
8
Timing of Initiation of HAART after Rx of OI

• Depend on - type of pathogen - organ
  system involvement (CNS vs Extra-CNS)
• PCP start HAART as soon as possible
• TB - Pulmonary 2 months after
  TB Rx - Extrapulmonary no data
• Cryptococcosis defer gt abrupt ??
  especially cryptomeningitis

9
Choosing Initial Antiretroviral Regimens

• Which antiretroviral agents are recommended for
  use in initial therapy?

10
Major Targets of Antiretroviral Agents
Protease Inhibitors SQV,RTV, IDV, NFV, AMV,
LPV/rtv, TPV, DRV
RT Inhibitors NRTI AZT, ddI, ddC, d4T, 3TC,
ABC NNRTI NVP, DLV, EFV, ETV NTRTI Tenofovir

Integrase Inhibitors RAL
6
ds DNA
Integrase
Genomic RNA
vpr
Protease
HIV
5
DNA
3
Proviral DNA
2
RT
1
Transcription
4
RNA
mRNA
Polyprotein Protein
Spliced mRNA
Entry Inhibitors CXCR4 AMD3100, T22 CCR5 MVC,
SCH-C, D TAK779 Fusion
gp41 T20
ETV Etravirine (Intelence ?) MVC Maraviroc
(Selzentry ?) RAL Raltegravir (Isentress?)
11
FDA-Approved Antiretroviral Drugs June
2005 (21 ARVs)
12
Timeline of ARV Development
DLV
RAL
NVP
TDF
ddC
ABC
d4T
ETV
ZDV
ddI
EFV
FTC
3TC
93
05
04
87
91
92
94
95
96
97
98
99
00
88
89
90
01
02
03
06
07
08
NFV
SQR
LPV/r
ATV
NRTI
NNRTI
DRV
FPV
APV
TPV
PI
RTV
Entry inhibitor
T-20
MVC
IDV
Integrase inhibitor
25 unique ARV agents, at
the first year of FDA approval
13
2009
25ARVs AVAILABLE
14
2008 Recommended Regimens for Treatment-Naive
Patients DHHS

• NNRTI 2 NRTIs or boosted PI 2 NRTIs

Except during first trimester of pregnancy or in
women with high pregnancy potential. Use caution
in patients with unstable psychiatric disease.
Or 3TC. Only in women with CD4 cell count lt
250 cells/mm3 or in men with CD4 cell count lt
400 cells/mm3. Use only if HLA-B5701 negative.
Use with caution in patients with cardiovascular
risk or HIV-1 RNA gt 100,000 copies/mL.
DHHS guidelines. Available at http//www.aidsinfo
.nih.gov. Accessed January 12, 2009.
15
2008 Recommended Regimens for Treatment-Naive
Patients IAS-USA

• NNRTI 2 NRTIs OR boosted PI 2 NRTIs

Except during first trimester of pregnancy or in
women with high pregnancy potential. Use caution
in patients with unstable psychiatric disease.
Use only if HLA-B5701 negative. Use with caution
in patients with cardiovascular risk or HIV-1 RNA
gt 100,000 copies/mL Only in women with CD4 cell
count lt 250 cells/mm3 or in men with CD4 cell
count lt 400 cells/mm3.
Hammer SM, et al. JAMA. 2008300555-570.
16
Components of Initial ART
DHHS Categories

• Preferred
• Clinical data show optimal efficacy and
  durability
• Acceptable tolerability and ease of use
• Alternative
• Clinical trial data show efficacy but also show
  disadvantages in ARV activity, durability,
  tolerability, or ease of use (compared with
  preferred components)
• May be the best option in select individual
  patients
• Other possible options
• Inferior efficacy or greater or more serious
  toxicities

17
Recommended Preferred or Alternative Regimens for
Initial ART TAS Guidelines 2008
18
ARVs Not Recommended in Initial
Treatment (1)
19
ARVs Not Recommended in
Initial Treatment (2)
20
ARV Medications
Should Not Be Offered at Any Time (1)

• ARV regimens not recommended
• Inferior virologic efficacy, rapid development of
  resistance
• Monotherapy with NRTI
• Dual-NRTI therapy
• 3-NRTI regimen (except ABC/3TC/ZDV or
  possiblyTDF 3TC ZDV, when other regimens are
  not desirable)

For pregnant women, see Public Health Service
Task Force Recommendations for the Use of
Antiretroviral Drugs in Pregnant HIV-Infected
Women for Maternal Health and Interventions to
Reduce Perinatal HIV Transmission in the United
States
21
ARV Medications
Should Not Be Offered at Any Time (2)
Women who are trying to conceive or who are not
using effectiveand consistent contraception.
22
ARV Medications
Should Not Be Offered at Any Time (3)
23
Choosing Initial Antiretroviral Regimens

• Which groups of patients are more suited to an
  NNRTI-based rather than a PI-based regimen and
  vice versa?

24
ACTG 5142 EFV vs LPV/RTV
Stratified by HIV-1 RNA lt or 100,000
copies/mL, presence or absence of chronic
hepatitis infection (B, C, or both), and NRTI
selection
Week 96
EFV 600 mg QD 2 NRTIs (n 250)
Antiretroviral-naive HIV-infected patients with
HIV-1 RNA 2000 copies/mL (N 753)
LPV/RTV 400/100 mg BID 2 NRTIs (n 253)
EFV 600 mg QD LPV/RTV 533/133 mg BID (n 250)
NRTIs 3TC 150 mg BID or 300 mg QD plus either
ZDV 300 mg BID, d4T extended release 100 mg QD
(participants lt 60 kg received 75 mg QD), or TDF
300 mg QD.
Riddler SA, et al. N Engl J Med.
20083582095-2106.
25
ACTG 5142 Time to VF

• Significantly longer time to VF for EFV plus 2
  NRTIs vs LPV/RTV plus 2 NRTIs
• No significant differences in time to VF with
  either NRTI-containing regimen vs EFV plus
  LPV/RTV
• Time to regimen failure not significantly
  different between 3 arms
• Trend toward longer time to regimen failure in
  EFV plus 2 NRTIs arm vs LPV/RTV plus 2 NRTIs arm
  (P  .03)

Riddler SA, et al. N Engl J Med.
20083582095-2106.
26
ACTG 5142 HIV-1 RNA lt 200 or lt 50 copies/mL at
Week 96

• Percentage of patients with HIV-1 RNA lt 200 or lt
  50 copies/mL at Week 96 significantly higher with
  EFV plus 2 NRTIs vs LPV/RTV plus 2 NRTIs in ITT
  analysis where switches included and missing
  values censored

P .04
P .003
100
93
92
89
86
83
EFV 2 NRTIs (n 250)
77
80
LPV/RTV 2 NRTIs (n 253)
60
EFV LPV/RTV (n 250)
Patients ()
40
20
0
lt 200 copies/mL
lt 50 copies/mL
HIV-1 RNA Levels at Week 96
Riddler SA, et al. N Engl J Med.
20083582095-2106.
27
ACTG 5142 Immunologic Response at Week 96

• All 3 arms demonstrated increased CD4 cell count
  with significantly higher increases in
  LPV/RTV-containing arms

P .01
P .01
350
287
300
273
250
230
200
Median CD4 Cell Count Increase at Week 96
(cells/mm3)
150
100
50
0
EFV 2 NRTIs (n 250)
LPV/RTV 2 NRTIs (n 253)
EFV LPV/RTV (n 250)
Riddler SA, et al. N Engl J Med.
20083582095-2106.
28
ACTG 5142 Resistance

• Incidence of any drug-resistance mutation or
  2-class resistance higher in patients with VF on
  EFV-containing regimens
• NNRTI mutations more common when failing on EFV
  LPV/RTV vs EFV 2 NRTIs

EFV LPV/RTV vs LPV/RTV NRTIs, P lt .001 EFV
NRTIs vs LPV/RTV NRTIs, P .002. LPV/RTV
NRTIs vs EFV NRTIs or EFV LPV/RTV, P lt .001.
LPV/RTV NRTIs vs EFV NRTIs, P lt .001 EFV
NRTIs vs EFV LPV/RTV, P .01.
Riddler SA, et al. N Engl J Med.
20083582095-2106.
29
EFV vs LPV/RTV in Tx-Naive Patients With CD4 lt
200 cells/mm3
Stratified by CD4 cell count gt and lt 100
cells/mm3
Week 48
EFV 600 mg QD ZDV/3TC (n 95)
Antiretroviral-naive, HIV-infected patients
with CD4 cell count lt 200 cells/mm3 andHIV-1
RNA 1000 copies/mL (N 189)
LPV/RTV soft-gel capsules 400/100 mg BID
ZDV/3TC (n 94)
ABC substitution for ZDV allowed.
Madero JS, et al. IAC 2008. Abstract TUAB0104.
30
EFV vs LPV/RTV HIV-1 RNA lt 50 copies/mL at Week
48

• EFV met criteria for superiority to LPV/RTV ?
  17 (CI 95 3.5 to 31.0 P .017)

100
100
P 0.012
P 0.15
70.5
79
EFV
80
80
LPV/RTV
64
60
60
57
49
HIV-1 RNA lt 50 copies/mL ()
HIV-1 RNA lt 50 copies/mL ()
53.2
40
40
EFV (n 95)
20
20
LPV/RTV (n 94)
0
0
32
8
24
40
n 42 45 53 49
0
16
48
Week
50 cell/mm3 gt 50 cell/mm3
No. of Patients With HIV-1 RNA lt 50 copies/mL
EFV 29 70 68
67
By BL CD4 Cell Count
LPV 8 53
56 50
Madero JS, et al. IAC 2008. Abstract
TUAB0104. Permission granted to CCO for use of
this graphic.
31
EFV vs LPV/RTV Resistance and Adverse Events

• Overall findings consistent with ACTG 5142
• EFV performed well in patients with very advanced
  disease
• Greater CD4 cell count increase with LPV/RTV
• Incidence of grade 2-4 adverse events similar
  between groups 62 in both arms
• Significantly greater increase in triglyceride
  levels in LPV/RTV arm at 48 weeks vs EFV (P
  .01)
• Changes in total cholesterol, HDL, and LDL
  similar between arms at Week 48
• Among the few patients genotyped at failure, EFV
  recipients more likely to have any resistance and
  2-class resistance

Madero JS, et al. IAC 2008. Abstract TUAB0104.
32
NNRTIs vs PIs
DHHS Guidelines November 2008. Available at
http//www.aidsinfo.nih.gov. Accessed January 13,
2008.
33
Choosing Initial Antiretroviral Regimens

• How much emphasis should be placed on the need to
  minimize regimen complexity when selecting
  first-line therapy?

34
Overview
FDA approved ABC/ZDV/3TC 2000
FDA approved LPV/RTV 2000
FDA approved ZDV 1987
FDA approved EFV/TDF/FTC 2006
FDA approved ZDV/3TC 1997
HIV first reported 1981
2010
2000
1990
1980
HAART ERA begins 1996
FDA approved ABC/3TC 2004
FDA approved TDF/FTC 2004
35
Fixed-Dose Combinations
Individual Agents


ZDV

ABC

TDF



FTC
EFV
TDF


LPV
36
FDA Approved Antiretroviral DrugsCombination
Drugs (5 drugs)October 2008
37
(No Transcript)
38
Monitoring
Clinical
Laboratory

• Treatment goal

• Maximal and durable suppression of HIV-RNA
• Restore CD4 number and function
• Reduce inflammation and immune activation
• Normalize survival
• Improve QOL
• Prevention of transmission

Efficacy
Toxicity
39
Monitoring

• Clinical monitoring
• Adherence assurance/assessment
• Immunological monitoring
• Virological monitoring
• Drug resistant testing
• Therapeutic drug monitoring

40
ART-Associated Adverse Effects

• Lactic acidosis/hepatic steatosis
• Hepatotoxicity
• Insulin resistance, diabetes mellitus
• Fat maldistribution
• Hyperlipidemia
• Increased bleeding in hemophiliacs
• Osteonecrosis, osteopenia, osteoporosis
• Rash

41
Adherence

• High adherence rates associated with virologic
  suppression, low rates of resistance, and
  improved survival
• Important to assess readiness for ART prior to
  initiating therapy, and to assess adherence at
  each clinic visit
• Suboptimal adherence is common

42
Monitoring CD4
Adapt from DHHS Guideline
43
Monitoring Viral Load
DHHS Department of Health and Human Services,
IAS International AIDS society
44
Treatment Failure

• Virologic failure
• HIV RNA gt400 copies/mL after 24 wks or
• gt50 copies/mL after 48 wks or
• gt400 copies/mL after viral suppression
• Immunologic failure
• Increase lt25-50 cells/µL in first year of therapy
  or
• Decline in CD4 count to below baseline
• Clinical progression
• Occurrence of HIV-related events (after gt3 months
  on therapy excludes immune reconstitution
  syndromes)

45
Treatment-Experienced Patients ART Failure

• Causes of treatment failure include
• Patient factors
  (eg, CD4 nadir,
  pretreatment HIV RNA, co-morbidities)
• Drug resistance
• Suboptimal adherence
• ARV toxicity and intolerance
• Pharmacokinetic problems
• Suboptimal drug potency

46
Treatment Regimen Failure Assessment

• Review antiretroviral history
• Physical exam for signs of clinical progression
• Assess adherence, tolerability, pharmacokinetic
  issues
• Resistance testing (while patient is on therapy
  or recent cessation within 4 weeks)
• Identify treatment options

47
Treatment-Experienced Patients Virologic Failure

• Incomplete virologic response
• In patient on initial ART, HIV RNAgt400 copies/mL
  after 24 weeks on therapy or gt50 copies/mL
  by 48 weeks(confirm with second test)
• Virologic rebound
• Repeated detection of HIV RNA after virologic
  suppression (eg, gt50 copies/mL)

48
Treatment-Experienced Patients Virologic Failure

• Assess drug resistance
• Drug resistance test
• Prior treatment history
• Prior resistance test results
• Drug resistance usually is cumulative consider
  all previous treatment history and test results

49
Treatment-Experienced Patients Virologic Failure

• Management
• Clarify goals aim to reestablish maximal
  virologic suppression (eg, lt50 copies/ML)
• Evaluate remaining ARV options
• Newer agents have expanded treatment options
• Base ARV selection on medication history,
  resistance testing, expected tolerability,
  adherence, and future treatment options
• Avoid treatment interruption, which may cause
  viral rebound, immune decompensation,
  clinicalprogression

50
Virologic Failure Changing an ARV
Regimen

• General principles
• Add at least 2 (preferably 3) fully active agents
  to an optimized background ARV regimen
• Determined by ARV history and resistance testing
• Consider potent RTV-boosted PIs, drugs with new
  mechanisms of action (eg, fusion inhibitor, CCR5
  inhibitor, integrase inhibitor, 2nd generation
  NNRTI) optimized ARV background
• In general, 1 active drug should not be added to
  a failing regimen (drug resistance is likely to
  develop quickly)
• Consult with experts