1. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series Treatment Failure, Resistance, and 2 nd line ART in Resource-Limited Settings Chris Behrens, MD May 2009

2. Detecting and Managing Treatment Failure in the absence of virologic monitoring  While access to CD4 testing has expanded considerably in recent years, access to routine viral load testing remains scarce in resource-limited settings  Clinicians are therefore obliged to monitor patients on HAART using only clinical & immunologic criteria to detect treatment failure  How well does this approach work? 2

3. 3 Time-Sensitivity of different failure definitions for detecting Tx Failure Tx Failure Virologic detection Immunologic detection Clinical detection Time Viral Load Clinical Status CD4 Count

4. Case 1  33 yo male on HAART after being diagnosed with pulmonary TB, CD4 = 220  Now has completed TB therapy, doing well on HAART with rise in CD4 count  You do not have access to viral load monitoring, hence for this (and all your other patients) you rely on WHO clinical and immunological (CD4) criteria to detect treatment failure  How sensitive is this screening method for detecting treatment failure? 4 How likely is it that your patients are failing therapy, but failure is not being detected?

5. Case 2  27 yo female on HAART for past year, seen for routine follow-up  Initial CD4 count 180, WHO Stage III  Reports excellent adherence. Feeling well. PE unremarkable  CD4 counts:  How should you manage this patient? 5 Pre-HAART180 3 months220 7 months250 12 months180 How likely is it that this patient is truly failing treatment?

6. Case 3  41 yo female on AZT/3TC/NVP for two years, seen for routine follow-up  Initial CD4 count 210, WHO Stage III  Reports excellent adherence. Feeling well. PE unremarkable, but CD4 counts are falling  Your national guidelines recommend a switch to 2 nd line ART  What 2 nd line regimen would be most appropriate?  How likely is it that she will respond to the 2 nd line HAART regimen? 6 What is the most effective 2 nd line ART regimen patients like her? How well do 2 nd line regimens work in this scenario?

7. How useful is it to detect treatment failure based on immunologic & clinical criteria? 1. How accurately does this strategy detect patients who are truly failing therapy? 2. What are the resistance profiles in patients whose failure is detected by immunologic/clinical criteria? 3. What options do these patients have for 2 nd line ART? 4. How effective is empirically-designed 2 nd line ART for these patients? 7

8. 8 Some Key Definitions  1st line regimen: “the initial regimen prescribed for a naïve patient when the patient fulfills national clinical and laboratory criteria to start ART.”  2nd line regimen: “the next regimen used in sequence immediately after first-line therapy has failed”  Treatment failure: “the loss of antiretroviral efficacy [that] triggers the switch of the entire regimen from first to second line”  Note: single substitutions of ARVs (usually within the same class) for toxicity, drug-drug interactions, or intolerance to not indicate a 2nd line regimen is being used. WHO: Prioritizing Second Line ART within a Public Health Approach, 2007

9. 9 Key Definitions, continued  Treatment Failure:  “loss of antiretroviral (ARV) efficacy, prompting a switch of the entire regimen from first- to second- line.” - WHO, 2007  “absence of a sustained favourable response to antiretroviral therapy” - 2007 Caribbean Guidelines  How do we recognize Treatment Failure?  Clinical Failure  Immunologic Failure  Virologic Failure

10. 10 Detecting Treatment Failure Clinical, CD4 Cell Count, and Virological Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen Clinical failure a Occurrence of new or recurrent WHO stage 4 condition b c CD4 cell failure d  Fall of CD4 count to pre-therapy baseline (or below) or  50% fall from the on-treatment peak value (if known) or  Persistent CD4 levels < 100 cells/mm 3 e Virological failure Plasma viral load >10,000 copies/ml f a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS) b. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not require consideration of second-line therapy; c. Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy; d. Without concomitant infection to cause transient CD4 cell decrease. e. Some experts consider that patients with persistent CD4 cell count <50/mm 3 after 12 months on ART may be more appropriate. f. The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

11. How useful is it to detect treatment failure based on immunologic & clinical criteria? 1. How accurately does this strategy detect patients who are truly failing therapy? 2. What are the resistance profiles in patients whose failure is detected by immunologic/clinical criteria? 3. What options do these patients have for 2 nd line ART? 4. How effective is empirically-designed 2 nd line ART for these patients? 11

12. Case 1  33 yo male on HAART after being diagnosed with pulmonary TB, CD4 = 220  Now has completed TB therapy, doing well on HAART with rise in CD4 count  You do not have access to viral load monitoring, hence for this (and all your other patients) you rely on WHO clinical and immunological (CD4) criteria to detect treatment failure  How sensitive is this screening method for detecting treatment failure? 12 How likely is it that your patients are failing therapy, but failure is not being picked up by checking CD4 counts?

13. Performance of WHO Clinical & Immunologic Criteria in detecting Virologic Treatment failure Study SiteSensitivitySpecificy Thailand 1 20% South Africa 2 21% Uganda 3 14 – 23% without confirmatory CD4 testing23% with confirmatory CD4 testing14% 13 1. Int J Infect Dis 2007; 11:413–416. 2. AIDS 2008; 22:1971–1977. 3. AIDS 2009, 23:697–700

14. Case 2  27 yo female on HAART for past year, seen for routine follow-up  Initial CD4 count 180, WHO Stage III  Reports excellent adherence. Feeling well. PE unremarkable  CD4 counts: 14 Pre-HAART180 3 months220 7 months250 12 months180

15. 27 yo woman on HAART for one year, CD4 back to baseline of 180, clinically stable  How would you classify and manage this patient? A. This likely represents treatment failure: switch to 2 nd line ART B. This might be treatment failure; repeat CD4 count and switch to 2 nd line regimen if CD4 remains 180 or below; C. Continue therapy without change since this does not likely represent treatment failure 15 How likely is it that this patient is truly failing treatment?

16. Performance of WHO Clinical & Immunologic Criteria in detecting Virologic Treatment failure Study SiteSensitivitySpecificy Thailand 1 20%86% South Africa 2 21%96% Uganda 3 14 – 23%90 – 95% without confirmatory CD4 testing23%90% with confirmatory CD4 testing14%95% 16 1. Int J Infect Dis 2007; 11:413–416. 2. AIDS 2008; 22:1971–1977. 3. AIDS 2009, 23:697–700

17. How useful is it to detect treatment failure based on immunologic criteria? 1. How accurately do immunologic criteria detect patients who are truly failing 1 st -line therapy? 2. What are the resistance profiles in patients whose treatment failure is detected by immunologic criteria? 3. What options do these patients have for 2 nd line ART? 4. How effective is empirically-designed 2 nd line ART for these patients? 17

18. Resistance profile of patients failing First Line ART in Malawi when using Clinical and Immunologic Monitoring  Clinical ART failure  New WHO Stage IV condition  Progressive WHO Stage IV condition  Immunological ART failure  > 50% Decline from peak or below pre-treatment value  ART failure confirmed with HIV-RNA > 400 copies/ml  Resistance test if viral load >1000 copies ml  Genotypic analysis (TruGene)  Phenotype (Monogram) for complex genotypes 18 17 th IAC, Mexico City 2008, Abstract TUAB0105

19. Malawi: resistance patterns in patients failing first line ART  On d4T/3TC/NVP or alternative first line (ZDV for d4T toxicity, EFV for NVP toxicity)  Enrollment from Dec 2005 to Jun 2007  96 patients identified as ART Failure with VL>1000 copies  16 clinical (WHO Stage IV), 87 Immunological (CD4 decline)  66 on d4T/3TC/NVP, 30 on ZDV/3TC/NVP  2 samples did not amplify => 94 samples for analysis  19 17 th IAC, Mexico City 2008, Abstract TUAB0105

20. Common Mutations  M184V or M184I 81%  NNRTI mutations 93%  Median 2 (range 0-3)  181C 55%, 190A 30%, 103N 28%  Wild Type Virus 5%  M184 only0%  NNRTI mutations only2%  M184V & NNRTI mutations only16% 17 th IAC, Mexico City 2008, Abstract TUAB0105

21. Resistance Patterns % NNRTI mutations +/-184V containing virus + additional mutations Thymidine Analogue Mutation (TAM) - Containing Virus56% Tenofovir mutations (K65R or K70E)23% Tenofovir & TAM7% Q151M Complex19% Pan-Nucleoside Mutation Combinations Q151M Complex & Tenofovir mutations16% 69 insertion1% Pan-Nucleoside (Q151 & TDF associated mutations or 69 insertion) 17%

22. Thymidine Analogue Mutations (TAMs) TAMPercentage T215Y73% D67N53% K70R36% M41L36% K219Q/E23% L210W23%  56% of patient samples had TAMs  28% with one  28% with 2  44% with 3 or more 17 th IAC, Mexico City 2008, Abstract TUAB0105

23. Multivariate analysis emergence K65R or K70E resistance OR95% CI CD4 count <100 cells/ml6.11.47 – 25.0 Use of AZT0.18 0.04-0.94 17 th IAC, Mexico City 2008, Abstract TUAB0105

24. Multivariate analysis emergence PAN-NRTI resistance OR95% CI CD4 count <100 cells/ml9.81.16 – 82.9 Use of AZT0.120.014 – 0.978 17 th IAC, Mexico City 2008, Abstract TUAB0105

25. TAM Pathways  Pathway I: 41L, 210W, 215Y  Associated with d4T use  Confers high-level AZT resistance and cross- resistance to other NRTIs, esp ddI and tenofovir  Pathway II: 70R, 67N, 215F, 219Q/E  Associated with AZT use  leads to less NRTI cross-resistance 25

26. Implications  High level resistance to 3TC/FTC and to NNRTIs very common in patients who fail 1 st line therapy  2 nd line regimen will need to be ‘anchored’ by a ritonavir-boosted PI  Challenge is to design a useful 2 nd line NRTI backbone to complement the r/PI  Use of AZT rather than d4T in first line ART regimen better preserves 2 nd line NRTI options  AZT prevents emergence of mutations associated with TDF resistance (K65R, K70E), which d4T can select for especially in HIV subtype C strains  Resistance to AZT associated with TAM II pathway, which confers less pan-NRTI resistance 26

27. How useful is it to detect treatment failure based on immunologic & clinical criteria? 1. How accurately does this strategy detect patients who are truly failing therapy? 2. What are the resistance profiles in these patients? 3. What options do these patients have for 2 nd line ART? 4. How effective is empirically-designed 2 nd line ART for these patients? 27

28. Detailed recommendations for switching to Second line ARV regimens in adults and adolescents First Line Regimen Second Line Regimen RTI ComponentPI Component b Standard Strategy (AZT or d4T) + 3TC a + (NVP or EFV) ddI + ABC or TDF + ABC or TDF + 3TC (± AZT) c PI/r d TDF + 3TC a + (NVP or EFV) ddI + ABC or ddI + 3TC (± AZT) c ABC + 3TC a + (NVP or EFV) ddI + 3TC (± AZT) c or TDF + 3TC (± AZT) c Alternative Strategy (AZT or d4T) + 3TC a + (TDF or ABC)(EFV or NVP) ± ddI a 3TC and FTC are considered interchangeable because they are structurally related and share pharmacological properties and resistance profile. b NFV does not need refrigeration and can be used as a PI alternative in places without cold chain. c 3TC can be considered to be maintained in second line regimens to potentially reduce the viral fitness, confer residual activity and maintain pressure on the M184V mutation to improve viral sensitivity to AZT or TDF. AZT may prevent or delay the emergence of K65R mutation. d There are insufficient data to detect differences among available RTV-boosted PIs (ATV/ r, FPV/r, IDV/r, LPV/r and SQV/r ) and the choice should be based on individual program priorities (see text). In the absence of a cold chain, NFV can be employed as the PI component but it is considered less potent than a RTV-boosted PI. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

29. ART backbone- 2 fully active NRTIs Drug CombinationPhenotyped Samples (n=70) Total Sample (n=94) Emtricitibine/Tenofovir 3%2% Abacavir/Didanosine 1% Zidovudine/Lamivudine/Tenofovir29%21% 17 th IAC, Mexico City 2008, Abstract TUAB0105

30. ART backbone- No fully active NRTIs Drug CombinationPhenotyped Samples (n=70) Total Sample (n=94) Emtricitibine/Tenofovir39%29% Abacavir/Didanosine67%50% Zidovudine/Lamivudine/Tenofovir30%22% 17 th IAC, Mexico City 2008, Abstract TUAB0105

31. 2 nd line ART options for Malawi patients failing 1 st line HAART  Based on resistance analysis, most potent 2 nd line regimen among WHO options is TDF + AZT + 3TC/FTC + r/PI  Highest percentage of patients with 2 fully active NRTIs  Lowest percentage of patients with no fully active NRTIs 31 17 th IAC, Mexico City 2008, Abstract TUAB0105

32. Synergy of TDF and AZT in 2nd line regimens for patients failing typical 1 st line regimen  Unless HIV has evolved multiple TAMs before switch to 2nd line regimen, the virus will likely be at least partially sensitive to both AZT and TDF  Combining AZT and TDF in the 2nd line regimen makes it very difficult for HIV to evolve resistance to both agents simultaneously  K65R mutation reverses TAM-mediated AZT resistance*  Only option for HIV would be to evolve more TAMs, which is difficult with TDF and an active PI in the regimen  This strategy may not work, however, for patients in whom failure is detected relatively late, as multiple TAMs impart high-level resistance to AZT and TDF (as well as d4T, ddI, and ABC) * Antivir Ther. 2006;11(2):155-63

33. Retain 3TC/FTC in 2nd line regimens?  The M184V mutation ‘hobbles’ HIV in two important ways:  Reduced replication capacity (approximately 1/2 log) - virus is less ‘fit’  Partially reverses TAM-induced resistance to AZT, d4T, and TDF  Keeping 3TC (or FTC) in the 2nd line regimen forces HIV to maintain this inconvenient M184V mutation  3TC (as well as FTC) is relatively well-tolerated, can be dosed once-daily, is present in many FDCs  Clinical outcomes data from a RCT suggests benefit of keeping 3TC in ‘salvage’ regimens* *Castagna A et al. E-184V study. Third IAS Conference, abstract WeFo0204, 2005.

34. How useful is it to detect treatment failure based on immunologic & clinical criteria? 1. How accurately does this strategy detect patients who are truly failing therapy? 2. What are the resistance profiles in these patients? 3. What options do these patients have for 2 nd line ART? 4. How effective are empirically-designed 2 nd line ART regimens for these patients? 34

35. 2 nd line ART Responses: Malawi  101 patients switched to 2 nd line ART on the basis of WHO clinical/immunological criteria for failure  2 nd line ART regimen: AZT/3TC/TDF/r-LPV  12 months of follow-up:  10 patients died;  3 lost to follow-up;  85% of remaining had VL < 400 at 12 months  Resistance patterns in these patients did not predict response! 35 16 th CROI, Montreal, 2009, abstract 605

36. 2 nd line ART Responses: South Africa  N = 382 patients from Themba Luthu clinic (Johannesburg) switched to 2 nd line ART regimen of AZT/ddI/r-LPV  89% of patients alive and in care one year after switch  78% had undetectable viral load  No data on response according to resistance profile 36 16 th CROI, Montreal, 2009, Abstract 606

37. 2 nd line ART Responses: Cambodia  N = 113 patients switched to 2 nd line HAART regimen of ddI/3TC/r-LPV  89% of patients had undetectable viral load a median of 10 months later  No data on response according to resistance profile 37 14 th CROI, Los Angeles, 2007, abstract 36LB

38. Favorable responses to 2 nd line ART – but will it last? Country2 nd line NRTIs (+ r-LPV) # of patients Length of f/uVirologic response MalawiAZT/TDF/3TC10112 months75% South AfricaAZT/ddI38212 months78% CambodiaddI/3TC11310 months89%  Success of 2 nd line ART in these settings may mostly reflect potency of r-LPV  Several studies suggest high efficacy of r-LPV monotherapy in patients who are naïve to ART or well- controlled on HAART  MONARK*: r-LPV monotherapy not as potent as traditional HAART in non-clade B HIV subtypes 38 *11 th European AIDS Conference, Madrid 2007, abstract PS1/2

39. Broader access to viral load testing for routine monitoring?  Pros: Would allow for earlier detection of treatment failure & earlier switch to 2 nd line  Avoid immunologic/clinical decline;  Minimize evolution of NRTI resistance  Eliminate unnecessary/premature regimen switches  Rakai, Uganda*: almost as many people were being switched unnecessarily as were being missed treatment failure; would have cost an estimated extra $75,000/year in 2 nd line drugs  Cons: cost, laboratory infrastructure, turn- around time: point-of-care technology needed! 39 *16 th CROI, Montreal 2009, abstract 144

40. Remaining Questions  Should 1 st line HAART regimens in RLS use TDF instead of AZT or d4T?  Advantages:  well-tolerated, convenient dosing  Activity of AZT likely in patients who fail TDF*  Disadvantages:  Cost  K65R with failure of TDF-based regimen => compromised efficacy of ABC, ddI for future use 40 *Landman R et al. Successful rescue therapy in patients developing K65R on tenofovir-containing regimens: long-term follow-up. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 710, 2005b

41. Remaining Questions  Should 1 st line HAART regimens include both TDF and AZT?  Advantages:  Improved durability: HIV has difficulty evolving resistance simultaneously to both drugs  Disadvantages:  Cost  Toxicity  Failure (though rare) could leave very few 2 nd line options 41

42. Remaining Questions  When will newer agents become available in resource-limited settings?  Etravirine: new NNRTI active against most strains of HIV that have evolved resistance to EFV, NVP  Darunavir: new PI active against most strains otherwise resistant to PIs  Raltegravir: integrase inhibitor  Maraviroc: CCR5 Inhibitor 42

43. 43 Extra slides

44. N Engl J Med, Vol. 344, No. 7 · February 15, 2001

45. ABC or 3TC (±AZT) # ddI or TDF EFV or NVP NRTI sparing option if the triple NRTI approach were used in first-line therapy Standard second-line option if NRTI/NNRTI approach were used in first-line therapy Second line ARV drugs in adults and adolescents PI/r* * Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be employed as the PI component but it is considered less potent than a RTV-boosted PI. # The use of 3TC (±AZT) are listed for “strategic” use as resistance to both drugs is predicted to be present following failure on the respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation. However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.

46. 46 Clinical staging events to guide decision-making on ART switching New or recurrent event on ART a RecommendationsAdditional management options Asymptomatic (T1) Do not switch regimen Maintain scheduled follow up visits including CD4 monitoring (if available) Continue to offer adherence support Stage 2 event (T2 ) Do not switch regimen b  Treat and manage staging eventAssess and offer adherence support Check if on treatment at least 6 months Assess continuation or reintroduction of OI prophylaxis Schedule earlier visit for clinical review and consider CD4 (if available) c Stage 3 event (T3) Consider switching regimen b d  Treat and manage staging event and monitor responseAssess and offer adherence support Check if on treatment at least 6 months Check CD4 cell count (if available) c d Assess continuation or reintroduction of OI prophylaxis Institute more frequent follow up Stage 4 event (T4) Switch regimen b e  Treat and manage staging event and monitor responseCheck if on treatment at least 6 months Assess continuation or reintroduction of OI prophylaxis Check CD4 cell count (if available) c Assess and offer adherence support a. Clinical stages refer to the clinical stage while on ART for at least 6 months (termed T1, T2, T3, T4) b. Differentiation of opportunistic infections from immune reconstitution syndrome is necessary. c. Treat and manage the staging event before measuring CD4 cell count. d. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need for switching of therapy. e. Some stage 4 conditions (simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need to switch of therapy. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

47. 47 Detecting Treatment Failure Clinical, CD4 Cell Count, and Virological Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen Clinical failure a Occurrence of new or recurrent WHO stage 4 condition b c CD4 cell failure d  Fall of CD4 count to pre-therapy baseline (or below) or  50% fall from the on-treatment peak value (if known) or  Persistent CD4 levels < 100 cells/mm 3 e Virological failure Plasma viral load >10,000 copies/ml f a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS) b. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not require consideration of second-line therapy; c. Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy; d. Without concomitant infection to cause transient CD4 cell decrease. e. Some experts consider that patients with persistent CD4 cell count <50/mm 3 after 12 months on ART may be more appropriate. f. The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000 copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

48. WHO Clinical Staging Clinical Failure (CD4 and VL not available) Immunologic Failure (VL not available) Immunologic and Virologic Failure (CD4 and VL available) 1 N/A Do Not SwitchConsider Switch 2 N/A Do Not SwitchConsider Switch 3 Switch 4 When to Switch from 1 st Line to 2 nd Line ARV Regimens for Treatment Failure Clinical failure is defined as a occurrence of new or recurrent WHO clinical stage 3 or 4 event (excluding IRIS). CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm 3. Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

49. 2006 WHO guidelines  Immunologic Failure if:  the CD4 cell count falls below baseline in the absence of other concurrent infections,  the CD4 cell count falls to less than 50% of peak levels without coexistent infections, or  the CD4 cell count is consistently below 100 cells/ml.  For either of the first two criteria, switching therapy NOT recommended for asymptomatic patients if the CD4 cell count remains above 200 cells/ml. 49

50. Performance of WHO Immunologic Failure Criteria – Rakai, Uganda  N =1133 participants enrolled in antiretroviral treatment program between June 2004 and September 2007, median follow-up 20.2 months  WHO immunologic failure criteria were reached by 125 (11.0%) participants.  virologic failure* reached by 112 participants (9.9%).  Only 26 participants (2.3%) experienced both an immunologic and virologic failure endpoint (2 viral load>400 copies/ml) during follow-up. 50 * defined as HIV-1 viral load more than 400 copies/ml on two measurements AIDS 2009, 23:697–700

51. Thank you! 51 Next session: 21 May, 2009 Listserv: itechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

52. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series 52 Next session: 21 May, 2009 Robert Harrington, MD Opportunistic Infections, Part 2