ADVANCES IN ANTI RETROVIRAL THERAPY. E. Omonge UON

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1 ADVANCES IN ANTI RETROVIRAL THERAPY E. Omonge UON KAP September 2008

2 Current Antiretroviral Medications PI NRTI Amprenavir APV Abacavir ABC Atazanavir ATV Didanosine DDI Darunavir DRV Emtricitabine FTC Fosamprenavir FPV Lamivudine 3TC Indinavir IDV Stavudine D4T Lopinavir LPV Nelfinavir NFV Zidovudine ZDV Ritonavir RTV Tenofovir TDF Saquinavir SQV NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP FDC Atripla TDF/FTC/EFV Combivir AZT/3TC (CBV) Epzicom ABC/3TC hard gel HGC tablet INV Tipranavir TPV Entry Inhibitors Enfuvirtide Maraviroc Vicriviroc T 20 Integrase Inhibitor Raltegravir RAL

3 Opportunistic Infections During Disease Progression Bacterial skin infections CD4 cell count (cells/mm3) Shingles Thrush (mouth & tongue) 500 Severe atheletes foot Oral hairy leukoplakia Tuberculosis PCP Cryptococcal meningitis Toxoplasmosis Herpes simplex infections Histoplasmosis Cytomegalovirus infections 7 Time after infection 9 10 Mycobacterium avium Complex infections 3-15 years

4 CDC Observational Study: Risk of Death 2 Year Survival (%) CD4 (cells/mm ) 3 Hazard Ratio 95% CI , , , , , , , , NE , , 1.8 > Kaplan J, et al. 8th CROI, Chicago, Abstract 520.

5 When to Start 2005/6 Clinical Stage CD4 available CD4 not available Treat if CD4 < 200 Do not treat Treat if CD4 < 200 (consider if CD4 count < 350 particularly closer to ) Treat if TLC < 1200 III Treat but consider CD4 for better management and decision making in some situations (e.g. TB) Treat irrespective of TLC IV Treat irrespective of CD4 Treat irrespective of TLC I II (consider if CD4 count < 350 particularly closer to )

6 DHHS Indications for initiating ART fro Chronic HIV patients Jan 2008 Clinical Condition and / or CD4 count History of AIDS defining illness Recommendation Antiretroviral Therapy should be initiated CD4 count < 200 cells/ml CD4 count cells/ml Pregnant women* Persons with HIV associated nephropathy Persons co infected with HBV, when HBV Rx is indicated ( Rx with suppressive ARVs active against both HBV and HIV recommended) Patients with CD4 count >350 cells /ml who do not meetoptimal time to initiate Rx in any of the specific conditions listed above asymptomatic with CD4 >350 cells/ml not well defined. Patient scenarios and comorbidities should be taken into consideration

7 Updated IAS USA Guidelines: When to Start Year Recommendation to Begin Immediate Therapy Active AIDS No history of active AIDS, but CD4+ cell count 200 cells/mm3 Recommendation to Consider Immediate Therapy Recommendation to Delay Therapy No history of active AIDS, but CD4+ CD4+ cell count > cell count from cells/mm3 350 cells/mm3 CD4+ cell count > 350 cells/mm3 but rapid CD4+ cell count decline, HIV 1 RNA > 100,000 copies/ml, CVD risk factors, other non AIDS risk factors* Active AIDS CD4+ cell count > 350 cells/mm3 but CD4+ cell count > No history of active rapid CD4+ cell count decline, HIV cells/mm3 AIDS, but CD4+ cell RNA > 100,000 copies/ml, CVD risk factors, other non AIDS risk factors* count 350 cells/mm3 *Non AIDS risk factors include HIV associated neuropathy, hepatitis C, hepatitis B Hammer SM, et al. JAMA. 2008;300:

8 When to Start: 2008 vs 2006 Guideline Recommendation to Begin Immediate Therapy Optimal Time Not Well Defined or Recommendation to Delay Therapy DHHS 2008[1] CD4+ cell count < 350 cells/mm3 Previous AIDS defining illness Pregnant women HIV associated nephropathy HBV coinfection, when HBV treatment indicated CD4+ cell count > 350 cells/mm3 EACS 2007[2] CD4+ cell count < 350 cells/mm3 CD4+ cell count from cells/mm3 with high HIV 1 RNA Opportunistic infection CD4+ cell count > 500 cells/mm3 IAS US 2008 CD4 Cell count <350 Cells/mm3 Active AIDS, and AIDS OIs CD4 > 350 cells/mm3 initiation depends on patient willing to start IAS US 2006[3] Active AIDS No history of active AIDS, but CD4+ cell count 200 cells/mm3 No history of active AIDS, but CD4+ cell count from cells/mm3 CD4+ cell count > 350 cells/mm3

9 Higher Risk of AIDS, Death at Lower CD4+ Counts Despite VL Suppression Prospective, longitudinal study of 249 virologically suppressed patients from MACS cohort with BL CD4+ cell count < 200 cells/mm3 Disease progression observed after achieving HIV 1 RNA < 50 copies/ml on HAART (most patients remained suppressed) 17 (6.8%) developed new AIDS defining illness 25 (10.0%) died Greater in CD4+ cell count during virologically suppressive HAART associated with decreased risk of AIDS defining illness or death CD4+ Cell Count During HAART With HIV 1 RNA < 50 copies/ml < 200 cells/mm3 Risk of AIDS Defining Illness HR P Value 1 (reference) Risk of Death HR P Value 1 (reference) cells/mm > 350 cells/mm <.001 Taiwo B, et al. IAC Abstract TUPE0090.

10 What to Start Efficacy, Durability safety and Convenience Characteristics Influencing Choice Cost of Drugs Availability of Generics Availability as fixed dose combination Potential Toxicities Usage in TB/HBV Co infection Usage in Women/Pregnancy Laboratory Monitoring Requirements Potency of most HAART regimens is considered similar

11 First line Regimens 2006 AZT or D4T NVP 3TC or FTC ABC or TDF Triple NRTI alternative EFV Classical preferred

12 DHHS Jan 2008 ARV Components Recommended for Treatment of HIV 1 To Construct an ARV Regimen, select 1 component from column A + 1 from column B Preferred components Alternative to preferred components COLUMN A COLUMN B + (NNRTI or PI options in alphabetical order) NNRTI Or EFV PI ATV/r (Dual NRTI options) Preferred components ABC/3TC (FDC, HLAB 5701 Alternative to preferred components ZDV/3TC (FDC) fapv/r 2x/day neg. test) TDF/FTC (FDC) LPV/r 2x/day NNRTI Or NVP PI ATV fapv fapv/r 1x/day LPV/r 1x/day (order of preference) ddi + FTC or 3TC

13 IAS USA Recommended Regimens for ARV Naive Patients, 2008 IAS USA Guidelines Recommended NNRTI based EFV* + regimen PI based regimen LPV/RTV ATV/RTV FPV/RTV DRV/RTV SQV/RTV TDF/FTC ABC /3TC *Except during first trimester of pregnancy or in women with high pregnancy potential. Or 3TC. Possible increased risk of CVD; possible increased risk of failure with high HIV 1 RNA. Or FTC. Hammer SM, et al. JAMA. 2008;300:

14 European AIDS Clinical Society Dec 2007 Guideline For Rx Of HIV 1 Adults in Europe Select 1 drug in column A and 1 A NRTI combination in Column B Recommended B Remarks ABC/3TC ABC/3TC (FDC) NNRTI EFV TDF/FTC (FDC) NVP Or ritonavir boosted PI fapv/r LPV/r SQV/r TDF/FTC fapv/r 700/100mg BD or 1400/200mg OD LPV/r 400/100mg BD 800/200mg OD or SGV/r 1000/100mg BD or 1500/100mg OD or 2000/100mg OD

15 BHIVA 2008 Guidelines for Rx of HIV 1 Adults Regimen A B C Preferred EFV1 TDF2 3TC3,4 ABC4 FTC1,2 Alternative LPV/r ddi fapv/r AZT3 ATV/r5 SQV/r Specific groups NVP6 ATV5, Co formulated as Atripla Co formulated as Truvada Co formulated as Combivir Corformulated as Kivexa / Epzicom 5. Currently unlicensed for naïve pts 6. CD4 <250 in female, & <400 males 7. where CVD risks and PI required

16 Tanzanian ART Guidelines Oct 2007 First line Rx (FDC preferred) AZT+3TC+NVP, d4t+3tc+nvp, TDF+FTC+EFV, TDF+3TC+EFV, AZT+ 3TC+EFV d4t+3tc+efv TDF+FTC +NVP TDF+3TC+NVP AZT 3TC Anaemia PN d4t or TDF EFV Women, Early pregnancy 3TC or FTC NVP

17 Tanzanian ART Guidelines Oct 2007 Second Line ART Abacavir (ABC) Didanosine (ddi) Tenofovir (TDF) Lopinavir boosted by Ritonavir (LPV/r) Second line combinations ABC + LPV/r (Kaletra) + ddi ABC + TDF + LPV/r ABC + ddi + Atazanavir

18 Zambian ART Guidelines June 2007 First Line TDF* FTC Second Line EFV AZT1 3TC2 Or Or Or NVP3 d4t4 TDF/FTC5 LPV/r6 * If CrCl <50ml/min initiate with ABC + 3TC 1 AZT/3TC/LPVr preferred second line on patients failing TDF first line 2 3TC/FTC maintained in second line due to reduced viral vigour and increased susceptibility to TDF or AZT 3 Avoid NVP in women exposed within 6 mths of PMTCT 4 Due to long term d4t toxicity, avoid in second line line unless AZT cannot be given 5 TDF mutations can increase AZT efficacy and TDF may maintain activity 6 If cannot tolerate LPVr, then refer to specialist for other options

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21 MIs per 1000 PY (95% CI) Incidence of Myocardial Infarction according to cart Exposure Events PYFU RR per year of cart: Univariable: 1.16 [ ] Adjusted: 1.16 [ ] None < cart Exposure (yrs) iis-møller N, et al. 13th CROI, Denver, CO, February 5-8, Abst. 144 >7 Total ,469

22 Resistance Patterns After Initial Failure of Common NRTI Backbones ZDV/3TC d4t/3tc TAMs M184V ZDV/3TC/ABC ABC/3TC M184V L74V or K65R TDF/FTC M184V K65R Gallant JE. Top HIV Med. 2005;13:

23 FTC vs. 3TC FTC 3TC Long intracellular half life Relatively shorter intracellular half life Less frequent emergence of M184V (study GS934 & 903) M184V frequently develop in 3TC based HAART OD FDC available Non OD 3TC FDC

24 High Rate of Resistance in Patients Failing First line Regimens in Malawi 94 patients who failed on first line d4t/3tc/nvp (or ZDV, EFV substituted for toxicity) analyzed for resistance Patients (%) M184V/I NRTI Mutations WT 19 M184V + TAM(s) TDF NNRTI containing mutations mutations virus (K65R or only K70E) TDF + TAM(s) Q151M complex + NNRTI mutations ± 184V Hosseinipour M, et al. IAC Abstract TUAB Pan NRTI (Q151 + TDF mutns or 69 insertion)

25 Few Active Second line NRTIs in Pts Failing First line Regimes in Malawi Many patients predicted to have no fully active NRTIs for second line regimen based on resistance selected during first line failure Potential NRTI Backbones for Second Line Therapy, % 2 Fully Active NRTIs* No Fully Active NRTIs FTC/TDF 2 29 ABC/ddI 1 50 ZDV/3TC + TDF *Based on lower limit of Monogram assay Hosseinipour M, et al. IAC Abstract TUAB0105.

26 Resistance Patterns Following First line Failure Vietnam (N = 136)[1]: patients receiving d4t/zdv + 3TC + NVP/EFV analyzed for treatment failure by clinical, immunologic criteria (mean time on ART: 17 months) 93% (326/350) of patients had 1 resistance mutation 89% (121/136) of patients had 1 resistance mutation 96% (116/121) had NRTI mutations (72% TAMs; 75% M184V; > 50% either > 3 TAMs with M184V or Q151M complex) 88% (107/121) had NNRTI mutations 7% (9/121) had PI mutations India (N = 350)[2]: patients failing first line HAART with d4t/zdv + 3TC + NVP/EFV analyzed for treatment failure by clinical, immunologic criteria 71% had M184V mutation 62% had TAMs Gabon (N = 36)[3]: 36% (13/36) had 1 resistance mutation 85% (11/13) had NRTI mutations 54% (7/13) had NNRTI mutations 8% (1/13) had a PI mutation 1. Truong Giang L, et al. IAC Abstract TUPDA Vidya M, et al. IAC TUPDA Ndjioyi Mbiguino A, et al. IAC TUPDA206.

27 Glomerular Filtration Rate GS 903E: No Significant Change in Renal Function on TDF + 3TC + EFV Cockcroft Gault in ml/min 20 Modification of Diet in Renal Disease in ml/min/1.73m2 0 CG: MDRD: n = 86 n = Cassetti I, et al. IAC Abstract TUPE0057. Year

28 GS 903E: Limb Fat Increased, BMD Mildly Decreased on TDF + 3TC + EFV P = n = Year Cassetti I, et al. IAC Abstract TUPE0057. Change in BMD (%) Median Limb Fat (kg) Hip Spine P = % 2.6% n = 86 n = Year

29 Management of VF in Multiclass Experienced Patients Raltegravir one of series of recently approved antiretrovirals that have increased options for multidrug experienced patients Darunavir Raltegravir Etravirine Tipranavir Maraviroc Renewed expectation that patients with extensive treatment experience can achieve HIV 1 RNA < 50 c/ml

30 DHHS Guidelines for Antiretroviral Experienced Patients Regimens prescribed to treatment experienced patients should include 2 new active agents Use of single active drug, even combined with partially active agents, not likely to be potent enough to ensure durable virologic suppression Higher response rates in multiclass experienced patients who begin a new antiretroviral plus OBR as number of active agents in the regimen increases Optimal number of active agents unclear Agents unlikely to be fully active identified based on treatment history, resistance data, and tropism testing For patients with treatment failure, resistance test should be done while on failing therapy Regimen optimization in experienced patients should involve standard assessments: potential toxicity, drug drug interactions, and each patient s likely adherence DHHS. Adult and adolescent HIV treatment guidelines.

31 Novel Antiretrovirals in Clinical Development Mature virus Entry inhibitors TNX 355 CCR5 antagonists CXCR4 antagonists Maturation inhibitors Bevirimat Raltegravir Elvitegravir Integrase inhibitors Reverse transcriptase inhibitors PIs

32 DUET 1 and 2: VL < 50 c/ml at Wk 48, Overall and by Active Agents in OBR Mean changes in CD4+ cell count response at Week 48 significantly greater in etravirine arm: +98 cells/mm3 vs +73 cells/mm3 in placebo[1,2] Time (Weeks) / /300 P < /196 40% /203 61% 100 0/35 ITT TLOVR ETR (n = 599) Placebo (n = 604) 12/ Patients With HIV 1 RNA < 50 c/ml (%) Patients With HIV 1 RNA < 50 c/ml (% ± 95% CI) 2 No. of Active Agents in OBR by PSS (DRV Considered Active if FC < 40) VircoType assay clinical cutoffs for ETR susceptibility defined: lower clinical cutoff (1.6), upper clinical cutoff (27.6)[3] 1. Haubrich R, et al. CROI Abstract Johnson M, et al. CROI Abstract Winters B, et al. CROI Abstract 873.

33 RPV (TMC278) vs EFV: HIV 1 RNA < 50 copies/ml at Week 96 Treatment naive patients with HIV 1 RNA 5000 copies/ml randomized to RPV or EFV, both plus 2 NRTIs (ITT TLOVR) Percent of Virologic Responders (95% CI) % 72% 71% 71% RPV 25 mg QD (n = 93) RPV150 mg QD (n = 91) Time (weeks) Santoscoy M, et al. IAC Abstract TUAB0103. RPV 75 mg QD (n = 95) EFV 600 mg QD (n = 89)

34 Week 48 Virologic Efficacy of New Drugs Defined as HIV 1 RNA < 50 c/ml Study Drug Regimen TORO[1] Enfuvirtide + OBR OBR alone Tipranavir + OBR Comparator PI + OBR Darunavir/ritonavir + OBR Comparator PI + OBR Etravirine + darunavir/ritonavir containing OBR Placebo + darunavir/ritonavir containing OBR Maraviroc QD + OBR Maraviroc BID + OBR Placebo + OBR Raltegravir + OBR Placebo + OBR RESIST[2] POWER[3] DUET[4,5] MOTIVATE[6] BENCHMRK[7,8] HIV 1 RNA < 50 copies/ml, % Nelson M, et al. J Acquir Immune Defic Syndr. 2005;40: Hicks CB, et al. Lancet. 2006;368: Clotet B, et al. Lancet. 2007;369: Haubrich R, et al. CROI Abstract Johnson M, et al. CROI Abstract Lalezari J, et al. ICAAC Abstract H 718a. 7. Cooper DA, et al. N Engl J Med In press. 8. Steigbigel R, et al. N Engl J Med In press.

35 Role of HIV Integrase Viral DNA synthesis Step 1: Assembly of PIC on viral DNA in nucleoprotein complex Step 2: Processing of 3' ends by PIC Nuclear membrane Host DNA Strand transfer Gap repair Mature provirus Hazuda D, et al. Science. 2000;287: Nuclear entry Step 3a: Target DNA binding Step 3b: Concerted target DNA cleavage and joining

36 BENCHMRK 1 and 2: Raltegravir in Treatment Experienced Patients Week 48: current analysis HIV infected patients with triple class resistance and HIV 1 RNA > 1000 copies/ml (BENCHMRK 1: N = 352; BENCHMRK 2: N = 351) Week 156: planned follow up Raltegravir 400 mg BID + OBR* (BENCHMRK 1: n = 232; BENCHMRK 2: n = 230) Placebo + OBR* (BENCHMRK 1: n = 118; BENCHMRK 2: n = 119) *Investigator selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

37 BENCHMRK 1: Patients With HIV 1 RNA < 50 c/ml at Week Patients (%) 80 62% 65% P <.001 P < % 31% Raltegravir* n = Placebo* n = Weeks * Each + OBR; P value was derived from a logistic regression model adjusted for BL HIV 1 RNA level (log10 ), first ENF use in OBR, first DRV use in OBR, active PI in OBR. Cooper DA, et al. CROI Abstract 788. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright 2008 Merck & Co., Inc., All Rights Reserved.

38 THANK YOU FDA approved ABC/ZDV/3TC 2000 FDA approved LPV/RTV 2000 FDA approved ZDV 1987 HIV first reported FDA approved ZDV/3TC HAART ERA begins 1996 FDA approved EFV/TDF/FTC FDA approved ABC/3TC 2004 FDA approved TDF/FTC

39 Main Findings Factors significantly associated with progression to AIDS or death Baseline Factor CD4+ cell count, cells/mm3 (vs > 350) < 200 n HCV coinfection P Value HIV 1 RNA 100,000 copies/ml (vs < 1000,000 copies/ml) HAART initiated (vs ) Multivariate HR (95% CI) < < Jaén A, et al. J Acquir Immune Defic Syndr. 2008;47:

40 Main Findings (cont d) Combination of high HIV 1 RNA and low CD4+ cell count associated with even higher risk of progression to AIDS/death When data adjusted for lead time, risk of progression to AIDS/death significantly higher for patients starting HAART with CD4+ cell counts cells/mm3 vs those with CD4+ cell counts > 350 cells/mm3 CD4+ Cell Count, cells/mm3 n < 200, unadjusted 650 < 200, adjusted for lead time* 670 > , unadjusted 650 HR (95% CI) , adjusted for lead time* *Lead time defined as time it took for patients who deferred therapy with early disease stage to reach later disease stage. Jaén A, et al. J Acquir Immune Defic Syndr. 2008;47:

41 Summary of Key Conclusions CD4+ cell count < 200 cells/mm3, HIV 1 RNA < 100,000 copies/ml, hepatitis C virus coinfection and starting HAART before 2001 associated with higher risk of progression to AIDS or death Significantly lower risk of progression to AIDS in patients starting HAART with CD4+ cell count cells/mm3 vs cells/mm3, when data adjusted for lead time Jaén A, et al. J Acquir Immune Defic Syndr. 2008;47:

42 Summary of Study Design HIV infected patients with CD4+ cell count > 350 cells/mm3 (N = 5472) Deferred Arm Intermittent antiretroviral therapy (n = 2720; 228 not receiving antiretroviral therapy at trial start) Immediate Arm Continuous antiretroviral therapy (n = 2752; 249 not receiving antiretroviral therapy at trial start) Study halted prematurely; mean follow up: 18 months Treatment definitions for subanalysis Deferred: antiretroviral therapy initiated when CD4+ cell count < 250 cells/mm3, CD4+ cell percentage < 15%, or HIV symptoms Immediate: antiretroviral therapy initiated immediately after randomization Primary endpoints OD or death from any cause (OD/death) Fatal or nonfatal OD Serious non AIDS events Fatal and nonfatal OD plus serious non AIDS events Emery S, et al. J Infect Dis. 2008;197:

43 Main Findings (cont d) Immediate group experienced substantially fewer events compared with deferred group Excess risk associated with deferring therapy: 5.4 events per 100 person years Event, n (Rate per 100 Person Yrs) OD/death Deferred Arm (n = 228) 15 (4.8) Immediate Arm (n = 249) 5 (1.3) HR (DC/VS) 95% CI P Value OD only 11 (3.5) 4 (1.1) Serious non AIDS events 12 (3.9) 2 (0.5) Composite 21 (7.0) 6 (1.6) Emery S, et al. J Infect Dis. 2008;197:

44 Rate/100 Person Yrs Main Findings (cont d) Deferred arm Immediate arm 50 2 < < < Total Population No Previous AIDS CD4+ Cell Count, cells/mm3 Emery S, et al. J Infect Dis. 2008;197: No Previous AIDS Defining Illness

45 Other Outcomes Higher grade 4 adverse events in deferred group Deferred: 25 patients Immediate: 18 patients HR (deferred/immediate): 1.6; 95% CI: OD events Herpes zoster Esophageal candidiasis Tuberculosis Mycobacterium avium complex Herpes simplex Death due to OD Kaposi sarcoma Non Hodgkin s lymphoma Death due to non Hodgkin s lymphoma Bacterial pneumonia Emery S, et al. J Infect Dis. 2008;197: Serious non AIDS events Hepatic cirrhosis End stage renal disease Death due to cardiovascular disease Myocardial infarction Coronary artery disease surgery Silent myocardial infarction Death from digestive system disease Accidental death Death due to renal disease Death due to non AIDS cancer

46 Summary of Key Conclusions Reduced risk of both OD and serious non AIDS events observed in patients who initiated and remained on antiretroviral therapy at CD4+ cell counts > 350 cells/mm3 Deferring antiretroviral therapy initiation until CD4+ cell count < 250 cells/mm3 resulted in 4 fold higher risk of OD and serious non AIDS events Current study provided rationale for randomized trial to directly test risk benefit ratio of early antiretroviral therapy initiation (ie, before decline of CD4+ cell count < 350 cells/mm3) Emery S, et al. J Infect Dis. 2008;197:

47 Botswana 6 Year Study: Survival High in Well Resourced Roll Out Programs BL and follow up data available for 53,423 adults Cumulative survival among HAART treated patients after 5 years of follow up: 88.6% (range: 88.1% to 89.2%) High 5 year survival rate in pts surviving 3 months: 94.3% Probability of survival greater among women (90.8%; 95% CI: 90.3% to 91.3%) vs men (85.1%; range: 84.0% to 86.2%; P <.05) Probability of survival lower with baseline CD4+ cell count < 100 cells/mm3 (P <.05) CD4+ count < 100 cells/mm3: 84.6% (95% CI: 83.9% to 85.4%) CD4+ count cells/mm3: 92.7% (95% CI: 92.1% to 93.3%) CD4+ count > 200 cells/mm3: 85.9% (95% CI: 83.5% to 88.4%) Puvimanasinghe J, et al. IAC Abstract MOAB0204.

48 ACTG 5202: Immunologic Response and Adverse Events Similar increases in CD4+ cell count in both arms, reaching approximately 400 cells/mm3 by Week 96 No association of suspected drug HSR and VF Rates of suspected HSR similar between arms Most patients with suspected HSR did not experience VF Adverse Events, % ABC/3TC (n = 398) TDF/3TC (n = 399) Any grade 3/4 adverse event* Lipid abnormalities 10 3 Gastrointestinal 7 5 Generalized symptoms Suspected drug HSR 7 7 *Occurring in 5% of patients reported. Sax PE, et al. IAS Abstract THAB0303.

49 HEAT: ABC/3TC Noninferior to TDF/FTC at Week 96 HIV 1 RNA < 50 copies/ml (%) ABC/3TC + LPV/RTV TDF/FTC + LPV/RTV *NRTI switches allowed. NRTI switches counted as failure. LPV/RTV could be switched to FPV/RTV M = F* TLOVR Obs MD = F VF occurred in 14% of patients in each arm according to conservative definition (failure to achieve VL < 200 copies/ml or confirmed VL 200 copies/ml after achieving VL < 50 copies/ml by Wk 24; confirmed VL > 200 copies/ml after Wk 24) Median CD4+ cell count increases similar in both ABC/3TC and TDF/FTC arms: +250 vs +247 cells/mm3 from BL to Week 96, respectively Smith KY, et al. IAC Abstract LBPE1138.

50 Possible Explanations for Differing Results in Similar Trials Differing study designs Longer vs shorter duration of follow up Endpoints: different definitions/time points for VF; TLOVR vs proportion of patients with HIV 1 RNA < 50 copies/ml Larger vs smaller sample size ABC/3TC compared with different NRTI strategies: ZDV/3TC, TDF/FTC Different third drug used: ATV/RTV, EFV, LPV/RTV, FPV/RTV

51 EFV vs LPV/RTV: HIV 1 RNA < 50 copies/ml at Week 48 EFV met criteria for superiority to LPV/RTV: Δ 17% (CI 95%: 3.5% to 31.0%; P =.017) P = P = % % 40 Efavirenz (n = 95) 20 LPV/RTV (n = 94) Week Number of Pts With HIV 1 RNA < 50 copies/ml EFV LPV Madero JS, et al. IAC Abstract TUAB0104. HIV 1 RNA < 50 copies/ml (%) HIV 1 RNA < 50 copies/ml (%) 79% 80 EFV LPV/RTV 64% 60 57% 49% n= cell/mm3 > 50 cell/mm3 By BL CD4+ Cell Count

52 EFV vs LPV/RTV: Resistance and Adverse Events Overall findings consistent with ACTG 5142 EFV performed well in patients with very advanced disease Greater CD4+ cell count increase with LPV/RTV Incidence of grade 2 4 adverse events similar between groups: 62% in both arms Significantly greater increase in triglyceride levels in LPV/RTV arm at 48 weeks vs efavirenz (P =.01) Changes in total cholesterol, HDL, and LDL similar between arms at Week 48 Among the few patients genotyped at failure, EFV recipients more likely to have any resistance and 2 class resistance Madero JS, et al. IAC Abstract TUAB0104.

53 Efficacy, Safety of Switching Agents in Patients With Virologic Suppression Patients (N = 244) who switched ZDV or d4t in suppressive HAART regimen to ABC maintained virologic suppression with significant increase in CD4+ cell counts at 1 year (P <.0001)[1] No difference in safety profile observed with switch GS903E (N = 85): Patients who switched d4t in effective HAART regimen to TDF maintained virologic suppression and experienced favorable immunologic outcomes at 4 years[2] Switch associated with significant triglyceride (P <.001) and cholesterol decreases (P <.001) Switch also associated with significant decrease in hip BMD (P <.001) and increase in limb fat (P <.001) Patients (N = 304) who switched from another PI to FPV (± 200 mg RTV) experienced favorable virologic, immunologic, and safety endpoints at 48 weeks[3] 1. Maggiolo F, et al. IAC Abstract TUPE Madruga JVR, et al. IAC Abstract TUPE Young B, et al. IAC Abstract TUPE0067.

54 First line NNRTI Based Antiretroviral Therapy for Acute HIV Infection TDF/FTC + EFV QD for acute HIV infection (N = 43) prior to genotype; subsequent switch for resistance Acute HIV infection: antibody or RNA negative 45 days of study entry, but reproducibly detectable antibody or RNA at BL Median BL HIV 1 RNA: 112,681 copies/ml Median BL CD4+ cell count: 521 cells/mm3 Higher HIV 1 RNA at BL associated with longer time to suppression Higher BL CD8+ activation associated with longer time to suppression Gay C, et al. IAC Abstract THPE0082. HIV 1 RNA < 400 copies/ml (all patients) HIV 1 RNA < 50 copies/ml (all patients) HIV 1 RNA < 400 copies/ml (BL VL > median) HIV 1 RNA < 400 copies/ml (BL VL median) HIV 1 RNA Suppressed (%) Days

55 Decreased Mortality in Pts Presenting for Care With Higher CD4+ Counts Mathematical model used to assess varying mortality rates in 3 HIV treatment centers in the Netherlands Only Dutch MSM included to minimize patient heterogeneity Risk of dying in first 3 years of treatment ranged from 0% to 8% among the 3 centers Low CD4+ cell counts at entry into care primary reason for intercenter variability in mortality rates Model estimates ~ 20% decrease in mortality for first 3 years if all patients presented for HIV care with CD4+ cell counts 400 cells/mm3 Smit C, et al. IAC Abstract TUPE0091.

56 Limitations of Studies and Clinical Considerations With ABC Use Results from both D:A:D and SMART are hypothesis generating, not definitive Recent ABC use associated with greater CV risk Addressing other CV risk factors in patients receiving ABC an important priority Currently unclear how these data should affect decisions regarding ABC in treatment naive patients and those already on therapy If an effective alternative to ABC exists for patients at high CV risk, it is reasonable to consider its use

57 No Difference Between Pregabalin vs Placebo for HIV Peripheral Neuropathy Pregabalin a common treatment for neuropathic pain syndromes Peripheral neuropathy occurs in > 30% of HIV infected individuals Common toxicity with certain antiretrovirals such as dideoxynucleoside drugs (ie, didanosine, stavudine) Pain primary symptom Current A study determined efficacy and safety of pregabalin for treatment of neuropathic pain in HIV infected patients* Mean pain scores at endpoint did not differ between pregabalin and placebo Significantly lower mean pain scores at Weeks 1, 2 in pregabalin arm compared with placebo (P.05) > 40% of patients in both arms had 50% reduction in pain score Few patients with d drug experience: 13% in pregabalin arm and 9% in placebo arm * Simpson DM, et al. IAC Abstract THAB0301.

58 Pharmacology of Raltegravir: Implications for Dosing & Interactions Raltegravir administered as one 400 mg pill BID without regard to food Raltegravir metabolized by glucuronidation May have fewer interactions with drugs metabolized by cytochrome P450 Strong inducers or inhibitors of UGT1A1 (enzyme responsible for raltegravir glucuronidation) Atazanavir: increases raltegravir levels but increases not shown to be clinically relevant[1] Tipranavir: reduces plasma levels of raltegravir[2] but comparable efficacy observed in 100 patients receiving raltegravir plus either tipranavir/ritonavir or a control PI[1] 1. Raltegravir package insert. 2. Wenning LA, et al. ICAAC Abstract A 0374.

59 Pharmacology of Elvitegravir: Implications for Dosing & Interactions Elvitegravir/ritonavir 150/100 mg being studied in ongoing clinical trials If coadministered with ritonavir boosted atazanavir or lopinavir, elvitegravir dose reduced to 85 mg Elvitegravir metabolized via cytochrome P450 3A4 Significant interactions with PIs reported Coadministration of elvitegravir/ritonavir with atazanavir resulted in increased ritonavir exposure, requiring reduction of elvitegravir dose Elvitegravir exposure enhanced by coadministration with low dose ritonavir Allows QD dosing Ritonavir itself associated with numerous drug drug interactions Mathias A, et al. ICAAC Abstract A Mathias A, et al. ICAAC Abstract A 1418.

60 Raltegravir in Experienced Patients With Virologic Failure High rate of integrase resistance at virologic failure highlights risk of prescribing raltegravir for experienced patients without other active agents in OBR Principles for use of raltegravir in this population Combine with other new active agents Regimen containing raltegravir plus 2 other active agents appears more effective than regimen containing raltegravir plus 1 other active agent[1,2] Likelihood of achieving virologic suppression greater if raltegravir introduced earlier rather than later while[1,2] HIV 1 RNA is relatively low and Patient still susceptible to at least some other antiretrovirals 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.

61 BENCHMRK 1 & 2: HIV 1 RNA < 50 c/ml at Week 48, Overall and by GSS Subgroup n Total Percent of Patients Raltegravir Placebo GSS: Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright 2008 Merck & Co., Inc., All Rights Reserved.

62 Protocol 004 (RAL) Phase IIb: Change in Lipids Through Week 48 Mean change from BL in total cholesterol Raltegravir: 2.3 mg/dl ( 0.06 mmol/l) Efavirenz: 20.7 mg/dl (+0.54 mmol/l) (P <.001) Low density lipoprotein cholesterol and triglycerides Raltegravir: unchanged from BL (P =.07) Efavirenz: increased (P =.016) High density lipoprotein cholesterol Smaller increases with raltegravir vs efavirenz (P =.01 for difference between raltegravir and efavirenz groups) Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:

63 Overview Safety and efficacy of raltegravir demonstrated in both antiretroviral experienced and antiretroviral naive patients Elvitegravir studied predominantly in treatment experienced patients to date Current clinical application of integrase inhibitors concerns management of treatment experienced patients with resistance to other antiretrovirals

64 > 95% adherence believed to be necessary for virologic suppression Based on data from non boosted PI regimens Lower levels of adherence may be sufficient for NNRTI based regimens Analysis of adherence and virologic response in REACH Cohort (n = 279) Compared with PIs, odds of virologic suppression were higher for boosted PIs and NNRTIs Similar viral suppression for boosted PIs and NNRTIs Levels of adherence comparable for all three groups despite pill count Patients with VL < 50 copies/ml, % Adherence and Outcome in NNRTI and PI based HAART Bangsberg DR, et al. IAS 2007, Abstract WEPEB111 NNRTI PI Boosted PI P =.04 P = % n = % % 83 Patient Adherence > 99% 71

65 PASPORT: Study Objectives Evaluate relative impact of regimen characteristics on patient adherence Different HAART regimen characteristics (i.e., dosing frequency) Strata within each regimen characteristic (i.e. BID, QD all at once, QD different times, mixed QD/BID) Stone VE, et al. JAIDS. 2004;36:

66 PASPORT: Impact of Regimen Characteristics on Adherence 6.06% 7.61% 13.74% 8.17% 13.02% 8.77% 12.67% 8.98% 9.64% Stone VE, et al. JAIDS. 2004;36: % Total pills per day Dosing frequency Diet restrictions Adverse effects Pill Size No. of refills No. of copays No. of prescriptions No. of bottles Bedtime dosing?

67 PASPORT: Conclusions Many regimen characteristics contribute to adherence, but pills per day, dosing frequency, diet restrictions, and side effects contribute more than others Once daily QD regimens only provide an adherence benefit over other HAART regimens if they can be taken all at 1 time, contain few pills and no dietary restrictions. Underscores the adherence benefit of new compact regimens using co formulated pills. Stone VE, et al. JAIDS 2004;36:

68 ICONA Study: Reasons for Failure of Initial HAART I.CO.N.A. Study Group 8% n = 25 Median Follow up 45 weeks Total N = 862 Discontinuations n = 312 (36%) Virologic failure Nonadherence Toxicity Other 20% n = 61 14% n = 44 d'arminio Monforte A, et al. AIDS. 2000;14: % n = 182

69 ACTG 5202: Shorter Time to VF in Pts With High VL Receiving ABC/3TC Shorter time to virologic failure in patients receiving ABC/3TC Proportion of patients with virologic failure receiving ABC/3TC vs TDF/FTC: 14% vs 7% HR: 2.33 (95% confidence interval [CI]: ; P =.0003) Outcome, n ABC/3TC (n = 398) TDF/FTC (n = 399) Virologic failure (VF), total Early VF with no previous suppression to HIV 1 RNA < 200 copies/ml 19 9 Late VF with no previous suppression to HIV 1 RNA < 200 copies/ml 9 2 Late VF with previous suppression to HIV 1 RNA < 200 copies/ml Similar proportions in each arm with VL < 50 c/ml at Wk 48 (P =.20) by ITT (prior regimen changes and virologic failures allowed) Post hoc analysis: for subjects achieving 2 VL < 50 c/ml on therapy, no significant difference in risk of viral rebound between arm (P =.247) Sax PE, et al. IAS Abstract THAB0303.

70 Possible Explanations for Differing Results in Similar Trials Differing study designs Longer vs shorter duration of follow up Endpoints: different definitions/time points for VF; TLOVR vs proportion of patients with HIV 1 RNA < 50 copies/ml Larger vs smaller sample size ABC/3TC compared with different NRTI strategies: ZDV/3TC, TDF/FTC Different third drug used: ATV/RTV, EFV, LPV/RTV, FPV/RTV

71 Efficacy, Safety of Switching Agents in Patients With Virologic Suppression Patients (N = 244) who switched ZDV or d4t in suppressive HAART regimen to ABC maintained virologic suppression with significant increase in CD4+ cell counts at 1 year (P <.0001)[1] No difference in safety profile observed with switch GS903E (N = 85): Patients who switched d4t in effective HAART regimen to TDF maintained virologic suppression and experienced favorable immunologic outcomes at 4 years[2] Switch associated with significant triglyceride (P <.001) and cholesterol decreases (P <.001) Switch also associated with significant decrease in hip BMD (P <.001) and increase in limb fat (P <.001) Patients (N = 304) who switched from another PI to FPV (± 200 mg RTV) experienced favorable virologic, immunologic, and safety endpoints at 48 weeks[3] 1. Maggiolo F, et al. IAC Abstract TUPE Madruga JVR, et al. IAC Abstract TUPE Young B, et al. IAC Abstract TUPE0067.

72 Patients With HIV 1 RNA < 50 copies/ml (%) Protocol 004: 96 Week Results of RAL vs EFV in Treatment Naive Pts (NC = F) * 83% 84% Using observed failure approach: RAL 92% and EFV 91% Week Number of Contributing Patients *After Week 48, patients in all RAL groups continued at 400 mg BID. All patients received TDF/3TC RAL 100 mg BID. RAL 200 mg BID. RAL 400 mg BID. RAL 600 mg BID. EFV 600 mg QD Markowitz M, et al. IAC Abstract TUAB

73 Higher Risk of AIDS, Death at Lower CD4+ Counts Despite VL Suppression Prospective, longitudinal study of 249 virologically suppressed patients from MACS cohort with BL CD4+ cell count < 200 cells/mm3 Disease progression observed after achieving HIV 1 RNA < 50 copies/ml on HAART (most patients remained suppressed) 17 (6.8%) developed new AIDS defining illness 25 (10.0%) died Greater in CD4+ cell count during virologically suppressive HAART associated with decreased risk of AIDS defining illness or death CD4+ Cell Count During HAART With HIV 1 RNA < 50 copies/ml < 200 cells/mm cells/mm3 Risk of AIDS Defining Illness HR P Value 1 (reference) Risk of Death HR P Value 1 (reference) > 350 B, cells/mm 0.25 Taiwo et al. IAC Abstract TUPE <.001

74 Decreased Mortality in Pts Presenting for Care With Higher CD4+ Counts Mathematical model used to assess varying mortality rates in 3 HIV treatment centers in the Netherlands Only Dutch MSM included to minimize patient heterogeneity Risk of dying in first 3 years of treatment ranged from 0% to 8% among the 3 centers Low CD4+ cell counts at entry into care primary reason for intercenter variability in mortality rates Model estimates ~ 20% decrease in mortality for first 3 years if all patients presented for HIV care with CD4+ cell counts 400 cells/mm3 Smit C, et al. IAC Abstract TUPE0091.

75 DUET 1 and 2: ETR + DRV/RTV Containing OBR, Phase III Trials Week 24: primary endpoint HIV infected patients with virologic failure on current HAART regimen, history of 1 NNRTI RAM, 3 PI mutations, and HIV 1 RNA > 5000 copies/ml (DUET 1: N = 612; DUET 2: N = 491) Week 48: current analysis Week 96: planned follow up ETR 200 mg BID + DRV/RTV containing OBR* (DUET 1: n = 304; DUET 2: n = 295) Placebo + DRV/RTV containing OBR* (DUET 1: n = 308; DUET 2: n = 296) *Investigator selected OBR comprising DRV/RTV 600/100 mg BID + 2 NRTIs ± ENF. Cahn P, et al. IAC Abstract TUPE0047.

76 DUET 1 and 2: Association of BL Variables and Response to ETR Rate of HIV 1 RNA < 50 copies/ml at Wk 48 significantly greater with ETR vs placebo (61% vs 40%, P <.0001)[1] ENF use, number of concomitant active agents, HIV 1 RNA, CD4+ cell count significantly predicted virologic response in both ETR and placebo treated pts Receipt of 2 previous NNRTIs predicted poorer response to ETR High response rates in pts with 3 combined ETR + DRV RAMs at Wk 24[2] ETR RAMs, n HIV 1 RNA < 50 copies/ml, % (n/n) DRV RAMs, n >3 78 (7/9) 67 (8/12) 100 (3/3) 67 (2/3) 0 (0/1) 1 83 (36/44) 71 (27/38) 93 (13/14) 57 (4/7) 40 (2/5) 2 73 (30/41) 75 (18/24) 56 (9/16) 29 (2/7) 17 (1/6) 3 78 (31/40) 50 (12/24) 45 (9/20) 60 (3/5) 30 (3/10) >3 63 (17/27) 35 (8/23) 27 (3/11) 27 (3/11) 0 (0/5) 1. Cahn P, et al. IAC Abstract TUPE Haubrich R, et al. IAC Abstract TUPE0048.

77 High Response Rates With ETR Based Regimens in US Early Access Program Outcome, Week 24 ETR + DRV/RTV + RAL + BR (n = 486) 66 ETR + DRV/RTV + BR (n = 338) 62 ETR + RAL + BR (n = 234) 65 ETR + BR (n = 140) Mean change in HIV 1 RNA from BL, log10 copies/ml (SD) 2.3 (1.14) 1.9 (1.28) 2.3 (1.18) 1.8 (1.43) Median change in CD4+ cell count from BL, cells/mm3 (IQR) 91 (39 154) 82 (18 148) 98 (31 175) 88 (17 188) HIV 1 RNA < 75 copies/ml, % HIV 1 RNA < 400 copies/ml, % 66 Similar low rates of serious adverse events, discontinuations due to adverse events in all arms Towner W, et al. IAC Abstract TUPE0066.

78 BENCHMRK 1 and 2: VL < 50 c/ml at Week 48, Overall and by GSS, PSS Patient Group Patients With HIV 1 RNA < 50 c/ml, % Raltegravir + OBR Placebo + OBR 64 (n = 443) 34 (n = 228) 0 45 (n = 112) 3 (n = 65) 1 67 (n = 166) 37 (n = 92) 2 75 (n = 158) 59 (n = 68) 0 51 (n = 65) 2 (n = 44) 1 61 (n = 137) 29 (n = 69) 2 71 (n = 221) 48 (n = 108) All patients GSS at baseline PSS at baseline (number of fully active agents, FC < lower cutoff) PSS at baseline (number of fully or partially active agents, FC < upper cutoff) 0 52 (n = 33) 8 (n = 12) 1 48 (n = 71) 13 (n = 54) 2 70 (n = 313) 43 (n = 153) Cooper DA, et al. CROI Abstract 788. Steigbigel R, et al. CROI Abstract 789.

79 MOTIVATE 1 and 2: MVC + OBR vs Placebo + OBR, Phase III Trials 1:2:2 randomization; stratified by ENF use and HIV 1 RNA < or 100,000 copies/ml Treatment experienced HIV infected patients with CCR5 tropic virus only, HIV 1 RNA 5000 copies/ml, stable ART or no ART for 4 weeks, resistance to and/or 6 months of 1 antiretroviral from 3 classes or 2 PIs (MOTIVATE 1: N = 601; MOTIVATE 2: N = 475) Week 48 Placebo + OBR* (n = 209) MVC QD (150 mg or 300 mg ) + OBR (n = 414) MVC BID (150 mg or 300 mg ) + OBR (n = 426) *OBR comprising 3 6 antiretroviral agents. Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. 1. Nelson M, et al. IAC Abstract TUPE Asmuth A, et al. IAC Abstract TUPE0050.

80 Subanalyses of MOTIVATE Double blind, phase III MOTIVATE 1 and 2 (N = 1076) studies of MVC + OBR demonstrated superior outcomes at 48 weeks vs placebo + OBR alone in patients with R5 using HIV 1 infection Significantly better virologic and immunologic outcomes with MVC vs placebo in both TCR and non TCR subgroups[1] TCR patients: HIV 1 RNA < 50 copies/ml in 42.9% vs 10% with MVC vs placebo Non TCR patients: HIV 1 RNA < 50 copies/ml in 49.7% vs only 25.8% with MCV vs placebo Early and greater increases in CD4+ cell and CD8+ cell counts with MVC treatment vs placebo (P =.0182 and P <.0001, respectively) Observed both in patients with HIV 1 RNA < 50 copies/ml by Week 48 and those who did not achieve undetectable HIV 1 RNA[2] 1. Nelson M, et al. IAC Abstract TUPE Asmuth A, et al. IAC Abstract TUPE0050.

81 MOTIVATE 1 and 2: Combined Virologic Efficacy at Week Placebo + OBR (n = 209) MVC QD + OBR (n = 414) MVC BID + OBR (n = 426) Patients With HIV 1 RNA < 50 copies/ml (%) %* 43.2%* % 10 0 *P <.0001 vs placebo Time (Weeks) Hardy D, et al. CROI Abstract 792.

82 TRIO Study: RAL + ETR + DRV/RTV Highly Effective as 3 Active Agents Multicenter, phase II study of DRV/RTV plus ETR plus RAL (N = 103); addition of NRTIs, ENF at discretion of physician Inclusion criteria included susceptibility to DRV and ETR based on 3 DRV and 3 ETR RAMs, respectively 59% of patients had < 1 active agent in OBR, as assessed by GSS 90% of patients attained HIV 1 RNA < 50 copies/ml at Week 24 (95% CI: 85% to 96%) Median increase in CD4+ cell count from BL to Week 24: 99 cells/mm3 (IQR: ) Of 10 patients with detectable HIV 1 RNA at Week 24, only 3 had confirmed HIV 1 RNA > 400 copies/ml 2 possibly drug related clinical grade 4 adverse events; only 1 led to treatment discontinuation Yazdanpanah Y, et al. IAC Abstract THAB0406.

83 Background: Previous D:A:D Findings on CV Risk Associated With ABC, ddi D:A:D a collaboration of 11 prospective cohorts at 212 clinics in the United States, Europe, and Australia with data on 33,347 HIV infected patients receiving antiretroviral therapy 517 (1.6%) of patients developed MI over 5 years Impact of cumulative, recent, and past use of select NRTIs on risk of MI in HIV infected individuals Recent use of ABC and ddi associated with 90% and 47% increased risk of MI, respectively Risk most prominent in individuals with underlying CV risk factors Increased risk not seen in those who had previously used these drugs Sabin CA, et al. Lancet. 2008;371:

84 Observational Analysis of SMART Study to Confirm/Refute D:A:D Results Analysis of SMART participants in 3 post hoc subgroups by NRTI use Patients receiving ABC and not ddi Patients receiving ddi, with ABC or other NRTIs Patients receiving NRTIs other than ABC and ddi CV endpoints MI Major CVD events: clinical and silent MI, stroke, surgery for CAD, and CVD death Expanded major CVD events: major CVD events plus peripheral vascular disease, CHF, pharmacotherapy for CAD, and unwitnessed deaths Minor CVD events: CHF, peripheral vascular disease, or CAD requiring pharmacotherapy Lundgren J, et al. IAC Abstract THAB0305.

85 No Difference Between Pregabalin vs Placebo for HIV Peripheral Neuropathy Pregabalin a common treatment for neuropathic pain syndromes Peripheral neuropathy occurs in > 30% of HIV infected individuals Common toxicity with certain antiretrovirals such as dideoxynucleoside drugs (ie, didanosine, stavudine) Pain primary symptom Current A study determined efficacy and safety of pregabalin for treatment of neuropathic pain in HIV infected patients* Mean pain scores at endpoint did not differ between pregabalin and placebo Significantly lower mean pain scores at Weeks 1, 2 in pregabalin arm compared with placebo (P.05) > 40% of patients in both arms had 50% reduction in pain score Few patients with d drug experience: 13% in pregabalin arm and 9% in placebo arm * Simpson DM, et al. IAC Abstract THAB0301.

86 Botswana 6 Year Study: Survival High in Well Resourced Roll Out Programs BL and follow up data available for 53,423 adults Cumulative survival among HAART treated patients after 5 years of follow up: 88.6% (range: 88.1% to 89.2%) High 5 year survival rate in pts surviving 3 months: 94.3% Probability of survival greater among women (90.8%; 95% CI: 90.3% to 91.3%) vs men (85.1%; range: 84.0% to 86.2%; P <.05) Probability of survival lower with baseline CD4+ cell count < 100 cells/mm3 (P <.05) CD4+ count < 100 cells/mm3: 84.6% (95% CI: 83.9% to 85.4%) CD4+ count cells/mm3: 92.7% (95% CI: 92.1% to 93.3%) CD4+ count > 200 cells/mm3: 85.9% (95% CI: 83.5% to 88.4%) Puvimanasinghe J, et al. IAC Abstract MOAB0204.

87 Clinical Monitoring Inaccurately Predicts Virologic Failure Virologic analysis of 910 pts in Haiti with failure by WHO criteria[1] 48% of patients with WHO stage III/IV clinical symptoms had undetectable viral loads Current WHO Guidelines to Define ART Failure in Settings Without Virologic Testing 50% or more decrease of CD4+ cell count Return of the CD4+ cell count to pretherapy 90% of patients with 50% decrease BL or lower in CD4+ cell count had detectable Occurrence of WHO stage III/IV conditions HIV 1 RNA 88% of viremic patients had resistance mutations 33% of patients had 2 TAMs Vietnam study also found lack of correlation between clinical or immunologic failures and VF[2] 1. Charles M, et al. IAC Abstract MOPDC van Nguyen K, et al. IAC Abstract MOPE0040.

88 Optimizing Adherence Optimal adherence plays a pivotal role in sustaining efficacy of ART Influenced greatly by patient motivation and knowledge but also by convenience and tolerability of treatment regimen Minimizing pill count and size, frequency of dosing, and dietary requirements important in supporting higher levels of adherence Reducing adverse effects of therapy vital to increased adherence Most boosted PIs administered twice daily ATV dosed once daily, but reduced efficacy with extensive PI resistance Less toxic, more convenient boosted PI regimens can improve adherence, but cannot replace ongoing patient education and adherence monitoring within clinic

89 Pharmacology of Boosted PIs High PI concentration can inhibit drug resistant virus and increase genetic barrier to wild type virus RTV boosting improves exposure, increases activity against resistant virus, improves durability in naive patients However, increased exposure may increase toxicities RTV inhibits cytochrome P450 isoenzymes such as CYP 3A4 In addition to boosting PIs, other drugs patient may be taking can be affected by this inhibition Other drugs that inhibit or induce CYP 3A4 may affect PI levels EFV commonly used NNRTI that induces CYP3A4 Use of EFV in patients receiving boosted PIs may cause drop in PI level and loss of activity if PI dosage not increased appropriately

90 Pharmacology of Boosted PIs (con t) Boosted PIs should not be combined until clinical trials have determined potential for drug drug interactions Non HIV medications also interact with boosted PIs Rifampin can greatly reduce PI levels Boosted PIs can dangerously increase concentration of sildenafil Must caution patients taking boosted PIs about taking any new medications and address potential interactions accordingly Therapeutic drug monitoring (TDM) remains somewhat controversial issue in routine management of ART treated patients PI drug levels correlate with efficacy and toxicities, but ability to effectively improve patient care by measuring PI levels and adjusting dosage unproven

91 Manipulating Dosage of Boosted PIs With Ritonavir: A Delicate Balance Improves exposure Impact on adherence Greater activity against resistant virus Risk of increased toxicity