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NORTHWEST AIDS EDUCATION AND TRAINING CENTER
Treatment-Experienced Patients in ResourceLimited Settings
Susan M. Graham
Assistant Professor, Medicine and Global Health
Adjunct Assistant Professor, Epidemiology
Presentation prepared by:
Susan M. Graham
Last Updated: October 29, 2014
NORTHWEST AIDS EDUCATION AND TRAINING CENTER
Treatment-Experienced Patients in ResourceLimited Settings
Susan M. Graham, MD MPH PhD
Dr. Graham is a member of the Kenya Research Group at the University of Washington. She began
working with the University of Nairobi/UW Mombasa Field Site in 2003 as an Infectious Diseases
Fellow, and developed the ART program offered at the UW research clinic here and another site north
of Mombasa. Her research interests focus on access to and engagement in care for most at-risk
populations in Kenya, including female sex workers and men who have sex with men. Dr. Graham
holds a medical degree from McGill University, an MPH from Boston University, and a PhD in clinical
epidemiology from the University of Toronto.
Outline
• HIV Care in RLS, Part II
-
Initial regimens (review)
Monitoring treatment
Diagnosing treatment failure
Second-line regimens
Third-line regimens
Switching and misdiagnosis
Switching and resistance
Switching and survival
• Conclusions and way forward
Initial Treatment Regimens
Population
2006
2010
HIV+ ARV-naive
adults and
adolescents
AZT or d4T + 3TC (or FTC) + EFV or
NVP
AZT or TDF + 3TC (or FTC) + EFV or
NVP
TDF possible as substitute for AZT,
but not widely available
Phase out d4T as feasible
AZT + 3TC + NVP
AZT or TDF + 3TC (or FTC) + EFV or
NVP
HIV+ pregnant
women
AZT preferred over TDF
EFV included as option (but not
during first trimester)
HIV/TB
coinfection
HIV/HBV
coinfection
AZT or d4T + 3TC (or FTC) + EFV
AZT or TDF + 3TC (or FTC) + EFV
AZT + 3TC + ABC
Initiated as soon as possible in all
patients with active TB (within 8 wks
after TB treatment)
TDF + 3TC (or FTC) + EFV
NNRTI regimens that contain both
TDF + 3TC
(or FTC) are required
WHO Treatment Guidelines
2013
TDF + 3TC (or FTC) + EFV
preferred
Alternatives:
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
Discontinue d4T
Monitoring Treatment
• CD4 cell count (every 6 months)
• HIV viral load (6 months after initiating ART and every 12
months thereafter) (if available)
- Mostly available in research or CDC-funded program settings
• Urine dipstick for glycosuria and serum creatinine for TDF
desirable (if feasible)
• Other tests symptom-directed and as needed
WHO 2013 ART guidelines
Diagnosing Treatment Failure
• Viral load preferred (new in 2013)
- Virologic failure: >1000 copies/ml based on two consecutive
measurements after 3 months, with adherence support
• If viral load is not routinely available, CD4 count and clinical
monitoring should be used to diagnose treatment failure
- Clinical failure: New or recurrent clinical event indicating severe
immunodeficiency (WHO clinical stage 3 or 4 condition)a after 6 months
of effective treatment
- Immunologic failure: CD4 count falls to baseline (or below) or
persistent CD4 levels below 100 cells/mm3
• Drug resistance testing not available
- At baseline or at treatment failure
WHO 2013 ART Guidelines
Second-Line Regimens
Population
2006
HIV+ ARV-naive
adults and
adolescents
ABC + ddI or
TDF+ ABC or
ddI +3TC or
TDF + 3TC (± AZT)
2010
2013
plus
ATV/r or FPV/r
or IDV/r or
LPV/r
or SQV/r
If d4T or AZT used in first-line
therapy, TDF + 3TC/FTC +
ATV/r or LPV/r
• If TDF used in first-line
therapy, AZT + 3TC/FTC
+ ATV/r or LPV/r
If TDF used in
first-line therapy, AZT + 3TC/FTC +
ATV/r or LPV/r
plus LPV/r or
NFV or SQV/r
Same as above
• If d4T or AZT used in
first-line therapy, TDF +
3TC/FTC + ATV/r or
LPV/r
HIV+ pregnant
women
ABC + ddI or
TDF+ ABC or
ddI +3TC or
TDF + 3TC (± AZT)
HIV/TB
coinfection
ABC + ddI or TDF+ ABC or ddI +3TC
or TDF + 3TC (± AZT) plus
LPV/r or SQV/r with adjusted
dose of RTV (LPV/r 400 mg/400 mg
twice a day or LPV/r 800 mg/200 mg
twice a day or SQV/r 400 mg/400 mg
twice a day)
HIV/HBV
coinfection
3TC- and/or
TDF-containing
regimens
Same as above if rifabutin possible
Same NRTI backbones as above
plus LPV/r or SQV/r with adjusted
dose of RTV (LPV/r 400 mg/400 mg
twice a day or LPV/r 800 mg/200 mg
twice a day or SQV/r 400 mg/400 mg
twice a day)
AZT + TDF + 3TC (or FTC) + ATV/r
or LPV/r
• HBV (HBsAg) serology should be checked before switching if this testing was
not done or if the result was negative at baseline
WHO ART Guidelines
• Use fixed-dose
combination NRTI
backbones when
possible
• Heat-stable fixed-dose
combinations ATV/r and
LPV/r are the preferred
boosted PI options
• Same options for HIV/TB
(dropping SQV) and
HIV/HBV
Third-Line Regimens
2006
2010
2013
•
For patients with no further
treatment options, continue
failing ART regimen unless
toxicities or drug interactions
are making patient worse
•
•
National programs should
develop policies for third-line ART
•
If clear clinical failure, stop
giving ARVs and to institute
an active palliative and endof-life care plan
•
Third-line regimens should
include new drugs with minimal
risk of cross-resistance to
previously used regimens, such
as integrase inhibitors and
second-generation NNRTIs and
PIs
•
Patients on a failing second-line
regimen with no new ARV options
should continue with a tolerated
regimen
•
•
WHO ART Guidelines
National programs should
develop policies for third-line
ART that consider funding,
sustainability and the
provision of equitable access
Third-line regimens should
include new drugs likely to
have anti-HIV activity, such as
integrase inhibitors and
second-generation NNRTIs
and PIs
Patients on a failing secondline regimen with no new ARV
options should continue with a
tolerated regimen
Switching and Misdiagnosis
• A systematic review found that current WHO clinical and
immunological criteria have low sensitivity and positive
predictive value for identifying individuals with virological
failure
- Clinical criteria: sensitivity 11.0%, PPV 44.9%
- Immunologic criteria: sensitivity 16.8%–54.9%, PPV 15.0%–38.8%
• Predicted value would be even lower with earlier ART
initiation and treatment failure at higher CD4 cell counts
WHO ART Guidelines, 2013; Rutherford AIDS 2014
Switching and Resistance
• Resistance mutations accumulate during treatment:
- Many patients with have multiple DRM and dual-class resistance at
failure diagnosis
- Most common DRMs M184V (53.5%), K103N (28.9%), Y181C
(15.5%), and G190A (14.1%)
- Thymidine analogue mutations present in 8.5%, and K65R frequently
selected by stavudine (15.0%) or tenofovir (27.7%)
• Pre-treatment resistance increasing
- Increased odds for virological failure (OR 2.13, 95% CI 1.44–3.14) in
participants with pretreatment drug resistance to at least one
prescribed drug
- CD4 count increased less in participants with pretreatment drug
resistance than in those without (35 cells per μL difference after 12
months, 95% CI 13–58)
Hamers CID 2014, Hamers Lancet Infect Dis 2012
Switching and Survival
• Failure to diagnose
treatment failure has
consequences
• Among 823 patients with
confirmed virologic failure,
the cumulative incidence of
switch 180 days after
failure was 30% (95% CI
27–33)
• Most (74%) had not failed
immunologically by the
time of virologic failure
• Adjusted mortality was
higher for individuals who
remained on first-line
therapy than for those who
had switched (OR 2.1, 95%
CI 1.1–4.2)
Petersen AIDS 2014
Conclusions and Way Forward
• The ART scale-up and public health approach are making
treatment widely available
• Mortality has decreased and gains are at relatively low cost
• However, monitoring treatment without VL testing is
frustrating for clinicians and patients
• Drug resistance testing is not likely to be available, so
treatment remains algorithmic
• Inequities in access to lab testing likely lead to differences
in treatment outcomes