Key Research From IDSA 2007: The 45th Annual Meeting of the Infectious Diseases Society of America This activity is supported by an educational grant from San Diego, California | October 4-7, 2007 Faculty Eric Daar, M.D.

The Body PRO The Body PRO Covers IDSA 2007 IDSA 2007: Faculty for This Activity Eric Daar, M.D. Dr. Daar is the chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles, Calif., and a professor of medicine at the University of California-Los Angeles' David Geffen School of Medicine. He has been an active HIV physician and researcher since the 1980s; during the past three decades, he has led dozens of studies on a vast range of HIV-related issues, with a particular focus on coinfections and other health complications associated with HIV and HIV treatment, including hepatitis C, metabolic complications, cardiovascular disease and psychosocial issues such as depression.

The Body PRO The Body PRO Covers IDSA 2007 IDSA 2007: Key Research About This Presentation This presentation was created to accompany The Body PRO's podcast summary of key research presented at IDSA 2007, featuring an interview with Eric Daar, M.D. For more information about this program, please visit us on the Web at: TheBodyPRO.com/IDSA2007 Please feel free to use this slide presentation for personal reference or for your own presentations; however, we ask that you not modify any aspects of the slides contained within this presentation so proper attribution can be retained. If you would like to publish all or part of this presentation, or repost any of these slides online, you must first obtain permission from Body Health Resources Corporation. Our gratitude goes out to all who granted permission for their slides to be adapted for this presentation. Disclaimer Knowledge about HIV changes rapidly. Note the date of this presentation's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this presentation.

The Body PRO The Body PRO Covers IDSA 2007 Challenges of Current Antiretroviral Therapy

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Methods Retrospective cohort study of patients initiated on HAART between January 1996 and July Inclusion criteria HIV-1 infection, age ≥ 18 years, baseline CD4+ T cells <350 cells/mm 3 and viral suppression for ≥ 52 weeks. Definitions Discordant and concordant responders defined by CD4+ T cell gains of <150 or ≥ 150 cells/mm 3 from HAART initiation through 52 weeks of viral suppression and followed to death, virologic failure (lack of re-suppression of viremia) or study termination. Data collection Socio-demographics, clinical, medication and laboratory data. Sample collection and analysis Blood samples from immune discordant and concordant responders (total n=45) with sustained viral suppression, were obtained to determine the percentage of CD4+ and CD8+ T lymphocytes that were memory (CD45RO+) or activated (CD38+,HLADR+), using three-color flow-cytometric analysis on cryopreserved peripheral mononuclear cells. Statistics Data analyzed using SPSS version Continuous variables compared using the Student’s t-test or Mann- Whitney U test. Chi square or Fisher’s exact tests used for categorical variables. All p values were two-tailed and significant at <0.05 and potential predictive factors for immune discordance were evaluated using multivariate logistic regression analyses. Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Absolute CD4+ T Cell Counts After HAART Initiation Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Results Characteristics Discordant (n=106) Concordant (n=192) OR (95% CI)P value Male gender Age, (years) a Caucasian African American 89 (84%) 41.2 ± (55%) 38 (36%) 134 (70%) 38.2 ± (39%) 108 (56%) 2.27( ) ( ) Mode of transmission Men who have sex with men Heterosexual 56 (53%) 30 (28%) 79 (41%) 96 (50%) 1.78( ) Years since HIV diagnosis a Previous OI Prior ARV experience 9.8 ± (57%) 34 (32%) 8.3 ± (54%) 62 (32%) ( ) 1.01( ) CD4+ T cell nadir b Highest HIV RNA viral load a 85 (21-180) 4.90 ± (12-189) 5.11 ± Chronic Hepatitis C Chronic Hepatitis B 17 (11%) 9 (6%) 16 (8%) 21 (11%) 1.97( ) 0.72( ) a Mean ±standard error of mean b Median (interquartile range), ARV = antiretroviral, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor. Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Results Characteristics Discordant (n=106) Concordant (n=192) OR (95% CI)P value At suppressive HAART initiation CD4+ T cell count b HIV RNA level a HAART regimen type NNRTI/ ≥ 2 NRTI All PI/ ≥ 2 NRTI Unboosted indinavir 126 (37-231) 4.68 ± (42%) 58 (55%) 27 (26%) 88 (19-222) 4.81 ± (48%) 87 (45%) 24 (13%) ( ) ( ) No. (%) with HAART-related side-effects 36 (34%)35 (18%)1.80( )<0.001 Weeks to viral suppression b 12 (6-23)16 (8-28)-0.04 One year CD4+ T cell gain b 99 (50-133)269 ( )-<0.001 a Mean ±standard error of mean b Median (interquartile range), ARV = antiretroviral, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, PI = protease inhibitor. Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Independent Factors Associated With Immune Discordance on Multivariable Analyses Male Gender Lower pre-HAART HIV-RNA viral load Any use of unboosted indinavir Greater number of HAART-related side effects per person Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Clinical Outcomes During Long-Term Follow-Up Clinical Outcomes Discordant (106) Concordant (192)OR (95% CI)P value Years of viral suppression on HAART a Highest CD4+ T cell count attained b 4.56 ± ( ) 4.51 ± ( ) <0.001 Death Remains in clinical care Lost to follow up 5 (5%) 75 (71%) 26 (25%) 9 (5%) 150 (78%) 33 (17%) 1.00 ( ) New opportunistic illness Type of opportunistic illness Years after viral suppression OI prophylaxis at 1 yr viral suppression at highest CD4+ T cell count 1 NHL 2 and 5 61 (58%) 37 (35%) 1 Kaposi’s sarcoma 8 73 (38%) 30 (16%) ( ) 2.90 ( ) - <0.001 Recurrent genital warts Recurrent shingles Recurrent genital herpes 5 (5%) 10 (9%) 0 1 (1%) 7 (4%) 6 (3%) 9.46 ( ) 2.75 ( ) 1.57 ( ) a Mean ± standard error of mean, b Median and interquartile range. NHL = non-Hodgkin’s lymphoma, OI = opportunistic infection. Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Immune Discordance While on HAART: Comparison of Activation and Memory T Cells Between Discordant vs. Concordant Immune Responders a Percentage of total events. CD38+HLADR+ = marker of activation, CD45RO+ = marker of memory cell. Data at the time of FACS analysis (mean ± S.E.M.) Discordant (n=20) Concordant (n=25) P value Age Gender: Male Female Race: Caucasian/Hispanic African American 48.7 ± (85%) 3 (15%) 15 (75%) 5 (25%) 48.7 ± (76%) 6 (24%) 10 (40%) 15 (60%) CD4+ T cell count (cells/mm 3 ) % <200 cells/mm 3 % cells/mm 3 % ≥ 350 cells/mm ± ± <0.001 Years of viral suppression5.6 ± ± CD4+ T cells a CD45RO+ Naïve:memory CD38+HLADR ± ± ± ± ± ± CD8+ T cells a CD45RO+ Naïve:memory CD38+HLADR ± ± ± ± ± ± Nur F. Önen et al. IDSA 2007; abstract 952. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 LPV/r Switch for Patients With Suboptimal Immune Responses to HAART Despite RNA Suppression: Study Design David Pitrak et al. IDSA 2007; abstract 955. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Mean Increase in CD4 Count After a Switch to Lopinavir/Ritonavir vs. Continuation of HAART Adapted from David Pitrak et al. IDSA 2007; abstract 955. Lopinavir/Ritonavir (N=8) Continuation (N=9) Baseline=177 %Δ=68.5 Baseline=264 %Δ=19.1

The Body PRO The Body PRO Covers IDSA 2007 Mean Apoptosis (Percent) of CD4CD45 RA+ (Naïve) T Cells After Switch to Lopinavir/Ritonavir vs. Continuation of Current Regimen Adapted from David Pitrak et al. IDSA 2007; abstract 955. Lopinavir/Ritonavir (N=8) Continuation (N=9) HIV-Negative Controls (N=10) Complete Responders (N=10)

The Body PRO The Body PRO Covers IDSA 2007 Mean Apoptosis (Percent) of CD4CD45 RO+ (Memory) T Cells After Switch to Lopinavir/Ritonavir vs. Continuation of Current Regimen Adapted from David Pitrak et al. IDSA 2007; abstract 955. Lopinavir/Ritonavir (N=8) Continuation (N=9) HIV-Controls Complete Responders

The Body PRO The Body PRO Covers IDSA 2007 LPV/r Switch for Patients With Suboptimal Immune Responses to HAART Despite RNA Suppression: Mean Change in CD4 Count Beyond 24 Months Adapted from David Pitrak et al. IDSA 2007; abstract 955. Lopinavir/Ritonavir (N=8) Continuation (N=9) Continuation Obs* (N=7)

The Body PRO The Body PRO Covers IDSA 2007 Cross Allergy Between NNRTIs: Patient Distribution Claudia P. Cortes et al. IDSA 2007; abstract 959. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Cross Allergy Between NNRTIs: Results  1547 patients were treated with efavirenz (Sustiva, Stocrin) and 946 with nevirapine (Viramune). 967 of these treatments required change of therapy. 554 (57.2%) of them, due to drug toxicity and 74 due to allergy.  35 patients with allergy to nevirapine switched to efavirenz. 2/35 (5.7%) developed rash within 30 days. This was not significantly different from 4.6% of primary allergy to efavirenz in the Chilean AIDS Cohort population. 31/33 (93%) of those without secondary allergy obtained viral suppression for at least 15 months.  Seven patients with efavirenz-induced rash underwent change to nevirapine. 2/7 (28.5%) developed rash. All remaining 5 patients obtained viral suppression for at least 15 months. Claudia P. Cortes et al. IDSA 2007; abstract 959. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 LPV/r Switch – Soft Gel Capsule to Tablet: Methods This was a prospective cohort study that enrolled clinically stable HIV-infected subjects receiving LPV/r-based antiretroviral regimen. Screening HIV-subjects age >18 years. Enrolled prior to, or within eight weeks of formulation switch. No CD4 cell count restriction. No pregnancy/breastfeeding. Laboratory Evaluations Clinical labs monitored at baseline and at week 12: Fasting lipid profile. HIV-1 RNA. CD4 cell count. Bowel Movement Evaluation Daily bowel habit (BH) was assessed prior to switch and at weeks 4 & 12. The bowel habit score was assessed using the scoring system below and dividing the sum by 4. The scale has a minimum of 1 (best BHS outcome) and a maximum of 5 (worst BHS outcome). Stool consistency:solid =1, loose =3, watery=5 Volume:small =1, moderate=3, large=5 Presence of blood in stools: no=1, yes=5 Frequency per day:1 – 5 (>4 BM per day scored as 5) Ighovwerha Ofotokun et al. IDSA 2007; abstract 962. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Study population (n = 74) Male sex [n (%)]61 (82) Race African American [n (%)] White [n (%)] Hispanic [n (%)] 55 (74) 17 (23) 2 (3) †On LPV/r tablet at entry No [n (%)] Yes [n (%)] 49 (66) 25 (34) On anti-diarrheal drug No [n (%)] Yes [n (%)] 67 (92) 6 (8) On lipid lowering drug No [n (%)] Yes [n (%)] 54 (74) 19 (26) Median age [years (IQR)]43 (39-47) Median weight [kg (IQR)]80.5 ( ) Median HIV-1 RNA [copies/ml (IQR)]135 (50-170) Median CD4 T-cell counts [cell/μl (IQR)]294 ( ) LPV/r Switch – Soft Gel Capsule to Tablet: Subject Demographic Data at Study Entry LPV/r = lopinavir/ritonavir SGC = soft gel capsule IQR = inter quartile range † Subjects were already switched from LPV/r SGC to tablets within eight weeks prior to enrollment; 75% percentile, 25 th to 75 th percentile. Ighovwerha Ofotokun et al. IDSA 2007; abstract 962. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 LPV/r Switch – Soft Gel Capsule to Tablet: Change in Self-Reported Bowel Habit Bowel habit (BH) score*Baseline to Week 4 (n= 70) Baseline to Week 12 (n=62) Overall change, mean ± SD ± ± Bowel habit improvements among those reporting a change Baseline to Week 4Baseline to Week 12 Improvement rateP-valueImprovement rateP-value Decrease in stool frequency among those reporting change 18/28 (64%)0.1318/32 (56%)0.48 Improved stool consistency among those reporting change 23/30 (77%) /27 (70%) Decrease in stool volume among those reporting change 11/16 (69%)0.138/13 (62%)0.41 Resolution of blood in stool among those reporting change 5/6 (83%)0.104/6 (67%)0.41 SD = standard deviation *BHS example, a subject with baseline responses of: solid, moderate, no blood in stool, and frequency of “2” would have a score of: ( )/4 = 1.75 for their baseline summary score. Ighovwerha Ofotokun et al. IDSA 2007; abstract 962. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 LPV/r Switch – Soft Gel Capsule to Tablet: Changes in Fasting Lipid Profile From Baseline to Week 12 Lipid Lowering DrugBaseline mean (SD) Week 12 mean (SD) Mean change (SD) P-value TCNo (n =38) Yes (n=16) Total population (n=54) 188 (35.1) 221 (66.2) 198 (48.4) 179 (34.7) 218 (55.8) 190 (45.3) (23.20) (44.30) (30.70) * TRIGNo (n=33) Yes (n=14) Total population (n=47) 187 (117) 410 (410) 254 (260) 154 (111) 329 (304) 206 (203) (86.30) (348.30) (199.90) 0.035* HDL-CNo (n=33) Yes (n=14) Total population (n=47) 47.0 (11.3) 35.1 (15.9) 43.2 (14.0) 42.6 (11.9) 36.8 (15.8) 40.7 (13.4) (9.40) 1.70 (9.50) (9.78) 0.012* LDL-CNo (n=33) Yes (n=14) Total population (n=47) 106 (29.4) 123 (54.5) 111 (38.8) 102 (24.4) 127 (32.3) 110 (29.0) (21.80) 3.60 (48.60) (31.80) TC = total cholesterol; TRIG = triglyceride; HDL-C = high density lipoprotein; LDL-C = low density lipoprotein; SD = standard deviation *Statistically significant (P ≤ 0.05). Ighovwerha Ofotokun et al. IDSA 2007; abstract 962. Reprinted with permission.

The Body PRO The Body PRO Covers IDSA 2007 Visit The Body PRO for comprehensive coverage of IDSA This presentation was created to accompany The Body PRO's summary of key research presented at IDSA 2007, by Eric Daar, M.D. Learn more at: TheBodyPRO.com/IDSA2007 In addition, be sure to browse through The Body PRO’s extensive coverage of IDSA 2007, which includes: –A full written summary with expert discussion and analyses of key research. –Downloadable MP3s: listen on your computer or download to your MP3 player. –Slides and in-depth data analyses. Visit TheBodyPRO.com/IDSA2007 today for a full listing of our conference materials! IDSA 2007: Key Research