1. N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER Treatment-Experienced Patients in Resource- Limited 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

2. N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 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.

3. 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

4. Initial Treatment Regimens Population200620102013 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 feasible TDF + 3TC (or FTC) + EFV preferred Alternatives: AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP Discontinue d4T HIV+ pregnant women AZT + 3TC + NVPAZT or TDF + 3TC (or FTC) + EFV or NVP AZT preferred over TDF EFV included as option (but not during first trimester) HIV/TB coinfection 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/HBV coinfection TDF + 3TC (or FTC) + EFVNNRTI regimens that contain both TDF + 3TC (or FTC) are required WHO Treatment Guidelines

5. 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

6. 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/mm 3 Drug resistance testing not available -At baseline or at treatment failure WHO 2013 ART Guidelines

7. Second-Line Regimens WHO ART Guidelines Population200620102013 HIV+ ARV-naive adults and adolescents ABC + ddI or TDF+ ABC or ddI +3TC or TDF + 3TC (± AZT) 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 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+ pregnant women ABC + ddI or TDF+ ABC or ddI +3TC or TDF + 3TC (± AZT) plus LPV/r or NFV or SQV/r Same as above 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) 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 coinfection 3TC- and/or TDF-containing regimens 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

8. Third-Line Regimens WHO ART Guidelines 200620102013 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

9. 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

10. 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

11. 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

12. 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