NORTHWEST AIDS EDUCATION AND TRAINING CENTERTreatment-Experienced Patients in Resource-Limited SettingsSusan M. Graham Assistant Professor, Medicine and Global HealthAdjunct Assistant Professor, Epidemiology

Presentation prepared by: Susan M. GrahamLast Updated: October 29, 2014

NORTHWEST AIDS EDUCATION AND TRAINING CENTER

Susan M. Graham, MD MPH PhD

Treatment-Experienced Patients in Resource-Limited Settings

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 2013

HIV+ ARV-naiveadults andadolescents

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 preferred

Alternatives: AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVP

Discontinue d4T

HIV+ pregnantwomen

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

AZT preferred over TDFEFV included as option (but not during first trimester)

HIV/TBcoinfection

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

AZT + 3TC + ABC

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

Initiated as soon as possible in all patients with active TB (within 8 wks after TB treatment)

HIV/HBVcoinfection

TDF + 3TC (or FTC) + EFV NNRTI regimens that contain both TDF + 3TC(or FTC) are required

WHO Treatment Guidelines

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

WHO ART Guidelines

Population 2006 2010 2013

HIV+ ARV-naiveadults andadolescents

ABC + ddI or TDF+ ABC orddI +3TC orTDF + 3TC (± AZT)

plusATV/r or FPV/ror IDV/r or LPV/ror SQV/r

If d4T or AZT used in first-line therapy, TDF + 3TC/FTC +ATV/r or LPV/r

If TDF used infirst-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

• If d4T or AZT used in first-line therapy, TDF + 3TC/FTC + ATV/r or LPV/r

• 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

HIV+ pregnantwomen

ABC + ddI orTDF+ ABC orddI +3TC orTDF + 3TC (± AZT)

plus LPV/r orNFV or SQV/r

Same as above

HIV/TBcoinfection

ABC + ddI or TDF+ ABC or ddI +3TC or TDF + 3TC (± AZT) plus

LPV/r or SQV/r with adjusteddose 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 mgtwice 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 mgtwice a day or LPV/r 800 mg/200 mg twice a day or SQV/r 400 mg/400 mgtwice a day)

HIV/HBVcoinfection

3TC- and/orTDF-containingregimens

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

Third-Line Regimens

WHO ART Guidelines

2006 2010 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 ART

• 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

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