Track B Clinical Science

Coding Guide Example: MOAA01 (Weekday) MO (Session type) AA (Session order) 01 Weekdays: SU (Sunday), MO (Monday), TU (Tuesday), WE (Wednesday), TH (Thursday), FR (Friday) Session types: oral abstract sessions AA (Track A), AB (Track B), AC (Track C), AD (Track D), AE (Track E), AX (Cross-Track), LBA (Late Breaker Track A), LBB (Late Breaker Track B), LBC (Late Breaker Track C), LBD (Late Breaker Track D), LBE (Late Breaker Track E), LBX (Late Breaker Cross-Track); oral poster discussions sessions PDA (Track A), PDB (Track B), PDC (Track C), PDD (Track D), PDE (Track E) PDX (Cross-Track) Session order: 01, 02, 03, 04, etc. Abstracts of the XIX International AIDS Conference Journal of the International AIDS Society 2012, 15 (Suppl 3) Track B Clinical Science

Background: Diagnosis of acute HIV infection (AHI) is uncommon in resource limited settings. This abstract describes acute HIV infection in women in three East African countries. Methods: Women at high risk of infection were recruited from 'hot spots' in Kericho (rural Kenya), Kampala (urban Uganda) and Mbeya (rural Tanzania). HIV negative eligible women were prospectively screened twice a week using HIV nucleic acid testing. A positive test led to entry into an intensive one-month diagnostic verification phase to definitively establish HIV infection status. Clinical and laboratory assessments were performed semiweekly. Supportive care and symptomatic treatment was provided. Results: Overall, 1197 high-risk volunteers have enrolled to date with 37 cases of AHI identified (31 prior to detectable antibodies). Mean age at HIV acquisition was 24.4 years (range 18Á34). Only six reported unprotected sex with a known HIV positive partner. Crude incidence was 2.77/100 PY (95% CI:90.87). Of the 37 AHI cases; 14 presented with malaria-like symptoms (all smear negative), 7 flu-like symptoms while 16 had 1Á2 mild complaints (8) or no symptoms (8). Overall, AHI cases were evaluated at 302 visits and at least one symptom was reported in only 75 visits (24.8%). Pregnancy did not increase the frequency of symptoms but dehydration due to vomiting resulted in 2 of the 3 hospitalizations observed. Conclusion: Identification of AHI is feasible in East Africa. Young, rural, females are most vulnerable. Individuals with clinical syndromes suggestive of malaria, but excluded by microscopy, should raise index of suspicion for AHI. The majority of cases had few or no symptoms or brief non-specific symptoms not requiring medical intervention. Screening protocols based on malaria syndromic presentation would not identify the majority of AHI cases.

TUPDB0204
Very early initiation of combination antiviral therapy results in normal levels of markers of immune activation Results: A total of 29 subjects, 11 on 3-drugs and 18 on 5-drugs remained on therapy, suppressed and were available for analysis at 48 weeks. After 96-weeks 25 subjects, 9 on 3-drugs and 16 on 5drugs were similarly analyzed. There are no statistically significant differences (Mann-Whitney, pB0.05) in markers of cellular or systemic immune activation between the 3-drug and 5-drug groups at baseline or after 48 and 96 weeks of therapy. Importantly, the early treated HIV-infected subjects display comparable levels of markers of cellular and systemic immune activation when compared to the healthy HIV-uninfected controls. Markers of Immu . . .

Conclusion:
These data suggest that the early initiation of cART may result in normalization of markers of immune activation that may provide clinical benefit. These results support well-designed prospective trials to confirm these findings.

B3 -Elite and viremic controllers WEAX0105
HLAB57 does not fully explain the ability of HIV controllers to spontaneously clear hepatitis C virus (HCV) infection Background: HIV controllers, maintaining low plasma HIV RNA levels ( B2000 copies/ml) in the absence of antiretroviral therapy, are also more likely to spontaneously clear HCV infection. HLAB57, the major histocompatibility class I gene, is highly enriched in HIV controllers and is associated with HCV spontaneous clearance. Whether HLAB57 explains the increased prevalence of spontaneous HCV clearance observed in HIV controllers remains unclear. Methods: Patients in the Study of the Consequences of Protease Inhibitor Era (SCOPE) were tested for anti-HCV using enzyme immunoassay (EIA3) and HCV RNA using discriminatory HCV transcription-mediated amplification assay (Norvatis † ). We compared the proportion of HIV controllers and HIV non-controllers with serological evidence of HCV clearance (anti-HCV'/RNA () by chisquare tests and assessed whether HLAB57 status explains the increased prevalence of HCV clearance in HIV controllers using adjusted prevalence ratio (APR) with Poisson regression models.
Results: Of 279 HIV/HCV seropositive subjects, 48 were HIV controllers. HIV controllers were significantly more likely to have evidence of spontaneous HCV clearance than HIV non-controllers (58% vs. 38%, p00.01). While HIV controllers were more likely to have HLAB57 than HIV non-controllers, (33% vs. 10%, pB0.01), HLAB57 was not significantly associated with HCV clearance among all participants (39% vs. 55% p00.06), and there was no evidence of increased prevalence of HCV clearance among HLAB57' vs. HLAB57in HIV controllers (p 00.83). In multivariate analyses adjusted for HLAB57, age, gender, and race/ethnicity, HCV clearance was significantly more likely in HIV controllers than HIV non-controllers (APR 1.44; 95% CI 1.04Á2.0; p 00.026). Conclusion: HIV controllers are more likely to spontaneously clear HCV than HIV-non-controllers even when controlling for HLAB57 status. Immunologic factors other than HLAB57 must contribute to the control of HIV and HCV in HIV controllers. Identifying these factors may support the development of novel treatments for and effective vaccines against both viruses.
B5 -Disease burden -morbidity/mortality THAB0304 Trends over time in underlying causes of death in the D:A:D study from 1999 to 2011 After accounting for factors including current CD4 count (Table), there was still evidence of decreases over time in LD and CVD deaths, but not AIDS-related. The proportion of all deaths attributed to AIDS (34% in 1999Á2000 to 22% in 2009Á2011), NADM (9%Á20%) and LD (16%Á9%) changed over time. Conclusion: Underlying causes of death have changed markedly over the last 12 years. AIDS remains the leading cause. Although there have been marked reductions over time in AIDS-related deaths, this effect is removed when accounting for current CD4 and other factors. NADMs are now the leading non-AIDS cause. Rates of LD and CVD-related deaths have decreased substantially, even after accounting for the factors listed below, suggesting other improvements in patient management during the study period. No trends in emerging causes of unexpected deaths were observed. Collection of specific causes of deaths is important to allow earlier interventions in HIV case management.

B7 -HIV testing, including new algorithms and strategies THAB0301
Non-adherence to HIV testing guidelines and late HIV diagnosis is common among U.S. black men who have sex with men (MSM) Background: US CDC guidelines recommend at least annual HIV testing for those at high risk. Nonadherence to testing guidelines and late diagnosis of infection may contribute to HIV transmission. Methods: HPTN 061 is a feasibility study of a multi-component HIV prevention intervention for at-risk black MSM in 6 US cities. At enrollment, participants were offered HIV testing. Participants reporting past HIV-uninfected or unknown status at enrollment and no HIV testing within the prior 12 months were considered nonadherent to HIV testing guidelines. Participants with newly diagnosed HIV and CD4 B200 at time of diagnosis were considered to have late diagnosis. Predictors of nonadherence to testing guidelines and late diagnosis were analyzed using logistic regression models and Fisher?s exact tests. HIV test data are from baseline testing performed at study sites; confirmatory testing is underway. Results: HPTN 061 enrolled 1553 black MSM. At enrollment, 1384 reported no prior HIV diagnosis, and 1335 (96%) of those participants agreed to testing; 98% were male, 3% transgender, 100% black, 8% Latino, with a median age of 39 years; 38% reported incomes below US poverty level, and 67% were unemployed. Among those tested, 309 (23%) reported no HIV test in prior 12 months; testing Ratio ratio (95% CI) for underlying cause of death over calender time (reference=1999/2000) 2001 Background: Recent data showing a high incidence of HIV infection among men who have sex with men (MSM) who had been tested during the past year suggest that MSM might benefit from more frequent HIV screening (e.g., every 3 to 6 months). We assessed the cost-effectiveness of HIV screening at 3 and 6 month intervals compared with annual screening. Methods: We used a published mathematical model of HIV transmission to evaluate screening intervals for a cohort of 10,000 MSM ages 14Á64. We incorporated HIV transmissions averted due to serostatus awareness for each screening interval (e.g. 3, 6, 12 months), as well as HIV testing costs and treatment costs for averted transmissions. We assumed an HIV incidence of 1.27% for MSM and conducted threshold analyses on incidence. We assumed conventional testing with a 3 rd generation antibody test and 75% receipt of results. In sensitivity analyses, we investigated the impact of all rapid testing and 100% receipt of results. We valued each HIV transmission averted using lifetime treatment costs of $367,134. Results: Compared to annual screening, conventional HIV testing every 3 months and 6 months averted 2.04 and 1.36 HIV transmissions, respectively, and both were cost-saving. The incremental cost-effectiveness of 3-month versus 6-month screening also was cost-saving. Threshold values for HIV incidence at which screening was cost-saving were 0.3% and 0.5% at the 3-month and 6-month screening intervals, respectively. Screening with a rapid test was cost-saving at both 3-and 6-month intervals compared to annual screening. The incremental cost-effectiveness of 3-month versus 6month screening was $813 per QALY saved. Conclusion: HIV screening with either conventional or rapid testing as frequently as every 3 months is cost-saving or very cost-effective. Reexamination of HIV screening intervals for MSM should be considered on the basis of the economic evidence. Background: Pooling techniques have been advanced to improve the cost effectiveness of nucleic acid testing for diagnosis of serologically undetectable acute HIV infections in resource limited settings. Previously reported methods have relied on serum samples. The goal of this study is to develop and apply a novel dried blood spot (DBS) based RT-PCR pooling technique to facilitate household sample collection, efficient diagnosis, and treatment-as-prevention strategies in Mochudi, Botswana. Methods: Laboratory-prepared DBS samples with plasma viral load !50,000 copies/mL are diluted with HIV negative DBS samples to generate estimates of sensitivity for pool sizes of 5, 10, 25, 50, and 100 samples. RT-PCR is performed using the Abbott RealTime HIV-1 assay. This analysis will inform the development of an acute HIV case detection pooling algorithm to be applied to all seronegative samples collected as part of a large prevention study cohort. Results: Preliminary findings based on 9 HIV positive samples used to create 90 pools, reflected sensitivities ranging from 27.8% for pools at 1/100 dilution to 100% for 1/5. We were able to detect the presence of an HIV positive sample in pools of 10 with a sensitivity of 94.1%. The difference in sensitivity between pool sizes of 25 and 50 was minimal.

Conclusion:
We have demonstrated the feasibility of using DBS pooling for acute HIV diagnosis. Because acute HIV infection involves high viral loads, we can reasonably expect to detect acute cases !50,000 copies/mL in pools of 10 with 94.1% sensitivity. Although increasing pool size decreases sensitivities, the false negative rate during the acute window period could be significantly reduced even  Background: In Kenya, HIV-1 viral load (VL) monitoring is commonly performed with the COBAS Amplicor using plasma specimens, but interest is growing in transitioning to real-time PCR (RT-PCR), including the COBAS Ampliprep/COBAS Taqman (CAP/CTM), using dried blood spots (DBS). RT-PCR has several advantages including full automation, lower detection limit, and broader measuring range. Benefits with DBS include sample collection via finger or heel stick, low biohazard risk, and specimen transportation under ambient conditions. Prior to implementation, a direct evaluation of the two assays using DBS field specimens is required.
Methods: This analysis compares sensitivity, specificity, negative (NPV) and positive (PPV) predictive values, concordance correlation, and agreement, as evaluated with Bland Altman analyses, between HIV-1 VL measurements using paired plasma and DBS specimens obtained from 512 HIV-1 infected treatment-naive pregnant women enrolled in the Kisumu Breastfeeding Study, and tested with the COBAS Amplicor and CAP/CTM assays.

MOAB0103
Determinants of penicilliosis seasonality in Ho Chi Minh City, Vietnam Background: Penicillium marneffei is an emerging dimorphic mycosis endemic in South and Southeast Asia, and a leading cause of mortality among HIV-infected people in the region. Factors governing the seasonal incidence of P. marneffei infection have yet to be identified, and may yield critical insights into possible reservoirs or modes of transmission. We used P. marneffei incidence data from Ho Chi Minh City (HCMC), Vietnam from 2004Á2010, as well as high-resolution weather data, to identify climactic factors that could account for the observed seasonality of P. marneffei infection.
Methods: This study included all P. marneffei, Cryptococcus neoformans, and HIV-related admissions to the Hospital for Tropical Disease (HTD) in HCMC from 2004Á2010, as well as temperature, humidity, wind, and precipitation data for the corresponding period. We used logistic regression modeling to identify factors significantly associated with P. marneffei and C. neoformans admissions. We also estimated the P. marneffei incubation period by incorporating different exposure-to-admission delays in our models.
Results: This analysis included 719 HIV-infected patients presenting with penicilliosis. P. marneffei admissions were closely associated with humidity (P B0.001) in univariate and multivariate analyses. Incorporating hypothetical exposure-to-admission delays revealed a significant association with incubation periods of up to three weeks (P for incubation of 1 week 00.0008, 2 weeks00.002, 3 weeks 00.002). Conclusion: Our findings suggest that humidity is the most important determinant of P. marneffei admissions, and that P. marneffei has an incubation period of 1Á3 weeks. Based on these results, we postulate that humidity may drive reported P. marneffei incidence, perhaps by promoting expansion of the environmental reservoir or by facilitating fungal growth and/or survival in the environment. Our findings provide clues to the environmental reservoir and transmission of P. marneffei, which may direct the design and timing of much-needed prevention strategies for people living with HIV/ AIDS in Asia.

MOAB0301
Relationship between weight, efavirenz (EFV) concentrations and virologic suppression in HIV' patients on rifampin (RIF)-based TB treatment in the ACTG 5221 STRIDE study EFV C min m/ml: median (IQR), Proportion (95% CI). *For comparison of EFV C min , by weight, Wilcoxon-rank sum p-value was used. For comparison of percent, chi-squared pvalue wos used. **p-value for comparison of C min on-RIF (n 0505) and off RIF (n0362) Wilcoxon-rank sum p-value was used, and % EFV B1 on-RIF and off-RIF, chi-square dp-value was used.

MOAB0305
A phase 2 trial of novel anti-tuberculosis regimens with increased efficacy and low potential to interact adversely with antiretroviral therapy Results: A total of 1672 sputum specimens were processed, of which 184 (11.0%) were smear-positive. Mycobacterium tuberculosis was detected by Xpert † MTB/RIF in 116 (7.8%) of the 1488 remaining smear-negative specimens. Comparing the period after implementing Xpert † with the period before, the proportion of TB notifications that were smear positive (33% versus 27%), smear-negative (48% versus 49%), sputum not tested (11% versus 12%), and extrapulmonary (8% versus 12%) was unchanged. The median time to TB treatment initiation among HIV/TB co-infected patients with sputumsmear-negative TB, decreased at decentralised sites (from 18.5 days to 7 days), but remained constant at the hospital level (5.5 days before and 6 days after). Conclusion: Xpert † MTB/RIF increased the number of laboratoryconfirmed TB cases in rural Zimbabwe, enabling further task shifting of TB management. In settings where access to chest X-Ray and trained doctors is lacking the impact on TB notifications may be greater. Time-to-initiation of TB treatment at the decentralized clinics was reduced, which has the potential to reduce morbidity in individuals and reduce the risk of TB transmission to others.

THAB0104
The value of universal TB screening with GeneXpert MTB/ RIF in pre-ART patients in Harare Background: PNU-100480 is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models that is time-dependent and unaffected by resistance mutations for standard TB drugs. PNU-100480 neither induces nor inhibits CYP3A4. This study is its first in TB patients. Methods: Sputum AFB smear positive South African patients (incl. HIV' not requiring ART) were randomly assigned to PNU-100480 600 mg BID (N 025) or 1200 mg QD (N 025), or standard 4-drug therapy (HREZ, N09) for the first 14 days of treatment. Sputum mycobacterial burden was monitored both as log CFU/ml and time to detection (TTP) in automated liquid culture system (MGIT). Results: 20% of subjects were women; 7% were HIV'. All subjects completed assigned treatments. There were no treatment-related serious adverse events nor any permanent discontinuations or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. At baseline, the mean log CFU/ml and TTP were 6 Background: More than 80% of patients with multidrug-resistant tuberculosis (MDR-TB) in Tugela Ferry, South Africa are co-infected with HIV. Concomitant treatment for both diseases is recommended, but concern about severe and additive toxicities of MDR-TB therapy and ART has slowed acceptance of community-based treatment.
Methods: Confirmed MDR-TB patients were treated at home by an injection team and returned to the clinic monthly where they were screened for common adverse events (AEs). Severity was graded using the DAIDS toxicity table. Safety labs were drawn monthly and TSH was drawn every 3 months. We reviewed clinical and laboratory AEs for all patients between November 2008 and April 2011. We examined the incidence of each AE in 6-month time blocks and the within-patient trend of each AE over time. We compared those who received concomitant MDR-TB/ART treatment to those who received MDR-TB treatment alone.
Results: Of 91 MDR-TB patients, 55% were female; median age was 34 (IQR 29Á41); and 84% were HIV co-infected. 74 patients (97% of HIV') were receiving ART and median baseline CD4 cell count was 207 cells/mm 3 (IQR: 89Á411). Ninety-nine percent of patients reported at least one AE during treatment, but most were mild and did not require therapy modification. The most common AEs were peripheral neuropathy (73%), injection site pain (66%), and arthralgia (43%). The most common severe AEs (grade03) were psychosis (10%) and hypothyroidism (29%). Patients receiving concurrent ART did not experience AEs more frequently than those on MDR-TB therapy alone. Patients were significantly less likely to report most AEs later in their treatment course ( Figure 1). Conclusion: Home-based treatment of MDR-TB and HIV is associated with high rates of mild AEs which are not increased by concurrent ART and can be managed symptomatically without changing MDR-TB therapy or ART. Treatment can be safely administered in a homebased care setting.   (1) Proportion with GMTs to HPV-6, -11, -16, and -18 of at least 20, 16, 20, and 24 mMU/mL, respectively.

B15 -Hepatitis B and D, including treatment
(2) P value assesses differences in mean GMTs or seroconversion rates 4 weeks after the third vaccine dose for all subjects vs. controls. When GMTs and seroconversion rates for Group A and Group B participants were compared to those of controls, the only significant differences were in Group A subjects vs. controls for HPV-18; no differences were found in Group B subjects vs. controls.

Track B Clinical Science
Results: At Week 96, the proportion of patients with HIV-1 RNA B50 andB400 copies/mL was 67.8% (40/59) and 78.0% (46/59), respectively, for MVC versus 82.0% (50/61) and 83.6% (51/61), respectively, for TDF/FTC. Protocol-defined treatment failure occurred in 5 patients (MVC: n 03; TDF/FTC: n 02). Median change from baseline in CD4' count was similar for both arms (MVC: 269 cells/mm 3 ; TDF/FTC: 305 cells/mm 3 ). Median change from baseline in creatinine clearance was (5.5 mL/min for MVC and (18 mL/min for TDF/FTC. Five patients (MVC: n 04; TDF/FTC: n01) had plasma HIV-1 RNA !500 copies/mL at failure or study discontinuation; virologic analyses detected no resistance, change in tropism or loss of susceptibility relevant to treatment in either arm. At Week 48, there was a greater reduction in immune activation on CD4' cells in patients receiving MVC versus TDF/FTC. Markers of bone formation were significantly different between arms at both 48 and 96 weeks. Conclusion: Durable virologic activity of MVC 150 mg QD'ATV/r was demonstrated through 96 weeks, with no differences between the arms in the rates of virologic failure, no resistance or change in tropism seen, and with most of the treatment difference due to lowlevel transient viremia. Differences between the arms in immune activation and bone markers require further investigation.

B24 -Clinical trials -phase III/post-licensing TUAB0103
Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results Background: Cobicistat is a novel investigational pharmacoenhancer with no anti-HIV activity. Methods: An international, randomized, double-blind, doubledummy, active controlled trial was conducted to evaluate the efficacy and safety of cobicistat vs ritonavir as pharmacoenhancers of atazanavir (ATV/co vs ATV/r group) in combination with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) in treatment-naïve patients. Key eligibility criteria were HIV-1 RNA ]5,000 copies/mL, estimated glomerular filtration rate by Cockcroft-Gault formula (eGFR)]70 mL/min. Primary endpoint was HIV-1 RNA B50 copies/ mL at Week 48 by snapshot algorithm, and noninferiority margin was (12%. Results: A total of 692 subjects were randomized and received at least 1 dose of study drug (344 in ATV/co group and 348 in ATV/r group) ( Table 1). At Week 48, virologic success was achieved in 85% (ATV/co) and 87% (ATV/r) (difference: (2.2%; 95% CI: (7.4 to 3.0) ( Table 2); among subjects with HIV-1 RNA !100,000 copies/mL, the response rates were similar (86 vs 86%). Two subjects in ATV/co and none in ATV/r group developed resistance mutations to study drugs; both were M184V/I. Similar percentages of subjects in both groups (ATV/co vs ATV/r) had serious adverse events (AEs) (11 vs 7%), discontinued study drug due to any AEs (7 vs 7%), or had bilirubin-related AEs (4 vs 3%). Median increases in total bilirubin at Week 48 in ATV/co and ATV/r group were 1.9 and 1.7 mg/dL. Median increases in serum creatinine were 0.13 and 0.09 mg/dL. Median increases in total cholesterol were 4 and 10 mg/dL; increases in triglycerides were 16 and 24 mg/dL. Plasma exposures of ATV (steady state mean C tau [ng/mL]) were comparable (796.1 vs 853.4). Conclusion: ATV/co was noninferior to ATV/r in combination with TDF/FTC at Week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the two regimens were comparable.  Background: Since the availability of viral load (VL) assay with a threshold of 20 copies/mL, some patients display VL values between 20 and 50 copies/mL. The aims of our study were to: (i) identify factors associated with low level viremia (LLV) in patients receiving stable suppressive antiretroviral therapy (cART); and (ii) assess virological outcome during the year following LLV detection. Methods: Retrospective study among the 4820 patients followed in our institution fulfilling the inclusion criteria: (i) stable cART for at least 6 months; (ii) all VLB50 copies/mL; and (iii) at least 3 VL determinations during a one-year period. We compared patients with all VLB20 copies/mL (Group LLV-) and patients with at least 2 VL between 20 and 50 copies/mL (Group LLV'). ''Blip Ratio'' was defined as: (number of VL !50 copies/mL)/(number of VL determinations) before study inclusion. Results: Among the 656 patients included, 5.8% were in group LLV'. The nature of the ongoing cART did not differ between LLV-and LLV' groups. In the multivariate analysis, only CDC clinical stage B/C at study inclusion (OR 02.9; 95% CI 01.4Á5.9; P 00.003) and a higher ''Blip Ratio'' before study inclusion (OR 00.9; 95% CI 00.9Á1.0; P00.001) were independently associated with LLV. During the follow-up, the proportion of patients experiencing virological failure (2 consecutive VL !50 copies/mL) was not different between LLV-and LLV' groups (4% vs 8%, respectively; P 00.32); and 40% of patients shifted from LLV' to LLV-status. Conclusion: LLV was infrequent in our series and the one-year followup did not evidence a higher rate of virological failure than in patients always fully-suppressed. LLV seems to be a transient phenomenon that might be driven by residual ongoing viral replication and/or viral release and/or accuracy of VL assay in lower values. Background: A5202 was a randomized equivalence study of four daily regimens of efavirenz (EFV) or atazanavir/ritonavir (ATV/r) with double-blinded tenofovir and emtricitabine or abacavir and lamivudine. Previous findings from A5202 reported women assigned ATV/r had higher-risk of virologic failure (VF) than women assigned EFV; also, women on ATV/r had higher risk of VF than men on ATV/r. This analysis relates ATV clearance (CL) to treatment efficacy and safety. Methods: The associations between ATV CL and times to VF and safety event (first increased grade 3/4 sign, symptom, or laboratory abnormality), while on ATV/r (as-treated), were estimated with hazard ratios (HR) from Cox proportional hazards models, adjusted for screening HIV-1 RNA (B10 5 or !10 5 copies/mL) and NRTIs. Additionally adjusted models included race-ethnicity (RE), age, baseline CD4 count, and body mass index. Interactions between ATV CL and sex, RE, and NRTIs were evaluated. A 1-compartment pharmacokinetic (PK) model including 815 subjects (88% of 928 randomized to ATV/r) was used to estimate subject-specific ATV CL. Atazanavir CL was categorized by overall sample tertiles (slow: B7; intermediate: 7 to B9; and rapid ! 9 L/hr). Analyses were restricted to 768 subjects of white, black, or Hispanic RE. Results: Atazanavir CL association with time to VF differed significantly by sex (p 00.003, Table 1). The association between ATV CL and time to VF did not differ significantly by NRTIs (p 00.6) or RE (p 00.085); additionally adjusted model results were similar. There was no significant association between ATV CL and time to safety event (rapid vs.

Conclusion:
The differential in CL association with time to VF by sex may reflect PK/pharmacodynamic reasons for failure, and will require further investigations.

TUPDB0102
Pharmacogenetics of intrapartum single-dose nevirapine (SD NVP) in AIDS Clinical Trials Group (ACTG) Protocol A5207 Background: Nevirapine (NVP) is metabolized by cytochrome P450 (CYP) 2B6. We investigated associations between single nucleotide polymorphisms (SNPs), haplotypes, and pharmacokinetics (PK) following SD NVP to prevent mother-to-child transmission (MTCT). Methods: Protocol A5207 evaluated strategies to prevent NVP resistance following intrapartum SD NVP. At onset of labor, participants received SD NVP (200 mg) and were randomized to lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir (LPV/r), for 7 or 21 days. Plasma for NVP assay was obtained at post-partum day 1 and week 1, 3 and 5. Derived PK parameters included the NVP elimination constant estimated using linear mixed effect models based on natural logarithm of NVP measured between day 1 and week 3. We assayed 214 SNPs in ABCB1, CYP2B6, CYP2C19, CYP3A4, CYP3A5 and NR1I2. CYP2B6 metabolizer status was based on *6/*18 haplotypes. SNP and CYP2B6 haplotype associations were based on parametric regression models adjusted for body mass index and treatment arm as indicated.

TUPDB0104
A single nucleotide polymorphism in CYP2B6 leads to !3-fold increases in efavirenz concentrations in intensive pharmacokinetic curves and hair samples Background: Prior studies investigating pharmacogenomics and efavirenz exposure use single plasma drug levels, which are limited by marked day-to-day variability. The Women's Interagency HIV Study (WIHS) performed 24 hour pharmacokinetics (PK) studies in a large number of HIV-infected women on efavirenz and calculated areasunder-the-curve (AUC) as measures of short-term exposure; concentrations in hair assessed long-term exposure. We typed 183 single nucleotide polymorphisms (SNPs) in 9 candidate genes known to influence efavirenz absorption, distribution, metabolism and elimination (ADME) and examined them in relation to AUC and hair levels in multivariate models.
Conclusion: A comprehensive search for SNPs in genes associated with efavirenz ADME demonstrated that CYP2B6 516TT was associated with !3-fold increases in short-term (AUC) and longterm (hair) EFV exposure. The effect of this SNP on exposure over the prolonged duration represented by hair levels is reported for the first time. Genetic testing may allow optimization of EFV dosing.
Genetic and non-genetic factors associated with short-term EFV exposure (AUC, n0111) Background: The pharmacokinetics of raltegravir in HIV-1 infected subjects is characterized by high inter/intra-patient variability. We investigated the potential contribution of the drug pharmaceutical formulation on raltegravir pharmacokinetics. Methods: We firstly compared in vivo the pharmacokinetics of raltegravir from 50 patients given the drug by swallowing with those obtained from 10 HIV-infected patients that chewed raltegravir due to swallowing difficulties. Subsequently we evaluated in vitro the dissolution of raltegravir tablets under different conditions (pH 1, pH 6.8 buffer and water). Dissolution tests were performed comparing raltegravir whole tablets with tablets crushed by grinding in mortar and pestle.
Results: In the in vivo study we found that the raltegravir pharmacokinetic profiles in patients given the drug by swallowing were highly variable, characterized in some cases by multiple peaks and irregular/ limited absorption. Conversely, patients given raltegravir by chewing presented regular pharmacokinetic profiles, characterized by single sharp drug peak and higher raltegravir absorption compared with patients given the drug by swallowing (Figure 1). The in vitro studies showed that the whole tablets presented relatively slow release profiles due to lacking disintegration. Crushed tablets tested in water and pH 6.8 buffer exhibited prompt and complete dissolution of raltegravir. For whole tablets tested in the acidic medium the raltegravir concentrations were very low, reaching less the 10% of the dose after 2h, owing to well-known poor solubility of raltegravir at low pH. However, when crushed tablets were tested in acid the profiles presented significantly higher concentrations of raltegravir ( Figure 2). Conclusion: HIV-infected patients given raltegravir by chewing showed higher drug absorption compared with patients given the drug by swallowing. This may be depends to problems related to the tablets disintegration leading to erratic drug release. The improvement of the raltegravir pharmaceutical formulation could reduce variability of raltegravir pharmacokinetics, eventually contributing to increase the response of HIV-infected patients.
B31 -When to start therapy?  Background: To inform optimal timing of ART initiation, we analyzed clinical outcomes during follow-up of HPTN 052 incorporating both AIDS and non-AIDS events related to HIV and ART. Methods: HIV' adults (CD4'350 550/mL) from Africa, Asia, and South America were randomized to ART immediately or after CD4' B250/mL or AIDS (delayed Methods: ART eligibility in the adult program is consistent with the Nigerian and WHO ART guidelines. Enrolled patients that gave written informed consent with greater than 6 months of ART were included in this study. Patients had clinical exams and laboratory tests, at baseline, month 3, 6, and every 6 months thereafter. All patient data was collected and stored electronically. Treatment failure was defined as 2 consecutive viral loads ! 1000 copies/mL following 6 months on ART.    Results: Overall, 101 patients were enrolled (63% female, 49% white) and 76 (75%) completed the trial; most discontinuations were for adverse events (AEs) or trial non-compliance (8% each). At W48, 65% of patients were adherent by PENTA adherence questionnaire. By pill count, 39% (children 46%, adolescents 35%) were !95% adherent; 70% were !80% adherent. The most common drug-related AE was rash (18%) (Table). Four percent discontinued due to rash. Serious AEs were seen in 5% of patients while 14% experienced a grade 3/4 AE. Laboratory toxicities were predominantly grade 1/2. At W48, 56% of patients achieved VL B50 copies/mL (intent-to-treat, non-completer0failure), with better responses in children than adolescents (Table). Median time to first response (VL B50 copies/mL) was 16 weeks (children) and 24 weeks (adolescents *Two children reported grade 4 thrombocytopenia and three patients had a grade 3 AE considered at least possibly related to etravirine (two children one with rash maculo-papular one with hypersensitivity, one adolescent with diarrhea): $ occuring in !10% of patients overall; z grouped term including rash not further specified, rash macula-papular, rash generalized, rash erythematous, rash macular rash papular and rash puritic; ' occurnng in !5% of patients overall; AE, adverse event NC 0 F, non-completer equals failure; SE standard error; TLOVR, time-toloss of virologic response algorithm.

MOAB0201
Lipid profile in children randomized to immediate versus deferred nevirapine-based antiretroviral therapy in the PREDICT study appropriate. Random effects model was used for multivariate analysis.
Results: Data from 129 immediate arm and 134 deferred arm children were included. The median (IQR) age was 6.5 (4.1Á8.5) years, 42% were male and 57% were Thai. Median fasting time was 8 hours. Parameters did not differ significantly between arms at week 0 (Table 1). By week 144, 60 deferred arm children had started ART. Dyslipidemia was significantly less common in the immediate arm. The immediate arm had significantly higher total cholesterol (TC), low-density lipoprotein (LDL), and high density lipoprotein (HDL) but lower triglyceride and TC/HDL ratio than the deferred arm. By multivariate analysis, the mean differences over 144 weeks between the immediate arm versus the deferred arm without ART (n 073) were significant for all lipid parameters: TC (20.2, pB0.001), triglyceride ((9.8, p00.006), LDL (9.1, pB0.001) and HDL (13.0, pB0.001) whereas only HDL was significantly different when the immediate arm were compared to the deferred arm children with ART (n 061) (4.9, p 0.001). Conclusion: After 3 years, children randomized to immediate nevirapine-based ART had less dyslipidemia and lower TC/HDL ratio than the deferred ART group. This supports earlier nevirapine-based initiation to achieve favorable lipid profile in children with mild to moderate HIV-associated immune deficiency. Track B Clinical Science considered in the analysis are shown in Table 1 and also included fasting glucose and lipids, insulin, use of statins, anthropometric parameters of obesity, years of protease inhibitors (PI) use, and nadir CD4' T cells. Significant (p B0.05) variables were considered in multivariate models. RANKL and OPG were assessed by ELISA and dys-HDL by a fluorometric assay based on the oxidation rate of dihydrorhodamine (DOR) which reflects the oxidative (functional) properties of HDL (J Lipid Res 2011;52:2341Á51).
Results: Baseline measurements of 91 subjects appear in Table 1.
HIV infection was associated with significantly lower baseline levels of RANKL and RANKL/OPG (Table 1). Within the HIV-infected subjects, baseline RANKL/OPG was significantly associated with baseline DOR (p 00.02, Table 2). Conclusion: RANKL/OPG axis may be regulated differently in HIVinfected compared to -uninfected adults and is independently associated with changes in functional properties of HDL in HIVinfected subjects. These data are consistent with previous in vitro results that have shown that oxidized HDL may affect the NF-kB pathway.

B51 -Immune activation and inflammatory state THLBB06
Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy (ART): AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202   Figure 1.
In every age-stratum the mean number of AANCC was higher among HIV-positives. Similar patterns of AANCC burden appeared to occur 5 years earlier among HIV-positive patients than HIV-negative subjects ( Figure 2). By ordinal logistic regression analysis, after adjustment for age, gender and packyears of smoking, longer documented duration of HIV-seropositivity was associated with a significantly higher risk of an increasing number of AANCC (OR 1.17 per 5 years, 95% CI 1.07Á1.27, p00.0003). Among HIV-positive patients, after adjustment for age, gender and packyears of smoking, duration of ART-use (OR 1.24 per 5 additional years of ART-use, 95% CI 1.06Á1.46, p00.009) and lower nadir CD4 count (OR 1.12 per 100 less cells, 95% CI 0.99Á1.28, p 00.074) were each associated with an increased risk of a higher number of AANCC, whereas documented duration of infection was no longer significant.
Conclusion: In HIV-positive persons]45 years of age non-communicable comorbidity was more prevalent compared to controls, and the risk of having an increased number of comorbidities was independently associated not only with age and smoking history, but also with duration of ART-use and severity of documented prior immunodeficiency.
B57 -Eradication / reservoir depletion TUAE0104 HIV cure strategies: how good must they be to improve on current antiretroviral therapy?
Background: The report of a successful HIV cure after allogeneic bone marrow transplant for acute leukemia has generated major interest in HIV eradication. We examined the efficacy, cost, and relapse rate combinations that would make 'cure' cost-effective compared with antiretroviral therapy (ART).
Prevalence of different AANCC.