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7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

IntroductionThe health condition of HIV‐1 infected patients has improved during the last years, but lifelong antiretroviral treatment is still needed. However resistance, multiple side effects and drug to drug interactions of antiretrovirals challenge the establishment of a long lasting regimen. The average running time of each antiretroviral drug composing the therapy episodes combination antiretroviral therapy (cART) may be seen as an indicator of effectiveness and tolerability.Materials and MethodsTo evaluate the running time of each drug used in HIV‐1 treatment, we extracted therapy episodes from the latest release of the EuResist database (www.euresist.org). The evaluation period was from Oct 2006 to Oct 2012. Inclusion criteria for this analysis were continuous patient monitoring for at least two years (i.e. latest therapy start in Oct 2010), and the extraction of at least 100 cases per drug analyzed. Drug intake interruptions of less than a month were ignored.ResultsAt the time of data extraction (Feb 2013), the EuResist database contained data from 61,953 patients of which 11,499 fulfilled the inclusion criteria. We obtained 37,035 drug treatment lines from 38,153 cARTs and the overall average length of drug intake was 18.7 months. For each single drug these average durations measured in months were: 18.3 (3TC); 20.8 (ABC); 12.3 (d4T); 14.3 (ddI); 23.2 (FTC); 23.0 (TDF); 13.4 (ZDV); 19.8 (EFV); 21.9 (ETR); 17.7 (NVP); 19.2 (ATV); 22.7 (DRV); 18.7 (FPV); 17.9 (LPV); 15.2 (SQV); 14.6 (TPV); 22.6 (RAL); 21.9 (MVC) and 8.9 (T20). Overall drug discontinuation rates at one, two and three years were 35.0, 48.8 and 95.8%, respectively. Average discontinuation rates for the different drug classes at two years these were: 46.2% for NRTIs; 49.7% for NNRTIs; 55.4% for PIs and 37.6% for Raltegravir/Maraviroc.ConclusionsIn this cohort the overall frequency of therapy changes is high. After two years of treatment, on average 49% of the patients change at least one drug in their cART. Thus, we have to expect numerous changes in the long term perspective of treatments. The observed differences in durations suggest that newer drugs might have advantages over older ones. However possible reasons and confounding factors (such as number of past treatment lines, co‐medication, risk group, etc.) were not addressed at this time of the analysis.

Intestinal fatty acid binding protein (I‐FABP) was proposed as a plasma marker of enterocyte turnover that could be applied to estimate the level of gut damage in HIV‐1 infected patients. We investigated the kinetics of I‐FABP in patients starting antiretroviral therapy (ART) in a clinical cohort (CC) (n=32), and in a clinical trial (RCT), where patients were randomized to lopinavir/r (LPV/r) or efavirenz (EFV)‐based therapy (n=71). I‐FABP was analyzed at baseline (BL) and after 48 and 72 weeks of ART, respectively. Additionally we estimated levels of LPS and sCD14 in both cohorts. At baseline, we found elevated plasma levels of I‐FABP, LPS, and sCD14 in patients with HIV‐1 infection as compared to controls. During ART I‐FABP levels increased from BL to week 48 (1.66 ng/ml [IQR 1.29–2.88] vs. 2.56 ng/ml [IQR 1.29–5.26]; p=0.02) in CC group. Similar pattern was seen in the RCT group at week 72 as compared to BL (2.26 ng/ml [IQR 1.4–3.6] vs 3.13 ng/ml [IQR 1.8–4.9]; p<0.0001). Levels of sCD14 decreased at the end of study period in both groups. The levels of LPS decreased in RCT cohort but not in CC cohort. Interestingly, we found that the I‐FABP levels increased in both cohorts despite 48–72 weeks of efficient ART. A subgroup analysis of the RCT cohort revealed that the I‐FABP increase occurred in the patients treated with EFV (2.32 ng/ml [IQR 1.5–3.8] vs. 4.29 ng/ml [IQR 2.4–5.9]; p<0.0001), but not in those with LPV/r. This finding was not confirmed in the CC group. The possibility of immune reconstitution in the gut as a cause of the increasing I‐FABP levels seems to be less likely, as CD4 T‐cell recovery tended to be lower in efavirenz‐treated patients. In RCT cohort, the established MT markers lipopolysaccharide (LPS) and sCD14 were both reduced after 72 weeks (data not shown), supporting a reduced MT. Most likely the systemic I‐FABP levels in patients on ART do not reflect only MT itself. Further studies should address this issue.

IntroductionThe role of microbial translocation (MT) in HIV patients living with HIV from low‐ and middle‐income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.MethodsCross‐sectional samples were obtained from treatment‐naïve patients living with HIV‐1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti‐flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme‐linked immunosorbent assay.ResultsAll three biomarkers were significantly increased in patients living with HIV‐1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti‐flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti‐flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.ConclusionsHigher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high‐income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Etravirine (ETR) is a next generation non‐nucleoside reverse transcriptase inhibitor (NNRTI). The studies for ETR EMA approval were almost exclusively performed together with the protease inhibitor (PI) darunavir. However the fact that ETR can be active against NNRTI‐pretreated HIV variants and that it is well tolerated suggests its application in PI‐free antiretroviral combination therapies. Although approved only for PI‐containing therapies, a number of ETR treatments without PIs are performed currently. To evaluate the performance of ETR in PI‐free regimens, we analyzed the EURESIST database. We observed a total of 70 therapy switches to a PI‐free, ETR containing antiretroviral combination with detectable baseline viral load. 50/70 switches were in male patients and 20/70 in females. The median of previous treatments was 10. The following combinations were detected in the EURESIST database: ETR+MVC+RAL (20.0%); ETR+FTC+TDF (18.6%); 3TC+ETR+RAL (7.1%); 3TC+ABC+ETR (5.7%); other combinations (31.4%). A switch was defined as successful when either ≤50 copies/mL or a decline of the viral load of 2 log10, both at week 24 (range 18–30) were achieved. The overall success rate (SR) was 77% (54/70), and for the different combinations: ETR+MVC+RAL=78.6% (11/14); ETR+FTC+TDF=92.3% (12/13); 3TC+ETR+RAL =80.0% (4/5), 3TC+ABC+ETR=100% (SR 4/4); and for other combinations=67.6% (23/34). These SR values are comparable to those for other therapy combinations in such pretreated patients.

Current therapeutic options for the treatment of HIV provide high rates of virological suppression and good tolerability. However, as long‐term treatment success has become a realistic goal, data evaluating the long‐term efficacy and safety of switching strategies become more needed. The purpose of this sub‐analysis is to describe the long‐term outcomes of ATV/r regimens after switching from combinations containing non‐nucleoside reverse transcriptase inhibitor (NNRTI) in a clinical setting. Non‐comparative, retrospective study including data from 3 European databases (France – DatAids, Germany‐KompNet, Sweden‐InfCare). Data from antiretroviral (ARV)‐experienced adults starting an ATV/r‐regimen between October 2004‐March 2007 were extracted every 6‐months (maximum follow‐up 5 years). Time to virological failure (VF) was analysed by the Kaplan‐Meier method. Reasons for discontinuation and safety data were also collected. Of 1294 patients analysed, 250 switched from a NNRTI‐based regimen. Patients were predominantly male (74%); median age 42 years (min, max: 23, 85); prior ARV exposure: median 5.0 years. At baseline (BL), 56% of patients had HIV‐1 RNA<500 c/mL and 31% had<50 c/mL; median (min, max) CD4 cell count: 388 (6, 1299) cells/mm3. After 3‐year follow‐up, the probability of not having VF was 79% (95% CI 65–88%) and 62% (95% CI 52%–70%) for patients with BL HIV‐1 RNA<or≥50 c/mL, respectively. The most frequent reasons for discontinuation were "unknown" (18%) and adverse events (8%). Hyperbilirubinemia was reported as reason for discontinuation in only 2 patients. In a clinical setting, switching from NNRTI to ATV/r‐based regimen is associated with sustained virological suppression and good tolerability.Time to virological failure (2 consecutive HIV‐1 RNA≥50 c/mL or 1 HIIV‐1 RNA≥50 c/mL followed by discontinuation).image

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Background. Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods. We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results. Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions. These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection. ; This study has been financed in part within the framework of the Swiss HIV Cohort Study (www.shcs.ch) project #651 and supported by the Swiss National Science Foundation (www.snf.ch) grant #148522 (J.F.). The International HIV Controllers Study was made possible through a generous donation from the Mark and Lisa Schwartz Foundation and a subsequent award from the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation (www.cavd.org). This work was also supported in part by the Harvard University Center for AIDS Research (cfar.globalhealth.harvard.edu) grant P-30-AI060354; University of California San Francisco (UCSF) Center for AIDS Research (cfar.ucsf.edu) grant P-30 AI27763; UCSF Clinical and Translational Science Institute (https://ctsi.ucsf.edu) grant UL1 RR024131; Center for AIDS Research Network of Integrated Clinical Systems (http://cfar.globalhealth.harvard.edu) grant R24 AI067039; and the National Institutes for Health (www.nih.gov) grants AI28568 and AI030914 (B.D.W.). The AIDS Clinical Trials Group was supported by NIH grants AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI28568, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI68634, AI069502, AI069419, AI068636, RR024975, AI077505, AI110527, and TR000445 (D.W.H.). For the CASCADE Consortium, the research leading to these results has received funding from the European Union Seventh Programme (FP7/2007–2013) under EuroCoord (www.eurocoord.net) grant agreement no. 260694 (K.P.) and the Spanish Network of HIV/AIDS grant nos. RD06/006, RD12/0017/0018 and RD16CIII/0002/0006 (J.DA.). A portion of the data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS). MACS (Principal Investigators): Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick, Todd Brown), U01-AI35042; Northwestern University (Steven Wolinsky), U01-AI35039; University of California, Los Angeles (Roger Detels, Oto Martinez-Maza, Otto Yang), U01-AI35040; University of Pittsburgh (Charles Rinaldo, Lawrence A. Kingsley, Jeremy J. Martinson), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson, Gypsyamber D'Souza), UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at http://aidscohortstudy.org/ ; Sí

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50 years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50 years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) ; Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors. ; info:eu-repo/semantics/publishedVersion

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50 years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.