ncrc-tx-experienced.pptx

File 1 of 1 from DHHS Adult ART Guidelines: Treatment-Experienced Patients

Management of Treatment-Experienced Patients

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Management of Treatment-Experienced Patients
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents

January 2020

About This Presentation
These slides were developed using the Guidelines updated in December 2019
The intended audience is clinicians involved in the care of patients with HIV.
Because the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly.
It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent.
January 2020

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC)
January 2020

Outline
Definitions
Causes of virologic failure (VF)
Management of VF
Clinical scenarios
Discontinuation or interruption of ART
Poor CD4 recovery and persistent inflammation despite viral suppression

January 2020

Treatment-Experienced Patients
The recommended initial ARV regimens should achieve and maintain HIV suppression to below the lower level of detection (LLOD) of HIV RNA assays
Virologic rebound or failure of virologic suppression often results in resistance mutations to one or more of the ARVs in the regimen
Assessment and management of patients with extensive ART resistance is complex: expert consultation is recommended

January 2020

Virologic Response, Definitions (1)
Virologic suppression (VS):
Confirmed HIV RNA below LLOD (eg, <50 copies/mL)
Virologic failure (VF):
Inability to achieve or maintain HIV RNA <200 copies/mL

Viral suppression
Graphic: National HIV Curriculum, hiv.uw.edu

January 2020

Virologic Response, Definitions (2)
Incomplete virologic response:
Lack of VS to <200 copies/mL after 24 weeks on ART
Virologic rebound:
Confirmed HIV RNA ≥200 copies/mL after VS
Virologic blip:
An isolated detectable HIV RNA level followed by a return to VS
Low-level viremia:
Detectable HIV RNA <200 copies/mL
Virologic rebound
Virologic blip
Low-level viremia
Graphics: National HIV Curriculum, hiv.uw.edu

January 2020

Causes of Virologic Failure (VF) (1)
Most common: suboptimal adherence, ARV intolerance; also transmitted drug resistance
Patient/adherence-related factors
Comorbidities that affect adherence (e.g., substance abuse, psychiatric or neurocognitive issues)
Unstable housing
Missed clinic appointments
Interruptions in access to ART
Cost/affordability of ARVs
Adverse drug effects
High pill burden, dosing frequency

January 2020

Causes of Virologic Failure (VF) (2)
HIV-related factors
Transmitted or acquired resistance mutations
Prior treatment failure
Higher pretreatment HIV RNA (depending on the ART regimen)

ARV regimen-related factors

Pharmacokinetic problems
Suboptimal ARV potency
Low genetic barrier to resistance
Prior exposure to nonsuppressive regimens
Food requirements
Drug-drug interactions with concomitant medications
Prescription errors

January 2020

Managing Patients with VF (1)
Carefully assess causes of VF; management will vary according to cause
Review HIV RNA, CD4 count, ART history, prior and current ARV resistance test results
Resistance is cumulative; consider all past resistance
Resistance test should be done while patient is taking the failing regimen, or within 4 weeks of treatment discontinuation
If >4 weeks since ARV discontinuation, resistance test may provide useful information, but it may not detect previously selected mutations 
January 2020

Managing Patients with VF (2)
Goal of treatment: virologic suppression (HIV RNA <LLOD)
New regimen should contain at least 2 (preferably 3) fully active agents
Based on ARV history, resistance testing, and/or novel mechanism of action
Some ARVs may have partial activity even if resistance mutations are present (e.g., some NRTIs and PIs)
1 active drug should not be added to a failing regimen (resistance likely to develop quickly)
If HIV/HBV coinfection – continue HBV-active agents, to avoid HBV flare
Consult with experts

January 2020

Managing Patients with VF: INSTIs in Persons of Childbearing Potential
Perform pregnancy test before INSTI start
DTG:
Preliminary data suggest small (0.3%) but increased risk of neural tube defects (NTDs) in women who were receiving DTG at time of conception
Discuss benefits and risks of DTG (incl. possible risk of NTD)
Other INSTIs: unclear risk of NTD; discuss possibility of class effect
BIC: no data; similar considerations as for DTG; BIC and DTG have similar chemical structures
EVG/c: not recommended in pregnancy: low EVG levels in 2nd and 3rd trimesters
RAL: no evidence of increased fetal malformations, but limited data
January 2020

Managing VF: Level of Viremia (1)
For all:
Confirm VL, assess/address adherence, possible drug-drug and drug-food interactions
VL >LLOD - <200:
ART change not usually required. Development of resistance unlikely. No consensus re management. Check VL q 3 months.
VL ≥200 - <1,000:
Drug resistance likely (esp. if VL >500). Manage as for VL ≥1000.

January 2020

Managing VF: Level of Viremia (2)
VL ≥1000 and no ARV resistance mutations identified:
Usually caused by suboptimal adherence: assess and address; consider changes, simplification
VL ≥1000 and ARV resistance mutations identified:
Modify regimen ASAP, to avoid more resistance mutations and higher viral loads
January 2020

Managing VF, Clinical Scenarios: Failure of 1st ART Regimen - INSTI + 2 NRTIs
Resistance considerations
ART options
If resistance to 3TC/FTC but no INSTI resistance
Boosted PI + 2 NRTIs (at least 1 active)
DTG + 2 NRTIs (include at least 1 active)
Boosted PI + INSTI
If EVG or RAL resistance +/- 3TC/FTC resistance
Boosted PI + 2 NRTIs (at least 1 active)
DTG BID (if HIV is sensitive to DTG) + 2 active NRTIs
DTG BID (if HIV is sensitive to DTG) + boosted PI
(BIC not recommended – no data)
January 2020

Managing VF, Clinical Scenarios: Failure of 1st ART Regimen (2) - NNRTI + 2 NRTIs
Resistance considerations
ART options
Most likely: resistance to NNRTI +/- 3TC/FTC (M184V/I)

Add’l NRTI mutations may be present
Boosted PI + 2 NRTIs (at least 1 active)
DTG + 2 NRTIs (at least 1 active)
Boosted PI + INSTI
January 2020

Managing VF, Clinical Scenarios: Failure of 1st ART Regimen (3) - Boosted PI + 2 NRTIs
Resistance considerations
ART options
Most likely: no resistance, or resistance only to 3TC/FTC (M184V/I)
Continue same regimen
Another boosted PI + 2 NRTIs (at least 1 active)
INSTI + 2 NRTIs (at least 1 active); DTG preferred if only 1 fully active NRTI
Another boosted PI + INSTI
January 2020

Managing VF, Clinical Scenarios: Failure of 2nd (or subsequent) ART Regimen – ARV resistance but active ARV options
Resistance considerations
ART options
Consider past and current resistance test results and ART history to design new ART regimen
At least 2 (preferably 3) fully active ARVs
Can use partially active ARVs if no other options
Consider ARVs with different mechanisms of action
January 2020

Managing VF, Clinical Scenarios: Failure of 2nd (or subsequent) ART Regimen (2) – Multiple or extensive resistance and few ARV options
Resistance considerations
ART options
Consider past and current resistance test results and ART history to design new ART regimen
Consider tropism test (if MVC is being considered)
Consult experts
Identify all active or partially active ARVs
Consider ARVs with different mechanisms of action
Consider investigational ARVs: clinical trial or expanded access program
ART discontinuation is NOT recommended
January 2020

Managing VF, Clinical Scenarios: Suspected ARV Resistance but Limited/Incomplete ARV and Resistance History - Unknown
Resistance considerations
ART options
Obtain records, if possible

Resistance testing: may identify mutations (if patient off ART, mutations may not be detected)
Consider restarting previous regimen and obtain VL and resistance test after 2-4 weeks
Consider regimen with ARVs with high genetic barriers to resistance (eg, DTG and/or boosted DRV)
January 2020

Discontinuation or Interruption of ART (1)
Treatment interruption should be avoided, if possible: may cause rapid increase in HIV RNA, immune decompensation, clinical progression
Unplanned ART interruption may occur, and sometimes may be necessary 
January 2020

Discontinuation or Interruption of ART (2)
Short-Term Interruptions (days-weeks)
Unanticipated:
Severe toxicity or inability to take oral medication:
Stop all ARV components simultaneously

Planned:
All ARVs have similar half-lives:
Stop all simultaneously
ARVs have different half-lives:
Some NNRTIs have long half-lives; may stop NNRTI first and stop other ARVs 2-4 weeks later, or replace NNRTI with boosted PI for 4 weeks, then stop all
January 2020

Discontinuation or Interruption of ART (3)
Planned Long-Term Interruptions
Not recommended outside controlled clinical trials
If ART must be discontinued, patients should understand risks (re personal health and re HIV transmission)
Follow closely: clinical and laboratory monitoring

January 2020

Poor CD4 Recovery and Persistent Inflammation Despite Viral Suppression
Morbidity and mortality are higher in HIV-infected individuals than in the general population, even with viral suppression
E.g., cardiovascular disease, many non-AIDS cancers and infections, COPD, osteoporosis, diabetes, liver disease, kidney disease, thromboembolic disease, neurocognitive dysfunction, frailty
Likely related to poor CD4 recovery, persistent immune activation, and inflammation, as well as health-related behaviors and ARV toxicity

January 2020

Poor CD4 Recovery Despite VS
Low CD4 (especially <200 cells/µL, but also up to at least 500 cells/µL) despite viral suppression on ART: associated with risk of illness and mortality
Lower pretreatment CD4 counts associated with suboptimal CD4 recovery – early ART initiation may enhance CD4 recovery

January 2020

Poor CD4 Recovery Despite VS: Management
Evaluate for underlying causes
Malignancy, coinfections (e.g., HCV), medical conditions
Medications that may decrease CD4 cells (e.g., cancer chemotherapy, interferon)
No consensus on management of patients without evident causes
Changing or intensifying the ARV regimen has not been shown to be beneficial, is not recommended
IL-2: no benefit, not recommended
Other immune-based therapies are being studied
January 2020

Persistent Immune Activation and Inflammation Despite VS (1)
Immune activation and inflammation improve with suppression of HIV through ART, but do not return to normal
Systemic immune activation and inflammation may be independent mediators of risk of morbidity and mortality in patients with viral suppression on ART
Poor CD4 recovery on ART (eg, CD4 <350 cells/µL) associated with greater immune system activation and inflammation
January 2020

Persistent Immune Activation and Inflammation Despite VS (2)
Causes not completely clear: likely include HIV persistence, coinfections, microbial translocation
No proven interventions
ART intensification or modification: not consistently effective in studies
Anti-inflammatory medications and others are being studied
Clinical monitoring with immune activation or inflammatory markers is not currently recommended
Focus on maintaining viral suppression with ART, reducing risk factors (e.g., smoking cessation, diet, exercise), managing comorbidities (e.g., hypertension, hyperlipidemia, diabetes)

January 2020

Websites to Access the Guidelines
AETC National Coordinating Resource Center https://aidsetc.org
AIDSInfo https://aidsinfo.nih.gov
January 2020

About This Slide Set
This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in March 2020.
See the AETC NCRC website for the most current version:
https://aidsetc.org