DIAGNOSING & MANAGEMENT OF

TREATMENT FAILURE
CASE STUDY

• Mr. G started ARVs 2 years ago after he suffered

from cryptococcal meningitis
• Regimen: TDF,3TC and EFV
• Clinically, he was doing well until 2 months ago
when he noticed a weight loss and increasing
severe fatigue
• Physical exam: nothing abnormal
• CD4 at baseline 45/mm3 → increased to 310/mm3,
currently 80/mm3
• What are possible differential diagnoses?
CASE CONTINUED: DIFFERENTIAL
DIAGNOSES

• Immunological and possibly clinical failure

• Virological failure
• Incident opportunistic infection (pTb, epTb)
• Lymphoma

What will you do next?

CASE CONTINUED

Laboratory tests:
• FBC: Hb 8, Lc 1.8, Tc 120
• CD4 80/mm3
• LFT’s 2 x UNL
• Viral load <20 copies/ml
• Abdominal ultrasound: enlarged lymph nodes,
no ascites, spleen and liver within normal limits
CASE CONTINUED

• Diagnosis:
– Immunological failure but viral suppression
– Probably lymphoma or abdominal TB

• Plan:
– Arrange for a lymph node biopsy
 Viral evolution: NO YES YES

CD4 decline: NO NO YES

Clinical progression: NO NO YES

IMMUNO-
RNA LOGICAL
FAILURE 

EVENTUALLY
VIROLOGICAL CLINICAL
FAILURE FAILURE

400 copies

50 copies

time
HOW DO WE MONITOR A PATIENT’S
PROGRESS ON ART?

• Clinically, by disease progression and WHO

staging
• Immunologically, generally by following changes
in CD4 cell counts over time
• Virologically, by measuring changes in plasma
viral load; or
• A combination of the above
WHO RECOMMENDATION FOR
DIAGNOSING TREATMENT FAILURE 2010
• Definitions apply for patients on a first-line antiretroviral
regimen (after at least six months on ART, and confirmed
good adherence)
• Clinical failure
– New or recurrent WHO stage 3 or 4 condition
– Exclude IRIS
• Immunological failure = CD4 cell failure
– 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 below 100 cells
• Virological failure
– Plasma viral load above 1’000 copies/ml
HOW SPECIFIC ARE WHO GUIDELINES
TO MONITOR TREATMENT FAILURE?
• 1133 adult patients enrolled in ART programme
in Uganda between 2004-2007, median follow
up 20.2 months
• 125 (11%) exhibited immunologic failure
according to WHO criteria
• 112 (9.9%) developed virological failure
(2x>400 copies/ml)
• But only 26 (2.3%) patients experienced both
immunological and virological failure
Reynolds et al. AIDS 2009,23:697
FAILURE OF IMMUNOLOGIC CRITERIA
TO IDENTIFY VIROLOGICAL FAILURE

IMMUNOLOGICAL VIROLOGICAL
FAILURE BOTH FAILURE
N= 125 N=26 N=112

PPV 0.21, NPV 0.91

Reynolds et al. AIDS 2009,23:697
HOW SPECIFIC ARE WHO GUIDELINES TO
MONITOR TREATMENT FAILURE IN
CHILDREN? (CAMBODIA)
• 457 children, age < 15 years, >3 years on HAART
• 92/457 (20%) had virological failure (>400 copies/ml)
• 33% of children with WHO stage I and II had
immunological failure but VL was undetectable
• 12% had no immunological failure but VL was
detectable
• 40% of children with WHO stage III and IV had
immunological failure but VL was undetectable and
• 22% had no immunological failure but VL was
detectable

Westley P. et al. CID 2012,55,432

RESISTANCE TESTING IN CHILDREN WITH
VIROLOGICAL FAILURE (CAMBODIA)

• Genotypic resistance testing was done in 51 children

with virological failure
• 50/51 had ≥ 1 NNRTI mutation
• 49/51 had ≥ 1 NRTI mutation
• Conclusions:
– Clinical and immunological failure is inadequate to
predict virological failure
– Lack of virological monitoring leads to accumulation
of broad cross resistance in 1st line regimens
(Malawi study)

Westley P. et al. CID 2012,55,432

MONITORING FOR CLINICAL FAILURE IS
INADEQUATE TO PREDICT VIROLOGICAL
FAILURE
• Clinical failure is usually a consequence of
immunological failure but can occur independently
– Tb and extrapulmonary Tb
– Malignant lymphoma
– Weight loss
– Chronic diarrhea
– Malnutrition
– Depression resulting in clinical deterioration
THE DILEMMA OF FALSE POSITIVE
AND FALSE NEGATIVE RESULTS

• “ False positives” are patients with an

undetectable viral load but with immunological
a/o clinical failure
• “False negatives” are clinically stable patients
with a detectable viral load, who will continue on
their 1st line ARV’s with subsequent
development of class resistance
CONCLUSIONS REGARDING THE UTILITY OF
IMMUNOLOGICAL AND CLINICAL MONITORING
FOR SWITCHING PATIENTS TO 2ND LINE ARV’s
• Clinical and immunological monitoring will only
identify a portion of patients who require treatment
switch and will misclassify many
• Treatment failure defined by either clinical or
immunologic markers will result in either
unnecessary regimen changes or delay of switching
• Switching patients who are not virologically failing is
a waste of resources
• Failure to identify patients who need 2nd line ARV’s
will have clinical consequences because of
emergence of cross resistance

15
DISCORDANT VIROLOGICAL AND
IMMUNOLOGICAL RESPONSE

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DISCORDANT VIROLOGICAL AND
IMMUNOLOGICAL RESPONSE
• Some patients experience slow recovery of CD4 counts
– especially if baseline CD4 are <100 cells/mm3 –
despite virological suppression
• However, the recovery of the immune system is
obvious:
– IRIS is observed in 25% with baseline CD4 <50
cells/mm3
– A rapid decrease of the incidence of new OI’s
– Disappearance of KS lesions
Persistent CD4 levels <100 cells/mm3 do not
predict immunological failure
WHAT IS THE RATE OF RECOVERY OF
CD4 AFTER STARTING ARV’s ?

ACHIEVED CD4 COUNT >500 OVER 6 YRS

85%
90%
66%
80%
70%
60% 42%
50%
40%
30%
20%
10%
0%
<200 200-350 >350 AT BASELINE
FACTORS ASSOCIATED WITH
POOR CD4 T-CELL RESPONSE
• CD4 count <200/mm3 when starting ART
• Older age
• Coinfection (e.g., hepatitis C virus)
• Persistent immune activation
• Loss of regenerative potential of the immune
system
• Malignancy and chemotherapy
ASSESSMENT OF IMMUNOLOGIC
FAILURE

• Confirm CD4 count by repeat testing

• Consider/rule out malignant lymphoma, leukemia,
cancers metastasizing to bone marrow,
tuberculosis, splenomegaly, folate deficiency
• Substitute ARV’s that can cause lymphopenia or
leukopenia: ZDV, TDF + ddI
• In many cases, no obvious cause for immunologic
failure can be identified
 ASSESS VIRAL LOAD
MANAGEMENT OF IMMUNOLOGIC
FAILURE
• Patients with CD4 counts <200 appear at greater risk of
clinical events (OI’s, organ damage)
• It is not clear if immunologic failure in the setting of
virologic suppression should prompt a change in the
ARV regimen: In Zimbabwe we do not!!
• Ongoing immune activation occurs in some patients
with suppressed HIV RNA levels, but adding or
changing ARV’s to an existing regimen does not result
in clear virologic or immunologic benefits
• No consensus exists on when or how to treat
immunologic failure
MONITORING TREATMENT SUCCESS
OF ART

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CLINICAL RELEVANCE OF VIRAL
LOAD
 Viral load correlates with progression of
disease: High viral loads are associated with
rapid disease onset and CD4 loss
 High viral load increases probability of
transmission, whereas undetectable viral load
makes transmission unlikely (e.g. mother to
child transmission is prevented, serodiscordant
couples, the HIV negative partner remains
uninfected, incidence of HIV may decrease)
CLINICAL RELEVANCE OF VIRAL
LOAD
 Monitoring of therapy: Undetectable viral load
(<50 copies/ml) correlates with decreased
morbidity and mortality
 Within 3-6 months after starting combination ARV’s
viral load becomes undetectable
 Detectable viral load indicates ongoing viral
replication and emergence of resistant virus and
eventually immunological and clinical failure
 In contrast, suppressing replication stops reverse
transcriptase, creation of mutations is stopped
INTERPRETATION OF VIRAL LOAD RESULTS
(http://www.aidsinfo.nih.gov/guidelines)

• Virologic suppression: A confirmed HIV RNA

level below the detection limit of an assay (e.g.,
<20 copies/ml)
• Virologic failure: The inability to achieve or
maintain suppression of viral replication to an
HIV RNA level <200 copies/ml
• Virologic blip: After virologic suppression, an
isolated detectable HIV RNA level that is
followed by a return to virologic suppression
INTERPRETATION OF VIRAL LOAD
RESULTS

• Virologic rebound: Confirmed detectable HIV

RNA (to >200 copies/ml) after virologic
suppression
• Persistent low-level viremia: Confirmed
detectable HIV RNA levels that are <1,000
copies/ml
VIRAL LOAD TESTING MUST
BECOME STANDARD OF CARE
• To confirm viral suppression after 6 months of
treatment (assessment of adherence, TDR),
ideally to be repeated every 6 months
• If adherence is doubtful  intensive counselling
• If symptoms and signs suggest clinical failure 
confirm or rule out virological failure
• If a “relevant” decrease of CD4 cells is
observed and confirmed  confirm or rule out
virological failure
 Viral Load >1,000 copies/ml means
Treatment Failure when…
Viral load >
1000
copies/ml

2 Regimen failure or
consecutiv
e times treatment failure
indicates possible
3 months drug resistance
apart

With good
the 1,2,3 Rule adherence
in between

28
MANAGEMENT OF VIROLOGICAL
FAILURE

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SWITCHING FROM FIRST LINE TO
SECOND LINE ARV’s

• Confirm virological failure: 1000 copies/ml

• Assess reasons for virological failure: Almost
always lack of adherence despite the patient’s
assurance to the contrary
• If possible: Perform resistance testing while
patient is on treatment (at most within 4 weeks)
• Intensive counseling may lead to renewed
suppression  check after 3 months
SWITCHING FROM FIRST LINE TO
SECOND LINE ARV’s: 3 SCENARIOS
1. If viral load becomes undetectable, continue
adherence counseling, maintain first line
ARV’s
2. If viral load remains high despite improved
adherence, switch to second line ARV’s
3. If viral load remains high and adherence
remains poor, consider “holding strategy” with
failing regimen
SWITCHING FROM FIRST LINE TO
SECOND LINE ARV’s: 3 SCENARIOS
 If viral load remains <1’000 copies/ml on holding
regimen (should include lamivudine), risk of
accumulation of further resistance mutations is low
 Immunologic and clinical benefit if HIV RNA
<10’000-20’000 copies/ml
 Even with partial virologic suppression, ART
decreases risk of HIV progression
Treatment interruption of failing regimen carries a
high risk of morbidity and mortality
THE CHOICE OF SECOND LINE
ARV’s
• A boosted protease inhibitor (PI/r) plus two NRTI’s
are recommended for second line ART
• Lamivudine should always be part of the regime
• ATV/r and LPV/r are the currently available
boosted PI's for second line ART
• If d4T or AZT have been used in first line, use
TDF+3TC or FTC as the NRTI backbone in second
line
• If TDF has been used in first line, use AZT + 3TC
as the NRTI backbone in second line
THANK YOU!

www.newlandsclinic.org.zw Zimbabwe