Co nowego na zjazdach CROI, ICAAC. EACS

Prezentacja na temat: "Co nowego na zjazdach CROI, ICAAC. EACS"— Zapis prezentacji:

1 Co nowego na zjazdach CROI, ICAAC. EACS

2 Leczenie pierwszego rzutu Nowe strategie leczenia Nowe leki Powikłania leczenia Koinfekcje

3 Leczenie pierwszego rzutu& strategie leczenia

4 Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Kiedy zacząć ?

5 HAART and Survival Based on Initial CD4+ Cell Count
Modeled data from ART Cohort Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs excluded from model Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART cells/mm cells/mm cells/mm3 1 2 3 4 5 0.00 0.02 0.04 0.06 0.08 0.10 0.12 Probability of AIDS or Death Progression and Death According to CD4+ Cell Count (cells/mm3) < 200 vs < 350 vs Hazard ratio for AIDS (95% CI) ( ) 1.52 ( ) Hazard ratio for AIDS or death (95% CI) ( ) 1.26 ( ) For more information, go to the Capsule Summary at Years Since Initiation of HAART Sterne J, et al. CROI Abstract 525.

6 CD4+ Cell Count Response Based on Baseline CD4+ Cell Count
Johns Hopkins HIV Clinical Cohort 1000 800 600 400 200 48 96 144 192 240 288 336 ATHENA National Cohort Weeks From Starting HAART 200 400 600 800 1000 Mean CD4+ Cell Count (cells/mm3) For more information, please see the Capsule Summary at 1 2 3 4 5 Years on HAART Magnitude of CD4+ cell count increase greatest if therapy started at low CD4+ cell counts, but greater likelihood of CD4+ cell count normalization with earlier therapy Keruly J, et al. CROI Abstract 529. Gras L, et al. CROI Abstract 530.

7 Związek pomiędzy śmiertelnością a supresją wiremii
Prospektywne, Danish HIV Cohort Study N = 3919 HIV(+) HAART ≥ 18 miesięcy Podzieleni na grupy w zależności od proporcji wykrywalnej wiremii w ciągu 18 miesięcy od włączenia leczenia Większe ryzyko śmierci u osób z niepełną lub brakiem supresji Proportion of Detectable Viral Loads Over 6-18 Months After Initiation of HAART 100% (all values VL ≥ 400) 1%-99% (of values VL ≥ 400) 0% (all values VL < 400) 0.25 0.20 0.15 0.10 0.05 0.00 18 36 54 72 HAART, highly active antiretroviral therapy; VL, viral load. For more information, please go online to: Cumulative Mortality Months After Baseline (baseline = 18 months after HAART initiation) Lohse N, et al. ICAAC Abstract H-515.

8 Kiedy rozpoczynać HAART : HOPS Cohort
Dane z kohorty >8000pts, obserwacja od 1993 U pacjentów, którzy zaczynali HAART przy wyższym CD4+ Mniejsza śmiertelność, mniej OI Lepsza odpowiedź CD4+ na HAART Rzadziej niewydolność nerek, neuropatia i lipoatrofia Lepszy efekt immunologiczny u osób stale leczonych HAART vs STI Korzyści z leczenia nawet u osób, którzy rozpoczynali leczenie z CD kom/mm³ i > 500 kom/mm³ ARVs associated with increased incidence of lipoatrophy in Year 1: IDV, NVP (P < .05); ≥ 2 years: d4T 30 mg BID (P < .05). ARVs associated with increased incidence of neuropathy in Year 1: d4T 30 mg BID, ddI, IDV, RTV ≥ 800 mg/day, NFV, SQV, APV (P < .05) Lichtenstein KA, et al. CROI Abstract 769.

9 Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Czym zacząć ?

10 Boosted vs Unboosted Atazanavir in Antiretroviral-Naive Patients
Randomization 1:1 ATV 400 mg QD (n = 105) ATV/r 300/100 mg (n = 95) Both with d4T-XR 100 mg QD + 3TC 300 mg QD Trend for more virologic failure in ATV arm* Patients with VF ATV: n = 10 ATV/r: n = 3 Mean CD4+ count change ATV: +224 ATV/r: +189 Weeks < 400 c/mL < 50 c/mL 20 40 60 80 100 BL 2 4 8 12 16 24 32 48 86% 75% 85% 70% Responders (%) HIV RNA < 400 c/mL and < 50 c/mL Through Week 48 (ITT) For more information, please see the Capsule Summary at Not powered to determine if ATV noninferior to ATV/r Difference estimate (95% CI): 1.5 (-8.2 to 11.1) Difference estimate (95% CI): 1.5 (-7.0 to 17.0) ATV 300/RTV (n = 95) ATV 400 (n = 105) *Not powered to determine if ATV noninferior to ATV/r Malan N, et al. CROI Abstract 107LB.

11 ACTG 5095: Założenia badania
Porównanie 2- vs 3 lekowego NRTI backbones i zestawu 3-NRTI vs zawierające EFV Ramię 3-NRTI przerwano po analizie danych pokazujących mniejsza efektywność w stosunku do ramion zawierających EFV Median follow-up: 144 weeks 3-NRTI arm Zidovudine/lamivudine/abacavir EFV, efavirenz; VL, viral load. For more information, please go online to: Antiretroviral-Naive VL ≥ 400 copies/mL (N = 82) 3 NRTIs + EFV arm Zidovudine/lamivudine/abacavir + efavirenz 2 NRTIs + EFV arm Zidovudine/lamivudine + efavirenz Gulick RM, et al. ICAAC Abstract H-416a.

12 ACTG 5095: EFV + ZDV/3TC vs EFV + ZDV/3TC/ABC jako terapia inicjująca
Ni stwierdzono różnicy w: Czasie osiągnięcia supresji Liczbie niepowodzeń terapeutycznych Proporcji z VL < 200 or < 50 c/mL Odpowiedzi CD4+ Profilu oporności Podobne rezultaty u osób z VL > 100,000 Czynniki niepowodzenia wirusologicznego HCV (HR: 1.57) Black race (HR: 1.67) Płeć, wiek, CD4+ nie ma wpływu 100 80 60 Virologic Failures* (%) 40 25 26 20 3TC, lamivudine; ABC, abacavir; BL, baseline; EFV, efavirenz; HCV, hepatitis virus C; HR, hazard ratio; VL, viral load; ZDV, zidovudine. For more information, please go online to: ZDV/3TC/ABC + EFV (n = 383) ZDV/3TC + EFV (n = 382) * Virologic failure defined as 2 consecutive VL ≥ 200 copies/mL at ≥ Week 16. Gulick RM, et al. ICAAC Abstract H-416a.

13 NRTI-Sparing Initial Therapy: LPV/r + SQV Compared With LPV/r + NRTIs
Otwarte, randomizowane, pilotażowe badanie N = 30 naive men LPV/r (400/100 BID) + SQV (800 BID) or ZDV/3TC (300/150 BID) Podobne wyniki w 48 tygodniu Nie różnią się objawami ubocznymi Mniejsza liczba tabletek nowych postaci LPV/r and SQV Potrzeba więcej badań nad efektywnością dual-PI 100 78% 80 77% 60 Patients With HIV-1 RNA < 50 copies/mL (Observed Data) (%) 40 3TC, lamivudine; BID, twice daily; LPV/r, lopinavir/ritonavir; PI, protease inhibitor; SQV, saquinavir; ZDV, zidovudine. In this trial, saquinavir was administered at 200 mg in the hard-gel capsule formulation. For more information, please go online to: 20 LPV/r + SQV LPV/r + ZDV/3TC 12 24 36 48 Week n = 13 13 n = 10 9 Cameron DW, et al. ICAAC Abstract H-523.

14 Odpowiedź na NNRTIs vs PIs u pacjentów z zaawansowanym AIDS
Poprzednie badania sugerowały różnice w efektywności pomiędzy NNRTIs a PIs u pacjentów z zaawansowaną chorobą Jednak oparte na badaniach obserwacyjnych i porównaniu różnych badań Randomizowane badanie porównujące EFV vs IDV/r u nieleczonych z CD4+ < 100 kom/mm3 Nie ma statystycznych różnic w odpowiedzi wirusologicznej Nie ma statystycznych różnic w odpowiedzi CD4+ w 24 miesiącu EFV, efavirenz; IDV/r, ritonavir-boosted indinavir. One of the most important choices made by HIV-treating clinicians is the initial antiretroviral regimen; this is particularly true in patients with very advanced HIV disease. Observational and cross-study comparisons have suggested that there may be a difference between using an NNRTI and a PI in patients with advanced disease. Furthermore, it has been suggested that patients with very advanced disease may have better responses with PIs. Investigators from Spain conducted a randomized controlled trial comparing the use of efavirenz with ritonavir-boosted indinavir in treatment-naive patients with advanced HIV disease, which was defined as a CD4+ cell count < 100 cells/mm3. Overall, there was no significant difference in virologic response to PIs or NNRTIs, and after 2 years, there was no significant difference in CD4+ cell counts between groups. This suggests that the choice of effective antiretroviral therapy in patients with advanced HIV disease is reasonably broad and should not be limited to one class of antiretroviral drugs. For more information, please go online to: Miro JM, et al. EACS Abstract PS1/4.

15 DART: Use of TDF + ZDV + 3TC in Resource-Limited Settings
Potential advantages of regimen No refrigeration No hypersensitivity No pregnancy concerns No rifampin interactions Randomized trial: clinical + lab vs clinical monitoring alone in naive pts starting ZDV/3TC + TDF 48-wk results presented on 300 pts in virology substudy BL median CD4+, 100 cells/mm3 BL median VL, 279,910 copies/mL 20 40 60 80 100 55% 65% 62% 74% % of Subjects < 50 at Wk 48 < 400 at Wk 48 ITT M=F OT 300 3.72 231 4.20 Mean log drop: n = Kaleebu P, et al. IAS Abstract WeOaLB0203.

16 Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Jak zmieniać? ?

17 Zmiana na prostszy schemat
SWAN study: efektywność i bezpieczeństwo zmiany z reżimu PI BID i/lub ≥ 3 tabl/dizennie na ATV (n = 253) lub ATV/r, jeśli z TDF (n = 25) Kryteria wejścia: na stabilnym HAART z PI-, na 1st lub 2nd zestawie, VL < 50 przez ≥ 3 months Randomizowano na dwie grupy-zmiana lub pozostanie na dotychczasowym leczeniu Patiencji, którzy otrzymali ATV: Utrzymali supresję wirusologiczną Mieli poprawę profilu liidów Total cholesterol, -16% vs +1% with comparator PI (P < .0001) Triglycerides, -38% vs +1% with comparator PI (P < .0001) Gatell JM, et al. IAS Abstract WePe6.3C15.

18 Leczenie podtrzymujące monoterapią PI
Monoterapia podtrzymująca stanowi atrakcyjną opcję dla u pacjentów z supresją wiremii Jednakże w poprzednich badaniach stwierdzono znaczne ryzyko niepowodzenia wirusologicznego PI/r mogą być dobrą opcją: ↑ potencjał, ↓ ryzyko oporności 20/24 miało wiremię nieoznaczalną 48 tygodniu po zmianie LPV/r + 2 NRTIs to LPV/r monoterapię [1] Niepowodzenie wirusologiczne nie powodowało rozwoju mutacji , a dodaniem NRTIs uzyskano supresję In virtually all monotherapy studies, there have been unexplained failures (no resistance, good adherence, adequate drug levels), which is one reason why compartment issues are being raised. 1. Arribas JR, et al. IAS Abstract WePe12.3C05. 2. Vernazza P, et al. IAS Abstract WeOa0204.

19 Pharmakokinetyka of Double-Boosted zestawów z ATV
Pharmacokinetics of double-boosted PI therapy assessed in observational Frankfurt HIV cohort Compared to each single-boosted PI + NRTIs ATV also reduces RTV levels when combined with LPV/r Secondary boosting effect of ATV on LPV AUCss After 3 Days of Treatment (ng·hr/mL) Effect on Concomitant Drug[1] Effect on ATV[2] Recommendation Lopinavir/ritonavir (400/100 BID) ↓ 16% (P = .21) ↓ 22% (P = .077) Use with TDM Saquinavir/ritonavir (1000 BID/100 QD) ↑ 40% (P = .001) ↑ 16% (P = .11) Use with low-dose ritonavir (100 mg QD) Fosamprenavir/ritonavir (700/100 BID) neutral ↓ 31% (P = .003) Further investigation required ATV, atazanavir; AUCss, area under the curve at steady state; BID, twice daily; LPV, lopinavir; LPV/r, ritonavir-boosted lopinavir; QD, once daily; RTV, ritonavir; TDM, therapeutic drug monitoring. The use of double-boosted PI regimens is practiced widely without substantial clinical evidence to suggest its effectiveness. Nevertheless, one of the challenges of using such regimens is the complicated drug interactions that occur between PIs. An analysis of patients in the Frankfurt HIV cohort examined the pharmacokinetic effects of using atazanavir in double-boosted PI regimens. In patients given atazanavir with ritonavir-boosted lopinavir, a modest 16% decrease in the area under the curve at steady state for lopinavir and a modest 22% reduction in the area under the curve at steady state for atazanavir was observed. The recommendation from the investigators was that therapeutic drug monitoring would be useful when using a double-boosted PI regimen consisting of atazanavir and ritonavir-boosted lopinavir. When atazanavir was used with ritonavir-boosted saquinavir, atazanavir increased the area under the curve at steady state of saquinavir quite significantly, by 40%, whereas saquinavir did not have a significant effect on atazanavir. The investigators recommended that if this combination is used, a lower dose of ritonavir may be appropriate. Finally, the use of atazanavir in combination with ritonavir-boosted fosamprenavir had no effect on fosamprenavir; however, ritonavir-boosted fosamprenavir reduced the area under the curve at steady state of atazanavir by 31%, suggesting that additional investigation is required. These data only serve to demonstrate the complexity of drug interactions in double-boosted PI regimens. Additional investigation is required, in general, regarding the concept of double-boosted PI use. For more information, please go online to: P values for PI/r + ATV vs PI/r alone. 1. von Hentig N, et al. EACS Abstract PS6/5. 2. von Hentig N, et al. EACS Abstract PS6/6.

20 COMET: Switch From ZDV/3TC to TDF/FTC
189 suppressed patients switched from ZDV/3TC to TDF/FTC Primary reason for switch: simplification (86%) All had BL VL < 400 copies/mL Small, but significant improvement in lipids TC ↓ 13 mg/dL at Week 12 TG ↓ 12.5 mg/dL at Week 12 Hb increased 0.6 g/dL by Week 24 By Week 24 after switch 26 (14%) had increases in VL 114 (60%) maintained VL 49 (26%) had decreases in VL Week 24 copies/mL (n) BL VL copies/mL > 400 50–400 < 50 50–400 (n = 78) < 50 (n = 111) 3TC, lamivudine; BL, baseline; FTC, emtricitabine; Hb, hemoglobin; TC, total cholesterol; TDF, tenofovir disoproxil fumarate; TG, triglycerides; VL, viral load; ZDV, zidovudine. Note to viewer: please view slide in slideshow mode There are several caveats that must be considered when interpreting these results. Caveats include that this was an uncontrolled nonrandomized study, that patients probably had reasons for wanting to switch, and that viral loads were not done centrally and may have been subject to false positives which are common with improper viral load specimen handling. For more information on this study, please go online to: 9 3 14 20 94 49 Ruane P, et al. EACS Abstract PE7.3/5.

21 Rekomendacje europejskie (EACS) Rekomendacje amerykańskie (DHHS) Rekomendacje polskie Jak nie zmieniać?

22 COL40263: Once-Daily ZDV/3TC/ABC + Tenofovir
Genotypes of Nonresponders* 100 All patients BL VL < 100,000 BL VL ≥ 100,000 K65R/K (2 of 14 isolates) 80 ≥ 1 TAMs only (3 of 14 isolates) M184V only (1 of 14 isolates) 60 ≥ 1 TAMs + M184V (4 of 14 isolates) Wild type (4 of 14 isolates) < 50 copies/mL (ITT: M=F) (%) Patients With HIV-1 RNA 40 14% 21% 7% 29% 3TC, lamivudine; ABC, abacavir; BL, baseline; ITT: M=F, intent to treat: missing equals failure; TAMs, thymidine analogue mutations; VL, viral load; ZDV, zidovudine. COL40263 is an open-label study of a novel once-daily regimen: coformulated abacavir/lamivudine/zidovudine plus tenofovir DF In an ITT (missing = failure) analysis, 51% of subjects achieved HIV-1 RNA < 400 copies/mL and 41% achieved < 50 copies/mL at Week 48 Rates of response were lower among patients with baseline viral load ≥ 100,000 copies/mL Genotyping was performed on 14 subjects at the time of study discontinuation or failure. 2/14 (14%) had K65R/K, 4/14 (29%) had wild-type virus, 1/14 had M184V without TAMs (7%), 3/14 (21%) had ≥ 1 TAMs without M184V, and 4/14 (29%) had ≥ 1 TAMs with M184V. 3/14 subjects had mutations at baseline, which included V118I/V, K103N, Y188F/H/L/Y, T215A/I/S. TAMs: mutations at codons 41, 67, 70, 210, 215, and 219 For more information, please go online to: 20 4 4 8 16 24 32 40 48 Study Week *≥ 400 copies/mL at ≥ 24 weeks Cohen C, et al. ICAAC Abstract H-521. Elion R, et al. ICAAC Abstract H-1068.

23 Problemy z Didanosine + Tenofovir + Efavirenz
Badanie TEDDI potwierdziło poprzednie doniesienia o większym odsetku pacjentów z niepowodzeniem wirusologicznym przyjmujących ddI + TDF + EFV [1] VF: 25% po 12 tygodniach of TDF + ddI + EFV Badanie EFADITE pts ze stabilną supresją, którzy przestawieni zostali na TDF + ddI + EFV albo zostali na dotychczasowym leczeniu [2] Utrzymano stłumienie wiremii u większości pts Jednak, CD4+ ↓ na TDF + ddI + EFV Median change in CD4+ at Yr 1, -25 vs +46 in controls (P = .007) Significantly larger CD4+ declines in pts on high vs low ddI doses 1. van Lunzen J, et al. IAS Abstract TuPp0306. 2. Barrios A, et al. IAS Abstract WePe12.3C16.

24 Mean CD4+ Decrease (ITT) Mean Change in CD4+ Cell Count (cells/mm3)
3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART Mean VL Increase (ITT) Mean CD4+ Decrease (ITT) 2.0 3TC TI Weeks P = .0015 4 12 24 36 48 1.5 Mean Change in HIV-1 RNA (log10 copies/mL) -50 1.0 -100 Mean Change in CD4+ Cell Count (cells/mm3) -150 0.5 -200 -250 P = NS 3TC TI The aim of this study was to verify whether maintaining the M184V mutation in failing patients by continuing lamivudine alone reduces immunologic and clinical failure in comparison with complete treatment interruption These were relatively healthy patients with CD4 > 450 on entry, had 3TC resistance, requested treatment interruption 4 12 24 36 48 -300 Weeks In contrast to treatment interruption arm, 3TC alone resulted in: Smaller recovery in replication capacity No further selection of resistance mutations Castagna A, et al. IAS Abstract WeFo0204.

25 Lower Incidence of M184V/I Following Virologic Failure With FTC vs 3TC
1363 treatment-naive patients experiencing virologic failure in 1 of 3 phase III studies FTC-301A: FTC QD + ddI + EFV vs d4T + ddI + EFV GS-903: 3TC BID + TDF + EFV vs 3TC BID + d4T + EFV GS-934: FTC QD + TDF + EFV vs 3TC BID + ZDV + EFV Significantly ↓ rate of M184V/I emergence with FTC QD vs 3TC BID (both in combination with another NRTI and EFV) 3.0 P = .015 2.4 2.5 2.0 Incidence of M184V/I in 3 Pooled Phase III Trials (%) 1.5 3TC, lamivudine; BID, twice daily; d4T, stavudine; ddI, didanosine; EFV, efavirenz; FTC, emtricitabine; NFV, nelfinavir; TDF, tenofovir; ZDV, zidovudine. An analysis of 1363 patients who failed treatment including emtricitabine or lamivudine in 3 large phase III studies suggested that virologic failure was less likely to be associated with the M184V/I mutation in patients who received emtricitabine vs lamivudine. The reasons for this result are not clear, but may be related to the better pharmacology of emtricitabine when used in combination regimens. For more information, please go online to: 1.0 0.6 0.5 FTC (n = 522) 3TC (n = 841) McColl D, et al. EACS Abstract PE7.3/17.

26 TOPS: Reducing Emergence of Resistance After Single-Dose NVP
Arm 3 Arm 2 Arm 1 sdNVP ZDV/3TC x 4d ZDV/3TC x 7d Intrapartum Postpartum Mother Baby McIntyre JA, et al. IAS Abstract TuFo0204.

27 TOPS Update on NVP Resistance
Coadministration of 4-7 days of ZDV/3TC with single-dose NVP reduced incidence of NVP resistance 41/68 (60%) vs 15/135 (11%); P = .0001 Study Arm N Maternal NVP Resistance*, n (%) sdNVP 68 41 (60%) sdNVP + ZDV/3TC x 4d 67 8 (12%) sdNVP + ZD/3TC x 7d 7 (10%) * Incidence determined by standard genotyping, which is not sensitive to minority variants McIntyre JA, et al. IAS Abstract TuFo0204.

28 RESIST-1 i -2: wyniki 48 tygodni
100 100 TPV/r CPI/r TPV/r CPI/r 80 80 52.0 60 60 Patients With HIV-1 RNA < 50 copies/mL (%) Patients With HIV-1 RNA < 400 copies/mL (%) 35.8 40 40 30.4 22.8 19.6 14.4 13.8 20 10.2 20 ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPI/r, ritonavir-boosted comparator protease inhibitor; ENF, enfuvirtide; TC, total cholesterol; TGs, triglycerides; TPV/r, ritonavir-boosted tipranavir. Tipranavir has recently been approved for the treatment of patients with multidrug-resistant HIV, particularly for patients with multiple PI resistance mutations. This approval was based on 24-week data from the RESIST trials; the 48-week results were presented at the European AIDS Clinical Society Conference. Overall, the 48-week results confirmed what was seen at 24 weeks, that ritonavir-boosted tipranavir was superior to comparator ritonavir-boosted PIs in terms of HIV-1 RNA suppression to < 50 copies/mL (left-hand figure) and < 400 copies/mL (right-hand figure). Also confirmed by the 48-week results was that the addition of a second, potent antiretroviral agent was associated with a better overall treatment response. Higher response rates were observed in patients who received enfuvirtide for the first time during the study, with 52% of patients given both ritonavir-boosted tipranavir and enfuvirtide for the first time achieving viral suppression to < 400 copies/mL. The superiority of ritonavir-boosted tipranavir over the comparator PIs was also seen in the subgroup of patients receiving enfuvirtide for the first time. No new toxicity data emerged from the 48-week analysis. The incidence of adverse events with ritonavir-boosted tipranavir was similar to that seen with the comparator PIs in all safety parameters, with 2 exceptions: more patients given ritonavir-boosted tipranavir showed elevated transaminases, and significantly elevated triglycerides and total cholesterol than in the comparator PI group. These parameters require monitoring in patients receiving ritonavir-boosted tipranavir. For more information, please go online to: n =746 n = 737 n = 123 n = 97 n =746 n = 737 n = 123 n = 97 All Patients First-Time ENF Use All Patients First-Time ENF Use TPV/r similar toxicity profile to CPI/r, with 2 exceptions Elevated ALT (9.7% vs 4.2%), AST (6.1% vs 1.8%) Elevated TGs (24.9% vs 13.0%), TC (2.1% vs 0.4%) Cahn P, et al. EACS Abstract LBPS3/8.

29 Niewystępowanie oporności na PI po niepowodzeniu leczenia PI/r
No primary PI resistance mutations in pts with failure of SQV/r regimen Staccato trial: Of 10 patients failing SQV/r 1600/100 mg QD + d4T/ddI (or TDF/3TC), none had primary PI mutations at failure [1] Consistent with previous reports on FPV/r, LPV/r SOLO trial: Of 32 pts failing FPV/r + ABC + 3TC, none developed primary or secondary PI mutations at failure [2] M trial: Of 51 pts failing LPV/r + d4T + 3TC, none had primary PI mutations at failure [3] 1. Ananworanich J, et al. IAS Abstract WePe4.4C12. 2. MacManus S, et al. AIDS. 2004;18: 3. Kempf DJ, et al. J Infect Dis. 2004;189:51-60.

30 Pharmacokinetics of Dual-boosted PI Regimens
Substantial reductions in APV and LPV levels previously shown when FPV and LPV/r coadministered [1] However, new study showed no apparent adverse PK effect with ATV (300 or 400 QD) + LPV/r (400/100 BID) [2] 20 treatment-experienced pts; 3 PI naive; 14 LPV/r naive Median ATV and LPV Cmin in target range 69% < 400 copies/mL at Week 24 Further formal drug interaction studies and clinical trials are warranted 1. Kashuba A, et al. AIDS. 2005;19: 2. Duvivier C, et al. IAS Abstract WePe3.2C10.

31 Nowe leki NRTIs/NtRTIs NNRTIs Entry inhibitors Protease inhibitors
SPD 754 (DOTC) Amdoxovir (DAPD) D-d4FC Racivir (± FTC) SN1212 Compound X NNRTIs TMC125 GW (prodrug = GW695634) TMC278 BILR 355 BS CSIC DAPY/DATA UC781 TMC120 (as microbicide) Entry inhibitors Aplaviroc Maraviroc Vicriviroc BMS TNX-355 NB-2, NB-64 A total of 20 antiretroviral agents have been approved by the FDA, in 4 therapeutic classes Important new data were presented at this meeting on a number of novel NRTIs and fusion/entry inhibitors These novel agents are highlighted in orange in this slide, and several will be considered in the following slides Protease inhibitors TMC114 GW0385

32 Antiretrovirals Potentially Active in Treatment-Experienced Patients
Enfuvirtide CCR5 inhibitors Tipranavir TMC114 D-d4FC (NRTI) TMC125 (NNRTI) PA-457 MK-0518 GS-9137

33 Virologic Response to D-d4FC
Randomized, dose-ranging trial of D-d4FC vs placebo in 199 experienced pts with VL > 2000 copies/mL D-d4FC active against NRTI-resistant viruses Response to D-d4FC (200 mg QD) during initial 2-wk add-on phase 0-3 TAMs 4-6 M41L+ L210W M184V alone M184V+ L74V/I K65R -0.00 -0.75 -0.50 -0.25 -1.00 Change in HIV-1 RNA at Wk 2 (log10 copies/mL) Cohen C, et al. IAS Abstract WeOaLB0103.

34 Change in Plasma HIV-1 RNA (log10 copies/mL)
Activity of Novel NNRTI GW695634 Multicenter, double blind, randomized 7-day add-on study N = 44 NNRTI-exp pts 27 ≥ 1 NNRTI mutation at BL Remaining 17 had history of NNRTI mutations Most common NNRTI mut: K103N, V108I, Y181C BL VL, log BL CD4+, -0.4 0.0 0.4 0.8 -2.0 -1.6 -1.2 -0.8 1 2 3 4 5 6 7 8 Placebo 100 mg 200 mg 300 mg 400 mg Change in Plasma HIV-1 RNA (log10 copies/mL) Study Day Becker S, et al. IAS Abstract WePe6.2C03.

35 TMC125-C223: Virologic Response in Pts With NNRTI and PI Resistance
Control (n = 40) 400 mg BID (n = 80) 800 mg BID (n = 79) 0.4 2 1 4 8 12 16 20 24 –0.19 -0.4 Mean (± SE) Change in HIV-1 RNA (log10 copies/mL) -0.8 BID, twice daily. Results from the phase II trial of TMC125 in patients with ≥ 3 primary PI mutations showed that both doses of TMC125 were associated with a sustained 1 log10 reduction in viral load out to 24 weeks, a significantly greater reduction than the 0.2 log10 reduction seen with optimized background therapy alone. Furthermore, in patients who had no other active drugs in their regimen, the 800-mg twice-daily dose of TMC125 was associated with a 0.6 log10 reduction in HIV-1 RNA. This suggests that even in patients with NNRTI resistance mutations, this new investigational NNRTI has activity. For more information, please go online to: -1.2 –1.04* –1.18* -1.6 *P < .05 TMC125 active in patients with no other active drugs -0.59 log10 reduction in HIV-1 RNA with 800 mg BID dose Nadler JP, et al. EACS Abstract LBPS3/7a

36 POWER-2: Darunavir/r (TMC114/r) in PI-Experienced Patients
Ongoing 96-week randomized trials of 3-class experienced patients  1 primary PI mutation BL HIV-1 RNA: log10 c/mL BL CD4+: cells/mm3 24-week data previously reported from POWER-1 cohort[1] Current analysis presented 24-week data from POWER-2 cohort[2] Same arms and entry criteria in POWER-1 and POWER-2 POWER-2 Treatment Arms Darunavir 400 mg QD + Ritonavir 100 mg QD + OBR (n = 57) Darunavir 800 mg QD + Ritonavir 100 mg QD + OBR (n = 56) Darunavir 400 mg BID + Ritonavir 100 mg BID + OBR (n = 55) BID, twice daily; BL, baseline; c/mL, copies/mL; OBR, optimized background regimen; PI, protease inhibitor; QD, once daily. For more information on the POWER-1 study, please go online to: For more information on the POWER-2 study, please go online to: Darunavir 600 mg BID + Ritonavir 100 mg BID + OBR (n = 57) Investigator-selected PI + OBR (n = 53) 1. Katlama C, et al. IAS Abstract WeOaLB0102. 2. Wilkin T, et al. ICAAC Abstract H-413.

37 Brecanavir (GW640385): PI Susceptibility vs Other PIs
Brecanavir retains in vitro susceptibility against virus resistant to commonly used PIs In vitro study of 55 isolates from PI-experienced patients Drug Mean IC50 (nM) Range (nM) Brecanavir 1.3 0.1 to 14.9 Amprenavir 404 61 to > 1500 Indinavir 515 27 to > 1500 Lopinavir 448 10 to 1455 Nelfinavir 368 69 to 1309 Viruses selected based on presence of protease mutations at codons 10, 32, 46, 47, 50, 54, 84, and/or 90 (mean: 8; range: 4-14) Reddy S, et al. ICAAC Abstract A-1800.

38 Brecanavir (GW640385) Novel PI Active in HIV-Infected Patients
Open-label, single-arm study in HIV-infected subjects N = 31 naive and experienced BL VL: 4.7 log10 copies/mL BL CD4+: 311 cells/mm3 Brecanavir/r 300/100 BID + 2 NRTIs 77% achieved VL < 50 copies/mL at Week 24 (ITT: missing = failure) 81% < 400 copies/mL at Week 24 6 PI sensitive at BL (n = 23) PI resistant at BL (n = 6) 5 4 Median Plasma HIV-1 RNA (log10 copies/mL) 3 BID, twice daily; BL, baseline; c/mL, copies/mL; ITT, intent to treat; PI, protease inhibitor; VL, viral load. For more information, please go online to: 2 Median change at Week 24 PI sensitive: -3.3 log10 c/mL PI resistant: -2.2 log10 c/mL 1 4 8 12 16 20 24 Study Week Ward D, et al. ICAAC Abstract H-412.

39 Virologic Response to Novel Integrase Inhibitor Monotherapy
MK-0518, novel integrase inhibitor Active against HIV resistant to current antiretrovirals Randomized, placebo-controlled 10-day monotherapy trial in treatment-naive patients BL VL: log10 c/mL BL CD4: cells/mm3 Good response seen with 10-day monotherapy No dose response All doses generally well tolerated MK mg (n = 7) MK mg (n = 7) MK mg (n = 6) MK mg (n = 8) -3 -2 -1 1 Placebo (n = 7) Change From Baseline in HIV-1 RNA (log10 copies/mL) An equally promising investigational agent that is at an earlier phase of development is the novel integrase inhibitor, MK In a randomized placebo-controlled trial of 10 days of MK-0518 monotherapy in treatment-naive patients, 4 different doses of the integrase inhibitor were studied and compared with placebo. All 4 doses of MK-0518 were associated with a significant reduction in viral load, ranging from log10 copies/mL. No significant adverse effects emerged from this phase I study, supporting its movement into phase II studies for further evaluation. For more information, please go online to: 1 2 3 4 5 8 10 Day on Therapy Morales-Ramirez JO, et al. EACS Abstract LBPS1/6.

40 MK-0518: Adverse Events Adverse events similar to placebo
Serious drug-related adverse events Acute pancreatitis, considered secondary to OBT, n = 1 Lipoatrophy, n = 1 Anemia, metabolic acidosis, renal insufficiency, death, n=1 Hepatomegaly, tenderness, fever (600 mg arm), n = 1 2 discontinuations Lack of efficacy (1); death (1) Most AEs mild to moderate Grinsztejn B, et al. CROI Abstract 159LB.

41 Integrase Inhibitor: GS-9137
10-day monotherapy study N = 40, HIV positive, HCV/HBV negative ARV naive or experienced off treatment Randomized 1:1 vs placebo Dosing 200 mg BID 400 mg BID 800 mg QD 800 mg BID 50 mg/RTV 100 mg QD PK studies Days 1 and 10 Trough sampling through Day 21 0.0 -0.5 -1.0 Log10 Change HIV-1 RNA Placebo 800 QD -1.5 200 BID 400 BID -2.0 800 BID 50 + RTV QD Dosing -2.5 BL 1 2 3 4 7 10 11 14 21 Day No serious adverse events Once-daily dosing with RTV to be investigated in phase II trial with experienced patients DeJesus E, et al. CROI Abstract 160LB.

42 Next-Generation Fusion Inhibitors
Animal data Enhanced pharmacokinetic properties Potential with once-weekly dosing In vitro data High genetic barrier Active against ENF-resistant virus 100 Cynomolgus monkey IV, 1 mg/Kg 1000 Clearance (mL/kg/hr) ENF TRI TRI ENF 10 100 Plasma Concentration (mm3/mL) For more information, see the Capsule Summary at Fold Decrease in Activity TRI-999 TRI-999 1 10 TRI-1144 TRI-1144 ENF 10 20 30 40 1 2 3 > 4 Time (Hours) (n) (6) (7) (8) (9) Number of Mutations Delmedico M, et al. CROI Abstract 48.

43 Novel Maturation Inhibitor, PA-457
Podawany doustnie; 70 godzin okres półtrwania u HIV (+) Efekt leczenia koreluje z poziomem w surowicy i trough concentration Liniowa farmakokinetyka prz różnych dawkach Badania In vitro oporności potwierdzają efekt działania studies confirm mode of action We wstępnych badaniach nie stwierdzono oporności For more information, see the Capsule Summary at Smith P, et al. CROI Abstract 52.

44 TNX-355: Novel CD4+ Attachment Inhibitor
Anti-CD4 monoclonal antibody blocks gp120 attachment to CD4+ receptor Delivered by IV infusion Phase II randomized trial in 82 3-class–experienced patients[1] TNX OBR or OBR alone TNX-355 doses: 15 mg/kg IV every 2 weeks 10 mg/kg IV every week x 8 weeks, then 10 mg/kg every 2 weeks Active against R5- and X4-tropic HIV[2] TNX OBR OBR Alone 15 mg/kg 10 mg/kg -0.20 -0.4 Mean Change in HIV-1 RNA at Week 24 (log10 copies/mL) gp120, glycoprotein 120; IV, intravenous; OBR, optimized background regimen. Mean baseline viral load was slightly higher in the 15-mg/kg TNX-355 group than in the 10-mg/kg group or the placebo group (5.00 vs 4.78 and 4.83 log10 copies/mL, respectively). While 57% of patients randomized to 15 mg/kg of TNX-355 had a viral load > 100,000 copies/mL, 33% in the placebo group and 26% in the 10-mg/kg group had a viral load that high. For more information, please go online to: -0.8 -0.95 (P = .003) -1.2 -1.16 (P < .001) 1. Norris D, et al. ICAAC Abstract LB2-26. 2. Godofsky E, et al. ICAAC Abstract LB26.

45 PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy
PA-457 first in new class called maturation inhibitors Targets late step in HIV life cycle Reduces viral load by disrupting production of HIV capsid protein, necessary for infecting other cells Randomized, phase IIa study of PA day monotherapy in 32 HIV-infected patients Median 1 log10 VL reduction with PA mg/day Generally well tolerated PA-457 Dose (mg/day) PL (n = 8) 25 (n = 6) 50 (n = 6) 100 (n = 6) 200 (n = 6) +0.03 +0.05 -0.17 (P = .02) -0.4 Median Change in HIV-1 RNA at Day 10 (log10 copies/mL) VL, viral load. For more information, please go online to: -0.48 (P = .004) -0.8 (P < .0001) -1.2 Beatty G, et al. ICAAC Abstract H-416d.

46 Zaburzenia metaboliczne i inne objawy uboczne

47 Prevalence of Metabolic Syndrome in MACS Cohort
HIV-positive men more likely to have metabolic syndrome than HIV-negative men Low HDL, elevated TGs, elevated glucose more likely in HIV+ Increased waist circumference less likely in HIV+ Estimated Odds Ratio for HIV+ vs HIV- Pts (95% CI) P Value Metabolic syndrome 1.50 ( ) .004 Elevated fasting triglycerides 2.81 ( ) < .001 Elevated fasting glucose 1.81 ( ) Increased waist circumference 0.38 ( ) Low HDL cholesterol 3.15 ( ) High blood pressure 1.04 ( ) .715 Study evaluated 646 HIV-positive men and 397 HIV-negative men in the MACS cohort. Differences in components of metabolic syndrome are differences between all HIV-positive and HIV-negative patients in the MACS cohort Palella F, et al. IAS Abstract TuPe2.2B18.

48 Lipid Effects of First-line Regimens
Swiss HIV Cohort Study (N = 1065; FU mos) ↑ cholesterol with either PIs or NNRTIs ↑ triglycerides with PIs, particularly with RTV regimens Patients primarily on LPV/r, IDV/r, or NFV ↑ HDL-C with NNRTIs Young J, et al. IAS Abstract TuPe2.2B16.

49 Dyslipidemia: Lipid-Lowering Therapy vs PI to NNRTI Switch
EFV NVP Pravastatin Bezafibrate 300 250 -10% -27% 200 Mean Total Cholesterol (mg/dL) -46% 150 In this Italian study published this summer, they compared the impact of substitution of a PI with the addition of lipid lowering therapy for managing dyslipidemia. The improvements in total cholesterol were statistically greater for the arms that added lipid lowering therapy compared with the switch to NNRTIs. -38% 100 50 3 6 9 12 Months Calza L, et al. AIDS. 2005;19: TuFo0105

50 RAVE: Switch Thymidine Analogue to ABC or TDF
Suppressed patients with self-defined lipoatrophy on thymidine analogue NRTI 105 patients randomized to replace TA with Tenofovir, or Abacavir Total limb fat increased to similar extent in both arms over 48 weeks TDF 1200 1061 ABC 1046 1000 791 800 Change in Fat Mass by DEXA at Week 48 (g) 600 522 393 400 316 ABC, abacavir; DEXA, dual energy x-ray absorptiometry; TA, thymidine analogue; TDF, tenofovir. The Randomized Abacavir Viread Evaluation (RAVE) study examined replacing a thymidine analogue with an alternative nucleoside or nucleotide analogue. In this study, patients with self-defined lipoatrophy were randomized to replace their thymidine analogue (stavudine or zidovudine) with either abacavir or tenofovir. Both strategies were associated with similar increases in total limb fat, with no significant differences between the treatment arms, suggesting that both abacavir and tenofovir are reasonable alternatives in patients with thymidine analogue–associated fat loss. For more information, go online to: 200 Limb Trunk Total Fat Within-group change in limb fat from baseline: TDF (P = .01), ABC (P = .001) Moyle G, et al. CROI Abstract 44LB.

51 No. of Patients With Events Risk of Disease Progression or Death
SMART: HIV Progression by Sex and Race; Severe Complications Subgroups No. of Patients With Events Relative Risk (95% CI) 2.5 All Patients 164 Sex 2.3 Male 118 3.4 Risk of Disease Progression or Death Female 46 Race 3.6 Black 71 2.0 Nonblack 93 1.5 For more information, please see the Capsule Summary at Severe Complications 114 1.4 CVD, liver, or renal deaths 31 1.5 Risk of Complications Nonfatal CVD events 63 1.4 Nonfatal hepatic events 14 2.5 Nonfatal renal events 7 0.1 Favors TI 1.0 Favors CT 10.0 El-Sadr W, et al. CROI Abstract 106 LB.

52 CD4+ Cell Count–Guided TIs: Summary
TI may be safe if patient has CD4+ cell count > 350 cells/mm³ and remains above that level In these trials, TI has led to some risk of progression and/or resistance and may potentially lead to increased risk of transmission In the US, if therapy is indicated, the best results are seen in patients who are on continuous therapy In developing countries, further investigation of TI is warranted due to limited ART availability In SMART, increased risk of poor outcome noted unexpectedly early in the interruption period In SMART, presence of viremia at baseline associated with poorer outcomes regardless of arm In viremic patients, no increased risk with CD4+-guided TI (RR 1.1) In aviremic patients, ↑ risk of progression or death with TI (RR 3.8)

53 Koinfekcje This section of slides is about hepatitis coinfection and opportunistic infections.

54 170-200 million carriers worldwide 10 million HIV coinfected*
Hepatitis C: A Global Health Problem million carriers worldwide 10 million HIV coinfected* W. Europe 5 M 30-50% HIV+* E. Europe 10 M Far East 60 M USA 3-4 M 30% HIV+* South East Asia M Africa M Americas M HIV 40 M Australia 0.2 M HCV M HBV 350 M *HCV/HIV coinfection linked to IDU WHO

55 Increase in Sexual Transmission of HCV
Great Britain; 3 cities; [1] 111 HIV-positive MSM with acute HCV Phylogenetic analysis of 91 E1/E2 sequences indicated common source transmission of HCV Risk factors for HCV infection by case-control analysis Meeting sexual partners in bathhouses or over the Internet Body piercing or tattooing Sexual partners and unsafe sex practices, including group sex Recreational drug use and drug use during sex STDs Amsterdam Cohort Study[2] 10-fold increase in HCV since 2000 29 cases of HIV-positive MSM with acute HCV Phylogenetic analysis (n = 24) identified 2 clusters, which are not related to other Dutch risk groups 18 reported unsafe sex practices or mucosal-damaging STDs Out of 20 surveyed, all denied IDU For more information see the Capsule Summary at 1. Danta M, et al. CROI Abstract Coutinho R, et al. CROI Abstract 87.

56 Increase in HCV RNA Detection After HAART Initiation
Analysis of HCV/HIV-coinfected pts in the HOMER cohort 20% of patients who were HCV-Ab (+)/HCV RNA (-) pre-HAART became HCV RNA (+) after HAART Possible explanations Blips Laboratory variation, error Immune restoration Baseline samples tested with unambiguous results (n = 1186) PCR (+): 70% (n = 425) PCR (-): 30% (n = 179) HCV Ab (+) and PCR (+) after mos of HAART: 20% (n = 24 of 118 evaluable samples) HCV-Ab (+): 51% (n = 606) HCV-Ab (-): 49% (n = 580) Braitstein P, et al. IAS Abstract TuPe1.1C30.

57 Complications in HCV/HIV-Coinfected vs HCV-Monoinfected Patients
Encepha- lopathy Variceal bleeding HCV/HIV coinfected HCV monoinfected Frequency as First Hepatic Decompensation (%) 10 20 30 40 50 60 70 14% 8% 4% 27% 66% 38% 11% 2% 3% 17% 1% Ascites Jaundice SBP HCC Hepatorenal syndrome P = .01 P < .001 P = NS P = .02 SBP, spontaneous bacterial peritonitis; HCC, hepatocellular carcinoma Miro J. IAS Abstract TuFo0303; Pineda JA et al, Hepatology. 2005, 41:779-89

58 HCV-3 Coinfection Associated With Greater Risk of Hepatotoxicity
N = 388 HIV/HCV-coinfected patients in Italian cohort 132 had HCV genotype 3 Factors associated with ↑ risk of grade ≥ 3 hepatotoxicity Male sex HBsAg positivity Baseline ALT HCV genotype 3 1.0 Cumulative Proportion of Patients Free of ≥ Grade 3 Hepatotoxicity HCV ≠ 3 0.9 0.8 0.7 P < .001 ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HCV-3, hepatitis C virus genotype 3; HCV≠3, non-hepatitis C virus genotype 3. Grade ≥ 3 hepatotoxicity defined as any increase by ≥ 5 x ULN in ALT or AST Data from other studies suggest HCV-3 associated with higher incidence of NASH For more information, please go online to: 0.6 HCV-3 0.5 0.4 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Time Since Entry (Years) Torti C, et al. ICAAC Abstract H-1484.

59 Rapid Fibrosis Progression in HCV/HIV-Coinfected Patients
100 91 First biopsy Second biopsy Mean time between biopsies: 50 months 80 60 *All patients were F1 at second biopsy. Patients (%) 40* 33 40 18 20 HCV, hepatitis C virus. A study by Bonnard and colleagues showed that liver fibrosis in HIV/HCV–coinfected patients can rapidly progress to cirrhosis and that coinfected patients may require more frequent liver biopsy than patients with HCV monoinfection. The investigators evaluated fibrosis stage at first and second biopsy in a cohort of HIV/HCV-coinfected patients. As shown in this slide, a significant proportion of patients with modest fibrosis (stage F2 or less) at first biopsy progressed to stage 3 or 4 fibrosis within a mean interval of only 50 months. Overall, 28% of patients progressed by 2 or more fibrosis points between biopsies. This is a greater rate of progression than one would anticipate in patients with HCV monoinfection, and suggests that specific guidelines should be developed for HIV/HCV-coinfected patients. Clearly, the clinical importance of this finding is that the morbidity of HCV infection is related to the development of fibrosis, with consequent cirrhosis of the liver and an increased risk for hepatocellular carcinoma. This will be an important consideration in future survival analyses and in regard to long-term management of HIV/hepatitis-coinfected patients. For more information, please go online to: 9 9 F0/1 F2 F3 F4 Fibrosis Stage 9/32 (28%) of HCV/HIV-coinfected patients progressed ≥ 2 fibrosis points between biopsies Bonnard P, et al. EACS Abstract PE13.2/2.

60 HAART and Liver Enzyme Elevations
Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection Grade 2 or higher liver elevations noted % LEE in HCV-Coinfected Patients by Drug Class P = .025 40 P = .004 32.00 P = .009 30 For more information see the Capsule Summary at Patients With LEE,% 18.44 20 15.96 14.67 13.62 10 5.26 NNRTI PI Mixed BPI NRTI Overall Drug Class Benhamou Y, et al. CROI Abstract 88.

61 Response to Treatment During Acute HCV in HIV-Coinfected Patients
59% SVR among pts with acute HCV treated with 24 wks Peg-IFN alfa 2b + RBV Similar to overall rate in treatment of chronic HCV in coinfected pts Better for genotype 1 coinfected pts vs treatment during chronic infection Lower than that with treatment of acute HCV in monoinfected pts High rate of spontaneous clearance w/o therapy (24%) 20 40 60 80 100 All Patients (n = 27) Genotype 1 (n = 20) Genotype non-1 (n = 4) 67% 65% 100% 59% 55% SVR ETR Virologic Response (%) Peg-IFN (1.5 g/kg/wk) + RBV ( mg/day) for 24 weeks Nelson M, et al. IAS Abstract TuPe1.1C10.

62 Low Numbers of HCV/HIV Patients Achieve SVR in an Urban HIV Clinic
Retrospective analysis of Johns Hopkins HIV Clinic n = 845 with HCV n = 277 referred (33%) n = 125 entered evaluation for treatment n = 29 initiated treatment For more information see the Capsule Summary at n = 6 (21%) of these attained SVR This represents 2.1% of those referred, or 0.7% of those with HCV Mehta S, et al. CROI Abstract 884.

63 Use of QuantiFERON-TB Gold in HIV-Infected Patients
QuantiFERON-TB Gold, new blood-based diagnostic test for TB infection Uses peptides absent from BCG and common non-tuberculous mycobacteria CDC recommends that QFT-G be used in all circumstances in which the TB skin test is currently used[1] Sensitivity unknown in HIV population Evaluated in 590 HIV-infected pts[2] 27 QFT-G positive Limitations No comparison with skin testing No means of assessing true TB infection rate 100 QTF-G(-) (n = 543) 89 QTF-G(+) (n = 27) 81 80 60 Patients (%) 40 BCG, Bacille Calmette-Guérin; CDC, Centers for Disease Control and Prevention; QFT-G, Quantiferon-Gold; TB, tuberculosis. For more information, please go online to: QFT-G results can be available < 24 hours after testing without the need for a second visit, whereas a tuberculin skin test (TST) requires a second visit to read the result 48–72 hours after administration of the test. QFT-G, unlike TST, requires drawing blood and errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of QFT-G. 20 10 6 7 4 2 0-99 > 300 Mean CD4+ Cell Count (cells/mm3) 1. Mazurek GH, et al. MMWR Morb Mortal Wkly Rep. 2005;54(RR- 15): Brock I, et al. ICAAC Abstract H-1494.

64 Hepatotoxicity with Rifampin + SQV/r
2/05 FDA letter warning of ↑ risk of hepatotoxicity when hard-gel SQV/r taken with rifampin in healthy volunteers Confirmed by data in TB/HIV-coinfected patients Prospective study of 20 coinfected patients who began SQV/RTV (400/400 BID) 30 days into TB treatment [1] 14 pts discontinued during TB-HIV therapy phase due to ARV intolerance (mostly hepatic and gastrointestinal events) Chart review of 12 coinfected pts on rifampin who began SQV/r (1000/100 BID) + 2 NRTIs during induction phase [2] 6 experienced hepatotoxicity 3 cases moderate to severe; all had HCV 1 pt permanently discontinued antiretroviral treatment SQV and RTV AUC slightly decreased, but concentrations still in normal range 1. Rolla V, et al. IAS Abstract WePe3.3C03. 2. Duran A, et al. IAS Abstract TuPe7.1C22.

65 EuroSIDA: Liver-Related Deaths in HIV-Infected Patients
Death rates from liver-related disease appear to have decreased in Europe ( /5) After adjusting for CD4+ cell count, small ↑ in liver disease–related deaths noted ↑ HAART exposure associated with ↑ liver disease–related death after adjusting for CD4+ cell count May be due to ARV-induced liver toxicity, progression of liver disease in HBV- or HCV-coinfected patients as patients survive longer, or other factors ARV, antiretroviral; HBV, hepatitis B virus; HCV, hepatitis C virus. An interesting analysis from the EuroSIDA cohort evaluated liver-related deaths in patients with HIV disease. Although overall death rates from liver disease decreased in Europe over the last 10 years, after adjusting for CD4+ cell count, there was a small increase in liver-related deaths. This increased risk of liver-related deaths also appeared to be associated with increased exposure to antiretroviral therapy. The reasons for this are not yet understood. The cause may be increased toxicity from antiretroviral therapy; however, it could also be due to an increase in hepatitis B and C coinfection, which is now becoming more evident as patients are living longer due to the increasing effectiveness of antiretroviral therapy. Clearly, this is an observation that requires further analysis and awareness of liver-related deaths, and highlights the importance of monitoring HIV-infected patients for liver disease. For more information, please go online to: Lundgren J, et al. EACS Abstract PS7/2.

66 Predictors of Anal Dysplasia in HIV-Positive and HIV-Negative MSM
UCSD anal dysplasia screening clinic[1] Pap screening not associated with decreased prevalence of invasive anal cancer, although earlier stage at detection suggested Pap correlated with biopsy (increasingly so with increased operator experience) Anal dysplasia referral population study[2] 36% of HIV-positive men and 30% of HIV-negative men had high-grade anal dysplasia Pap results did not correlate with biopsy ARV use and duration not predictive of high-grade anal dysplasia For more information see the Capsule Summary at Results conflict with those of Palefsky et al who suggested that receipt of HAART was associated with higher rate of anal dysplasia (Palefsky JM, et al. JAIDS. 1997;14: ) 1. Press N, et al. CROI Abstract Montaner J, et al. CROI Abstract 807.