Treatment-Experienced Patients in Resource-Limited Settings - PowerPoint Presentation

Slide1

Treatment-Experienced Patients in Resource-Limited Settings

Susan M. Graham Assistant Professor, Medicine and Global HealthAdjunct Assistant Professor, Epidemiology

Presentation prepared by:

Susan M. Graham

Last Updated:

October 29, 2014Slide2

Susan M. Graham, MD MPH PhD

Treatment-Experienced Patients in Resource-Limited SettingsDr. 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.Slide3

Outline

HIV Care in RLS, Part IIInitial regimens (review)Monitoring treatmentDiagnosing treatment failureSecond-line regimensThird-line regimensSwitching and misdiagnosisSwitching and resistanceSwitching and survivalConclusions and way forwardSlide4

Initial Treatment Regimens

Population2006

2010

2013

HIV+ ARV-naive

adults and

adolescents

AZT or d4T + 3TC (or FTC) + EFV or NVP

TDF possible as substitute for AZT, but not widely available

AZT or TDF + 3TC (or FTC) + EFV or NVP

Phase out d4T as feasibleTDF + 3TC (or FTC) + EFV preferredAlternatives: AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVPDiscontinue d4THIV+ pregnantwomenAZT + 3TC + NVPAZT or TDF + 3TC (or FTC) + EFV or NVPAZT preferred over TDFEFV included as option (but not during first trimester)HIV/TBcoinfectionAZT or d4T + 3TC (or FTC) + EFVAZT + 3TC + ABCAZT or TDF + 3TC (or FTC) + EFVInitiated as soon as possible in all patients with active TB (within 8 wks after TB treatment)HIV/HBVcoinfectionTDF + 3TC (or FTC) + EFVNNRTI regimens that contain both TDF + 3TC(or FTC) are required

WHO Treatment GuidelinesSlide5

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 settingsUrine dipstick for glycosuria and serum creatinine for TDF desirable (if feasible)Other tests symptom-directed and as needed

WHO 2013 ART guidelinesSlide6

Diagnosing Treatment Failure

Viral load preferred (new in 2013) Virologic failure: >1000 copies/ml based on two consecutive measurements after 3 months, with adherence supportIf viral load is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failureClinical 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/mm3Drug resistance testing not availableAt baseline or at treatment failureWHO 2013 ART GuidelinesSlide7

Second-Line Regimens

WHO ART GuidelinesPopulation2006

2010

2013

HIV+ ARV-naive

adults and

adolescents

ABC +

ddI

or

TDF+ ABC orddI +3TC orTDF + 3TC (± AZT)plusATV/r or FPV/ror IDV/r or LPV/ror SQV/rIf d4T or AZT used in first-line therapy, TDF + 3TC/FTC +ATV/r or LPV/rIf TDF used infirst-line therapy, AZT + 3TC/FTC +ATV/r or LPV/rIf TDF used in first-line therapy, AZT + 3TC/FTC + ATV/r or LPV/rIf d4T or AZT used in first-line therapy, TDF + 3TC/FTC + ATV/r or LPV/rUse fixed-dose combination NRTI backbones when possibleHeat-stable fixed-dose combinations ATV/r and LPV/r are the preferred boosted PI optionsSame options for HIV/TB (dropping SQV) and HIV/HBVHIV+ pregnantwomenABC + ddI orTDF+ ABC orddI +3TC orTDF + 3TC (± AZT)plus LPV/r orNFV or SQV/rSame as aboveHIV/TBcoinfectionABC + 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)

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)

HIV/HBV

coinfection3TC- and/orTDF-containingregimensAZT + 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

baselineSlide8

Third-Line Regimens

WHO ART Guidelines20062010

2013

For patients with no further treatment options, continue failing ART regimen unless toxicities or drug interactions are making patient worse

If clear clinical failure, stop giving ARVs and to institute an active palliative and end-of-life care plan

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 second-line regimen with no new ARV options should continue with a tolerated regimen

National programs should develop policies for third-line ARTThird-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 PIsPatients on a failing second-line regimen with no new ARV options should continue with a tolerated regimenSlide9

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 failureClinical 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 2014Slide10

Switching and Resistance

Resistance mutations accumulate during treatment:Many patients with have multiple DRM and dual-class resistance at failure diagnosisMost 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 2012Slide11

Switching and Survival

Failure to diagnose treatment failure has consequencesAmong 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 failureAdjusted 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 2014Slide12

Conclusions and Way Forward

The ART scale-up and public health approach are making treatment widely availableMortality has decreased and gains are at relatively low costHowever, monitoring treatment without VL testing is frustrating for clinicians and patientsDrug resistance testing is not likely to be available, so treatment remains algorithmicInequities in access to lab testing likely lead to differences in treatment outcomes