HIV Life Cycle. Update ARV and Opportunistic infection 23/12/54. Current ARV. DHHS Guidelines 2011: When to Start

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1 HIV Life Cycle Update ARV and Opportunistic infection 2. Membrane fusion & entry Maturation Ploenchan Chetchotisakd, MD Professor of Medicine Division of Infectious Diseases and Tropical Medicine Faculty of Medicine Khon Kaen University 1. Receptor binding 3. Uncoating & reverse transcription 7. Nuclear export 8. Translation & Assembly 6. Transcription & RNA processing 9. Budding 4. Nuclear uptake 5. Integration Current ARV NRTI NNRTI PI AZT NVP ATV ddi d4t 3TC FTC ABC TDF ETV RPV DRV FPV IDV LPV/r NFV RTV TPV Entry inhibitor Fusion inhibitor T2 CCR5 inhibitor Maraviroc Integrase inhibitor RAL CD4+ Counts, cells/mm 3 > < 2 or symptomatic disease Changing Guidelines for Initiation of Antiretroviral Therapy Offer if VL > 2, copies/ml Offer if VL > 2, copies/ml Consider if VL> 55, copies/ml Offer, but controversy exists Consider if VL 1, copies/ml Offer after discussion with patient Consider in certain groups* Treat Treat at 35-5; consider for > 5 Treat Treat Treat Treat Treat Treat Asymptomatic Infection CD4+ cell count < 35 cells/mm 3 CD4+ cell count 35-5 cells/mm 3 CD4+ cell count > 5 cells/mm 3 DHHS Guidelines 211: When to Start Recommendation Start HAART Start HAART Panel divided Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count History of AIDS-defining illness Certain acute opportunistic infections Pregnancy HIVAN HBV coinfection when HBV treatment is indicated CD4+ count decline > 1 cells/mm 3 /yr HIV-1 RNA > 1, copies/ml Serodiscordant relationships Specific conditions IAS-USA 21: Guidelines for When to Start ARV Therapy Symptomatic HIV disease Pregnancy Measure High HIV-1 RNA Level (>1, copies/ml) Rapid CD4 count decline (>1 cells/mm 3 per year) Active hepatitis B or C* virus co-infection Active or high risk for cardiovascular disease* HIV-associated nephropathy Symptomatic primary HIV infection* Risk for secondary HIV transmission is high* CD4 cell count 5 cells/mm 3 Recommendation ART recommended regardless of CD4 cell count ART recommended CD4 cell count >5 cells/mm 3 ART should be considered DHHS Guidelines. October, 211. * Differs from 29 DHHS guidelines Unless patient is an elite controller (HIV-1 RNA <5 copies/ml) or has stable CD4 cell count and low-level viremia in the absence of ART Thompson MA, et al. JAMA 21;34(3): ; US Department of Health and Human Services Guidelines; Revised December 1, 29. Available at: 1

2 European AIDS Guidelines: Thailand Guidelines: Initiation of ART in the Chronically HIV-Infected Patient Clinical Category CD4 Recommendation AIDS Any Treat Symptomatic HIV Any Treat Asymptomatic <35 Treat Pregnancy Any Treat, D/C after delivery if CD4>35 R= Recommended, C= Considered, D=Deferred Sungkanuparph S. Asian BMC 21 CIPRAHT1: Early (CD4< 35) vs Standard (CD4<2) Therapy in Haiti CIPRAHT1: Early (CD4< 35) vs Standard (CD4<2) Therapy in Haiti Treatment naive patients with CD and No history of AIDS Defining illness (n=816) Severe P. NEJM 21;363: Early Antiretroviral therapy Initiated within 2 wks of enrolment (n=48) Study halted early 29 deaths report Standard Antiretroviral therapy Initiated when CD4 < 2 cells/mm3 Or upon development of AIDS-defining illness (n=48) Outcomes Early ARV N=48 Standard ARV N=48 Hazard ratio P-value Death, n Gastroenteritis 1 7 TB 5 Pneumonia 4 Cholangitis/sepsis 1 Other 5 6 Incident TB Severe P. NEJM 21;363: Early vs. standard antiretroviral therapy for HIV-infected adults in Haiti เร มยาเม อ CD เซลล /ลบ.มม เร มยาเม อ CD4 < 2 เซลล /ลบ.มม สปสช 6 กค. 211 อน ม ต ให เร มการร กษาผ ป วยต ดเช อ HIV เม อ CD4 < 35 cell/mm3 เม อผ ป วยม ความพร อมและกรณ ต อไปน 1. Coinfection with HBV or HCV 2. Age > 5 yr with DM, HT or DLD 3. HIV-associated nephropathy 4. Postpartum women who had CD4 < 35 during pregnancy Note: any patients who have OI or TB can start ARV at any CD4 count Severe P. NEJM 21;363:

3 Recommended Alternative Preferred First-line Regimens: 211 DHHS Guidelines Alternate First-line Regimens: 211 DHHS Guidelines Preferred regimens: those with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use. (AI) NNRTI based Boosted PI based Integrase inhibitor based Pregnancy * + ATV/RTV** + DRV/RTV + RAL + AZT + 3TC + LPV/r * Caution with pregnancy, ** should net be used in pt taking omiprazole>2mg/d US Department of Health and Human Services. Available at: Alternate regimens: Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. (BI) NNRTI based Boosted PI based Integrase inhibitor based + ABC/3TC (BI) RPV/ (BI) RPV+ ABC/3TC (BIII) ATV/RTV + ABC/3TC (BI) DRV/RTV +ABC/3TC (BIII) FPV/RTV + or ABC/3TC (BI) LPV/r + or ABC/3TC (BI) RAL + ABC/3TC (BI) US Department of Health and Human Services. Available at: Acceptable First-line Regimens: 211 DHHS Guidelines Antiretroviral Components Not Recommended as Part of an Antiretroviral Regimen Acceptable Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens. (CI) NNRTI based Boosted PI based Integrase inhibitor based CCR5 based + AZT/3TC NVP + or ABC/3TC or AZT/3TC RPV + AZT/3TC ATV or ATV/r + ABC or AZT+3TC DRV/RTV +AZT+3TC FPV/r + AZT+3TC LPV/r + AZT+3TC RAL + AZT+3TC MVC + AZT+ 3TC MVC + or ABC/3TC ATV+IDV (AII) ddi +d4t (AII) ddi +TDF (AII) 2NNRTI (AI) in 1 st trimester (AIII) AZT +d4t (AII) FTC + 3TC (AIII) ETR + ATV/r, FPV/r, TPV/r (AII) ETR + unboosted PI (AII) Unboosted DRV, SQV, TPV (AII) NVP in ARV naïve (BI) Female CD4 > 25 Male CD4 > 4 US Department of Health and Human Services. Available at: IAS-USA 21: Guidelines for Initial ARV Regimens European Guideline 211 Dual NRTI Key 3 rd Drug Recommended Regimens + ATV/r DRV/r RAL ABC/3TC LPV/r FPV/r MVC Comparison to 29 DHHS Guidelines: Recommended therapies are the same as Preferred regimens In addition to Alternative therapies listed, 29 DHHS Guidelines Alternative and Acceptable regimens include ZDV/3TC, ddi + 3TC, NVP, unboosted ATV, and SQV/r Thompson MA, et al. JAMA. 21;34; Thompson MA, et al. JAMA 21;34(3): ; US Department of Health and Human Services Guidelines; Revised December 1, 29. Available at: 3

4 Probability of Remaining Free of Virologic Failure Patients Without Virologic Failure (%) Mean in BMD From BL to Wk 96 (%) Patients Without Virologic Failure (%) Mean in BMD From BL to Wk 96 (%) Alternative Regimens European Guideline 211 ACTG 522: First-line Therapy With ABC/3TC vs + vs ATV/RTV Stratified by HIV-1 RNA < or 1, copies/ml Wk 96 primary endpoint * 3/2 mg QD + 6 mg QD (n = 464) *Double blind. Open label. Antiretroviral-naive patients with HIV-1 RNA 1 copies/ml and any CD4+ cell count (N = 1857) ABC/3TC* 6/3 mg QD + 6 mg QD (n = 465) * 3/2 QD + ATV/RTV 3/1 mg QD (n = 465) ABC/3TC* 6/3 mg QD + ATV/RTV 3/1 mg QD (n = 463) Daar E, et al. CROI 21. Abstract 59LB. ACTG 522: Virologic Failure With ATV/RTV vs at Wk 96 ACTG 522: Virologic Failure With ABC/3TC vs Similar time to virologic failure with ATV/RTV vs when combined with either ABC/3TC or in overall population analysis With ABC/3TC, HR: 1.13 (95% CI: ) With, HR: 1.1 (95% CI: ) ABC/3TC ATV/RTV In pts with screening VL < 1, c/ml Similar time to virologic failure with ABC/3TC vs regardless of ATV/RTV or With ATV/RTV, HR: 1.26 ( ) With, HR: 1.23; ( ) In pts with screening VL 1, c/ml Shorter time to VF with ABC/3TC vs. with either or ATV/RTV With, HR: 2.22 ( ) With ATV/RTV, HR: 2.46 ( ) Virologic Failure Free at 96 Wks for Pts With Screening VL < 1, copies/ml ABC/3TC ATV/RTV Daar E, et al. CROI 21. Abstract 59LB. Daar E, et al. CROI 21. Abstract 59LB. ACTG 522: Shorter Time to VF in Patients With High HIV-1 RNA Receiving ABC/3TC Metabolic Substudy of ACTG 522: Lumbar Spine and Hip BMD Changes (ITT) ABC/3TC (57 events) (26 events) Log rank P =.3 HR: 2.33 (95% CI: ) Wks From Randomization Sax PE, et al. N Engl J Med. 29;361: Outcome, n ABC/3TC (n = 398) (n = 399) Virologic failure (VF), total Early VF with no previous suppression to VL< 2 Late VF with no previous suppression to VL< 2 Late VF with previous suppression to VL< Similar proportions in each arm with VL < 5 at Wk 48 (P =.2) by ITT (switching NRTIs failure) Post hoc analysis: for subjects achieving 2 VL < 5 on ART, no significant difference in risk of rebound between arms (P =.247) Comparison of ABC/3TC vs ABC/3TC P =.4 P =.25 n = Difference: 2.% Lumbar Spine McComsey G, et al. CROI 21. Abstract 16LB. Difference: 1.5% Hip Comparison of vs ATV/RTV ATV/RTV P =.35 P =.59 n = Lumbar Spine Initial loss in BMD in all arms stabilized after Wk 48 No significant differences in fracture rates between arms Difference : 1.5% Difference:.3% Hip 4

5 Patients (%) 1% Limb Fat Loss From BL to Wk 96 (%) Median Change (%) Median Change (%) Median Change (%) Median Change (%) Patients (%) Patients (%) Pts With HIV-1 RNA < 5 copies/ml (%) Patients (%) Metabolic Substudy of ACTG 522: Limb Fat Changes Boosted PIs in ARV-Naive Pts: Virologic Suppression at Wk Limb Fat Primary Endpoint 14.3 n = 56 + ABC/3TC + + ATV/RTV ABC/3TC + ATV/RTV P = NS 18.9 McComsey G, et al. CROI 21. Abstract 16LB. 53 Regimen Similar absolute and % increases in limb fat with ABC/3TC and in ITT analysis (P >.1) In as-treated analysis, greater increase in limb fat with ABC/3TC vs (difference: 1 kg; P =.23) Greater absolute and % increases in limb and trunk fat with ATV/RTV vs in ITT and as-treated analyses (P <.5) KLEAN [1] (ITT-E, TLOVR) NRTIs: ABC/3TC GEMINI [2] (ITT) NRTIs: CASTLE [4] ARTEMIS [3] (ITT) (ITT) NRTIs: NRTIs: 84* * n = LPV/RTV FPV/RTV LPV/RTV SQV/RTV LPV/RTV ATV/RTV LPV/RTV DRV/RTV 4/1 7/1 4/1 1/1 4/1 3/1 4/1 8/1 BID BID BID BID BID QD BID or QD 8/2 QD This slide is an illustration only and not meant to be a cross-study comparison. *P <.5 between LPV/RTV QD and DRV/RTV QD; no other significant differences in any comparisons above. Use of LPV/RTV BID or QD was not randomized and was dependent on site and pt preference. SGC or tablet until Wk 8; tablet after Wk Eron J Jr, et al. Lancet. 26;368: Walmsley SL, et al. J. Infect Dis. 29;5: Molina JM, et al. Lancet. 28;372: Ortiz R, et al. AIDS. 28;22: Lipid Changes From BL to Wk 48 ECHO, THRIVE: Rilpivirine vs in Treatment-Naive Patients KLEAN [1] FPV/RTV LPV/RTV TC LDL HDL TG TC LDL HDL TG P <.1 ARTEMIS [3] 7 P < CASTLE 6 [4] DRV/RTV ATV/RTV 51 5 LPV/RTV LPV/RTV 4 P <.1 32 P < TC LDL HDL TG This slide is an illustration only and not meant to be a cross-study comparison. 1. Eron J Jr, et al. Lancet. 26;368: Walmsley SL, et al. J. Infect Dis. 29;5: Nelson M, et al. Inter Congress on Drug Therapy in HIV Infection 28. Abstract P Reprinted from The Lancet, v 372, Molina JM, et al, pp GEMINI [2] SQV/RTV LPV/RTV P = TC LDL HDL TG 47 Randomized, double-blind phase III trials Stratified by BL Wk 48 HIV-1 RNA < 1, primary analysis vs 1, copies/ml, NRTI use* RPV 25 mg QD + 3/2 mg QD ECHO (n = 346) (N = 69) 6 mg QD + 3/2 mg QD Treatment-naive, (n = 344) HIV-1 RNA 5 copies/ml, no NNRTI RAMs, susceptible to NRTIs RPV 25 mg QD + 2 NRTIs THRIVE (n = 34) (N = 678) 6 mg QD + 2 NRTIs (n = 338) *THRIVE only. Selected by investigator from ABC/3TC,, ZDV/3TC. Cohen C, et al. AIDS 21. Wk 96 final analysis ECHO, THRIVE: Rilpivirine vs in Treatment-Naive Patients ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events at Wk n = RPV HIV-1 RNA < 5 copies/ml (ITT-TLOVR) at Wk * Pooled ECHO *P <.1 for noninferiority at -12% margin. 85.6* 82.9* Cohen C, et al. AIDS 21. Abstract THLBB26. Cohen C, et al. Glasgow 21. Abstract O THRIVE 338 HIV-1 RNA < 5 copies/ml at Wk 48 by BL VL 1, copies/ml 6.6 ( ) / 276/ 162/ 136/ 17/ 14/ Pooled ECHO THRIVE > 1, copies/ml (-9.8 to +2.5) / 285/ 125/ 149/ 121/ 136/ Pooled ECHO THRIVE Treatment Failure in ECHO and THRIVE n = VF Resistance at VF AE RPV Wk 48 Outcome RPV VF with resistance data, n No NNRTI or NRTI RAMs, % emergent NNRTI RAM, % Most frequent NNRTI RAM E138K K13N 1 emergent NRTI RAMs, % Most frequent NRTI RAM M184I M184V HIV-1 RNA < 5 copies/ml (ITT-TLOVR) by Adherence Level Self-Reported Adherence Wk 48 Outcome, % RPV P Value DC for AE Most Common AEs of Interest, % RPV (n = 627) (n = 587) > 95% > 9% - 95% < 9% AEs and Discontinuation Any neurologic AE <.1 Any psychiatric AE Any rash 3 14 <.1 Cohen C, et al. AIDS 21. Abstract THLBB26. Cohen C, et al. Glasgow 21. Abstract O48. 5

6 HIV RNA Decline (log 1 copies/ml) Riplivirine Riplivirine Once-daily dosing Coformulated with (Endurance) Compared with : - Fewer discontinuations for CNS adverse effects - Fewer lipid effects - Fewer rashes More virologic failures in patients with pretreatment HIV RNA >1, copies/ml than with -based regimen More NNRTI- and 3TC-associated mutations at virological failure than with regimen containing + two NRTIs Food requirement Absorption depends on lower gastric ph, caution with H2 blocker and antacid Contraindicated with PPIs RPV-associated depression reported Use RPV with caution when coadministered with a drug having a known risk of torsades de pointes. Thailand ARV regimens 21 NRTI Preferred AZT+3TC TDF+FTC/3TC Alternative ABC+3TC d4t+3tc ddi+3tc NNRTI NVP If patients Cannot Tolerate NNRTI PI Preferred LPV/r Alternative ATV/r DRV/r SQV/r TDF: Caution in abnormal creatinine clearance and elderly patients. TDF +3TC/FTC is recommended in HBV co-infection. ABC: hypersensitivity reactions and should not be used with NVP. d4t: replaced with other NRTI after 6-12 : cannot be used in the first trimester of pregnancy. NVP: should be used in caution in females with CD4+ >25 cells/mm3 Sungkanuparph S. Asian BMC 21 Relative Potency of Approved NRTIs. AZT [1] d4t [2] ddi [3] 3TC [4] ABC [5] TDF [6] FTC [7] AZT VS. TDF AZT/3TC VS. (TDF+3TC) Eron JJ, et al. N Engl J Med. 1995;333: Riddler SA, et al. Antiviral Res. 1995;27: Katzenstein DA, et al. N Engl J Med. 1996;335: Rousseau F, et al. J Infect Dis. 23;188: Staszewski S, et al. AIDS. 1998;12:F197-F Louie M, et al. AIDS. 23;17: Rousseau FS, et al. J Antimicrob Chemother. 21;48:

7 % Change in BMD Responder (% of Patients) Efficacy of Select -Based Regimens (< 4 c/ml TLOVR, 48 wks) Study 934: 96 weeks Proportion with HIV-RNA <5 c/ml (TLOVR) EPV-21 ZDV BID + 3TC BID EPV-21 ZDV BID + 3TC QD DMP-6 ZDV BID + 3TC BID CNA-321 ABC QD + 3TC QD CNA-324 ZDV BID + 3TC BID CNA-321 ABC BID + 3TC QD CNA-324 ABC BID + 3TC BID GS-934 ZDV/3TC BID GS-93 TDF QD + 3TC BID FTC-31 A ddl QD + FTC QD GS-93 d4t BID + 3TC BID GS-934 TDF QD + FTC QD (n = 276) (n = 278) (n = 422) (n = 384) (n = 325) (n = 386) Indicates the TLOVR response rate at < 5 copies/ml (n = 324) (n = 243) (n = 299) 8 84 (n = 286) (n = 31) (n = 244) 9 8 TDF+FTC+ (n = 232) 7 67%* 6 AZT+3TC+ (n = 231) 5 61%* B L Weeks 48-week TLOVR results: HIV RNA <5 c/ml 8% FTC+TDF+ (n = 244) vs 7% AZT+3TC+ (n = 243) (%) Bartlett JA, et al. HIV Clin Trials. 27;8: Pozniak A.L., et al. JAIDS 26; 43(5): Gallant 38 JE et al. NEJM 26; 354:251-6 Study 934: ZDV/3TC vs TDF + FTC Mean Change Lipid Profile Mean Change From Baseline (mg/dl) Triglycerides Fasting LDL 5 TDF + FTC + TDF + FTC + ZDV/3TC + ZDV/3TC Study Week P =.67 P =.12 Pozniak AL et al. JAIDS. 26;43: Gilead 93/934: Mean (95% CI) limb fat Campo et al. IAC 28 GS93E: TDF and Bone Loss Over 7 Yrs GS93E [1] : ongoing, open-label extension phase of randomized, double-blind phase III study GS93 [2] d4t vs TDF, both + 3TC and After 144 wks, all participants continued Spine Hip -1.5% % Yr Spine n = Hip n = on TDF Bone loss in spine (-2.2%) and hip (-2.8%) in Wks 24-48; stabilized by Wk Cassetti I, et al. IAC 28. Abstract TUPE Gallant J, et al. JAMA. 24; 292: Gilead 93/934: 3 year median estimated GFR Gallant et al. IAC 28 7

8 Pts (%) Pts (%) Mean DAVG 24 (log 1 c/ml) TDF and Renal Function in Initial HAART GFR decreases similar in pts receiving TDF vs other NRTIs during first 2 yrs of therapy in retrospective analysis of pts from Hopkins cohort [1] Older age, lower CD4+ count, hypertension, use of boosted PI independently associated with higher risk of 25% decline in GFR by multivariate analysis (P <.5) TDF Other NRTI GFR decline 25% GFR decline 5% Days Philadelphia clinic cohort observed no association between TDF and renal function decline over 2 yrs, regardless of concomitant PI vs NNRTI [2] 1. Moore R, et al. ICAAC/IDSA 28. Abstract Short WR, et al. ICAAC/IDSA 28. Abstract Graphics reproduced with permission * 25.1* > 25% GFR Decline TDF + boosted PI Other NRTI + boosted PI TDF + NNRTI Other NRTI + NNRTI *P <.1 vs NNRTI P <.5 vs NNRTI > 5% GFR Decline TDF used in Thai patients Retrospective study at Bamrasnaradura ID institute 13 cases changed to TDF 45% NVP based 37% based 18% PI based egfr baseline 13 ml/min/1.73m2 decrease to 1 at 36 months (p<.1) Retrospective at Chonburi Hosp. 45 cases 29.3% had egfr a 25% decreased Median time 28 months Risk Factors Low body weight Low BMI Based line GFR PI used Nephrotoxic drug Manosuthi W. Southeast Asian J Trop Med Public Health 211;42: Chaisiri K. Curr HIV Res 21; 8:54-9. Switching from d4t/3tc to TDF/3TC in Thai patients Tenofovir Resistance and Virologic Response 28 cases 34 cases Manosuthi W. AIDS Res Ther 21;7: All Patients No TAMs 1 or 2 TAMs 3 TAMs With M41L or L21W 3 TAMs, no M41L or L21W n = 222 n = 68 n = 55 n = 57 n = 42 * * * * Response rate in patients with 3 TAMs with M41L or L21W was significantly lower than all other groups Miller M, et al J Infect Dis. 24;189: *P <.1 vs placebo P =.13 vs placebo Drug Specific Toxicities Zidovudine (AZT 2-3mg BID) 5% grade III/IV nausea Anemia/leucopenia Headache Myopathy Lactic acidosis Fat atrophy Blue nails Management Start AZT in healthy patients Follow CBC both short term and long term If anemia change to d4t or ddi or TDF Drug Specific Toxicities Tenofovir (3mg OD) Potential for renal impairment Fanconi syndrome and acute renal insufficiency, rare report Potential for decrease in bone mineral density Lactic acidosis Management Monitor renal function and UA Adjust dose according to renal function 8

9 % patients Fanconi syndrome Proximal tubule dysfunction Nephrogenic DI: polyurea, malaise Hypokalemia Hypophosphatemia Glycosuria Mild proteinuria NRTI adjustment for renal failure ARV Normal dose > <1 AZT 3 q12h 3 q 12h 3 q 12h 1 q 8h ddi q 12h Buffered tabs 4 q 24h Enteric coat tabs 2 q 12h 2 q 24h < 6 kg:1 q 24h >6 kg:15 q24h 4 q 24h q 24h Do not use EC tabs 3TC 3 q 24 3 q 24h 5-15 q 24h 25-5 q 24h d4t 3-4 q12 h 1% 5% q12-24h <6 kg: 15 q 24h >6 kg: 2 q 24h TDF 3 q 24h 3 q 24 h 3-49: 3 q48h 1-29:3 q 72-96h No data Sanford guide to antimicrobial therapy 21 Advantage Coformulated (ZDV/3TC and ZDV/3TC/ABC) No food effect (although better tolerated with food) Preferred dual NRTI in pregnant women AZT/3TC Disadvantage Bone marrow suppression, especially anemia and neutropenia GI intolerance, headache Mitochondrial toxicity, including lipoatrophy, lactic acidosis, hepatic steatosis Inferior to in combination with Less CD4 increase compared with ABC/3TC Twice-daily dosing Advantage Better virologic responses than with ZDV/3TC Better virologic responses than with ABC/3TC in patients with baseline HIV RNA >1, copies/ml in ACTG 522 study; however, this was not seen in the HEAT study. Active against HBV; recommended dual- NRTI for HBV/HIV coinfection Once-daily dosing No food effect Coformulated (, / and RPV/) No cumulative TAM-mediated resistance Disadvantage Potential for renal impairment, including rare reports of Fanconi syndrome and acute renal insufficiency Early virologic failure of NVP + TDF + (FTC or 3TC) in small clinical trials Potential for decrease in bone mineral density 2NN Study: NVP vs vs NVP+ Treatment success and failure VS. NVP n=22 n=387 n=4 n= NVP QD NVP BID * NVP+* Failure component: whichever comes first Change therapy Disease progression Virologic failure Success * Success: only significant difference vs NVP+ (p<.1) 2 deaths attributed to NVP (toxic hepatitis, Stevens-Johnson leading to MRSA sepsis) 1 death attributed to d4t (lactic acidosis) Coadministration of NVP and not advisable due to enhanced toxicity van Leth H, et al. Lancet 24 9

10 CD4+ Count at Initiation of Therapy HIV-1 RNA < 5 c/ml at Wk 48 (%) Advantage Virologic responses equivalent or superior to all comparators to date Once-daily dosing Coformulated with Disadvantage Neuropsychiatric side effects Teratogenic in nonhuman primates. Several cases of neural tube defect reported in infants of women exposed to in the first trimester of pregnancy. use should be avoided in women with potential for pregnancy and is contraindicated in the first trimester. Dyslipidemia Advantage No food effect Fewer lipid effects than Once-daily dosing with extended-release tablet formulation Safe in pregnant women NVP Disadvantage Higher incidence of rash, including rare but serious HSRs (SJS, TEN), than with other NNRTIs Higher incidence of hepatotoxicity, including serious and even fatal cases of hepatic necrosis, than with other NNRTIs Contraindicated in patients with moderate or severe (Child-Pugh B or C) Some data suggest that ART-naive patients with high pre-nvp CD4 counts (>25 cells/mm3 for females, >4 cells/mm3 for males) are at higher risk of symptomatic hepatic events. Risk of NVP Hepatotoxicity by CD4+ Count and Sex ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts Women 11.% Symptomatic Hepatic Events.9% 4 NVP should not be initiated in adult women or men with CD4+ cell counts > 25 cells/mm 3 and 4 cells/mm 3, respectively, unless the benefit outweighs the risk Viramune [package insert]. January Men 6.3% Symptomatic Hepatic Events 1.2% Stratified by HIV-1 RNA or > 1, copies/ml and CD4+ count < or 5 cells/mm³ Antiretroviral-naive pts with MDRD 5 ml/min; CD4+ count < 4 (males) or < 25 cells/mm³ (females) (N = 569) *Preceded by 2-wk lead-in dose of NVP 2 mg daily. Soriano V, et al. IAS 29. Abstract LBPEB7. NVP 2 mg BID* + (n = 188) NVP 4 mg QD* + (n = 188) ATV/RTV 3/1 mg + (n = 193) Wk 48 primary endpoint ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts NVP either once daily or twice daily noninferior to ATV/RTV at Wk 48 Rates of AEs similar overall but higher rate of discontinuation due to toxicity in NVP arms (13.6% vs 3.6%) ITT, NC = F P = Outcome at Wk 48, % NVP QD (n = 188) NVP BID (n = 188) ATV/RTV (n = 193) Virologic failure Investigatordefined virologic failure No confirmed response at Wk n = OPPORTUNISTIC Any NVP ATV/ RTV NVP QD NVP BID INFECTIONS Soriano V, et al. IAS 29. Abstract LBPEB7. 1

11 Survival Survival Probability SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients Significantly Improved Outcomes With Integrated HIV and TB Treatment HIV-infected patients diagnosed with TB and CD4+ cell count < 5 cells/mm 3 (N = 642) Primary endpoint: all-cause mortality Early ART ART initiated during intensive or continuation phase of TB therapy (n = 429) Sequential ART ART initiated after TB therapy completed (n = 213) 56% lower rate of death associated with concurrent ART and TB treatment (early ART) Mortality: HR:.44 (95% CI: ; P =.3) Early ART: 5.4/1 person-yrs Sequential ART: 12.1/1 person-yrs Outcome, % Early ART Sequential ART HIV-1 RNA <1 copies/ml at 12 mos 91.* 8. TB treatment successful Incidence of IRIS 12.1* 3.8 Mortality in MDR-TB patients 2 71 *P <.5 Note: 83% early ART vs 62% sequential ART patients had initiated ART data provisional. Abdool Karim SS, et al. CROI 29. Abstract 36a. Abdool Karim SS, et al. CROI 29. Abstract 36a. SAPiT: Increased Survival With Concurrent HIV and TB Treatment Early ART Sequential ART Intensive.75 Continuation Post-TB treatment phase phase of TB of TB treatment treatment Months Postrandomization Abdool Karim SS, et al. N Engl J Med. 21 Feb 25;362(8): SAPiT: Early vs Late ART Initiation During Integrated TB/ART Therapy Early integrated: ART started within 4 wks of starting TB Rx Late integrated: ART started within 4 wks of completing TB Rx intensive phase 68% lower AIDS/death rate with early integrated Rx in patients with CD4+ counts < 5 cells/mm Mos of Follow-up Early events/# at risk Late events/# at risk AIDS/Death in Patients With CD4+ < 5 cells/mm 3 Intensive phase of TB Rx Continuation phase of TB Rx Post-TB treatment 6 12 /37 2/33 4/31 /35 7/27 9/24 IRIS (per 1 Person-Yrs) Early Integrated Rx Late Integrated Rx IRR (95% CI) P Value CD4+ < 5 cells/mm (n = 37) 9.9 (n = 35) 4.7 ( ).1 CD4+ 5 cells/mm (n = 177) 7.2 (n = 18) 2.2 ( ).2 Abdool Karim S, et al. CROI 211. Abstract 39LB. Early integrated therapy Late integrated therapy IRR:.32 (95% CI: ; P =.6) 18 4/29 1/21 AIDS/Death in Patients With CD4+ 5 cells/mm 3 Intensive phase of TB Rx Continuation phase of TB Rx Late integrated therapy Early integrated therapy Post-TB treatment IRR: 1.51 (95% CI: ; P =.34) 6 12 /177 8/149 1/137 /18 4/48 7/ /121 9/121 STRIDE Study (ACTG 5221): Immediate vs Early ART Initiation in TB Patients CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-Coinfected Patients HIV-infected patients, confirmed/suspected TB, CD4+ count < 25 cells/mm 3 (N = 86) Havlir D, et al. CROI 211. Abstract 38. Stratified by CD4+ cell count < or 5 cells/mm 3 Wk 48 Immediate ART* Begun within 2 wks after TB therapy initiation (n = 45) Early ART* Begun 8-12 wks after TB therapy initiation (n = 41) *ART comprised, FTC, and TDF. TB therapy comprised standard rifampicin-based regimen. Outcome, % Deaths or new AIDS-defining events by Wk 48 Immediate (n = 45) Early (n = 41) 95% CI for Difference Overall population to CD4+ cell count < 5 cells/mm to CD4+ cell count 5 cells/mm to P Value TB IRIS WHO 21 guidelines recommend to [1] Initiate HAART in all HIV-infected patients with TB, regardless of CD4+ cell count Initiate TB therapy before HAART, with HAART added as soon as possible 1. WHO. Available at: 2. Blanc FX, et al. AIDS 21. Abstract THLBB26. CAMELIA: randomized, open-label trial of HIV-infected patients with newly-diagnosed AFB-positive TB and CD4+ cell count 2 cells/mm 3 [2] Compared HAART initiation (d4t + 3TC + ) at Wk 2 (n = 332) vs Wk 8 (n = 329) of TB therapy All patients received standard TB therapy for 6 mos Baseline median CD4 25 cells/mm 3 and HIV RNA 5.6 log 1 c/ml 11

12 Probability of Survival Patients Progressing to AIDS or Death at Week 48 (%) CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients DHHS 211: Indications for initiation of ART in patients with HIV and TB Survival Probability, Early vs Late Therapy 1. Early arm.9 Late arm Wk Log rank P = Wks From TB Treatment Initiation Survival Probability, % (95% CI) Early Arm 86.1 ( ) 82.6 ( ) 82. ( ) Late Arm 8.7 ( ) 73. ( ) 7.2 ( ) Blanc FX, et al. AIDS 21. Abstract THLBB26. P Factors Independently Associated With Mortality Factor Multivariate Adjusted HR (95% CI) Late therapy 1.52 ( ).7 BMI ( ).1 Karnofsky score 4 Pulmonary + extrapulmonary TB 4.96 ( ) <.1` 2.26 ( ) Significantly higher incidence of IRIS with early vs late HAART 4.3 vs 1.44 per 1 person-mos, respectively (P <.1) P <.1 NTM 2.84 ( ) <.1 MDR-TB 8.2 ( ) <.1 CD4 count Recommendation <2 Start ART 2-4 weeks after the initiation of TB treatment (AI) 2-5 Prefer 2-4 weeks, or within 8 weeks after the initiation of TB treatment (AIII) >5 Within 8 weeks after TB therapy (BIII) IRIS may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII). DHHS Guideline 211 Indications for initiation of ART in patients with HIV and TB CD4 count Recommendation <2 Start ART 2-8 weeks after the initiation of TB treatment 2-35 Start ART 2 months after the initiation of TB treatment Prednisolone vs. placebo in TB IRIS symptom score in week 2 and 4 RCT trial for non fatal IRIS Prednisolone 1.5mg/kg/dx2wk.75mg/kg/dx2wk >35 Defer and follow up CD4 every 6 months Thai Guideline 21 Meintjes G. AIDS 21, 24: ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs ACTG A5164: Improved Outcomes With Immediate ART During Acute OI Stratified by CD4+ cell count < or 5 cells/mm 3, PCP, BI, or other OI HIV-infected patients receiving treatment for presumed or confirmed acute OI/BI* (N = 282) *Patients with TB excluded. Zolopa A, et al. PLoS One 29;4:e5575 Immediate Antiretroviral Therapy (initiation within 48 hours of randomization and within 14 days of starting OI treatment) (n = 141) Deferred Antiretroviral Therapy (initiation between Weeks 4 and 32) (n = 141) 48 weeks 48 weeks 92% treatment naive Median baseline CD4+ cell count 29 cells/mm 3 ; HIV-1 RNA 5.7 log 1 copies/ml OIs with effective antimicrobial therapy only: PCP, bacterial infections, cryptococcal disease, MAC, toxoplasmosis Median duration from start of OI treatment to initiation of HAART Immediate group: 12 days Deferred group: 45 days Week 48 virologic outcomes similar between groups Zolopa A, et al. PLoS One 29;4:e Immediate P = Deferred Safety and incidence of IRIS similar between groups 12

13 Survival Early ART Decreases Survival in HIV+ Patients With Cryptococcal Meningitis AIDS defining illness in Thailand Sep1984-Feb24 HIV-infected African patients diagnosed with cryptococcal meningitis randomized to receive 1 wks of fluconazole 8 mg QD + ART (n = 26) or fluconazole alone (n = 28) After 1 wks, all patients received fluconazole 2 mg QD + ART Delayed ART Early ART P = Time to Death (in Days) After 2 yrs of follow-up: 23 deaths in early ART group (87% mortality rate) vs 9 deaths in delayed ART group (37% mortality rate) (P =.2) Median survival, early ART vs delayed ART: 35 vs 274 days (P =.28) Percentage Makadzange AT, et al. CID 21 Primary Prophylaxis of Cryptococcosis in Thailand Recommended CD4 < 1 /mm 3 No sign/symptom of cryptococcal disease Negative serum crypto Ag (if available) Regimen Fluconazole 4 mg weekly Discontinuation of primary prophylaxis On ART with CD4> 1 /mm for 3 months Primary prophylaxis of cryptococcal disease with fluconazole in HIV +ve Ugandan: RCT double blind study Primary outcomes Cryptococcal disease Placebo N=759 Fluconazole N=76 Unadjusted log-rank test (p value) (p=.1) Death (P=.82) Adjusted HR (95%CI) 18.7 ( ).96 ( ) Thailand National Guidelines on HIV/AIDS 21 Parkes-Ratanshi R. Lancet Infect Dis 211;11: WHO guideline WHO guideline WHO RAPID ADVISE, December 211 WHO RAPID ADVISE, December

14 Successful outcomes % What is the recommended as preferred regimen in initial induction therapy for CM in Thai guidelines? A. Ampho B.7 mg/kg/d + 5FC 1 mg/d B. Ampho B.7 mg/kg/d C. Ampho B.7 mg/kg/d + Fluconazole 4 mg/d D. Ampho B.7 mg/kg/d + Fluconazole 8 mg/d E. Fluconazole 8-12 mg/d Treatment of Cryptococcosis in Thailand Induction Phase Recommend Ampho B 1 mg/kg/d Amopho B.7 mg/kg/d + Fluconazole 8 mg/d Alternative Fluconazole 8-12mg/d in Cryptococcosis without meningitis Consolidation Phase Maintenance Phase Recommend Recommend Fluconazole 8 mg/d Fluconazole 2 mg/d Alternative Alternative Itraconazole 4mg/d Itraconazole 2mg/d Ampho + Fluconazole for CM: Phase II study Overall (MITT) Thank you for your attention AmB AmB+Flu 4 AmB+Flu Day 14 Day 42 Day 7 Day 14 Day 42 Day 7 Day 14 Day 42 Day 7 Pappas P. CID 29; 48: