C A Sabin

UK Department of Health, Londinium, England, United Kingdom

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Publications (468)3236.87 Total impact

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    ABSTRACT: End-stage kidney disease (ESKD) is a major complication of HIV infection. We observed a 3.8 fold increase in ESKD prevalence among black patients in the UK CHIC cohort during the 12 year study period. As of 2005, 107 patients had an ESKD diagnosis, 69 (64%) of whom were considered suitable for kidney transplantation (KT) and 34 (32%) had received a KT. Survival was similar for KT recipients and those awaiting KT (85% and 89% at five years respectively, p=0.53). Our results endorse the use of KT to manage ESKD in HIV positive patients.
    Journal of acquired immune deficiency syndromes (1999). 07/2014;
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    ABSTRACT: Background With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Methods Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. Findings 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Interpretation Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Funding Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.
    07/2014; 384(9939):241–248.
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    ABSTRACT: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown.METHODS: HIV-infected, antiretroviral therapy-naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8-9), or high (>9) CPE score. We estimated "intention-to-treat" hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up.RESULTS: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58).CONCLUSIONS: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.
    Neurology 06/2014; · 8.25 Impact Factor
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    ABSTRACT: Objectives The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations.Methods We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores.ResultsA total of 24 323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40–45 years to 6.53, 11.91 and 15.89 in those aged 60–65 years, respectively. The best-fitting models included inverse age for MI and age + age2 for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population.Conclusions We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.
    HIV Medicine 06/2014; · 3.16 Impact Factor
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    ABSTRACT: No consensus exists on how to define abnormally rapid deterioration in renal function (Rapid Progression, RP). We developed an operational definition of RP in HIV-positive persons with baseline estimated glomerular filtration rate (eGFR) >90ml/min/1.73m2 (using Cockcroft Gault) in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study from 2004 to 2011. Two definitions were evaluated; RP definition A: An average eGFR decline (slope) >=5ml/min/1.73m2/year over four years of follow-up with >=3 eGFR measurements/year, last eGFR <90 ml/min/1.73m2 and an absolute decline >=5ml/min/1.73m2/year in two consecutive years. RP definition B: An absolute annual decline >=5ml/min/1.73m2/year in each year and last eGFR <90ml/min/1.73m2. Sensitivity analyses were performed considering two and three years' follow-up. The percentage with and without RP who went on to subsequently develop incident chronic kidney disease (CKD; 2 consecutive eGFRs <60ml/min/1.73m2 and 3 months apart) was calculated. 22,603 individuals had baseline eGFR >=90ml/min/1.73m2. 108/3655 (3.0%) individuals with >=4 years' follow-up and >=3 measurements/year experienced RP under definition A; similar proportions were observed when considering follow-up periods of three (n=195/6375; 3.1%) and two years (n=355/10756; 3.3%). In contrast under RP definition B, greater proportions experienced RP when considering two years (n=476/10756; 4.4%) instead of three (n=48/6375; 0.8%) or four (n=15/3655; 0.4%) years' follow-up. For RP definition A, 13 (12%) individuals who experienced RP progressed to CKD, and only (21) 0.6% of those without RP progressed to CKD (sensitivity 38.2% and specificity 97.4%); whereas for RP definition B, fewer RP individuals progressed to CKD. Our results suggest using three years' follow-up and at least two eGFR measurements per year is most appropriate for a RP definition, as it allows inclusion of a reasonable number of individuals and is associated with the known risk factors. The definition does not necessarily identify all those that progress to incident CKD, however, it can be used alongside other renal measurements to early identify and assess those at risk of developing CKD. Future analyses will use this definition to identify other risk factors for RP, including the role of antiretrovirals.
    BMC Nephrology 03/2014; 15(1):51. · 1.64 Impact Factor
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    ABSTRACT: Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started. Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression. In adjusted analyses, ART-naive (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS. In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman's health.
    BMC Infectious Diseases 03/2014; 14(1):127. · 3.03 Impact Factor
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    ABSTRACT: Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline on TDF.Methods. Cox Proportional Hazards models assessed factors associated with discontinuing TDF in those with >6 months exposure. In those who discontinued TDF, linear piecewise regression models estimated eGFR slopes (mL/min/1.73 m(2)/yr) before, during and after TDF exposure. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression.Results. We observed eGFR declines during TDF exposure (mean (95% CI) slopes -15.7 (-20.5, -10.9) during the first 3 months; -3.1(-4.6, -1.7) thereafter), and evidence of eGFR increases following discontinuation (12.5 (8.9, 16.1) during the first 3 months; 0.8 (0.1, 1.5) thereafter). Following TDF discontinuation, 38.6% of patients with eGFR decline did not experience recovery. A higher baseline eGFR, lower discontinuation eGFR and more prolonged TDF exposure were associated with increased risk of incomplete recovery at 6 months post-TDF discontinuation.Conclusions. This study shows that eGFR decline on TDF was not fully reversible in one third of patients, and suggests that prolonged TDF exposure at low eGFR should be avoided.
    The Journal of Infectious Diseases 02/2014; · 5.85 Impact Factor
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    ABSTRACT: Few data describe antiretroviral treatment (ART)-related adverse events when treatment is initiated at CD4 cell counts more than 350 cells/μl. We compared rates of laboratory-defined adverse events (LDAEs) according to CD4 cell count at initiation. A cohort study. ART-naive persons initiating ART from 2000 to 2010 were included. Chi-square, analysis of variance (ANOVA) and Kruskal-Wallis tests compared characteristics among those starting ART with a CD4 cell count of 350 or less, 351-499 and at least 500 cells/μl. Time-updated Poisson regression compared rates of LDAE in the three CD4 cell strata. Cox proportional hazard models compared risk of ART discontinuation. Nine thousand four hundred and six individuals were included: median age 37 years, 61% white, 80% men, median viral load 4.8 log copies/ml. Four hundred and forty-seven (4.9%) and 1099 (11.7%) started ART with a CD4 cell count at least 500 and 351-499 cells/μl, respectively. One thousand two hundred and eighty-three (13.6%) patients experienced at least one LDAE. The rate of LDAE did not differ between those starting ART with a CD4 cell count 351-499 and less than 350 cells/μl [relative rate 0.90, 95% confidence interval (CI) 0.74-1.09)], but an increased risk of ART discontinuation was observed (hazard ratio 1.58, 95% CI 1.10-2.27). Those starting ART at CD4 cell count at least 500 cells/μl had an increased rate of LDAE (relative rate 1.44, 95% CI 1.13-1.82) but were not more likely to discontinue ART (hazard ratio 1.15, 95% CI 0.64-2.09). This study demonstrates the need to consider ART-related toxicities when initiating therapy at CD4 cell counts at least 500 cells/μl. Although evidence from randomized controlled trials is awaited, the timing of ART initiation in terms of benefits and risks of ART remains an important question.
    AIDS (London, England) 02/2014; · 4.91 Impact Factor
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    ABSTRACT: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). Patients aged more than 20 years who started ART during 2000-2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4 cell count and viral load before ART and in each of years 1-5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4 cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20-85 years. Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years.At start of ART, expected age at death [95% confidence interval (95% CI)] of 35-year-old men with CD4 cell count less than 200, 200-349, at least 350 cells/μl was 71 (68-73), 78 (74-82) and 77 (72-81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five year old men who increased their CD4 cell count in the first year of ART from less than 200 to 200-349 or at least 350 cells/μl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48-61) (CD4 cell count <200 cells/μl and no viral suppression) to 80 (76-83) years (CD4 cell count ≥350 cells/μl and viral suppression). Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4 cell count significantly improve their life expectancy if they have a good CD4 cell count response and undetectable viral load.
    AIDS (London, England) 02/2014; · 4.91 Impact Factor
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    ABSTRACT: Association of hepatitis B virus (HBV) genotype C with hepatocellular carcinoma (HCC) development remains controversial. HBV basal core promoter (BCP) double mutations (T(1762)A(1764)) are very strong confounding factors of genotypes B and C in HCC development. To investigate the association of HBV genotype C with HCC development after controlling for BCP double mutations. Four hundred and two serum samples from patients with HCC, liver cirrhosis (LC) and chronic hepatitis (CH) and also from asymptomatic HBsAg carriers were analyzed. Genotypes B (31.1%), C (62.8%), and I (6.1%) were detected. With the severity of liver disease the prevalence of genotype B decreased, but genotype C increased. No trend was found for genotype I. The prevalence of BCP double mutations in genotypes C and I viruses was significantly higher than genotype B. BCP double mutations are risk factors for CH, LC and HCC. Genotype C was not identified as a particular risk factor for HCC prior to the stratification analysis but after that genotype C viruses with BCP double mutations were found to be a particular risk factor for HCC (P = 0.008, OR = 17.19 [95% CI: 2.10 - 140.41]), but those with the wild-type BCP were not. In the interaction analysis, genotype C and BCP double mutations were found to have a synergistic effect on HCC development (P < 0.0001, OR = 52.56 [95% CI: 11.49-240.52]). The effect of HBV genotype C on the development of HCC differs between wild-type viruses and those with BCP double mutations, suggesting that not all individuals infected with genotype C HBV are at increased risk of HCC.
    Hepatitis Monthly 02/2014; 14(2):e16214. · 1.25 Impact Factor
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    ABSTRACT: Background. Some HIV infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after three years of sustained viral suppression and (2) the association of achieved CD4 count with subsequent mortality. Methods. We included treated HIV infected adults from two large international HIV cohorts, who were virally suppressed (≤500 HIV-1 RNA copies/ml) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. Results. Of 5550 eligible individuals, 835 (15%) did not reach CD4 count >200 cells/µL after three years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998 and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after three years of viral suppression had substantially increased mortality (adjusted hazard ratio 2.60; 95% confidence interval 1.86-3.61) compared to those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death. Conclusions. Virally suppressed HIV positive individuals on cART who do not achieve CD4 count >200 cells/µL have substantially increased long-term mortality.
    Clinical Infectious Diseases 01/2014; · 9.37 Impact Factor
  • HIV Medicine 01/2014; 15 Suppl 1:1-85. · 3.16 Impact Factor
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    ABSTRACT: To assess CD4 cell count recovery in people severely immunosuppressed at start of antiretroviral therapy (ART) who achieve and maintain viral load suppression. Eligible participants from the UK Collaborative HIV Cohort Study started ART with at least three drugs after 1 January 2000. Participants were required to have pre-ART CD4 cell count below 100 cells/μl, at least 2 years of follow-up on ART, have achieved viral load suppression (≤50 copies/ml) by 9 months after starting ART and to have maintained this throughout follow-up. Participants were further required to be regularly engaged with care. We calculated the proportion of people who failed to achieve a CD4 cell count of more than 100, 150, 200, 350 and 500 cells/μl by the time of the last follow-up, or 5 years from start of ART, whichever occurred first (censoring date). Of the 400 participants [median interquartile range pre-ART CD4 cell count of 38 (14-65) cells/μl], 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4 cell count of more than 100, 150, 200, 350 and 500 cells/μl, by the censoring date, respectively. Kaplan-Meier estimates of the proportion of people reaching each CD4 cell count threshold after 1 year on ART were 88, 70, 50, 14 and 3%, respectively, and after 3 years on ART, 98, 95, 90, 59 and 25%, respectively. Median (interquartile range) follow-up on ART was 3.9 (2.7-4.8) years. Given a person with pre-ART CD4 cell count below 100 cells/μl survives and maintains consistent viral load suppression on ART, there is over a 90% chance of reaching a CD4 cell count above 200 cells/μl by 3 years.
    AIDS (London, England) 12/2013; · 4.91 Impact Factor
  • Jason V Baker, Caroline A Sabin
    Current opinion in HIV and AIDS 11/2013; · 4.75 Impact Factor
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    AIDS 10/2013; 27(16):2587-2592. · 6.41 Impact Factor
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    ABSTRACT: Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004--2010, and described subsequent mortality and predictors of these. Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression. Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004--2010 in this large observational cohort. The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC.
    BMC Infectious Diseases 10/2013; 13(1):471. · 3.03 Impact Factor
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    ABSTRACT: Background Lamivudine (3TC) and emtricitabine (FTC) are guideline choices for combination highly active antiretroviral therapy (HAART). 3TC has a shorter intracellular half life than FTC and may be more likely to lead to the development of drug resistant HIV variants. Methods In this study we analysed linked data from the observational UK Collaborative HIV Cohort (CHIC) Study and UK HIV Drug Resistance Database (HDRD) to investigate the rate of development of K65R or M184V resistance mutations in patients failing on combinations containing tenofovir (TDF) and efavirenz (EFV) with either 3TC or FTC. Virological failure was defined as 1 viral load > 400 copies/ml. Rates were stratified by demographic variables, baseline viral load, current CD4 count, current viral load and year of starting regimen. Significant associations were identified using Poisson regression models and multivariable analyses were performed adjusting for the variables above. Logistic regression was used to determine whether there were any significant associations between type of regimen and detection of resistance mutation. Results 5455 patients received either (or both) 3TC, TDF and EFV or FTC, TDF and EFV contributing 6465 treatment episodes over 9962 person-years follow up. 47 of these episodes were preceded by resistance tests showing development of K65R or M184V mutation and were hence excluded. The majority of treatment episodes consisted of FTC- (n=5190) rather than 3TC- (n=1228) based regimens. 21 cases of K65R were detected over the course of follow up, giving an overall event rate of 0.21 (95% CI: 0.12-0.31)/100 person years follow up (PYFU). The overall event rate for detection of M184V was 0.38 (95% CI: 0.26-0.5)/100 PYFU. 201 patients receiving either regimen for the first time experienced virological failure. Of those receiving 3TC (n=53), 7 (13.2%), 12 (22.6%) and 15 (28.3%) developed K65R, M184V and either K65R or M184V respectively. Of those receiving FTC (n=148), 13 (8.8%), 20 (13.5%) and 26 (17.6%) developed K65R, M184V and either K65R or M184V respectively. Although patients on 3TC were more likely to develop resistance, this was not statistically significant in univariable (OR 1.85 (95% CI: 0.89-3.85, p=0.09)) or multivariable analyses (OR 1.89 (95% CI: 0.89-4.01, p=0.1)). Conclusions We have not found evidence of an increased risk of development of M184V and K65R in patients exposed to 3TC.
    Journal of Infection 09/2013; 68(77):e84. · 4.07 Impact Factor
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    ABSTRACT: HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART. Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks. Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure. The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.
    AIDS (London, England) 09/2013; 27(14):2245-53. · 4.91 Impact Factor
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    ABSTRACT: HIV-controllers spontaneously maintain HIV viraemia at an undetectable level. We aimed to describe the delay to control from seroconversion, the duration of control, and risk factors for losing control. HIV-controllers were identified from a pooled dataset of 24 seroconverter cohorts from Europe, Australia and Canada (CASCADE). HIV-controllers had ≥5 consecutive viral loads (VL) <400/500 copies/mL, while ART-naïve, for ≥5 years after seroconversion. End of control was defined as two consecutive VL >2000 copies/mL.Duration of control was described using Kaplan-Meier estimates; factors associated with duration of control identified using a Cox model. CD4 count evolution during control was described using a mixed model. Of 9,896 eligible seroconverters, we identified 140 (1.4%) HIV-controllers, the largest database of HIV-controllers followed from seroconversion. For 64 with VL measured within 24 months from seroconversion, median delay to control was 16.7 (IQR: 7.8-37.9) months. Probability of maintaining control 20 years after seroconversion was 0.74 (95% confidence interval (CI): 0.64-0.85). Occurrence of blips followed by return to undetectability did not increase the risk of loss of control (hazard ratio: 0.81 (95% CI: 0.10-6.70). However, CD4 cell loss during control was significantly accelerated in individuals with blips. In most individuals, control occurred rapidly after seroconversion; however, >3 years were required to achieve control in 25% of HIV-controllers. Control may be sustained even while CD4 levels are below 500 cells/mm, opening important new perspectives to understand the physiopathology underlying control.
    AIDS (London, England) 08/2013; · 4.91 Impact Factor
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    ABSTRACT: To consider associations between the latest/nadir CD4 count, and time spent with CD4 count < 200 cells/mm (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke or CVD (CHD or stroke) in 33,301 HIV-positive individuals. Longitudinal cohort study METHODS:: Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included stroke-like events and rejected strokes into the stroke endpoint. Participants experienced 716 MI, 1056 CHD, 303 stroke and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4 counts after adjustment (current CD4 < 100 cells/mm: relative rate [95% confidence interval] 0.96 [0.62-1.50] for MI, 0.89 [0.30-2.36] for CHD; nadir CD4 < 100 cells/mm: 1.36 [0.57-3.23] for MI, 0.98 [0.45-2.16] for CHD), stroke and CVD rates were higher in those with a latest CD4 count < 100 cells/mm (2.26 [1.29-3.94] and 1.14 [0.84-1.56], respectively). All events occurred less frequently in those who had not experienced immune depression, although evidence for a linear association with duration of immune depression was weak. The association between stroke risk and the latest CD4 count strengthened as stroke-like and rejected strokes were included; conversely, associations with established stroke risk factors weakened. We do not find strong evidence that HIV-positive individuals with a low CD4 count are more likely to experience MI/CHD. Although strokes appear to occur more commonly at low CD4 counts, this may be partly explained by misclassification or other biases.
    AIDS (London, England) 07/2013; · 4.91 Impact Factor

Publication Stats

14k Citations
3,236.87 Total Impact Points

Institutions

  • 2014
    • UK Department of Health
      Londinium, England, United Kingdom
  • 1998–2014
    • University College London
      • • Department of Infection and Population Health
      • • Department of Primary Care and Population Health (PCPH)
      Londinium, England, United Kingdom
  • 2011–2013
    • Imperial College London
      • Section of Infectious Diseases
      London, ENG, United Kingdom
    • University of Barcelona
      Barcino, Catalonia, Spain
    • University of Minnesota Twin Cities
      Minneapolis, Minnesota, United States
  • 2007–2013
    • University of Copenhagen
      • Copenhagen HIV Programme (CHIP)
      Copenhagen, Capital Region, Denmark
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
  • 2012
    • North Bristol NHS Trust
      Bristol, England, United Kingdom
    • Royal College of Obstetricians and Gynaecologists
      Londinium, England, United Kingdom
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2010–2012
    • British HIV Association
      Londinium, England, United Kingdom
  • 2008–2012
    • King's College London
      Londinium, England, United Kingdom
    • St George's, University of London
      Londinium, England, United Kingdom
    • Centre Hospitalier Universitaire Saint-Pierre
      Bruxelles, Brussels Capital Region, Belgium
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 2006–2012
    • University of Bristol
      • School of Social and Community Medicine
      Bristol, England, United Kingdom
    • Public Health England
      Londinium, England, United Kingdom
    • The University of Calgary
      • Department of Microbiology, Immunology and Infectious Diseases
      Calgary, Alberta, Canada
    • University of New South Wales
      Kensington, New South Wales, Australia
  • 2005–2011
    • Chelsea and Westminster Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
    • Brighton and Sussex University Hospitals NHS Trust
      Brighton, England, United Kingdom
    • Federal University of Minas Gerais
      Cidade de Minas, Minas Gerais, Brazil
    • Queen Mary, University of London
      • The Blizard Institute of Cell and Molecular Science
      London, ENG, United Kingdom
    • International Society for Disease Surveillance
      Brighton, England, United Kingdom
  • 2002–2011
    • Royal Free London NHS Foundation Trust
      • Department of Virology
      Londinium, England, United Kingdom
  • 2008–2009
    • Medical Research Council (UK)
      • MRC Clinical Trials Unit
      London, ENG, United Kingdom
  • 2005–2009
    • Université Victor Segalen Bordeaux 2
      Burdeos, Aquitaine, France
  • 2005–2008
    • University of Milan
      • Department of Health Science - DISS
      Milano, Lombardy, Italy
  • 2000–2008
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 2004
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2003
    • Copenhagen University Hospital Hvidovre
      Hvidovre, Capital Region, Denmark
  • 1999–2003
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 2001–2002
    • Brunel University
      • Health Economics Research Group
      London, ENG, United Kingdom
  • 1997
    • Johns Hopkins Medicine
      • Department of Epidemiology
      Baltimore, MD, United States
  • 1993–1997
    • The Haemophilia Society
      Londinium, England, United Kingdom
  • 1994
    • University of London
      Londinium, England, United Kingdom