The 18th International AIDS Conference (AIDS 2010)

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The 18th International AIDS Conference (AIDS 2010)

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  • The Vienna Declaration is a statement seeking to improve community health and safety by calling for the incorporation of scientific evidence into illicit drug policies. Scientists, health practitioners and the public are invited to endorse this document in order to bring these issues to the attention of governments and international agencies, and to illustrate that drug policy reform is a matter of urgent international significance. The website address for the declaration is on the slide.
  • Demographic data as stated
  • Demographic data as stated
  • Background: In a randomized controlled trial in Kisumu, Kenya, involving 2,874 men aged 18-24 years at enrollment, we previously reported a 60% protective effect of male circumcision against HIV acquisition at 24 months after enrollment, and 64% at 42 months, based on modified as-treated analyses. We now report sustained protection against HIV infection extending to at least 54 months of follow-up. Methods: The trial was unblinded in December 2006, when all participants were offered circumcision, regardless of initial treatment assignment (immediate versus delayed circumcision). HIV/STI testing and behavioural interviews were conducted semiannually in extended follow-up. Relative risk was estimated using a modified as-treated analysis. Results: As of March 2010, 1552 of 1740 men (89%) consented to extended follow-up (n=767 circumcision group; n=785 controls); 1469 remain on study. 619 of 1393 controls (44%) were circumcised. Age and number of sexual partners at baseline were the same in controls who did and did not elect to be circumcised. The median follow-up was 36 months. There were 36 HIV seroconversions in men randomized to circumcision and 82 in controls over 54 months. The 54 month cumulative seroincidence was 4.1% (95% CI 2.9, 5.8) among men randomized to immediate circumcision and 8.8% (7.0, 10.9) among controls (p< 0.0002). The relative risk of HIV infection in circumcised men was 0.37 (0.25, 0.54), corresponding to a 63% (46, 75) protective effect. Conclusions: The protective effect of circumcision against HIV acquisition among sexually active men seen after 24 and 42 months of follow-up was sustained to at least 54 months. Concerns about the potential for reduced protection offered by circumcision over time appear unfounded based on follow up of 4.5 years. Our results support expeditious provision of safe, voluntary male circumcision services as part of comprehensive HIV prevention strategies.
  • Background: Infection and diseases caused by human papillomavirus (HPV) are common in men. Here we report on the safety of quadrivalent HPV (types 6/11/16/18) vaccine (qHPV) and its efficacy against external genital lesions (EGL) and anogenital HPV 6/11/16/18 infection in males. Methods: A total of 4,065 healthy men (3,463 heterosexual men and 602 men who have sex with men) aged 16-26 years were enrolled from 18 countries into a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to demonstrate that qHPV vaccine reduced the incidence of HPV 6-, 11-, 16-, or 18-related EGL. Efficacy analyses were conducted in per protocol and intention-to-treat (ITT) populations. Results: Three HPV 6/11/16/18-related EGL were observed in the per-protocol qHPV vaccine arm and 31 in the perprotocol placebo arm (observed efficacy of 90.4% [95% CI: 69.2, 98.1]). The majority of EGL observed were condylomata acuminata; no cases of penile/perianal/perineal intraepithelial neoplasia were observed in qHPV vaccinees. Efficacy against EGL in the ITT population was 65.5% (95% CI: 45.8, 78.6). Efficacy against HPV 6/11/16/18-related persistent infection and DNA detection at any time was 85.6% (97.5% CI: 73.4, 92.9) and 44.7% (95% CI: 31.5, 55.6), respectively in the per-protocol population and 47.8% (95% CI: 36.0, 57.6) and 27.1% (95% CI: 16.6, 36.3), respectively in the ITT population. Overall, qHPV vaccine was well-tolerated in men, though injection-site pain occurred significantly more frequently among those receiving qHPV vaccine (57% vs. 51%; p< 0.001). Conclusions: Quadrivalent HPV vaccine effectively prevents HPV 6/11/16/18-related EGL and infection in men 16-26 years of age and has a favorable safety profile.
  • Study of TDF gel, applied intravaginally, as prophylaxis against HIV infection. Study design is shown.
  • As shown, the TDF gel was effective in preventing HIV infection, with a effectiveness of 39% at 30 months. The gel was even more effective in patients who used the gel as they were directed to, as evidenced by the lower and less frequent detection of TDF levels in women treated with the gel who became HIV infected. TDF gel also appears to have some anti-HSV activity, which may be concentration related. Safety data were unremarkable.
  • PATTERSON STUDY: Background: Current oral PrEP trials use tenofovir DF (TDF) + emtricitabine (FTC) both of which require intracellular phosphorylation (TFV-DP, FTC-TP). As intermittent PrEP dosing strategies are being considered, single dose pharmacokinetics (PK) in vulnerable mucosa were evaluated. Methods: Eight HIV negative men and 7 women received one dose of TDF/FTC. Blood plasma (BP), cells (PBMC), cervical (CT), vaginal (VT) and rectal (RT) biopsies were collected 1, 2, 5, 7, 10, and 14 days post-dose. LC/MS/MS sample analysis had an LLOQ of 0.1ng/mL (TFV, FTC) and 2-10 fmol (TFV-DP, FTC-TP). PK data were generated non-compartmentally, and penetration ratios (PR) calculated as tissue AUC0-14d ÷ blood AUC0-14d. Median (range) data are reported. Results: Subjects were 23 (19-37) yrs and 23.7 (18.8-28.6) kg/m2 : 11 were white. After one dose, TFV could be detected for 14d in BP, VT, & RT; 7d in CT. TFV-DP was detected in all matrices for 14d. FTC could be detected for 14d in BP & RT; 10d in VT and CT. FTC-TP could be detected for 10d in PBMCs, 2d in VT & RT, and 1d in CT. [Table 1] Conclusions: Following one TDF/FTC dose, TFV and FTC AUC were highest in RT and CT, respectively. Over 7d, all analytes were detected in all matrices. Measurable 14d BP TFV+FTC imply that plasma adherence monitoring is feasible in PrEP trials. Although tissue TFV-DP exposures were similar to PBMCs, FTC-TP exposures were low. Wide variability of drug exposures in tissues highlights the need for accurate PK information to inform clinical studies. GLOHSKOPF STUDY: Background: Animal studies suggest PrEP may protect against HIV acquisition. This double-blinded randomized trial evaluated clinical and behavioral safety of daily oral TDF among HIV-1 negative MSM in Atlanta, San Francisco, and Boston. Methods: HIV-1 negative men reporting anal sex with another man in the past year were randomized to initiate oncedaily TDF (300mg) or placebo at enrollment or after a 9-month delay. Quarterly visits included HIV testing, riskreduction counseling, and assessments of biomedical and behavioral safety, adherence, and acceptability. Bone density (DEXA) was assessed in San Francisco. Results: From February 2005 through July 2007, 400 men (median age 39 years) enrolled; 373 initiated study drug (TDF or placebo). Seventy-three percent were white, 15% African American, 4% Asian/Pacific Islander; 9% were Hispanic. Treatment-emergent adverse events are summarized On the slide. 3 or 4 creatinine elevations were observed. A total of 27 protocol-defined serious adverse events occurred, 16 on TDF and 11 on placebo (p=0.56). Among 186 San Francisco participants who had DEXA scans, 11 discontinued drug (per protocol) for >5% decrease in bone density (total hip or spine) from baseline (8[8%] on TDF, 3[3%] on placebo; p=0.21). Seven participants became HIV infected; four were placebo recipients (including one seronegative at enrolment but subsequently found to be acutely infected); three were in the delayed arm and seroconverted before starting study drug. Conclusions: No significant biomedical safety issues were identified. This study was not designed to detect efficacy of TDF in preventing HIV infection. Adequately powered efficacy trials are underway to address this question.
  • Summary of PrEP trials in later phases.
  • Background: In Denmark HIV-testing is encouraged among men who have sex with men (MSM). More than 80% of HIV-positive MSM are treated with antiretrovirals (ART), 86% of these having immeasurably low viral load. National HIV-surveillance and behavioural studies are used to monitor trends in risk-behaviour and HIV-transmission-rates. Methods: Stable annual numbers of MSM notified with HIV are used as proxy for newly infected and used to calculate number of MSM living with HIV and HIV-transmission-rates. Proportions of HIV-positive respondents in the MSM Sex- Life Surveys reporting unprotected anal intercourse (UAI) and unsafe sex (US, defined as UAI with non-positive partners) are used to estimate trends in sexual risk-behaviour. Results: Despite increasing numbers of MSM living with HIV, numbers of newly infected MSM remain stable, indicating a decline in transmission-rates, figure 1. This decline can not be ascribed to safer sex-practices among HIV-positive MSM, as both UAI and US are increasing (p< 0.001), figure
  • GE STUDY: Background: In China, heterosexual sex has surpassed injection drug use and homosexual sex to become the dominant mode of HIV transmission. This study aimed to determine the incidence of HIV transmission and assess risk factors for HIV seroconversion among serodiscordant couples in China. Methods: Between January 2006 and December 2008, initially seronegative spouses were enrolled in an open cohort study and tested for HIV at six month intervals. Participants were interviewed through face-to-face questionnaire. Cox proportional hazards model was used to assess the relationship between behavioral risk factors and HIV seroconversion. Results: Out of 1927 couples, 84 (4.3%) seroconverions occurred, representing a seroconversion rate of 1.71 per 100 person-years. The cumulative incidence rate was 4.92% and seroconversion rates increased over time. Not always using condoms (RR=8.42; 95% CI, 4.83-14.67), sexual activity ≥ 4 times per month (RR=5.24; 95% CI, 2.55-10.77), not switching anti-retroviral treatment (ART) regimen (RR=1.99; 95% CI, 0.85- 4.65), and a quality of life score < 12 on the psychological domain (RR=2.33; 95% CI, 1.21-4.48) were associated with increased risk of seroconversion. Seventy one percent of index spouses were on ART, and ART use was associated with decreased risk for HIV transmission, but this result was not statistically significant (RR=0.76; 95% CI, 0.45-1.28). There was no association between rate of HIV seroconversion and level of the most recent CD4 count in the index spouse. Conclusions: Effective HIV prevention interventions targeting discordant couples should focus on sustaining health education, increasing psychosocial support services, and increasing medication adherence monitoring. FAIRBURN STUDY: Background: Increasing crystal methamphetamine (CM) use worldwide poses a significant threat to HIV prevention and treatment strategies. CM has been linked to sexual and parenteral risk behaviours and increased likelihood of HIV seroconversion, as well as poor adherence to antiretroviral therapy. We examined the impact of CM injection on HIV RNA suppression among a prospective cohort of HIV-positive injection drug users (IDUs) initiating antiretroviral therapy. Methods: We enrolled HIV-positive IDUs into a community-recruited prospective cohort study. We modeled factors associated with HIV RNA suppression using Cox regression to determine factors independently associated with viral load suppression. Results: Between September 1996 and April 2008, 384 (54.2%) antiretroviral-naïve patients initiated highly active antiretroviral therapy (HAART) among whom 163 (42.5%) were women. Overall, 36 (9.4%) reported CM injection at any time during follow-up. A multivariate Cox regression analysis found CM injection to be negatively associated with viral load suppression (RH = 0.63 [95% CI: 0.40 - 0.98]; p = 0.039), even after adjustment for age, baseline CD4 cell count and viral load, heroin injection and cocaine injection. Conclusions: This study is the first to our knowledge to demonstrate an association between CM use and HIV RNA suppression. These data contribute further evidence to the negative health outcomes associated with CM use among HIV-positive individuals. Our findings are most likely explained by the fact that the psychopharmacological effects of CM may undermine antiretroviral treatment adherence. Given the continued increases in CM consumption despite attempts to deter use, strategies to improve drug treatment, as well as improved HIV prevention and treatment adherence strategies for this high risk group require urgent implementation.
  • Model assumptions Annual HIV testing ($12/test) Yearly ARV cost 1st line: $127 Monitoring cost: $23 Hospitalization costs $80-$140/day for 2-9 days depending upon CD4 count Scale up over 5 years 80% community participation 92% lower transmission rate on ARV 3% annual transfer from 1 st to 2 nd line Rx 1% drop-out rate Model indicates that ultimately a test and treat approach may be less expensive than other options The list at the bottom of the slide is the ongoing studies in test and treat, which show that this is a very active area of research.
  • Treatment guidelines have been updated by the IAS-USA – last iteration was in 2008. This table summarizes when to start therapy. Some items mentioned as indications for ART regardless of CD4 are not specifically cited in DHHS guidelines of 2009; these include HCV, CV disease, primary HIV infection, and risk for secondary transmission.
  • The unique contibution of Cascade was the use of seroconverters to track the duration of seroconversion, and the time spent in a specific CD4 strata. This is a large european cohort that contributed almost 10,000 seroconverters to the study who were then followed for a median of 4. 7 years. The cumulative risk difference and the Number needed to treat illustrate the benefit of CD4 counts <500 as an initial threshold for starting ARV treatment. The benefit of early treatment seems to diminish above CD4 counts of 500.
  • Tuberculosis (TB) is the largest cause of death in HIV positive people and it is worse in those with lower CD4 counts. among those with profound immunosuppression. Most deaths in new TB diagnoses amongst HIV positive people occur in the first few months after initiation of TB treatment. The current WHO guidelines suggest initiating treatment between 2 and 8 weeks. This study clearly illustrates the benefit of earlier treatment in a setting primarily in the developed world that can save many lives. THLBB106 - Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis F.X. Blanc1, T. Sok2, D. Laureillard2,3, L. Borand4, C. Rekacewicz5, E. Nerrienet4, Y. Madec6, O. Marcy2, S. Chan2, N. Prak7, C. Kim8,9, K.K. Lak2,10, C. Hak11, B. Dim2,9,12, C.I. Sin13, S. Sun2,10, B. Guillard4, B. Sar4, S. Vong4, M. Fernandez2, L. Fox14, J.F. Delfraissy5, A.E. Goldfeld2,15 Background: Tuberculosis (TB) remains the largest cause of death among people living with HIV/AIDS, especially among those with profound immunosuppression. Case-fatality among co-infected patients occurs mainly in the first months after TB treatment initiation. Therefore, robust data regarding optimal timing of HAART initiation within this early period are critically needed. Methods: CAMELIA (CAMbodian Early vs. Late Introduction of Antiretroviral drugs: ANRS 1295/12160-CIPRA KH001/10425), an open-labeled randomized clinical trial, was designed to compare the impact upon mortality of early (2 weeks) vs. late (8 weeks) HAART initiation after TB treatment onset in treatment-naïve adults with newly diagnosed acid-fast bacilli (AFB) positive TB and CD4+ cell count < 200 cells/mm3. Patients received standard 6-month TB treatment plus stavudine, lamivudine and efavirenz in 5 sites in Cambodia and were followed through 50 weeks after the last patient was enrolled. A log-rank test was used to compare Kaplan-Meier survival curves. Results: 661 patients (early, n=332; late, n=329) were enrolled. Median age was 35 years, body mass index 16.7 kg/m2, CD4+ cell count 25 cells/mm3 and viral load 5.64 log copies/ml. All AFB-positive samples, including sputum in 538 (81.4%) patients, were cultured. As of May 13, 2010, 146 patients were known dead (59, early arm; 87, late arm). Enhanced survival was observed in the early arm (p< 0.01, figure). At week 50, median CD4+ gain was 114 cells/mm3; 96.5% of patients had an undetectable viral load. Conclusions: Initiation of HAART 2 weeks after onset of TB treatment significantly improves survival in severely immunosuppressed HIV-infected adults with newly diagnosed TB.
  • Note the following details from the IAS-USA Guidelines: TDF/FTC: Available as fixed-dose combination alone and with efavirenz Once daily Low genetic barrier to resistance (emtricitabine) Renal dysfunction, decreased bone mineral density associated with tenofovir influence choice EFV: NNRTI class Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care comparator regimen in most clinical trials Low genetic barrier Major psychiatric illness, first trimester of pregnancy, or intention to become pregnant influences choice Atazanavir/r PI/r class Once daily Widely prescribed when PI/r is chosen for initial therapy Leaves options for future regimens Less lipidogenic potential than lopinavir/r Hyperbilirubinemia, need for acid-reducing agents, and risk of nephrolithiasis influence choice Darunavir/r: PI/r class Once daily in treatment-naive patients Limited experience in treatment-naive patients, presence of other options in most naive patients, and efficacy inpatients with treatment experience and multidrug resistant virus influence choice Raltegravir INSTI class (only 1 FDA approved at present time) Twice daily Low drug interaction potential Rapid decline in HIV-1 RNA slope after initiation Low genetic barrier Limited experience in naive patients, presence of other options in most naive patients, and efficacy in treatment-experienced patients with multidrug resistant virus influence choice
  • ECHO and THRIVE: trial designs ECHO and THRIVE are randomized, double-blind, double dummy, Phase III trials in treatment-naïve HIV patients comparing once-daily RPV 25mg vs. once-daily EFV 600mg, both given in combination with a dual N[t]RTI background regimen. Screening viral load ( VL) was assayed using the Taqman assay whereas baseline VL was assayed using the Amplicor assay. In ECHO, the N[t]RTI background regimen is tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), while in THRIVE it is an investigator choice of TDF/FTC, zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/lamivudine (3TC). In ECHO, patients had to demonstrate sensitivity to TDF and FTC, while in THRIVE, patients only needed to be sensitive to the two N(t)RTIs that were chosen for the background regimen. Selection was a stratification factor and was done pre-randomisation and started on Day 1. The primary objective is to show non-inferiority in confirmed virologic response (VL <50 copies/mL, intent-to-treat-time-to-loss of virologic response [ITT-TLOVR] algorithm) of RPV vs. EFV at Week 48 with a non-inferiority margin (delta) of 12%. If non-inferiority was demonstrated at the 12% margin, then non-inferiority at a 10% margin and superiority were evaluated. Key secondary objectives: virologic response over time; safety and tolerability; resistance; immunologic response; pharmacokinetics and PK/PD. Countries that participated in ECHO: United States, France, United Kingdom, Portugal, Canada, Denmark, Italy, Spain, Australia, Austria, Romania, Netherlands, Sweden, South Africa, Thailand, Russian Federation, Taiwan, Brazil, Argentina, Mexico, Puerto Rico countries unique to ECHO that participated: Denmark, Romania, Netherlands, Sweden, Taiwan, and Argentina Countries that participated in THRIVE: USA, Germany, Canada, Belgium, Spain, United Kingdom, France, Italy, Australia, Portugal, Brazil, Chile, Panama, Mexico, Costa Rica, Puerto Rico, China, Thailand, Russian Federation, India, South Africa countries unique to THRIVE that participated: Germany, Belgium, Chile, Panama, Costa Rica, China and India The ongoing DEXA substudy has a primary endpoint at Week 96. Reference Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing RPV versus efavirenz in treatment-naïve, HIV-1-infected patients. 18th International AIDS Conference, Vienna, Austria, 18–23 July 2010. Abstract THLBB206.
  • Demographics and baseline characteristics The demographics of the two groups were well matched, and stratified equally according to median CD 4 count and median viral load.
  • The use of once-daily oral RPV 25mg administered with different background N[t]RTIs showed a high virologic response after 48 weeks. The percentages of patients with confirmed VL <50 copies/mL (ITT-TLOVR algorithm; pooled data) at Week 48 were 84.3% (RPV) and 82.3%(EFV), Each trial met the primary objective of non-inferiority regarding virologic efficacy of RPV compared to EFV after 48 weeks. TLOVR per-protocol responses (VL <50 copies/mL) (excludes major protocol violators and used to demonstrate non-inferiority): ECHO: RPV: 282/335 (84.2%) vs EFV: 275/330 (83.3%) THRIVE: 287/334 (85.9%) vs 273/332 (82.2%) Pooled: 569/669 (85.1%) vs 548/662 (82.8%). RPV: high and sustained virologic response over 48 weeks Once-daily oral RPV 25mg administered with background N[t]RTIs showed a high virologic response at Week 48. The percentages of patients with confirmed VL <50 copies/mL (ITT-TLOVR algorithm; pooled data) at Week 48 were 84.3% and 82.3%, respectively. Both trials met the primary objective of non-inferiority in confirmed virologic response of RPV compared to EFV after 48 weeks. There were no notable differences between the RPV and EFV groups regarding the percentage of responders over time. TLOVR per-protocol responses (VL <50 copies/mL) (excludes major protocol violators and used to demonstrate non-inferiority): ECHO: RPV: 282/335 (84.2%) vs. EFV: 275/330 (83.3%) THRIVE: 287/334 (85.9%) vs. 273/332 (82.2%) Pooled: 569/669 (85.1%) vs. 548/662 (82.8%). Reference Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing RPV versus efavirenz in treatment-naïve, HIV-1-infected patients. 18th International AIDS Conference, Vienna, Austria, 18–23 July 2010. Abstract THLBB206 .
  • Response by baseline viral load The two regimens were non inferior relative to virologic efficacy. There was not a difference greater than 12% between the two regimens in either viral load strata. There were greater number of virologic failures in the Rilpivirine group compared to Efavirenz( 62 vs 28). There was no difference in efficacy based on NRTI backbone, gender or region.
  • A limited number of patients experienced virologic failure and developed RAMs on RPV-based therapy For the resistance analysis, incidences of virologic failures were determined in the ITT population. In comparison to the definition of virologic failure determined by TLOVR in the ITT population, in addition to including rebounders and patients who were never suppressed, virologic failures in the resistance analysis also included patients who discontinued with a last observed VL ≥50 copies/mL (stopped treatment while not suppressed) and included all resistance information available at the time of the Week 48 analysis; a substantial number of patients were treated for longer than 48 weeks (median treatment duration 56 weeks). ECHO: 13% (RPV) vs. 5.5% (EFV) THRIVE: 7.9% (RPV) vs. 5.9% (EFV) and Pooled ECHO + THRIVE: 10.5% (RPV) vs. 5.7% (EFV). Considering virologic failures with paired baseline/endpoint failure genotypes (RPV n=62; EFV n=28), the most frequent NNRTI RAMs in the RPV group (n≥2 virologic failures for pooled RPV group) were E138K (45.2%), K101E (12.9%), H221Y (9.7%), V189I (8.1%), Y181C (8.1%), V90I (8.1%), F227C (3.2%), L100I (3.2%), V179I (3.2%) and E138Q (3.2%). The most frequent IAS-USA N(t)RTI RAMs were M184I (46.8%), M184V (22.6%), K65R (4.8%), K219E (4.8%), Y115F (3.2%) and A62V (3.2%). For EFV, the most frequent NNRTI RAMs were K103N (39.3%), V106M (10.7%), Y188C (7.1%), L100I (3.6%) and K101E (3.6%). The most frequent IAS-USA N(t)RTI RAMs were M184V (21.4%), M184I (7.1%) and K65R (7.1%). M184I is an intermediate amino acid substitution preceeding the emergence of M184V (respectively, one and two nucleotide substitutions in the methionine codon). Both the M184I and M184V N(t)RTI RAMs confer resistance to 3TC and FTC and low-level resistance to ABC and didanosine (ddI), but in isolation do not appear to compromise clinical responses to ABC and ddI. In the HEAT trial of ABC/3TC vs. TDF/FTC, M184V or mixtures were found in 7/343 patients receiving ABC/3TC and in 14/346 patients receiving TDF/FTC. M184I is often found together with E138K in patients treated with 3TC or FTC and therefore, this specific combination may contribute to RPV resistance, although the clinical significance of this is uncertain. In 37 of 45 RPV virologic failures with RT RAMs at failure, NNRTI and N(t)RTI RAMs were present in combination; 7 RPV VF patients had more than one NNRTI RAM. The phenotypic susceptibility is provided for completeness but is not meant to imply that NNRTIs can be used sequentially; In ECHO and THRIVE at time of virologic failure: In the RPV group, 31/62 of RPV failures lost phenotypic susceptibility to RPV. In patients who lost phenotypic susceptibility to RPV, 17/31 remained phenotypically susceptible to nevirapine, 4/31 to EFV and 3/31 to etravirine In patients who retained phenotypic susceptibility to RPV (31/62), 31/31 remained phenotypically susceptible to nevirapine, 29/31 to EFV and 28/31 to etravirine. In the EFV group, 12/28 of EFV failures lost phenotypic susceptibility to EFV. In patients who lost phenotypic susceptibility to EFV, none were phenotypically susceptible to nevirapine and all remained susceptible to RPV and etravirine In patients who retained phenotypic susceptibility to EFV (16/28), 14/16 were phenotypically susceptible to nevirapine and all remained susceptible to RPV and etravirine. The 454 assessment of minority variants at baseline is pending. Reference Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing RPV versus efavirenz in treatment-naïve, HIV-1-infected patients. 18th International AIDS Conference, Vienna, Austria, 18–23 July 2010. Abstract THLBB206.
  • T here were no differences in the overall AE s or the serious AE s between the two groups. There was however a significant higher rate of discontinuations due to adverse events with EFV compared to RPV (3.4% vs. 7.6%; *p≤0.001, post-hoc analysis) with a higher overall rate of AE s seen with EFV compared to RPV as well. The most common AE s leading to discontinuation were neurological disorders such as dizziness (8.0% vs. 26.2%; *p<0.0001) or psychiatric disorders such as abnormal dreams (8.2% vs. 12.8%; *p=0.0061). There was also a higher incidence of rash in the EFV arm (3.1% vs 13.6%, respectively; *p<0.0001). RPV does seem to have less discontinuations than EFV secondary to issues of tolerability. It was well tolerated regarding renal effects and there were no changes in Qtc intervals. RPV 25mg qd was well tolerated over the treatment period The safety results include all information at the time of the Week 48 analysis cut off; a substantial number of patients were treated for longer than 48 weeks (median treatment duration 56 weeks). The incidences of serious AEs and any AEs were similar with RPV and with EFV, while there was a significantly lower incidence of discontinuations due to AEs with RPV than with EFV (3.4% vs. 7.6%; *p ≤ 0.001, post-hoc analysis), and the incidence of grade 2–4 AEs at least possibly related to treatment † in the RPV group was approximately half that reported in the EFV group (16% vs. 31%, respectively; *p<0.0001). AEs leading to trial discontinuation in >0.5% of patients in the pooled RPV or EFV group psychiatric disorders: 1.5% vs. 2.2%, including depression: 0.3% vs. 0.6% investigations: 0.6% vs. 0.9% skin and subcutaneous tissue disorders 0.3% vs. 1.8%, including rash: 0.1% vs. 1.2% infections and infestations: 0.3% vs. 1.3% general disorders and administration site conditions: 0.3% vs. 0.7% nervous system disorders: 0.3% vs. 0.7%. There were statistically significant differences in the incidences of the following events (all classified as at least possibly related to treatment) (pre-planned analyses): neurological events of interest † (RPV: 17.1% vs. EFV: 37.8%; *p<0.0001), including dizziness † (8.0% vs. 26.2%; *p<0.0001) psychiatric events † (14.9% vs. 22.7%; *p=0.0002), including abnormal dreams/nightmare † (8.2% vs. 12.8%; *p=0.0061) any rash † (3.1% vs. 13.6%, respectively; *p<0.0001). *p-value vs. EFV for Fisher’s Exact test, † Predefined analysis Observations were consistent across the two studies Reference Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing RPV versus efavirenz in treatment-naïve, HIV-1-infected patients. 18th International AIDS Conference, Vienna, Austria, 18–23 July 2010. Abstract THLBB206.
  • Although some studies have supported once-daily dosing of NVP, it is not approved for once-daily dosing in the USA. BI is evaluating an extended release formulation dosed at 400 mg daily, and is testing it in this study. As shown in the PK curves, once-daily NVP XR gives a flatter PK curve than BID dosing, but still exceeds the IC50 of wild-type virus. Baseline characteristics in the study are typical of studies of NVP-based therapy, as they exclude men with cd4 > 400 and women with cd4 > 250, hence skewing the population to somewhat more advanced disease.
  • Here the virologic efficacy results are shown, clearly demonstrating non-inferiority of the nvp xr formulation. As noted previously in studies of NVP, lipid changes were favorable. During the question and answer period after the presentation, the lead author stated that there were 5 cases of S-J syndrome (some occurred in both arms), but that none was fatal.
  • In the SUPPORT study, FPV/r was compared with EFV in a target population of under-represented minorities. The NRTI backbone was TDF/FTC. More than half the study participants were of African descent. Virologic responses at a protocol-specified 24 week analysis showed comparable results, with similar rates of AEs. Given the small sample size, the results should be viewed as exploratory rather than definitive in defining the antiviral efficacy of efv vs FPV/r.
  • All of the treatment-naïve studies of raltegravir thus far have been with tdf-based NRTIs. In this small (n=35) single-armed study, abc/3tc + RAL is used in HLA B5701 negative subjects, and response rates appear good, with over 90% having HIV RNA < 50 at week 48. Statistically significant increases in median fasting total, HDL, and LDL cholesterol, while triglyceride levels and total: HDL cholesterol ratio remained stable. No cases of suspected ABC HSR occurred, and there were no significant changes in inflammatory markers.
  • Three studies at IAS evaluated NRTI-sparing approaches to initial therapy. Importantly, each of them is relatively small in sample size, so they can be viewed as exploratory rather than definitive. Regardless, there are several interesting findings that elucidate the potential strengths and weaknesses of this approach. In the PROGRESS study, LPV/r was combined with either tdf/ftc or raltegravir. Primary endpoint: plasma HIV-1 RNA <40 copies/mL at week 48 (FDA ITT TLOVR) Noninferiority assessed by 95% CI for the difference ([LPV/r + RAL] – [LPV/r + TDF/FTC]) using a -20% threshold. If non-inferiority with respect to the -20% margin was demonstrated, then non-inferiority with respect to a -12% margin was to be evaluated.
  • The 48 week results demonstrated non-inferiority of the lpv/r + RAL approach at the 20% and 12% threshold. There were similar adverse events, though changes in lipids were somewhat worse for the LPV/r + RAL arm. Additional analyses are planned.
  • Here, in the SPARTAN study, an approach that spares BOTH NRTIs and RTV is tested. Treatment naïve subjects were randomized to either ATV 300 mg bid + RAL 400 mg bid vs a standard tdf/ftc, ATV/r regimen. Projected ATV ATV exposures (24 hour AUC and Cmin) are higher than those observed in CASTLE for ATV+RTV + TDF/FTC, with RAL overall exposures are comparable to historical data.
  • 24 week results showed comparable antiviral responses, though as has been seen multiple times previously, the RAL-containing regimen had a faster HIV RNA decline. However, despite these results, the study sponsor has elected to stop this study due to higher rates of grade 4 hyperbilirubinemia and resistance in the ATV + RAL arm.
  • In the last of the pilot NRTI-sparing studies, a standard tdf/ftc + atv/r regimen was compared to atv/r + maraviroc, with the MVC dosed at 150 mg once daily. (Only twice-daily MVC is currently approved). Patients were required to be R5 at screening and to have a CD4 > 100.
  • Virologic results for the two approaches were quite similar, though the small sample size does not allow for formal conclusions to be made about comparable efficacy. There was a slightly higher rate of hyperbili in the mvc arm. No resistance occurred, nor did tropism “shift” take place. The presenter stated that this mvc + PI/r approach will be studied further in larger clinical trials. In aggregate, results from these studies would suggest that none of the NRTI-sparing approaches to therapy tested here would be ready to replace our currently recommended approach, which is to use two NRTIs plus a 3 rd active drug. Other studies are ongoing, including a relatively large one looking at DRV/r + RAL being done in Europe.
  • The primary analysis of the MONET trial was at Week 48. The Week 96 analysis was a secondary endpoint. Main efficacy endpoint: TLOVR, switch equals failure analysis If a patient shows a confirmed elevation in HIV RNA >50 copies/mL at two visits, this is a failure, even if the HIV RNA is then suppressed <50 copies/mL at Week 96. Stopping DRV/r in either arm, or adding NRTIs in the monotherapy arm is also a failure. Missing data is failure. Secondary endpoint: Switch included analysis This analysis only includes the HIV RNA level at Week 96. If HIV RNA is re-suppressed at Week 96 following an earlier elevation, this is counted as success. Changes in treatment are permitted. Missing data is failure. All results were consistent between the ITT and Per Protocol populations. ITT analysis is shown here.
  • By the ITT switch = failure analysis, DRV mono was not “noninferior” to DRV plus two NRTIs. However, using the Switch=included analysis, DRV mono was noninferior despite having more virologic blips on the mono arm. The authors reported that Hep C coinfection was the strongest predictor of treatment failure rather than study arm. This was attributed to behavioral issues in this group of pts and not Hep C itself. There was just one case of PI mutations noted per arm but no phenotypic resistance noted in either case.
  • Atazanavir and Lamivudine Simplification Study, ATLAS pilot study design. This was to assess the ability of ATV/r plus one NRTI – 3TC – to maintain suppression in pts on two NRTIs (usually TDF/3tc) and boosted ATV/r. Exclusions: virological failure of 3TC or PI-containing regimens or exposure to mono-dual NRTI
  • Atazanavir and Lamivudine Simplification Study, ATLAS Safety: Serious AEs: 2 renal colic 1 hypertensive crisis 1 brain hemorrhage
  • ODIN design slide – summarized here. Added design features: * DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V ‡ Individualized OBT included ≥2 N(t)RTIs based on ARV history and resistance testing Only restrictions on previous therapy: use of enfuvirtide, tipranavir, DRV, current use of investigational drugs This analysis focuses on the impact of adherence. The main point is that adherence impacts BID and QD DRV similarly.
  • In this ODIN analysis, the predictors of response were analyzed. In addition to viral load and adherence, the presence of resistance mutations predicted a better response. This somewhat paradoxical finding is explained by the observation that the least adherent pts with viremia will have minimal resistance – the presence of resistance in pts who have partial suppression are more likely to be taking at least some drug – and thus resistance to either 184V or the PI class suggests better adherence than does wild type.
  • The SPRING study assesses the new integrase inhibitor 572 in combination with two NRTIs. The randomized design is summarized here and is comparing 572 to efavirenz for 16 weeks. The baseline demographics are summarized here. This study was designed to pick a dose for phase III development.
  • All three doses of 572 showed the expected prompt suppression by week 16 – and faster than is seen with efavirenz. Only one person discontinued 572 for adverse events on 572 – with dyspepsia. Four people DC EFV for the usual reasons.
  • This study assessed the impact of 572 – a new integrase inhibitor – for pts who had a history of raltegravir resistance. It was noted that there are two pathways to RAL resistance that differentiate the predicted activity of 572. The Q148 pathway is predicted to have broader cross resistance to 572 while the other pathways were predicted to have less cross resistance. This single arm study started 50 mg. of 572 at study entry instead of raltegravir (pts were either on RAL or had a history of RAL use and known resistance). The day 10 endpoint is presented here – after that pts could optimize the background regimen.
  • The results of shown here. The pathways of resistance had a major impact on 572 activity. All pts responded who had resistance with mutations other than the Q148 pathway responded with at least a 0.7 log decline at day 10. However only one third responded who had the Q148 pathway. Thus this arm was halted when these results were noted. The side effects are summarized here as well with a few AEs noted.
  • These data from the STARTMRK study indicate that, unlike NNRTI resistance, integrase resistance follows M184V resistance. This may indicate a higher reistance barrier for RAL than EFV, but this requires further study to confirm.
  • This is the first report of transmitted RAL resistance. As can be seen, this patient had significant multi-class resistance. Given this level of resistance, including NRTI resistance, failure of a RAL + ABC/3TC regimen is not surprising.
  • Background: Raltegravir (RAL) has demonstrated good antiviral activity and safety profile being dosed twice-daily (BID). However, its long terminal elimination half-life might allow once-daily (QD) administration. Methods: All HIV-infected individuals under protease inhibitor (PI)-based regimens with plasma HIV-RNA < 50 copies/mL for longer than 24 weeks were identified at our clinic and replaced PIs by RAL. Patients were randomly assigned to RAL 800mg QD, 400mg BID, or BID for the first three months and then QD (www.clinicaltrials.gov-NCT00941083).
  • Results: 222 patients completed 24 weeks on RAL (149 QD, 35 BID, and 38 BID to QD arm). The most frequently replaced PIs were atazanavir (48%), lopinavir (28%) and fosamprenavir (13%). Up to 69% of patients received RAL along with tenofovir-emtricitabine and 31% with abacavir-lamivudine. Baseline mean CD4 count was 574±308 cells/μL and 46% were HCV-coinfected. Within 24 weeks, 13 (5.9%) patients experienced virological failure, 12 (6.4%) in the QD and 1 (2.9%) in the BID arm (p=0.18). Virological failure rate was 16.2% (12/74) in patients with prior NRTI resistance but only 0.7% (1/148) in the rest (p< 0.001). Significant reductions in total, LDL and HDL cholesterol were observed at 24 weeks of RAL switching. Conclusions: A switch from PIs to RAL in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen comparing RAL BID or QD in this context, although QD dosing tended to perform less well.
  • Background: Ritonavir-boosted protease inhibitors are recommended agents for HIV infection, but they have been associated with a higher risk of cardiovascular disease due at least in part to lipid effects. Raltegravir-based antiretroviral therapy may show a better lipid profile while being as effective as ritonavir-boosted protease inhibitorbased antiretroviral therapy in selected patients. Methods: SPIRAL is a 48-week multicentre, comparative, open-label trial in which HIV-infected adults with < 50 copies/mL of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1:1) to switch from ritonavir-boosted protease inhibitor to raltegravir or to continue on same regimen. Primary endpoint was the proportion of patients free of treatment failure (Non-completer=failure) at 48 weeks. SPIRAL study was powered to show non-inferior efficacy of raltegravir-based therapy with a margin of -12.5%. DSMB recommended continuing SPIRAL study after an unplanned analysis following SWITCHMRK studies interruption. Results: Two hundred and seventy three patients assigned to switch to raltegravir (n=139) or to continue ritonavirboosted protease inhibitors (n=134) were included in the efficacy analysis. At 48 weeks, 89% (raltegravir-based therapy) and 87% (ritonavir-boosted protease inhibitor-based therapy) of patients remained free of treatment failure (difference 2.6%; 95% CI -5.2% to 10.6%). A total of 97% (raltegravir-based therapy) and 95% (ritonavir-boosted protease inhibitor-based therapy) of patients remained free of virological failure (difference 1.8%; 95% CI -3.5% to 7.5%). Switching to raltegravir was associated with significant decreases in plasma lipids relative to continuing ritonavir-boosted protease inhibitors. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4% and 2% of patients respectively in each group. Conclusions: In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitors to raltegravir demonstrated non-inferior efficacy and resulted in lower lipids at 48 weeks than continuing ritonavir-boosted protease inhibitors.
  • See VIKING design and discussion in slides 45 and 46 and accompanying speakers notes. This slide demonstrates that day 11 response to 572 is related to the pattern of II mutations on failure of RAL.
  • Background: In the Phase 3 DUET trials of the NNRTI etravirine (TMC125), 77.0% and 74.1% of etravirine-treated patients with a Tibotec susceptible etravirine weighted genotypic score (WGS) ≤2 or an Antivirogram fold-change (FC) ≤3 at baseline, respectively, achieved < 50 HIV-RNA copies/mL at Week 48. The prevalence of etravirine susceptibility was investigated in clinical samples referred for routine resistance testing (RT) using Monogram Biosciences (MGR) etravirine WGS and PhenoSense assay. Methods: 14,940 samples submitted to MGR for RT from June 2008 to June 2009 were analysed. Samples were defined as NNRTI-resistant if they carried at least one of the following mutations: A98G, L100I, K101E, K101P, K103N, K103S, V106A, V106I, Y181x, Y188x, G190x, P225x, F227x, M230L, and P236L where x represents any amino acid substitution. MGR's etravirine WGS consisting of 30 mutations (Benhamida 2008) was used to define viral susceptibility to etravirine, with a genotypic score ≤3 denoting full susceptibility. Phenotypic susceptibility to etravirine was determined using 2.9 and 10 as low and high clinical cutoffs, respectively. The impact of K103N on genotypic susceptibility to etravirine was also investigated. Results: Among 5,482 (36.7%) NNRTI-resistant samples, 67.2% were classified as genotypically susceptible and 76.4% as phenotypically susceptible (median FC 0.8) to etravirine, with 10.7% having FC≥10. Using Tibotec's WGS, 67.4% of NNRTI-resistant samples were etravirine-susceptible (WGS≤2). Among NNRTI-susceptible samples (n=9,458), 99.5% had etravirine FC< 2.9 (median 0.8) and 0.5% had FC≥2.9 and < 10 (median 3.5). In a subset of NNRTI-resistant samples (n=4,514), with (n=3,598) or without (n=916) K103N mutation, the proportion of etravirine genotypicallysusceptible samples (average median FC 1) was 76.9% and 48.6%, respectively. Conclusions: Using different interpretation systems, most samples received for RT with or without evidence of NNRTI resistance were susceptible to etravirine. Among NNRTI-resistant samples, more were etravirinesusceptible phenotypically than genotypically, and more were etravirine-susceptible among those with K103N.
  • See PROGRESS design and discussion in slides 30 and 31 and accompanying speakers notes. This slide demonstrates resistance patterns in patients failing LPV/r plu RAL or TDF/FTC.
  • Background: Although lopinavir/r monotherapy is considered by some as an attractive simplification strategy, others have expressed concerns relative to the potential lack of efficacy in sites with poor drug penetration, such as the genital tract. Methods: KalMo was a randomized, open label 96-week study to assess the efficacy and safety of using LPV/r monotherapy in patients with no prior virologic failure and on a stable, successful HAART regimen for at least 6 months. Patients were randomized (1:1) to either switch from HAART to LPV/r monotherapy or to maintain their previous regimen. Semen samples were collected at the end of follow-up. Seminal viral load was measured by Real- time PCR. Genotypic resistance analysis was performed on every sample that had a detectable viral load. Results: Semen samples were collected from 15 male patients randomized to monotherapy, all of whom had undetectable plasma viral load at the end of the follow-up period. Only one patient had a detectable seminal viral load (260cp/mL). This was a patient who experienced virologic blips during his follow-up, and had a plasma viral load of 850 copies/mL at a post-study visit performed two weeks after semen was collected. Genotypic resistance analysis on the semen sample showed a pattern similar from that obtained in plasma at week 48 and at the post- study visit, including 2 primary mutations on positions 46 and 84 and minor substitutions on positions 15 and 63. Conclusions: In our study Lopinavir/r monotherapy was effective in suppressing viral load in semen samples. Virus present in seminal and blood plasma had similar resistance associated mutations.
  • Background: Cardiovascular disease is prevalent among HIV patients. We investigated the relative association of antiretroviral medications, immunologic and virologic factors with incident AMI rates among HIV patients. Methods: We used a clinical data registry-based cohort comprising all patients with HIV and at least two encounters between 12/98 and 2/08 in a U.S. healthcare system. Demographics, comorbidities (hypertension, diabetes, dyslipidemia, chronic kidney disease), medication, CD4, and HIV viral load data were obtained. We used multivariate logistic regression to assess associations between AMI and each antiretroviral medication in separate models additively adjusting for 1) demographics; 2) concurrent antiretroviral medications significant in univariate analysis; 3) comorbidities; 4) CD4 count/HIV viral load. Results: Of 6517 HIV patients (30.6% female), 273 (4.2%) had an AMI. The figure shows the odds ratios and 95% confidence intervals for each of the four models for each medication. In fully adjusted individual models, indinavir (OR 1.93; 95% CI 1.04-3.57) and nelfinavir (OR 1.75; 95% CI 1.02-3.01) were significantly associated with AMI. In a combined model adjusting simultaneously for cardiovascular, immunologic and virologic factors and antiretroviral medications significantly associated with AMI, hypertension (OR 1.97; 95% CI 1.25-3.12) and CD4 count less than 200/ mm3 (OR 1.74; 95% CI 1.07-2.81) were significantly associated with AMI, whereas individual medications were not. Conclusions: Several individual antiretroviral medications are associated with increased risk of AMI, but the effects are attenuated when other factors are considered. Immunologic control as reflected by the CD4 count appears to be a more important factor than the effects of individual medications.
  • Background: The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease within the setting of cohort studies and of a randomized trial (RCT). However, no excess risk of myocardial infarction with ABC therapy has been observed in others RCTs and in the aggregated clinical trials database maintained by the manufacturer of ABC. The principal aim of this study is to combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on major cardiovascular event. Methods: A comprehensive search of the available literature was carried out. Information about unpublished trials was attempted by contacting drug manufacturers. Data extracted included: any cardiovascular events and overall mortality. We used a conventional Mantel-Haenszel method, with odds ratio (OR) and 95% confidence intervals (CI) or, in the presence of heterogeneity, a random-effect model. Results: We obtained data from 36 RCTs conducted from 1996 to 2009, comparing cART with ABC to other NRTI . Data of 13 RCTs with at least 24 wks of ABC exposure were available from HIV data repository of the manufacturer of ABC. Data on cardiovascular events were available from 16 RCTs (5,051 pts; 1,045 from published trials and 4,006 from data repository), data on mortality from 23 published RCTs (6,372 pts). Compared to the controls, ABC use did not increase the occurrence of major cardiovascular events (OR, 1.10; 95% CI, 0.56-2.10), and the overall mortality (OR, 1.84; 95% CI, 0.71-4.76). Conclusions: Observational studies are prone to biases and should be interpreted with caution given the potential for confounding. By contrast, randomized trials provide stronger evidence than do observational studies. Our metaanalysis was based on RCTs, and did not show an increase in the occurrence of major cardiovascular events and overall mortality in ABC recipients.
  • Background: Pooled 48-week primary analysis results of two Phase III trials with TMC278, ECHO (TMC278- C209, NCT00540449) and THRIVE (TMC278-C215, NCT00543725), are presented. Methods: These international trials include treatment-naïve adult patients receiving (1:1) TMC278 25mg qd or efavirenz 600mg qd, plus either tenofovir disoproxil fumarate (TDF)/emtricitabine (ECHO) or TDF/emtricitabine, lamivudine/zidovudine or abacavir/lamivudine (THRIVE). The primary objective was to demonstrate non-inferiority of TMC278 to efavirenz in confirmed virologic response (viral load [VL] < 50 copies/mL ITT-TLOVR algorithm) at Week 48. Results: A total of 1368 patients were randomised and treated. Median baseline VL was 5.00 log10 copies/mL and median CD4 256 cells/mm3. TMC278 showed non-inferior efficacy versus efavirenz (Table). The virologic failure rate was 9.0% in the TMC278 group and 4.8% in the efavirenz group. There were lower incidences with TMC278 of adverse events (AEs) leading to discontinuation, and grade 2-4 AEs at least possibly related to treatment, rash, dizziness and abnormal dreams/nightmare (Table). Grade 3/4 laboratory abnormalities for cholesterol (0.1% vs. 2.5%), LDL-cholesterol (0.7% vs. 4.1%) and triglycerides (0.3% vs. 2.2%) were lower with TMC278 versus efavirenz, respectively (p=0.001). There was no difference in QTc interval between groups. Increases in lipid parameters were lower with TMC278 than with EFV
  • Background: Nucleoside and ritonavir (RTV) toxicities have led to interest in NRTI- and RTV-sparing regimens. SPARTAN is a multicenter, randomized, open-label, non-comparative pilot study to evaluate the efficacy and safety of an investigational NRTI- and RTV-sparing regimen of ATV experimental dose of 300mg BID plus RAL 400mg BID (ATV+RAL) in treatment-naïve HIV-infected subjects. Methods: Subjects with HIV-RNA = 5,000 c/mL were randomized 2:1 to ATV+RAL (n=63) or reference regimen of ATV/ RTV 300/100mg QD + tenofovir/emtricitabine (TVD) 300/200mg QD (n=31). Primary analysis at week 24 (HIV-RNA < 50c/ mL) uses confirmed virologic response (CVR NC=F). Results: Grade 2-4 treatment-related AE hyperbilirubinemia occurred in 19% (12/63) of subjects on ATV+RAL and 16.7% (5/30) on ATV/RTV+TVD; Grade 4 hyperbilirubinemia were 20.6% (13/63) and 0%, respectively. 3.2% (2/63) on ATV+RAL and 0% on ATV/RTV +TVD discontinued due to treatment-related AEs. ATV PK exposures (n=13) on ATV+RAL were higher than historically observed with ATV/RTV+TVD. RAL exposures were comparable to historical data. Conclusions: Through week 24, the investigational regimen of ATV+RAL BID achieved efficacy rates consistent with current standard of care. Hyperbilirubinemia was consistent with previous ATV BID studies.
  • Background: A three drug combination including two nucleoside reverse transcriptase inhibitors (NRTIs) is currently recommended to treat antiretroviral (ARV) naïve patients. The current study directly compares an NRTI-sparing dual agent regimen of lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) to a regimen of LPV/r combined with tenofovir and emtricitabine (TDF/FTC) in ARV-naïve subjects. Methods: Study M10-336 (PROGRESS) is an ongoing, randomized, open-label, 96-Week trial of LPV/r 400/100 mg BID combined with either RAL 400 mg (BID) (n=101) or with TDF/FTC 300/200 QD (n=105) in ARV-naïve subjects. The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 40 copies/mL at week 48, based on the FDA time to loss of virologic response (ITT-TLOVR) algorithm. Per protocol, the non-inferiority of the RAL regimen is demonstrated if the lower bound of the 95% confidence interval for the difference in response (RAL - TDF/FTC) is = -20%. Results: Demographics were similar across treatment groups. Mean baseline HIV-1 RNA was 4.25 log10 copies/ml, mean baseline CD4 count was 293.5 cells/mm3. A similar proportion of subjects in each arm discontinued the study prematurely (12% RAL, 11% TDF/FTC). The RAL regimen was non-inferior to the TDF/FTC regimen: 83% (RAL) and 85% (TDF/FTC) had HIV-1 RNA < 40 copies/mL at Week 48 (95% CI for the difference: -12%, 8%). The mean CD4+ Tcell increases through 48 weeks were similar (215 cells/mm3 RAL, 245 cells/mm3 TDF/FTC, P=0.237). Treatment emergent moderate/severe study drug-related adverse events were similar between groups; the most common of these events were diarrhea (8% RAL, 13% TDF/FTC, P=0.261) and hypercholesterolemia (8% RAL, 5% TDF/FTC; P=0.401). Conclusions: The novel NRTI-sparing regimen of LPV/r+RAL resulted in non-inferior efficacy and similar tolerability as a traditional 3-drug antiviral regimen. These results demonstrate that a two drug NRTI-sparing regimen can provide an alternative approach to treatment of ARV-naïve patients..
  • Background: Protease inhibitors (PIs) may contribute to metabolic complications associated with HIV infection. Methods: METABOLIK is a 48-week, Phase 4, multicenter study comparing changes in fasting lipids, insulin sensitivity, inflammatory biomarkers and efficacy parameters in HIV-infected, antiretroviral-naïve adults randomized to darunavir/ritonavir (DRV/r; 800/100mg qd) or atazanavir/ritonavir (ATV/r; 300/100mg qd), both with emtricitabine/tenofovir (FTC/TDF; 200/300mg qd). The primary endpoint was the change in fasting triglycerides (TGs) from baseline to Week 12. We report descriptive statistics for Week 12 primary and secondary endpoints. Results: 32/34 subjects (men, n=29) receiving DRV/r and 30/31 receiving ATV/r (men, n=27) completed Week 12. DRV/ r arm had more advanced disease at baseline than ATV/r arm according to median baseline viral load (137,000 versus 46,100 copies/mL), CD4 count (267 versus 316 cells/mm3) and total cholesterol (TC; 142 versus 165mg/dL). Baseline apolipoprotein A1 (apoA1) was lower for DRV (114.9mg/dL) than ATV (127.6mg/dL). Differences between arms (DRV/r-ATV/r) in Week 12 changes in TG levels (13.8mg/dL) and TC/HDL ratios (0.06) were small. Larger differences between arms (DRV/r-ATV/r) were noted in changes in TC (15.7mg/dL), apoA1 (11.4mg/dL) and TNF-a (-893.8pg/mL). There were no differences in changes between arms for HDL (4.0mg/dL), LDL (4.0mg/dL) or apoB (4.4mg/dL); no differences were seen between arms for changes in glucose, insulin, insulin sensitivity, other inflammatory biomarkers or efficacy parameters. Conclusions: Results of this first prospective comparison of DRV/r versus ATV/r suggest similar changes in TG levels over 12 weeks. Both arms saw modest changes in lipids and inflammatory markers, and insulin sensitivity stability. Changes from baseline were similar between arms; somewhat larger changes in TC and apoA1 with DRV/r were likely due to lower baseline values in this arm. Antiretroviral therapy may, therefore, improve inflammation and lipids over the short term and support the 'return to health' phenomenon observed in other studies.
  • Background: Protease inhibitors (PIs) may contribute to metabolic complications associated with HIV infection. Methods: METABOLIK is a 48-week, Phase 4, multicenter study comparing changes in fasting lipids, insulin sensitivity, inflammatory biomarkers and efficacy parameters in HIV-infected, antiretroviral-naïve adults randomized to darunavir/ritonavir (DRV/r; 800/100mg qd) or atazanavir/ritonavir (ATV/r; 300/100mg qd), both with emtricitabine/tenofovir (FTC/TDF; 200/300mg qd). The primary endpoint was the change in fasting triglycerides (TGs) from baseline to Week 12. We report descriptive statistics for Week 12 primary and secondary endpoints. Results: 32/34 subjects (men, n=29) receiving DRV/r and 30/31 receiving ATV/r (men, n=27) completed Week 12. DRV/ r arm had more advanced disease at baseline than ATV/r arm according to median baseline viral load (137,000 versus 46,100 copies/mL), CD4 count (267 versus 316 cells/mm3) and total cholesterol (TC; 142 versus 165mg/dL). Baseline apolipoprotein A1 (apoA1) was lower for DRV (114.9mg/dL) than ATV (127.6mg/dL). Differences between arms (DRV/r-ATV/r) in Week 12 changes in TG levels (13.8mg/dL) and TC/HDL ratios (0.06) were small. Larger differences between arms (DRV/r-ATV/r) were noted in changes in TC (15.7mg/dL), apoA1 (11.4mg/dL) and TNF-a (-893.8pg/mL). There were no differences in changes between arms for HDL (4.0mg/dL), LDL (4.0mg/dL) or apoB (4.4mg/dL); no differences were seen between arms for changes in glucose, insulin, insulin sensitivity, other inflammatory biomarkers or efficacy parameters. Conclusions: Results of this first prospective comparison of DRV/r versus ATV/r suggest similar changes in TG levels over 12 weeks. Both arms saw modest changes in lipids and inflammatory markers, and insulin sensitivity stability. Changes from baseline were similar between arms; somewhat larger changes in TC and apoA1 with DRV/r were likely due to lower baseline values in this arm. Antiretroviral therapy may, therefore, improve inflammation and lipids over the short term and support the 'return to health' phenomenon observed in other studies.
  • In the 48-week analysis of ODIN, a Phase IIIb, randomized, open-label study, DRV/r 800/100mg qd was non-inferior to DRV/r 600/100mg bid and showed favorable overall tolerability. The 48-week lipid profile of ODIN patients is reported. Methods: Fasting (=8 hours) lipids were assessed throughout the study (intent-to-treat population). Lipid levels were classified above or below NCEP cut-offs at any time during the observation period (between baseline and a mean of 44.8 [DRV/r qd] or 43.1 [DRV/r bid] weeks). Lipid-lowering agents (except lovastatin and simvastatin) were allowed. In the DRV/r qd and DRV/r bid arms, 5.4% and 11.1% of patients received lipid-lowering agents. Results: Median lipid concentrations showed small increases Conclusions: At Week 48 in the ODIN study, the incidence of NCEP treatment-emergent abnormalities in triglycerides and total cholesterol was significantly lower with once-daily DRV/r 800/100mg compared with DRV/r 600/100mg bid.
  • Background: Ritonavir-boosted protease inhibitors are recommended agents for HIV infection, but they have been associated with a higher risk of cardiovascular disease due at least in part to lipid effects. Raltegravir-based antiretroviral therapy may show a better lipid profile while being as effective as ritonavir-boosted protease inhibitor based antiretroviral therapy in selected patients. Methods: SPIRAL is a 48-week multicentre, comparative, open-label trial in which HIV-infected adults with < 50 copies/mL of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1:1) to switch from ritonavir-boosted protease inhibitor to raltegravir or to continue on same regimen. Primary endpoint was the proportion of patients free of treatment failure (Non-completer=failure) at 48 weeks. SPIRAL study was powered to show non-inferior efficacy of raltegravir-based therapy with a margin of -12.5%. DSMB recommended continuing SPIRAL study after an unplanned analysis following SWITCHMRK studies interruption. Results: Two hundred and seventy three patients assigned to switch to raltegravir (n=139) or to continue ritonavir boosted protease inhibitors (n=134) were included in the efficacy analysis. At 48 weeks, 89% (raltegravir-based therapy) and 87% (ritonavir-boosted protease inhibitor-based therapy) of patients remained free of treatment failure (difference 2.6%; 95% CI -5.2% to 10.6%). A total of 97% (raltegravir-based therapy) and 95% (ritonavir-boosted protease inhibitor-based therapy) of patients remained free of virological failure (difference 1.8%; 95% CI -3.5% to 7.5%). Switching to raltegravir was associated with significant decreases in plasma lipids relative to continuing ritonavir-boosted protease inhibitors. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4% and 2% of patients respectively in each group. Conclusions: In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitors to raltegravir demonstrated non-inferior efficacy and resulted in lower lipids at 48 weeks than continuing ritonavir-boosted protease inhibitors.
  • Background: Dyslipidemia in persons with HIV contributes to cardiovascular risk. Tenofovir DF-based regimens may have a favorable lipid profile relative to abacavir-based regimens. We investigated changes in fasting total cholesterol (TC) in hypercholesterolemic subjects switching to Atripla [ATR] from ABC/3TC + efavirenz [ABC/3TC+EFV]. Methods: A 24-week, UK-multicenter study in subjects stable on KVX+EFV, with HIV RNA < 50 copies/mL for ³6 months and TC ³5.2mmol/L (200mg/dL) at screening, randomized to switch to ATR or continue KVX+EFV. At Week 12, subjects randomized to KVX+EFV were switched to ATR. The primary endpoint was change from baseline to Week 12 in fasting TC. Fasting lipid parameters were also assessed using NCEP thresholds. Results: 157 subjects (125 men, 32 women), mean age 43.8 years (range 28-73), were randomized and treated; 79 switched to ATR, 78 continued KVX+EFV, and 73 switched to ATR at Week 12. Subjects were well matched for baseline characteristics. Switching to ATR from KVX+EFV significantly reduced TC and other atherogenic lipids at Week 12. Mean (95% CI) differences at Week 12 (change from baseline in mmol/L, ATR minus KVX+EFV): TC -0.74 (-1.01, - 0.47), p< 0.001; LDL -0.49 (-0.71, -0.26), p< 0.001; TG -0.42 (-0.75, -0.10), p< 0.001. Week 12 results were confirmed at Week 24 for subjects with delayed switch to ATR. There were no protocol-defined virologic failures or study-drug related SAEs. Conclusion: Switching to ATR from KVX+EFV significantly improved atherogenic lipid parameters towards desirable levels (per NCEP guidelines) while maintaining virologic suppression. Findings support using ATR rather than KVX+EFV in the management of appropriate hypercholesterolemic patients.
  • Background: Dyslipidemia in persons with HIV contributes to cardiovascular risk. Tenofovir DF-based regimens may have a favorable lipid profile relative to abacavir-based regimens. We investigated changes in fasting total cholesterol (TC) in hypercholesterolemic subjects switching to EFV/TDF/FTC from ABC/3TC+efavirenz. Methods: A 24-week, UK-multicenter study in subjects stable on KVX+EFV, with HIV RNA < 50 copies/mL for ³6 months and TC ³5.2mmol/L (200mg/dL) at screening, randomized to switch to ATR or continue KVX+EFV. At Week 12, subjects randomized to KVX+EFV were switched to ATR. The primary endpoint was change from baseline to Week 12 in fasting TC. Fasting lipid parameters were also assessed using NCEP thresholds. Results: 157 subjects (125 men, 32 women), mean age 43.8 years (range 28-73), were randomized and treated; 79 switched to ATR, 78 continued KVX+EFV, and 73 switched to ATR at Week 12. Subjects were well matched for baseline characteristics. Switching to ATR from KVX+EFV significantly reduced TC and other atherogenic lipids at Week 12. Mean (95% CI) differences at Week 12 (change from baseline in mmol/L, ATR minus KVX+EFV): TC -0.74 (-1.01, - 0.47), p< 0.001; LDL -0.49 (-0.71, -0.26), p< 0.001; TG -0.42 (-0.75, -0.10), p< 0.001. Week 12 results were confirmed at Week 24 for subjects with delayed switch to ATR. There were no protocol-defined virologic failures or study-drug related SAEs. Conclusion: Switching to ATR from KVX+EFV significantly improved atherogenic lipid parameters towards desirable levels (per NCEP guidelines) while maintaining virologic suppression. Findings support using ATR rather than KVX+EFV in the management of appropriate hypercholesterolemic patients. Background: Dyslipidemia in persons with HIV contributes to cardiovascular risk. Tenofovir DF-based regimens may have a favorable lipid profile relative to abacavir-based regimens. We investigated changes in fasting total cholesterol (TC) in hypercholesterolemic subjects switching to EFV/TDF/FTC from ABC/3TC+efavirenz [ABC/3TC+EFV]. Methods: A 24-week, UK-multicenter study in subjects stable on KVX+EFV, with HIV RNA < 50 copies/mL for ³6 months and TC ³5.2mmol/L (200mg/dL) at screening, randomized to switch to ATR or continue KVX+EFV. At Week 12, subjects randomized to KVX+EFV were switched to ATR. The primary endpoint was change from baseline to Week 12 in fasting TC. Fasting lipid parameters were also assessed using NCEP thresholds. Results: 157 subjects (125 men, 32 women), mean age 43.8 years (range 28-73), were randomized and treated; 79 switched to ATR, 78 continued KVX+EFV, and 73 switched to ATR at Week 12. Subjects were well matched for baseline characteristics. Switching to ATR from KVX+EFV significantly reduced TC and other atherogenic lipids at Week 12. Mean (95% CI) differences at Week 12 (change from baseline in mmol/L, ATR minus KVX+EFV): TC -0.74 (-1.01, - 0.47), p< 0.001; LDL -0.49 (-0.71, -0.26), p< 0.001; TG -0.42 (-0.75, -0.10), p< 0.001. Week 12 results were confirmed at Week 24 for subjects with delayed switch to ATR. There were no protocol-defined virologic failures or study-drug related SAEs. Conclusion: Switching to ATR from KVX+EFV significantly improved atherogenic lipid parameters towards desirable levels (per NCEP guidelines) while maintaining virologic suppression. Findings support using ATR rather than KVX+EFV in the management of appropriate hypercholesterolemic patients.
  • Background: Dyslipidemias are an increasingly important cardiovascular risk factor affecting HIV patients receiving HAART. Previous studies have shown that abacavir has a dyslipidemic effect, whereas tenofovir has not shown such effects. Methods: Virologically stable subjects on ABC/3TC+LPV/r, with HIV RNA < 50 copies/ml for =6 months and screening cholesterol =5.2 mmol/L were randomized (1:1) to continue ABC/3TC+LPV/r or switch to TDF/FTC+LPV/r. The 12 week primary endpoint was change from baseline in fasting total cholesterol (TC). Additional analyses assessed changes in fasting metabolic parameters and 10 year-risk for CHD (Framingham equation). Results: 85 subjects were randomized and received at least one dose of study medication. Both treatment groups were similar at baseline (BL) in regard to age, sex, and mean [SD] BMI (26.2 [5.04]), time since first HIV therapy (6.4 [5.1] years) and since start of ABC/3TC (2.6 [1.6] years). At Week 12 HIV RNA control was well maintained in both arms. The TDF/FTC arm showed a significant improvement from baseline in TC. Comparing TDF/FTC vs. ABC/3TC, at W12 improvements were statistically significant for TC (p< 0.001), LDL cholesterol (p=0.005), but not for triglycerides. 10 year CHD risk [median (Q1, Q3)] at BL and W12 was 8 (4, 13) and 7 (4, 10) for TDF/FTC, while 10 year CHD risk remained unchanged for ABC/3TC (TDF/FTC vs. ABC/3TC p=0.027). Conclusions: After 12 weeks, switching from an ABC/3TC+LPV/r regimen to a TDF/FTC+LPV/r regimen maintained HIV RNA control and resulted in improved abacavir-associated dyslipidemias and CHD risk.
  • Background: Dyslipidemia in persons with HIV contributes to cardiovascular risk. Tenofovir DF-based regimens may have a favorable lipid profile relative to abacavir-based regimens. We investigated changes in fasting total cholesterol (TC) in hypercholesterolemic subjects switching to EFV/TDF/FTC from ABC/3TC+efavirenz [ABC/3TC+EFV]. Methods: A 24-week, UK-multicenter study in subjects stable on KVX+EFV, with HIV RNA < 50 copies/mL for ³6 months and TC ³5.2mmol/L (200mg/dL) at screening, randomized to switch to ATR or continue KVX+EFV. At Week 12, subjects randomized to KVX+EFV were switched to ATR. The primary endpoint was change from baseline to Week 12 in fasting TC. Fasting lipid parameters were also assessed using NCEP thresholds. Results: 157 subjects (125 men, 32 women), mean age 43.8 years (range 28-73), were randomized and treated; 79 switched to ATR, 78 continued KVX+EFV, and 73 switched to ATR at Week 12. Subjects were well matched for baseline characteristics. Switching to ATR from KVX+EFV significantly reduced TC and other atherogenic lipids at Week 12. Mean (95% CI) differences at Week 12 (change from baseline in mmol/L, ATR minus KVX+EFV): TC -0.74 (-1.01, - 0.47), p< 0.001; LDL -0.49 (-0.71, -0.26), p< 0.001; TG -0.42 (-0.75, -0.10), p< 0.001. Week 12 results were confirmed at Week 24 for subjects with delayed switch to ATR. There were no protocol-defined virologic failures or study-drug related SAEs. Conclusion: Switching to ATR from KVX+EFV significantly improved atherogenic lipid parameters towards desirable levels (per NCEP guidelines) while maintaining virologic suppression. Findings support using ATR rather than KVX+EFV in the management of appropriate hypercholesterolemic patients.
  • Background: The exact contribution of particular classes of ARV to BMD remains unclear. Methods: A5142 was an open-label study in 753 treatment-naïve subjects randomized equally to: Efavirenz (EFV) +2NRTI versus lopinavir/ritonavir(LPV/r)+2NRTI versus LPV/r+EFV (no NRTI). Zidovudine(ZDV), stavudine(d4T), or tenofovir(TDF) with lamivudine(3TC) was selected prior to randomization. Whole body DEXA was used to assess total body BMD at baseline, 48 and 96 weeks. Analysis was modified intent-to-treat ignoring regimen changes with no imputation for missing values. Results: There were significant mean declines in BMD at week 48 that persisted to week 96 (table) among subjects starting each of the regimens. In repeated measures analysis of changes (including randomized regimen, NRTI used and time), there was a significant difference in the NRTI-containing arms in mean percentage change in BMD at both weeks 48 and 96 according to NRTI used (p< 0.001). Compared to subjects taking ZDV, those taking d4T had similar changes (p=0.97) whereas those taking TDF had larger declines (p< 0.001). There was a non-significant trend toward greater declines among subjects taking LPV/r versus EFV (p=0.080). In the repeated measures analysis, compared to the NRTI sparing regimen, the mean decline in BMD for the LPV/r+TDF+3TC regimen was greater (p=0.004) while the EFV+ZDV +3TC and d4T+3TC+EFV regimens had smaller BMD changes (p=0.024 for each). Overall, fracture rates in the study were low. Conclusions: Among the NRTI-containing arms, NRTI selection, especially use of TDF, had a greater effect on BMD change than randomized regimen, which showed a trend for greater declines in the LPV arm. The long term clinical significance remains to be demonstrated.
  • Background: Lopinavir/ritonavir (LPV/r) increases tenofovir exposure by inhibiting drug transporters. We examined relationships between change in creatinine clearance (CrCl) among patients initiating tenofovir disoproxil fumarate (TDF) with concomitant antiretrovirals (LPV/r or efavirenz [EFV]) and drug transporter gene polymorphisms. Methods: We compared change in CrCl among 474 treatment-naive patients initiating LPV/r+TDF/3TC (n=56), EFV +TDF/3TC (n=60), (LPV/r or EFV) + 2NRTIs without TDF (n=201) or LPV/r+EFV without NRTIs (n=157). CrCl was estimated using Cockcroft-Gault. We evaluated polymorphisms across ABCB1, ABCC2, ABCC4 and SLC22A6. Wilcoxon tests and mixed-effects models compared regimen type and change in CrCl from baseline to weeks 24, 48, 72 and 96. Jonckheere Terpstra tests analyzed associations between polymorphisms and week 96 change in CrCl. Analyses were not corrected for multiple comparisons. Results: Combined, TDF-containing regimens had greater CrCl declines than non-TDF-containing regimens (Table - univariate analyses). Decline in CrCl was greater with LPV/r+TDF/3TC vs. EFV+TDF/3TC at week 24 and vs. LPV/r +2NRTIs (non-TDF) through week 96. Adjusting for age, gender, baseline CD4 and HIV RNA, and pre-therapy CrCl, patients receiving LPV/r+TDF/3TC had greater CrCl declines over 96 weeks than patients receiving EFV+TDF/3TC (difference: -7.6 ml/min, 95% CI [-12.6, -2.7]; P< 0.01). ABCC2 3972C>T (rs3740066) was associated with preserved CrCl (CC -6.4 ml/min, n=166; CT -3.7 ml/min, n=142; TT +4.4 ml/min, n=27; P=0.021). Conclusions: Treatment with TDF and LPV/r+TDF was associated with greater CrCl declines over 96 weeks. A tentative association with ABCC2 requires replication in other studies.
  • Background: Neuropsychiatric adverse events (AEs) are a common problem with efavirenz treatment. Methods: In the double-blinded, placebo controlled SENSE trial, 157 treatment-naïve patients with HIV RNA >5000 copies/ mL were randomized to ETR 400mg once daily (n=79) or EFV 600mg once daily (n=78), plus two investigator-selected NRTIs (TDF/FTC, ABC/3TC or ZDV/3TC). The primary endpoint was the percentage of patients with Grade 1-4 drug related treatment-emergent neuropsychiatric AEs at Week 12. Results: The patients were 81% male and 85% Caucasian, with median age 36 years, baseline CD4 count 302 cells/uL and HIV RNA 4.8 log10 copies/mL, well balanced between the arms. In the Intent to Treat analysis, Grade 1-4 drug related neuropsychiatric (NPS) AEs were reported in 13/79 patients (16.5%) in the ETR arm versus 36/78 (46.2%) in the EFV arm (p< 0.001). Grade 2-4 drug-related NPS AE´s were reported in 4/79 (5.1%) in the ETR arm versus 13/78 (16.7%) in the EFV arm (p=0.019). Consistent results were seen for the Per Protocol analysis. Using the HIV-Patient Symptoms Profile questionnaire, patients in the ETR arm also reported better neuropsychiatric tolerability than patients in the EFV arm. The reduction in HIV RNA to Week 12 was -2.9 log10 in both treatment arms. The median rise in CD4 count was +146 cells/uL in the ETR arm and +121 cells/uL in the EFV arm. Eighteen patients discontinued the trial by Week 12 (10 in ETR arm, 8 in EFV arm). There were fewer Grade 2-4 elevations in total cholesterol and LDL cholesterol in the ETR arm (3 and 6 patients) versus the EFV arm (18 and 13 patients). Conclusions: After 12 weeks, first-line treatment with ETR 400mg once daily +2NRTIs led to significantly fewer neuropsychiatric adverse events and an improved lipid profile, compared with EFV+2NRTIs. The virologic and immunologic efficacy profiles were similar in the two arms.
  • Background: Neuropsychiatric adverse events (AEs) are a common problem with efavirenz treatment. Methods: In the double-blinded, placebo controlled SENSE trial, 157 treatment-naïve patients with HIV RNA >5000 copies/ mL were randomized to ETR 400mg once daily (n=79) or EFV 600mg once daily (n=78), plus two investigator-selected NRTIs (TDF/FTC, ABC/3TC or ZDV/3TC). The primary endpoint was the percentage of patients with Grade 1-4 drug related treatment-emergent neuropsychiatric AEs at Week 12. Results: The patients were 81% male and 85% Caucasian, with median age 36 years, baseline CD4 count 302 cells/uL and HIV RNA 4.8 log10 copies/mL, well balanced between the arms. In the Intent to Treat analysis, Grade 1-4 drug related neuropsychiatric (NPS) AEs were reported in 13/79 patients (16.5%) in the ETR arm versus 36/78 (46.2%) in the EFV arm (p< 0.001). Grade 2-4 drug-related NPS AE´s were reported in 4/79 (5.1%) in the ETR arm versus 13/78 (16.7%) in the EFV arm (p=0.019). Consistent results were seen for the Per Protocol analysis. Using the HIV-Patient Symptoms Profile questionnaire, patients in the ETR arm also reported better neuropsychiatric tolerability than patients in the EFV arm. The reduction in HIV RNA to Week 12 was -2.9 log10 in both treatment arms. The median rise in CD4 count was +146 cells/uL in the ETR arm and +121 cells/uL in the EFV arm. Eighteen patients discontinued the trial by Week 12 (10 in ETR arm, 8 in EFV arm). There were fewer Grade 2-4 elevations in total cholesterol and LDL cholesterol in the ETR arm (3 and 6 patients) versus the EFV arm (18 and 13 patients). Conclusions: After 12 weeks, first-line treatment with ETR 400mg once daily +2NRTIs led to significantly fewer neuropsychiatric adverse events and an improved lipid profile, compared with EFV+2NRTIs. The virologic and immunologic efficacy profiles were similar in the two arms.
  • Background: Efavirenz (EFV) causes neuropsychiatric side effects and sleep disturbance. We investigated the effect of replacing EFV with etravirine (ETR) on patient preference, sleep quality, daytime sleepiness and anxiety. Method: Study subjects had been on EFV for at least 3 months, and had undetectable (< 50 copies/ml) HIV-RNA. They were randomized into two groups; the ETR-first group received ETR (400 mg once daily) for 6 weeks, plus EFV placebo. The EFV-first group received EFV first, plus ETR placebo. After 6 weeks, both groups switched to the alternate regimen. The primary endpoint was patient preference for the first or the second regimen, elicited after 12 weeks. Results: 58 subjects (87% male, median age 48, median duration of EFV treatment 6.2 years) were randomized and 55 completed the study. Plasma concentration at week 0 was 2058 [IQR 1588-2648]. There was no difference between the 2 treatment phases with regards to biological safety and HIV-RNA, except for lipids levels which were significantly lower in ETR recipients (p=0.0001 for total cholesterol). Sleep quality, depression, anxiety and stress scores did not differ significantly between groups (p > 0.2 for all comparisons). When asked about treatment preference after 12 weeks, 16 preferred EFV, and 22 preferred ETR, while 17 did not express a preference (p = NS). Patients who started with EFV were more likely to prefer EFV (15/21, 71%), whereas patients who started with ETR were more likely to prefer ETR (n=16/17, 94%). This order effect was strongly significant (p< 0.0001). Conclusion: Patients on long term EFV tend to prefer staying on their original treatment. There was an order effect in the crossover design favoring the first treatment tested. This may be due to the recrudescence of symptoms when EFV was re-started after a 6 week break, in the ETR-first group.
  • Background: 2NRTI+EFV is recommended for initial therapy. Most EFV-related CNS toxicity resolves early; some experience persistent symptoms. We studied switching EFV to ETR in these individuals. Methods: A randomized, double-blind, placebo-controlled trial; subjects with CNS AE after =12 weeks EFV-based HAART were randomized to 2NRTI/EFV/ETR-placebo (delayed switch [DS]) or 2NRTI/ETR/EFV-placebo (immediate switch [IS]) for 12 weeks followed by 12-week open label phase (all received 2NRTI/TMC125). CNS AE were graded by 5-point scale (0=absent,1=mild,2=moderate,3=severe,4=life-threatening). Primary end-point: % G2-4 CNS AE at 12 weeks; secondary endpoints: HIV-RNA, CD4, CNS score (sum of CNS AE grades) and median number G2-4 CNS AE. Results: 38 male subjects (median age 43, 37 Caucasian) were randomized: 20 to IS, 18 to DS. Baseline NRTI: Trivia 58%, Kieta 29%, other 13%. All had HIV-RNA < 50; median CD4 468. Baseline G2-4 CNS AE were similar in both arms. 19 IS patients completed follow-up (1 LFU) and 13 on DS (2 LFU, 2 withdrawn consent, 1 AE). IS group G2-4 CNS AE: 90% at baseline (median no. 5); 60% at week 12 (median no. 1.5); p=0.041 (p=0.003). DS group G2-4 CNS AE: 88.9% at baseline (median no. 4); 81.3% at week 12 (median no. 3); p=ns for both. IS CNS score at week 12 declined from 14 to 6 (p=0.001); DS score from 10 to 7.5 (p=0.192). Combined (both arms) % decline in G2-4 CNS AE after 12 weeks of ETV was significant for overall AE, insomnia, abnormal dreams and nervousness (p=0.009, 0.016, 0.001, 0.046 respectively). Combined reduction after 12 weeks ETV in median CNS AE/CNS score were also significant. All maintained HIV-RNA < 50. 2 experienced new G3/4 AE. Conclusions: Switching EFV to ETR led to significant reductions in G2-4 CNS AE overall, insomnia, abnormal dreams and nervousness. Lack of improvement for some AE and patients suggests causes other than ARV.
  • Background: HIV-associated distal sensory polyneuropathy (HIV-DSP) is a serious morbidity of HIV infection. NGX- 4010 (QUTENZA®) is an 8% capsaicin patch, approved in the EU for peripheral neuropathic pain in non-diabetic adults. The recommended treatment duration is 30 minutes for the feet and 60 minutes for other locations. Integrated analyses evaluated the efficacy of a 30-minute application to the feet in patients with HIV-DSP. Methods: Integrated analyses from two randomized, double-blind, 12-week controlled HIV-DSP trials included 239 patients receiving a single 30-minute treatment with NGX-4010 and 100 patients receiving a 0.04% capsaicin control patch. Patients recorded their 'average pain for the past 24 hours' daily using the Neuropathic Pain Rating Scale (NPRS) and completed the subject-rated Patient Global Impression of Change (PGIC) at study conclusion. The percentage change in average NPRS score from baseline to Weeks 2-12 was compared between treatment groups using a gender stratified ANCOVA model with baseline pain score as the covariate. The percentage of patients with =30% reduction in NPRS score or a decrease of =2 units from baseline to Weeks 2-12 was compared using logistic regression with baseline pain and gender as covariates. The PGIC was compared using a Cochran-Mantel-Haenszel test. Safety was monitored by adverse events (AEs). Results: During Weeks 2-12, NGX-4010 reduced the NPRS score 27.0% versus 15.7% for control (p=0.0020); 39% of NGX-4010 patients experienced a =30% reduction in NPRS score (23% in control, p=0.0051); 37% of NGX-4010 patients had a decrease of =2 units (24% in control, p=0.0284); 36% of NGX-4010 patients reported being much or very much improved on the PGIC (22% in control, p< 0.0001). Mild-to-moderate, transient application site pain and erythema were the most common AEs. Conclusions: A single 30-minute NGX-4010 application reduces neuropathic pain associated with HIV-DSP for 12 weeks and is well tolerated.
  • Background: Specific causes of mortality in human immunodeficiency virus type 1 (HIV-1)–infected patients who initiated antiretroviral therapy (ART) in Europe and North America were examined from 1996 through 2006. Subsequently associations of prognostic factors with cause-specific mortality were quatified. Methods. Retrospective classification of all deaths among 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) into the categories specified in the Cause of Death (CoDe) project protocol. Results. In 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Rates of AIDS-related death (hazard ratio [HR] per 100 cell decrease, 1.43; 95% confidence interval [CI], 1.34– 1.53) and death from renal failure (HR, 1.73; 95% CI, 1.18–2.55) were strongly inversely related to CD4 count at initiation of ART, whereas rates of death attributable to AIDS (HR for viral load 15 vs 5 log copies/mL, 1.31; 95% CI, 1.12–1.53), infection (HR, 1.85; 95% CI, 1.25–2.73), cardiovascular (HR, 1.54; 95% CI, 1.05–2.27), and respiratory causes (HR, 3.62; 95% CI, 1.30–10.09) were higher in patients with baseline viral load 15 log copies/ mL than in other patients. Rates of each cause of death were higher in patients with presumed transmission via injection drug use than in other patients, with marked increases in rates of liver-related (HR for injection drug use vs non–injection drug use, 6.06; 95% CI, 4.03–9.09) and respiratory tract–related (HR, 4.94; 95% CI, 1.96– 12.45) mortality. The proportion of deaths classified as AIDS related decreased with increasing duration of ART. Conclusions. Important contributors to non-AIDS mortality in treated HIV-1–infected individuals must be addressed if decreases in mortality rates are to continue. Reference: The Antiretroviral Therapy Cohort Collaboration: Causes of Death in HIV-1–Infected Patients Treated with Antiretroviral Therapy, 1996–2006: Collaborative Analysis of 13 HIV Cohort Studies. Clin Infect Dis 2010; 2010; 50(10):1387–1396
  • Background of the ATLIS study:_ Multi-country, comparative, treatment awareness survey of 2,035 people living with HIV/AIDS (PLWHA) e xamining global attitudes and perceptions of HIV. The m ain survey objectives were: Explore different treatment practices and awareness levels to reveal different ways in which people live with HIV/AIDS across the world Explore how different social and cultural factors affect and impact the lives of HIV-positive patients Investigate how patients interact with their primary healthcare provider (HCP), and understand the dialogue that takes place between HCPs and patients Methods: Fieldwork conducted January – March 2010. 20-minute interviews by internet, phone, face-to-face. Respondent qualification: Informed consent to participate in survey Age 18+ Diagnosed with HIV/AIDS by a primary HCP Taken antiretroviral therapy (ART) in the past five years Institutional Review Board (IRB) approval, Task Force review of data TALKING POINT: ATLIS showed that despite the high prevalence of co-morbid conditions, respondents were not addressing these condition consistently with their HCPs. TALKING POINT : Globally, less than half (47%) of respondents had discussed depression with their HCP. 38% percent of all respondents had discussed sleep disorders, 35% had discussed GI issues, and 34% had discussed high cholesterol with their HCP. TALKING POINT : Although the highest rates of hepatitis C virus co-infection were seen in Europe, only 38% of respondents in Europe had discussed it with their HCP.
  • Table summarizing the current anti-HCV drugs in development. Overall, 84 phase I-III anti-HCV studies are currently conducted. Phase III studies are currently ongoing for the HCV protease inhibitors telaprevir and boceprevir. For both of these drugs FDA approval is expected for late 2011. In contrast to the many studies carried out in HCV mono-infection so far only two pilot studies are currently recruiting in HIV/HCV coinfection underlining the gab in drug development in this particular challenging patient group with a clearly demonstrated unmet medical need.
  • Methods: Comparison of Fibroscan results and endoscopic findings in clinical database in patients with or without esophageal varices All patients with liver stiffness measurement (LSM) values higher than 12.5 kPa underwent esophago-gastro-duodenoscopy (n=69) Results: 68 patients were included. Of those, 29% were female and 88% caucasian. Median age was 49 years, median body mass index (BMI) was 23.42 kg/m2. Liver disease was caused by hepatitis C virus (HCV) infection in 29%, bý human immunodeficiency virus (HIV)-HCV coinfection in 46%, by HIV monoinfection in 9% and miscellanous in 16%. LSM was strongly correlated with the presence of EV: the LSM value was 41+/-20.6 kPa (mean+/-standard deviation) in patients with EV (n=17) and 28+/-18.7 kPa in patients without EV (n=51), p< 0.02. Median LSM values were 35.8 kPa in the varices group and 19.2kPa in the non-varices group. Patients with varices were mainly male, but were not different to the non-varices group with regards to age, BMI or diagnosis. Conclusions: In cirrhotic patients (stiffness >12.5 kPa) transient elastometry indicates the presence of esophageal varices by higher values („the higher, the stiffer“) HCV infected and HIV/HCV coinfected patients with esophageal varices had median stiffness values >36 kPa Fibroscan cannot replace gastroscopy for the diagnosis of varices Stiffness values <19 kPa strongly indicate the absence of esophageal varices
  • Background: High HIV viral load in HIV/HCV-coinfected patients is associated with faster fibrosis progression. The influence of HIV viral load on HCC is unknown Methods Retrospective analysis in 22 centers in 7 countries: North America: Canada and United States South America: Argentina and Brazil Europe: Germany, Spain and United Kingdom All HCC cases in HIV-infected patients from 1995-2009 with data on initial presentation. N=115 total of 117 patients, of whom 2 had no HCV RNA data Diagnosis by AASLD criteria (Bruix & Sherman, Hepatology, 2005) Patients were divided into: Undetectable: HIV RNA <400 copies/ml n=68 Detectable: HIV RNA 400+ copies/ml n=47 Summary of findings and Conclusion: Undetectable HIV RNA (<400 copies/ml) is associated with better survival This phenomenon is only observed in patients receiving no HCC therapy Any effective HCC therapy obliterates the beneficial effect of suppressed HIV infection on survival In this study, there were only n=79 deaths, precluding a meaningful multi-variable Cox regression analysis This will be performed in the future, when the sample size has increased.
  • Background: Decreased bone mineral density is increasingly reported in the aging HIV-positive population. An estimated 15 to 30% of HIV-infected patients are co-infected with hepatitis C, which by itself is associated with osteoporosis. While these findings have raised concern for increased fracture risk, few studies have assessed this risk. Methods: Patients with any osteoporotic fracture (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by ICD9 code in the Veterans Affairs' Clinical Case Registry in the HAART era (1996-2004). The incidence of osteoporotic fractures was calculated among HIV mono-infected and HIV/HCV co-infected patients. The impact of age, race, antiretroviral therapy, and chronic kidney disease (CKD) on fracture risk was also evaluated. Overall 56,660 patients were included in the analysis; 98.1% male; 31.2% HCV+; 45 years mean age at entry The follow-up consisted of 305,237 patient-years; mean: 5.4 yrs/pat. (range: 0 – 23.8 yrs)
  • Results: During follow-up 948 individual patients sustained at least one osteoporotic fracture (106) vertebral, 451 wrist and 308 hip). Fracture rates/1000 patient-years for HIV and HIV/HCV patients were 2.54 and 3.25, respectively. The total risk was significantly higher in the HIV patient population than in the general population.
  • The following table summarizes the factors predicting osteoporotic fracture among HIV-infected patients in a multi-variable Cox model. Risk Factors Hazard Ratio (95% Confidence Interval; p value). In Univariate Analysis Multi-variable Analysis HCV Co-infection, CKD (estimated glomerular filtration rate <60), white race, Age (per 10 year increase), tabacco use, diabetes and BMI <20 were independent predictors for osteoporotic fractures. Interestingly ART use per se was the only protective factor. In multivariate analyses all factors remained significant except diabetes and CKD. Conclusions: In the HAART era, HCV co-infection and advancing age are associated with a higher risk of osteoporotic fractures in HIV-infected patients. Cumulative years of HAART use and CKD are not. As described in the general population, Black race was protective.
  • Combination antiretroviral therapy (ART) has dramatically improved life expectancy for human immunodeficiency virus type 1 (HIV-1)–infected patients, primarily because of reductions in deaths attributable to AIDS-related conditions. However, an increasing number of deaths are attributable to causes not conventionally considered to be HIV-1 related. Indeed in a recent analysis from the Antiretroviral Therapy Cohort Collaboration half of the deaths documented in 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) were non-AIDS related causes (1). Overall, in 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Clearly in this study non-AIDS malignancies have emerged as the main non-AIDS cause of mortality in HIV-infected persons highlighting the need for more cancer surveillance data in these patients. New interesting data on the cancer burden in HIV/AIDS patients from the US can be seen on this slide from a study presented orally at the malignancy session in Vienna (2). Data on all U.S. HIV cases was collected by the CDC. Cancer incidence rates were obtained through linkage of HIV and cancer registries in 15 U.S. areas. For persons with AIDS, cancer counts were estimated for 1991-2005 by applying the cancer incidence rates to the U.S. AIDS population by year, age, sex, race/ethnicity, transmission category, and time since AIDS. For persons with HIV-only (not AIDS), counts were estimated for 2004-2007 by applying overall cancer rates for 1998-2005 to HIV data from 34 states with confidential name-based HIV reporting since 2004. The first finding of the study was that the U.S. AIDS population increased from 93,802 people (8% 50+ years old) in 1991 to 399,762 (29% 50+years old) in 2005 not only highlighting an increase in numbers but also an increasing proportion of elder patients. During 1991-2005, 76,558 cancers occurred in this population. AIDS-defining cancers (mainly Kaposi sarcoma and non-Hodgkin lymphoma) declined from 7,284 cases in 1993 to 1,736 cases in 2005. References: 1The Antiretroviral Cohort Colloberation: Causes of Death in HIV-1–Infected Patients Treated with Antiretroviral Therapy, 1996–2006: Collaborative Analysis of 13 HIV Cohort Studies. Clin Infec Dis 2010;50:1388-1396 ²Shiels MS et al. The burden of cancer among HIV-infected persons in the US population. 18th WAC, Vienna, Austria, July 18-23, 2010; abstract #WEAB0101
  • In contrast to the previous slide demonstarting a sharp decline in AIDS-related malignancies, non-AIDS-defining cancers increased across years (n= 416 in 1991 vs. n=2,437 in 2005). Anal cancer (n=18 in 1991, n=358 in 2005) and prostate cancer (n=10 in 1991, n=123 in 2005) increased steeply, partially due to rising rates. Although lung cancer and Hodgkin lymphoma rates remained relatively stable, cases increased (lung cancer: n=112 in 1991, n=478 in 2005; Hodgkin lymphoma: n=72 in 1991, n=169 in 2005). During 2004-2007 in 34 states, 2,191 cancers occurred among persons with HIV-only (person years of follow-up 946,936 person years), including 454 lung cancers, 154 anal cancers, 166 female breast cancers, 147 prostate cancers and 150 Hodgkin lymphomas. Interestingly, looking at all cancer events in all HIV-only as well as in all AIDS-patients around one half of all cancer events were attributable to non-AIDS defining cancers again highlighting the clinical importance of these clinical entities. The authors conclude that dramatic increases in non-AIDS-defining cancers among persons with AIDS can be observed which are mainly driven by growth and aging of the AIDS population. Moreover, rising incidence rates for some cancers such as anal and liver cancer need to be noted. Cancer prevention and treatment in HIV-infected persons are becoming increasingly important and warrant further research in this area.
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