Treatment Failure, Resistance, and 2 nd line ART in Resource-Limited Settings

Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series

Treatment Failure, Resistance, and 2nd line ART in Resource-Limited Settings

Chris Behrens, MD May 2009

Detecting and Managing Treatment Failure in the absence of virologic monitoring

While access to CD4 testing has expanded considerably in recent years, access to routine viral load testing remains scarce in resource-limited settings

Clinicians are therefore obliged to monitor patients on HAART using only clinical & immunologic criteria to detect treatment failure

How well does this approach work?

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Time-Sensitivity of different failure definitions for detecting Tx Failure

Tx Failure

Virologic detection

Immunologic detection

Clinical detection

Time

Viral LoadClinical Status

CD4 Count

Case 1

33 yo male on HAART after being diagnosed with pulmonary TB, CD4 = 220

Now has completed TB therapy, doing well on HAART with rise in CD4 count

You do not have access to viral load monitoring, hence for this (and all your other patients) you rely on WHO clinical and immunological (CD4) criteria to detect treatment failure

How sensitive is this screening method for detecting treatment failure?

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How likely is it that your patients are failing therapy, but failure is not being detected?

Case 2

27 yo female on HAART for past year, seen for routine follow-up

Initial CD4 count 180, WHO Stage III

Reports excellent adherence. Feeling well. PE unremarkable

CD4 counts:

How should you manage this patient?

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Pre-HAART 180

3 months 220

7 months 250

12 months 180

How likely is it that this patient is truly failing treatment?

Case 3

41 yo female on AZT/3TC/NVP for two years, seen for routine follow-up


Reports excellent adherence. Feeling well. PE unremarkable, but CD4 counts are falling

Your national guidelines recommend a switch to 2nd line ART

What 2nd line regimen would be most appropriate?

How likely is it that she will respond to the 2nd line HAART regimen?

6What is the most effective 2nd line ART regimen patients like her?How well do 2nd line regimens work in this scenario?

How useful is it to detect treatment failure based on immunologic & clinical criteria?

1. How accurately does this strategy detect patients who are truly failing therapy?

2. What are the resistance profiles in patients whose failure is detected by immunologic/clinical criteria?

3. What options do these patients have for 2nd line ART?

4. How effective is empirically-designed 2nd line ART for these patients?

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Some Key Definitions 1st line regimen: “the initial regimen prescribed for a

naïve patient when the patient fulfills national clinical and laboratory criteria to start ART.”

2nd line regimen: “the next regimen used in sequence immediately after first-line therapy has failed”

Treatment failure: “the loss of antiretroviral efficacy [that] triggers the switch of the entire regimen from first to second line”

Note: single substitutions of ARVs (usually within the same class) for toxicity, drug-drug interactions, or intolerance to not indicate a 2nd line regimen is being used.

WHO: Prioritizing Second Line ART within a Public Health Approach, 2007

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Key Definitions, continued

Treatment Failure: “loss of antiretroviral (ARV) efficacy, prompting a

switch of the entire regimen from first- to second-line.” - WHO, 2007

“absence of a sustained favourable response to antiretroviral therapy” - 2007 Caribbean Guidelines

How do we recognize Treatment Failure?

Clinical Failure

Immunologic Failure

Virologic Failure

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Detecting Treatment FailureClinical, CD4 Cell Count, and Virological Definitions of Treatment Failure

for Patients on a First-Line Antiretroviral Regimen

Clinical failure a Occurrence of new or recurrent WHO stage 4 condition b c

CD4 cell failure d Fall of CD4 count to pre-therapy baseline (or below) or 50% fall from the on-treatment peak value (if known) or Persistent CD4 levels < 100 cells/mm3 e

Virological failure Plasma viral load >10,000 copies/ml f

a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)b. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of

treatment failure, and thus not require consideration of second-line therapy; c. Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis,

recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy;

d. Without concomitant infection to cause transient CD4 cell decrease.e. Some experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on ART may be more

appropriate.f. The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000

copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline.

Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)



2. What are the resistance profiles in patients whose failure is detected by immunologic/clinical criteria?



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Case 1

33 yo male on HAART after being diagnosed with pulmonary TB, CD4 = 220

Now has completed TB therapy, doing well on HAART with rise in CD4 count

You do not have access to viral load monitoring, hence for this (and all your other patients) you rely on WHO clinical and immunological (CD4) criteria to detect treatment failure

How sensitive is this screening method for detecting treatment failure?

12

How likely is it that your patients are failing therapy, but failure is not being picked up by checking CD4 counts?

Performance of WHO Clinical & Immunologic Criteria in detecting Virologic Treatment failure

Study Site Sensitivity Specificy

Thailand1 20%

South Africa2 21%

Uganda3 14 – 23%

without confirmatory CD4 testing 23%

with confirmatory CD4 testing 14%

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1. Int J Infect Dis 2007; 11:413–416.2. AIDS 2008; 22:1971–1977.3. AIDS 2009, 23:697–700

Case 2

27 yo female on HAART for past year, seen for routine follow-up


Reports excellent adherence. Feeling well. PE unremarkable

CD4 counts:

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Pre-HAART 180

3 months 220

7 months 250

12 months 180

27 yo woman on HAART for one year, CD4 back to baseline of 180, clinically stable How would you classify and manage this

patient?

A. This likely represents treatment failure: switch to 2nd line ART

B. This might be treatment failure; repeat CD4 count and switch to 2nd line regimen if CD4 remains 180 or below;

C. Continue therapy without change since this does not likely represent treatment failure

15How likely is it that this patient is truly failing treatment?

Performance of WHO Clinical & Immunologic Criteria in detecting Virologic Treatment failure

Study Site Sensitivity Specificy

Thailand1 20% 86%

South Africa2 21% 96%

Uganda3 14 – 23% 90 – 95%

without confirmatory CD4 testing 23% 90%

with confirmatory CD4 testing 14% 95%

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1. Int J Infect Dis 2007; 11:413–416.2. AIDS 2008; 22:1971–1977.3. AIDS 2009, 23:697–700

How useful is it to detect treatment failure based on immunologic criteria?

1. How accurately do immunologic criteria detect patients who are truly failing 1st-line therapy?

2. What are the resistance profiles in patients whose treatment failure is detected by immunologic criteria?



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Resistance profile of patients failing First Line ART in Malawi when using Clinical and Immunologic Monitoring Clinical ART failure

New WHO Stage IV condition

Progressive WHO Stage IV condition

Immunological ART failure

> 50% Decline from peak or below pre-treatment value

ART failure confirmed with HIV-RNA > 400 copies/ml

Resistance test if viral load >1000 copies ml

Genotypic analysis (TruGene)

Phenotype (Monogram) for complex genotypes

1817th IAC, Mexico City 2008, Abstract TUAB0105

Malawi: resistance patterns in patients failing first line ART On d4T/3TC/NVP or alternative first line (ZDV for d4T

toxicity, EFV for NVP toxicity)

Enrollment from Dec 2005 to Jun 2007

96 patients identified as ART Failure with VL>1000 copies

16 clinical (WHO Stage IV), 87 Immunological (CD4 decline)

66 on d4T/3TC/NVP, 30 on ZDV/3TC/NVP

2 samples did not amplify => 94 samples for analysis


Common Mutations

M184V or M184I 81%

NNRTI mutations 93%

Median 2 (range 0-3)

181C 55%, 190A 30%, 103N 28%

Wild Type Virus 5%

M184 only 0%

NNRTI mutations only 2%

M184V & NNRTI mutations only 16%


Resistance Patterns%

NNRTI mutations +/-184V containing virus + additional mutations

Thymidine Analogue Mutation (TAM) - Containing Virus 56%

Tenofovir mutations (K65R or K70E) 23%

Tenofovir & TAM 7%

Q151M Complex 19%

Pan-Nucleoside Mutation Combinations

Q151M Complex & Tenofovir mutations 16%

69 insertion 1%

Pan-Nucleoside

(Q151 & TDF associated mutations or 69 insertion)

17%

Thymidine Analogue Mutations (TAMs)

TAM Percentage

T215Y 73%

D67N 53%

K70R 36%

M41L 36%

K219Q/E 23%

L210W 23%

56% of patient samples had TAMs

28% with one

28% with 2

44% with 3 or more


Multivariate analysisemergence K65R or K70E resistance

OR 95% CI

CD4 count <100 cells/ml 6.1 1.47 – 25.0

Use of AZT 0.18 0.04-0.94


Multivariate analysisemergence PAN-NRTI resistance

OR 95% CI

CD4 count <100 cells/ml 9.8 1.16 – 82.9

Use of AZT 0.12 0.014 – 0.978


TAM Pathways

Pathway I: 41L, 210W, 215Y

Associated with d4T use

Confers high-level AZT resistance and cross-resistance to other NRTIs, esp ddI and tenofovir

Pathway II: 70R, 67N, 215F, 219Q/E

Associated with AZT use

leads to less NRTI cross-resistance

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Implications

High level resistance to 3TC/FTC and to NNRTIs very common in patients who fail 1st line therapy

2nd line regimen will need to be ‘anchored’ by a ritonavir-boosted PI

Challenge is to design a useful 2nd line NRTI backbone to complement the r/PI

Use of AZT rather than d4T in first line ART regimen better preserves 2nd line NRTI options

AZT prevents emergence of mutations associated with TDF resistance (K65R, K70E), which d4T can select for especially in HIV subtype C strains

Resistance to AZT associated with TAM II pathway, which confers less pan-NRTI resistance

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2. What are the resistance profiles in these patients?



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Detailed recommendations for switching to Second line ARV regimens in adults and adolescents

First Line Regimen

Second Line Regimen

RTI Component PI Component b

Standard Strategy

(AZT or d4T) + 3TC a + (NVP or EFV)ddI + ABC orTDF + ABC orTDF + 3TC (± AZT) c

PI/r dTDF + 3TC a + (NVP or EFV)

ddI + ABC orddI + 3TC (± AZT) c

ABC + 3TC a + (NVP or EFV)ddI + 3TC (± AZT) c orTDF + 3TC (± AZT) c

Alternative Strategy

(AZT or d4T) + 3TC a + (TDF or ABC) (EFV or NVP) ± ddI

a 3TC and FTC are considered interchangeable because they are structurally related and share pharmacological properties and resistance profile.b NFV does not need refrigeration and can be used as a PI alternative in places without cold chain.c 3TC can be considered to be maintained in second line regimens to potentially reduce the viral fitness, confer residual activity and maintain pressure on the M184V mutation to improve viral sensitivity to AZT or TDF. AZT may prevent or delay the emergence of K65R mutation.d There are insufficient data to detect differences among available RTV-boosted PIs (ATV/ r, FPV/r, IDV/r , LPV/r and SQV/r ) and the choice should be based on individual program priorities (see text). In the absence of a cold chain, NFV can be employed as the PI component but it is considered less potent than a RTV-boosted PI.


ART backbone- 2 fully active NRTIs

Drug Combination PhenotypedSamples (n=70)

Total Sample

(n=94)

Emtricitibine/Tenofovir 3% 2%

Abacavir/Didanosine 1% 1%

Zidovudine/Lamivudine/Tenofovir 29% 21%


ART backbone- No fully active NRTIs

Drug Combination PhenotypedSamples (n=70)

Total Sample

(n=94)

Emtricitibine/Tenofovir 39% 29%

Abacavir/Didanosine 67% 50%

Zidovudine/Lamivudine/Tenofovir 30% 22%


2nd line ART options for Malawi patients failing 1st line HAART

Based on resistance analysis, most potent 2nd line regimen among WHO options is TDF + AZT + 3TC/FTC + r/PI

Highest percentage of patients with 2 fully active NRTIs

Lowest percentage of patients with no fully active NRTIs


Synergy of TDF and AZT in 2nd line regimens for patients failing typical 1st line regimen

Unless HIV has evolved multiple TAMs before switch to 2nd line regimen, the virus will likely be at least partially sensitive to both AZT and TDF

Combining AZT and TDF in the 2nd line regimen makes it very difficult for HIV to evolve resistance to both agents simultaneously K65R mutation reverses TAM-mediated AZT resistance*

Only option for HIV would be to evolve more TAMs, which is difficult with TDF and an active PI in the regimen

This strategy may not work, however, for patients in whom failure is detected relatively late, as multiple TAMs impart high-level resistance to AZT and TDF (as well as d4T, ddI, and ABC) * Antivir Ther. 2006;11(2):155-63

Retain 3TC/FTC in 2nd line regimens?

The M184V mutation ‘hobbles’ HIV in two important ways:

Reduced replication capacity (approximately 1/2 log) - virus is less ‘fit’

Partially reverses TAM-induced resistance to AZT, d4T, and TDF

Keeping 3TC (or FTC) in the 2nd line regimen forces HIV to maintain this inconvenient M184V mutation

3TC (as well as FTC) is relatively well-tolerated, can be dosed once-daily, is present in many FDCs

Clinical outcomes data from a RCT suggests benefit of keeping 3TC in ‘salvage’ regimens*

*Castagna A et al. E-184V study. Third IAS Conference, abstract WeFo0204, 2005.



2. What are the resistance profiles in these patients?


4. How effective are empirically-designed 2nd line ART regimens for these patients?

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2nd line ART Responses: Malawi 101 patients switched to 2nd line ART on the

basis of WHO clinical/immunological criteria for failure

2nd line ART regimen: AZT/3TC/TDF/r-LPV

12 months of follow-up:

10 patients died;

3 lost to follow-up;

85% of remaining had VL < 400 at 12 months

Resistance patterns in these patients did not predict response!

3516th CROI, Montreal, 2009, abstract 605

2nd line ART Responses: South Africa

N = 382 patients from Themba Luthu clinic (Johannesburg) switched to 2nd line ART regimen of AZT/ddI/r-LPV

89% of patients alive and in care one year after switch

78% had undetectable viral load

No data on response according to resistance profile

3616th CROI, Montreal, 2009, Abstract 606

2nd line ART Responses: Cambodia

N = 113 patients switched to 2nd line HAART regimen of ddI/3TC/r-LPV

89% of patients had undetectable viral load a median of 10 months later

No data on response according to resistance profile

3714th CROI, Los Angeles, 2007, abstract 36LB

Favorable responses to 2nd line ART – but will it last?

Country 2nd line NRTIs (+ r-LPV)

# of patients

Length of f/u Virologic response

Malawi AZT/TDF/3TC 101 12 months 75%

South Africa AZT/ddI 382 12 months 78%

Cambodia ddI/3TC 113 10 months 89%

Success of 2nd line ART in these settings may mostly reflect potency of r-LPV

Several studies suggest high efficacy of r-LPV monotherapy in patients who are naïve to ART or well-controlled on HAART

MONARK*: r-LPV monotherapy not as potent as traditional HAART in non-clade B HIV subtypes

38*11th European AIDS Conference, Madrid 2007, abstract PS1/2

Broader access to viral load testing for routine monitoring?

Pros: Would allow for earlier detection of treatment failure & earlier switch to 2nd line

Avoid immunologic/clinical decline;

Minimize evolution of NRTI resistance

Eliminate unnecessary/premature regimen switches

Rakai, Uganda*: almost as many people were being switched unnecessarily as were being missed treatment failure; would have cost an estimated extra $75,000/year in 2nd line drugs

Cons: cost, laboratory infrastructure, turn-around time: point-of-care technology needed!

39*16th CROI, Montreal 2009, abstract 144

Remaining Questions

Should 1st line HAART regimens in RLS use TDF instead of AZT or d4T?

Advantages:

well-tolerated, convenient dosing

Activity of AZT likely in patients who fail TDF*

Disadvantages:

Cost

K65R with failure of TDF-based regimen => compromised efficacy of ABC, ddI for future use

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*Landman R et al. Successful rescue therapy in patients developing K65Ron tenofovir-containing regimens: long-term follow-up. Twelfth Conference onRetroviruses and Opportunistic Infections, Boston, abstract 710, 2005b

Remaining Questions

Should 1st line HAART regimens include both TDF and AZT?

Advantages:

Improved durability: HIV has difficulty evolving resistance simultaneously to both drugs

Disadvantages:

Cost

Toxicity

Failure (though rare) could leave very few 2nd line options

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Remaining Questions

When will newer agents become available in resource-limited settings?

Etravirine: new NNRTI active against most strains of HIV that have evolved resistance to EFV, NVP

Darunavir: new PI active against most strains otherwise resistant to PIs

Raltegravir: integrase inhibitor

Maraviroc: CCR5 Inhibitor

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Extra slides

N Engl J Med, Vol. 344, No. 7 ·

February 15, 2001

ABC or 3TC (±AZT)#

ddI or TDF

EFV or NVPNRTI sparing option if the triple NRTI approach were used in first-line therapy

Standard second-line option if NRTI/NNRTI approach were used in first-line therapy

Second line ARV drugs in adults and adolescents

PI/r*

* 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.

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Clinical staging events to guide decision-making on ART switching

New or recurrent event on ART a Recommendations Additional management options

Asymptomatic(T1)

Do not switch regimen

• Maintain scheduled follow up visits including CD4 monitoring (if available) • Continue to offer adherence support

Stage 2 event(T2 )

Do not switch regimen b

Treat and manage staging eventAssess and offer adherence support • Check if on treatment at least 6 months • Assess continuation or reintroduction of OI prophylaxis • Schedule earlier visit for clinical review and consider CD4 (if available) c

Stage 3 event(T3)

Consider switchingregimen b d

Treat and manage staging event and monitor responseAssess and offer adherence support

• Check if on treatment at least 6 months • Check CD4 cell count (if available) c d

• Assess continuation or reintroduction of OI prophylaxis• Institute more frequent follow up

Stage 4 event(T4)

Switch regimen b e

Treat and manage staging event and monitor responseCheck if on treatment at least 6 months

• Assess continuation or reintroduction of OI prophylaxis• Check CD4 cell count (if available) c

• Assess and offer adherence support

a. Clinical stages refer to the clinical stage while on ART for at least 6 months (termed T1, T2, T3, T4)b. Differentiation of opportunistic infections from immune reconstitution syndrome is necessary.c. Treat and manage the staging event before measuring CD4 cell count.d. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not

require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need for switching of therapy.e. Some stage 4 conditions (simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may

not be an indicator of treatment failure and thus not require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need to switch of therapy.


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Detecting Treatment FailureClinical, CD4 Cell Count, and Virological Definitions of Treatment Failure

for Patients on a First-Line Antiretroviral Regimen

Clinical failure a Occurrence of new or recurrent WHO stage 4 condition b c

CD4 cell failure d Fall of CD4 count to pre-therapy baseline (or below) or 50% fall from the on-treatment peak value (if known) or Persistent CD4 levels < 100 cells/mm3 e

Virological failure Plasma viral load >10,000 copies/ml f

a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)b. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of

treatment failure, and thus not require consideration of second-line therapy; c. Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis,

recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy;

d. Without concomitant infection to cause transient CD4 cell decrease.e. Some experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on ART may be more

appropriate.f. The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000

copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline.


WHO Clinical Staging

Clinical Failure(CD4 and VL not

available)

Immunologic Failure

(VL not available)

Immunologic and Virologic

Failure(CD4 and VL available)

1 N/A Do Not Switch Consider

Switch

2 N/A Do Not Switch Consider Switch

3Consider Switch

Switch Switch

4Switch Switch Switch

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 < 100 cells/mm3.

Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.


2006 WHO guidelines Immunologic Failure if:

the CD4 cell count falls below baseline in the absence of other concurrent infections,

the CD4 cell count falls to less than 50% of peak levels without coexistent infections, or

the CD4 cell count is consistently below 100 cells/ml.

For either of the first two criteria, switching therapy NOT recommended for asymptomatic patients if the CD4 cell count remains above 200 cells/ml.

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Performance of WHO Immunologic Failure Criteria – Rakai, Uganda

N =1133 participants enrolled in antiretroviral treatment program between June 2004 and September 2007, median follow-up 20.2 months

WHO immunologic failure criteria were reached by 125 (11.0%) participants.

virologic failure* reached by 112 participants (9.9%).

Only 26 participants (2.3%) experienced both an immunologic and virologic failure endpoint (2 viral load>400 copies/ml) during follow-up.

50* defined as HIV-1 viral load more than 400 copies/ml on two measurements

AIDS 2009, 23:697–700

Thank you!

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Next session: 21 May, 2009Listserv: [email protected]

Email: [email protected]

Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series

52

Next session: 21 May, 2009Robert Harrington, MD

Opportunistic Infections, Part 2

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Treatment Failure, Resistance, and 2 nd line ART in Resource-Limited Settings