PATHOPHYSIOLOGY OF ANTIRETROVIRAL

(ARV )TREATMENT FAILURE

DIVISION OF INFECTIOUS AND TROPICAL DISEASES, DEPARTMENT OF

INTERNAL MEDICINE, UNIVERSITY OF SUMATERA UTARA/ADAM MALIK
HOSPITAL, MEDAN
 ANTIRETROVIRAL (ARV) TREATMENT FAILURE

• ARV TREATMENT FAILURE IS A CONDITION, WHEN USING ARV REGIMENT AT LEAST 6 MONTHS
WITH GOOD ADHERENCE UNABLE TO CONTROL HIV INFECTION.
• TREATMENT FAILURE IS DEFINED BY A PERSISTENTLY DETECTABLE VIRAL LOAD ABOVE 1000
COPIES/ML (BASED ON TWO CONSECUTIVE VIRAL LOAD MEASUREMENTS WITHIN A THREE
MONTH-INTERVAL, WITH ADHERENCE SUPPORT BETWEEN MEASUREMENTS) AFTER A LEAST SIX
MONTHS OF USING ARV DRUGS
 MONITORING THE RESPONSE TO ART AND DIAGNOSIS OF TREATMENT
FAILURE

Recommendations for routine monitoring

• ROUTINE VIRAL LOAD MONITORING CAN BE CARRIED OUT AT 6 MONTHS, AT 12 MONTHS
AND THEN EVERY 12 MONTHS THEREAFTER IF THE PATIENT IS STABLE ON ART TO
SYNCHRONIZE WITH ROUTINE MONITORING AND EVALUATION REPORTING A .
• IN SETTINGS WHERE ROUTINE VIRAL LOAD MONITORING IS AVAILABLE, CD4 CELL COUNT
MONITORING CAN BE STOPPED IN INDIVIDUALS WHO ARE STABLE ON ART AND VIRALLY
SUPPRESSED B.
• A VIRAL
LOAD TESTING SHOULD BE PERFORMED EARLY AFTER INITIATING ART (WITHIN 6 MONTHS), AT 12 MONTHS AND THEN AT LEAST EVERY 12 MONTHS TO DETECT
TREATMENT FAILURE. IF VIRAL LOAD TESTING IS NOT ROUTINELY AVAILABLE, CD4 COUNT AND CLINICAL MONITORING SHOULD BE USED TO DIAGNOSE TREATMENT FAILURE,
WITH TARGETED VIRAL LOAD TESTING TO CONFIRM VIRAL FAILURE WHERE POSSIBLE.

• B WHO DEFINES PEOPLE STABLE ON ART ACCORDING TO THE FOLLOWING CRITERIA: ON ART FOR AT LEAST 1 YEAR, NO CURRENT ILLNESSES OR PREGNANCY, GOOD
UNDERSTANDING OF LIFELONG ADHERENCE AND EVIDENCE OF TREATMENT SUCCESS (TWO CONSECUTIVE VIRAL LOAD MEASUREMENTS BELOW 1000 COPIES/ML). FOR
SERVICE DELIVERY RECOMMENDATIONS IN THESE GUIDELINES (SEE CHAPTER 6 “SERVICE DELIVERY”), AN ADDITIONAL CRITERION IS THAT THERE ARE NO ADVERSE DRUG
REACTIONS REQUIRING REGULAR MONITORING, BUT THIS IS NOT RELEVANT TO THIS RECOMMENDATION.
 RECOMMENDATIONS FOR DIAGNOSIS OF TREATMENT FAILURE
• VIRAL LOAD IS RECOMMENDED AS THE PREFERRED MONITORING APPROACH TO DIAGNOSE AND CONFIRM TREATMENT
FAILURE.A
• IF VIRAL LOAD IS NOT ROUTINELY AVAILABLE, CD4 COUNT AND CLINICAL MONITORING SHOULD BE USED TO DIAGNOSE
TREATMENT FAILURE.

• VIRAL FAILURE IS DEFINED BY A PERSISTENTLY DETECTABLE VIRAL LOAD EXCEEDING 1000 COPIES/ML (THAT IS, TWO
CONSECUTIVE VIRAL LOAD MEASUREMENTS WITHIN A 3-MONTH INTERVAL WITH ADHERENCE SUPPORT BETWEEN
MEASUREMENTS) AFTER AT LEAST 6 MONTHS OF STARTING A NEW ART REGIMEN.
• DRIED BLOOD SPOT SPECIMENS USING VENOUS OR CAPILLARY WHOLE BLOOD CAN BE USED TO DETERMINE THE HIV
VIRAL LOAD. A THRESHOLD OF 1000 COPIES/ML CAN BE USED TO DETERMINE VIRAL FAILURE WHEN USING DRIED
BLOOD SPOT SAMPLES, AS DEFINED FOR TESTING IN PLASMAA
• APLASMA SPECIMENS ARE PREFERRED FOR VIRAL LOAD TESTING. DRIED BLOOD SPOT SPECIMENS ARE RECOMMENDED FOR
USE IN SETTINGS WHERE LOGISTICAL, INFRASTRUCTURAL OR OPERATIONAL BARRIERS PREVENT ROUTINE VIRAL LOAD
MONITORING USING PLASMA SPECIMENS
 BACKGROUND
• MONITORING PEOPLE ON ART IS IMPORTANT TO ENSURE SUCCESSFUL TREATMENT, IDENTIFY
ADHERENCE PROBLEMS AND DETERMINE WHETHER ART REGIMENS SHOULD BE SWITCHED IN
CASE OF TREATMENT FAILURE.
• IN 2013, WHO RECOMMENDED VIRAL LOAD TESTING AS THE PREFERRED MONITORING
APPROACH TO DIAGNOSE AND CONFIRM ARV TREATMENT FAILURE.
• MEASURING VIRAL LOAD CAN ALSO HELP TO DISTINGUISH BETWEEN TREATMENT FAILURE AND
NON-ADHERENCE, INDICATING NON-ADHERENCE AS THE REASON FOR THE HIGH VIRAL LOAD
IN THE MAJORITY OF CASES.
• VIRAL LOAD CAN ALSO SERVE AS A PROXY MEASURE FOR THE RISK OF TRANSMISSION AND
EFFECTIVENESS OF PREVENTION INTERVENTIONS AT BOTH THE INDIVIDUAL LEVEL, ESPECIALLY
FOR PREGNANT WOMEN, AND AT THE POPULATION LEVEL
• IN SETTINGS WITH LIMITED ACCESS TO VIRAL LOAD TESTING, A TARGETED VIRAL LOAD
STRATEGY TO CONFIRM SUSPECTED TREATMENT FAILURE BASED ON IMMUNOLOGICAL OR
CLINICAL CRITERIA SHOULD BE USED TO AVOID UNNECESSARY SWITCHING TO SECOND-LINE
ART REGIMENS.
 WHAT IS A TREATMENT FAILURE

• ACCORDING TO WHO 3 TYPES OF TREATMENT FAILURE, CAN BE:

• CLINICAL FAILURE
• IMMUNOLOGICAL FAILURE
• VIROLOGICAL FAILURE
• OR ANY COMBINATION ON THE THREE

• FACTORS THAT CAN CONTRIBUTE TO TREATMENT FAILURE INCLUDE DRUG

RESISTANCE, DRUG TOXICITY, OR POOR TREATMENT ADHERENCE.
 WHO DEFINITIONS OF CLINICAL, IMMUNOLOGICAL AND VIROLOGICAL
FAILURE FOR THE DECISION TO SWITCH ART REGIMENS
Failure Definition Comments
Clinical failure Adults and adolescents The condition must be differentiated from immune
New or recurrent clinical event indicating severe reconstitution inflammatory syndrome occurring after
immunodeficiency (WHO clinical stage 4 condition)a after 6 initiating ART
months of effective treatment For adults, certain WHO clinical stage 3 conditions
Children (pulmonary TB and severe bacterial infections) may also
New or recurrent clinical event indicating advanced or indicate treatment failurea
severe immunodeficiency (WHO clinical stage 3 and 4
clinical condition with the exception of TB) after 6 months of
effective treatment

Immunological Adults and adolescents Without concomitant or recent infection to cause a

failure CD4 count at or below 250 cells/mm3 following clinical transient decline in the CD4 cell count
failure Current WHO clinical and immunological criteria have low
or sensitivity and positive predictive value for identifying
Persistent CD4 levels below 100 cells/mm3 individuals with virological failure. There is currently no
Children proposed alternative definition of treatment failure and no
Younger than 5 years validated alternative definition of immunological failure
Persistent CD4 levels below 200 cells/mm3
Older than 5 years
Persistent CD4 levels below 100 cells/mm3

Virological Viral load above 1000 copies/mL based on two consecutive An individual must be taking ART for at least 6 months
failure viral load measurements in 3 months, with adherence before it can be determined that a regimen has failed
support following the first viral load test
 THRESHOLD FOR DEFINING VIRAL FAILURE

• WHO RECOMMENDS A THRESHOLD OF 1000 COPIES/ML BASED ON THE FACT THAT THE RISK
OF HIV TRANSMISSION AND DISEASE PROGRESSION IS VERY LOW WHEN VIRAL LOAD IS
LOWER THAN 1000 COPIES/ML ,
• BELOW THIS THRESHOLD, VIRAL BLIPS OR INTERMITTENT LOW-LEVEL VIRAEMIA (50–1000
COPIES/ML) CAN OCCUR DURING EFFECTIVE TREATMENT BUT HAVE NOT BEEN ASSOCIATED
WITH AN INCREASED RISK OF TREATMENT FAILURE .
 DETERMINING TREATMENT FAILURE IN THE ABSENCE OF
VIRAL LOAD MONITORING
• WHERE VIRAL LOAD MONITORING IS NOT AVAILABLE: CLINICAL MONITORING AND CD4
MONITORING ARE RECOMMENDED.
• IMMUNOLOGICAL AND CLINICAL CRITERIA HAVE POOR SENSITIVITY AND SPECIFICITY TO DETECT
TREATMENT FAILURE, PARTICULARLY AT HIGHER CD4 CELL COUNTS .
• IN THE ABSENCE OF BETTER CRITERIA TO PREDICT TREATMENT FAILURE, IT IS IMPORTANT TO USE
CD4 CELL COUNT AND CLINICAL ASSESSMENT TO IDENTIFY THOSE AT THE HIGHEST RISK OF
DISEASE PROGRESSION AND MORTALITY.
• SEVERAL STUDIES HAVE PROPOSED ALTERNATIVE APPROACHES, INCLUDING A SINGLE CD4
COUNT AT OR BELOW 250 CELLS/MM3 FOLLOWING CLINICAL FAILURE
 VIRAL LOAD FOR ASSESSING TRANSMISSION RISK

• VIRAL LOAD TESTING MAY HAVE ADDITIONAL VALUE FOR ASSESSING THE RISK OF
TRANSMISSION. THIS IS ESPECIALLY TRUE IN THE CASE OF PREGNANT WOMEN WHERE IN THE
ABSENCE OF ART, VIRAL LOAD IS PROPORTIONATE TO THE RISK OF MOTHER-TO-CHILD
TRANSMISSION.
• ALTHOUGH ART MARKEDLY REDUCES TRANSMISSION RISK, THE SAME ASSOCIATION BETWEEN
TRANSMISSION AND VIRAL LOAD PERSISTS. VIRAL LOAD TESTING MAY HAVE ADDITIONAL VALUE
FOR ASSESSING THE RISK OF TRANSMISSION.
 MONITORING ARV DRUG RESISTANCE

• CURRENT APPROACHES TO RESISTANCE TESTING REMAIN TOO COSTLY AND COMPLEX FOR ROUTINE
USE AS PART OF A PUBLIC HEALTH APPROACH, AND WHO DOES NOT CURRENTLY RECOMMEND
ROUTINE RESISTANCE TESTING TO GUIDE ART REGIMEN SELECTION.
• WHO RECOMMENDS ROUTINE SURVEILLANCE FOR HIV DRUG RESISTANCE (HIV-DR) IN POPULATIONS
INITIATING ART AND IN POPULATIONS ON ART FOR 12 MONTHS AND MORE THAN 48 MONTHS. THE
RESULTS OF THESE SURVEYS SUPPORT THE CHOICE OF RECOMMENDED FIRST- AND SECOND-LINE ART,
AND PRE- AND POST-EXPOSURE PROPHYLAXIS.
• EMERGENCE OF HIV-DR IN TREATED POPULATIONS IS ASSOCIATED WITH FACTORS RELATED TO PATIENT
CARE (AND VIRAL SUPPRESSION AT 12 MONTHS), PATIENT BEHAVIOUR (ADHERENCE) AND CLINIC-LEVEL
AND PROGRAMME MANAGEMENT (RETENTION ON FIRST-LINE ART, AND PROCUREMENT AND SUPPLY
MANAGEMENT OF ARV DRUGS).
• MANY FACTORS ARE ASSOCIATED WITH THE EMERGENCE OF HIV-DR. BROADLY, THESE FACTORS
MAY BE DIVIDED INTO THREE CATEGORIES:
• (I) VIRAL FACTORS (SUCH AS HIV SUBTYPE, REPLICATION CAPACITY AND PRE-EXISTING
POLYMORPHISMS);
• (II) DRUG-RELATED FACTORS (SUCH AS DRUG POTENCY, PHARMACOKINETICS, DRUG–DRUG
INTERACTIONS, TOLERANCE AND GENETIC BARRIER TO RESISTANCE); AND
• (III) PROGRAMME FACTORS (SUCH AS ADHERENCE TO PRESCRIBED ART, DRUG SUPPLY
CONTINUITY AND RETENTION OF PATIENTS ON TREATMENT).