Wendy Bannister

The Coding Causes of Death in HIV (CoDe) project: initial results and evaluation of methodology

Background: The Coding Causes of Death in HIV (CoDe) Project aims to deliver a standardized method for coding the underlying cause of death in HIV-positive persons, suitable for clinical trials and epidemiologic studies. Methods: The project incorporates detailed data collection, a classification system, and a centralized adjudication process performed by 2 independent reviewers. The methodology was tested in the Data Collection on Adverse events of Anti-HIV Drugs Study, and independent reviews of causes of death were compared. Logistic regression models identified factors associated with initial agreement by reviewers on underlying cause of death. Results: A total of 491 reported fatal cases were adjudicated; in only 5% of cases the cause of death remained undetermined after adjudication. Reviewers initially agreed on the underlying cause for 339 (69%) deaths. As compared with deaths due to AIDS-related causes, the odds of agreement were more than 80% lower when deaths were ultimately deemed to be due to non-AIDS-related causes (odds ratio = 0.17 [95% confidence interval = 0.08–0.37]) or undetermined causes (0.11 [0.04–0.36]). The odds of initial agreement were also lower for deaths occurring in subjects with hypertension (0.43 [0.22–0.85]) and depression (0.43 [0.23–0.80]). Conclusions: The extent and format of data collected in the CoDe Project appear to be sufficient for an informed review, and the proposed coding scheme is adequate for obtaining an underlying cause of death.

Transmitted drug resistant HIV-1 and association with virologic and CD4 cell count response to combination antiretroviral therapy in the EuroSIDA Study.

Objectives:To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy. Methods:In this study, 525 mostly chronically infected EuroSIDA patients were included who had genotypic resistance tests performed on plasma samples collected while antiretroviral therapy naive. TDR was defined as at least one resistance mutation from a list proposed for genotypic TDR surveillance. Multivariable logistic regression was used to analyze factors associated with detection of TDR, with virological (viral load <500 copies/mL) and CD4 count response (≥50% increase) to combination antiretroviral therapy at months 6 -12. Results:The overall prevalence of TDR was 11.4%, which was stable over 1996-2004. There were no significant differences in virological suppression (those resistant to at least one drug prescribed versus susceptible), adjusted odds ratio: 0.68 (95% confidence interval: 0.27 to 1.71; P = 0.408) or CD4 count response, adjusted odds ratio: 1.65 (95% confidence interval: 0.73 to 3.73; P = 0.231). Conclusions:Prevalence of TDR in antiretroviral-naive patients was found to be in line with other European studies. No significant differences were found in virological and CD4 count response after initiation of first-line combination antiretroviral therapy between resistant and susceptible patients, possibly due to the small number of patients with resistance and consequently low power.

Regional changes over time in initial virologic response rates to combination antiretroviral therapy across Europe.

Background: Changes in virologic response to initial combination antiretroviral therapy (cART) over calendar time may indicate improvements in cART or emergence of primary resistance. Regional variations may identify differences in available antiretroviral drugs or patient management. Methods: Virologic response (viral load < 500 copies/mL) 6 to 12 months after starting cART was analyzed in antiretroviral-naive EuroSIDA patients. Analyses were stratified by region (south, central west, north, east) or time started cART (early, 1996-1997; mid, 1998-1999; late, 2000-1904). Results: Virologic suppression was achieved by 60% of 2102 patients: 57% south (n = 560), 61% central west (n = 466), 63% north (n = 606), 58% east (n = 470) (P = 0.091). An increase was observed over time: 52% early cART, 56% mid cART, 69% late cART (P < 0.001). Overall, there were significant effects of region (P = 0.026) and time (P < 0.001) on virologic response after adjustment for confounders. Stratified by period, regional differences were less evident (early cART, P = 0.967; mid cART, P = 0.291; late cART, P = 0.163). Stratified by region, temporal changes were observed (south, P = 0.061; central west, P < 0.001; north: P = 0.070; east, P = 0.001). Conclusions: There was some evidence of regional differences in initial virologic response to cART. Improvements over time were observed, suggesting that so far, the effect of primary resistance has not been of sufficient magnitude to prevent increasing suppression rates.

A376S in the Connection Subdomain of HIV-1 Reverse Transcriptase Confers Increased Risk of Virological Failure to Nevirapine Therapy

BACKGROUND The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. METHODS The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. RESULTS Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. CONCLUSIONS The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

Tuberculosis among HIV-positive patients across Europe: changes over time and risk factors

Objective:To describe temporal changes in the incidence rate of tuberculosis (TB) (pulmonary or extrapulmonary) among HIV-positive patients in western Europe and risk factors of TB across Europe. Methods:Poisson regression models were used to determine temporal changes in incidence rate of TB among 11 952 patients from western Europe (1994–2010), and to assess risk factors for TB among 12 673 patients from across Europe with follow-up after 2001. Results:Two hundred and seventy-seven TB events occurred during 84 221 person-years of follow-up (PYFU) in western Europe. The incidence rate declined from 1.91 [95% confidence interval (CI) 1.51–2.37)] in 1994–1995 to 0.12 (0.07–0.21)/100 PYFU in 2002–2003, and remained stable thereafter. After January 2001, 159 TB events were diagnosed; 65 cases in western Europe and 94 cases in eastern Europe; resulting in incidence rates of 0.12 (0.09–0.14) and 0.65 (0.52–0.79)/100 PYFU, respectively. In multivariable analysis, incidence rate of TB was approximately four-fold higher in eastern Europe compared with western Europe [incidence rate ratio (IRR) 4.25 (2.78–6.49), P < 0.001]. There were no significant temporal changes after 2001 and risk factors did not differ significantly between eastern Europe and western Europe. Lower CD4 cell counts, higher HIV-RNA levels, male sex, intravenous drug usage and African origin were all associated with higher risk of TB. Conclusion:Incidence rates of TB in western Europe remained at a very low and stable level since 2001. After 2001, patients in eastern Europe were at substantially higher risk of TB than in western Europe. TB is of great concern in HIV-positive patients, especially in areas with high TB prevalence, high levels of immigration from TB-endemic regions, and with suboptimal access to combination antiretroviral therapy.

The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression.

BACKGROUND The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression. METHODS A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4(+) T-cell count ≤200 cells/mm(3) were stratified into five groups: group 1, viral load (VL)<50 copies/ml on cART; group 2, VL 50-99,999 copies/ml on cART; group 3, VL 50-99,999 copies/ml off cART; group 4, VL≥100,000 copies/ml on cART; and group 5, VL≥100,000 copies/ml off cART. Poisson regression was used to identify the risk of (non-fatal or fatal) AIDS- and non-AIDS-related events considered together (AIDS/non-AIDS) or separately as AIDS or non-AIDS events within each group. RESULTS There were 428 AIDS/non-AIDS events during 3,780 person-years of follow-up. Compared with group 1, those in group 2 had a similar incidence of AIDS/non-AIDS events (incidence rate ratio [IRR] 1.04; 95% CI 0.79-1.36). Groups 3, 4 and 5 had significantly higher incidence rates of AIDS/non-AIDS events compared with group 1; incidence rates increased from group 3 (IRR 1.78; 95% CI 1.25-2.55) to group 5 (IRR 2.36; 95% CI 1.66-3.40), demonstrating the increased incidence of AIDS/non-AIDS events associated with increasing viraemia. After adjustment, the use of cART was associated with a 40% reduction in the incidence of AIDS/non-AIDS events in patients with VL 50-99,999 copies/ml (IRR 0.59; 95% CI 0.41-0.85) and in those with a VL>100,000 copies/ml (IRR 0.66; 95% CI 0.44-1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately. CONCLUSIONS In patients with ongoing severe immunosuppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure.

O332 Opportunistic infections in immunocompromised but virologically suppressed HIV-1 infected patients

Address: 1Royal Free and University College Medical School, London, UK, 2Copenhagen HIV Programme, Panum Institute, Copenhagen, Denmark, 3Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, Netherlands, 4Istituto Di Clinica Malattie Infettive e Tropicale, Milan, Italy, 5Hospital Clinic i Provincial, Barcelona, Spain, 6Royal Sussex County Hospital, Brighton, UK, 7Medical University, Gdansk, Poland and 8Medical Academy Botkin Hospital, St Petersburg, Russian Federation * Corresponding author

Relating protease inhibitor resistance at time of virological failure with drug exposure

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