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OBJECTIVES: The long-term side effects of stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. METHODS: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. RESULTS: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA > 400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA < 400 copies/mL. CONCLUSIONS: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.

Objective To estimate annual employment rates and disability retirement rates (DRRs) among HIV-infected individuals and population controls during the period 1996-2011. Design A population-based cohort study including all HIV-infected individuals born in Denmark and not reporting intravenous (i.v.) drug abuse as a route of HIV infection or diagnosed with hepatitis C infection (n = 2799) and 22,369 individually matched persons from the background population. Study inclusion was 1 January 1996 or HIV diagnosis, which ever came last. Methods Data on employment status and disability pension were extracted from Danish national registries. Employment rate and DRR were estimated in each calendar year after study inclusion for the cohorts included before 1996 (pre-1996), 1996-1999 and 2000-2011. Results Employment rate in the year of study inclusion increased from 54.8% [95% confidence interval (CI) 50.5-59.6] in the pre-1996 cohort to 74.6% (66.9-83.2) and 77.4% (72.8-82.2) in the 1996-1999 and 2000-2011 cohorts, respectively, compared with 85.9-87.2% in the comparison cohorts. Five years from study inclusion, employment rates were 56.1 (51.4-61.1), 66.2 (58.7-74.6) and 70.9% (65.0-77.3) in the pre-1996, 1996-1999 and 2000-2011 cohorts, respectively, compared with 82.5-85.6% in the comparison cohorts. Five years from study inclusion, DRRs were 32.3 (28.9-36.3) in the pre-1996 cohort and decreased to 17.8 (14.1-22.4) and 11.6% (9.4-14.4) in the 1996-1999 and 2000-2011 cohorts, respectively, compared with 5.1-7.2% in the comparison cohorts. Conclusion After the introduction of HAART, employment rates have increased profoundly among HIV-infected individuals, but have remained lower than in the background population. During the same period, DRRs decreased among HIV-infected individuals, but still remained higher than in the background population.

Background. Limited data exist on factors predicting the development of opportunistic infections (OIs) at higher-than-expected CD4(+) cell counts in human immunodeficiency virus (HIV) type 1-infected adults. Methods. Multivariate Poisson regression models were used to determine factors related to the development of groups of OIs above their respective traditional upper CD4(+) cell count thresholds: group 1 (>= 100 cells/mu L), OIs caused by cytomegalovirus, Mycobacterium avium complex, and Toxoplasma gondii; group 2 (>= 200 cells/mu L), Pneumocystis pneumonia and esophageal candidiasis; and group 3 (>= 300 cells/mu L), pulmonary and extrapulmonary tuberculosis. Results. In groups 1, 2, and 3, 71 of 9219, 125 of 7934, and 36 of 7838 patients, respectively, developed >= 1 intragroup OI. The strongest predictor of an OI in groups 1 and 2 was current CD4(+) cell count (for group 1, incidence rate ratio [IRR] per 50% lower CD4(+) cell count, 5.37 [95% confidence interval {CI}, 3.71-7.77]; for group 2, 4.28 [95% CI, 2.98-6.14]). Injection drug use but not current CD4(+) cell count predicted risk in group 3. Use of antiretroviral treatment was associated with a lower incidence of OIs in all groups, likely by reducing HIV-1 RNA levels (IRR per 1-log(10) copies/mL higher HIV-1 RNA levels for group 1, 1.50 [95% CI, 1.15-1.95]; for group 2, 1.68 [95% CI, 1.40-2.02]; and for group 3, 1.89 [95% CI, 1.40-2.54]). Conclusion. Although the absolute incidence is low, the current CD4(+) cell count and HIV-1 RNA level are strong predictors of most OIs in patients with high CD4(+) cell counts.

The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials.SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression and death in HIV-infected patients receiving antiretroviral therapy. We report definitions used for HIV progression of disease endpoints, procedures for site reporting of such events, processes for independent review of reported events by an Endpoint Review Committee (ERC), and the procedure for adjudication of differences of opinion between reviewers.Of 473 events reported through May 1, 2006, 28% were judged by an ERC to meet "confirmed" criteria and 38% to meet "probable" criteria; 34% were classified "does not meet criteria." For diseases with5 case reports, the proportion accepted as either "confirmed" or "probable" events was highest for cervical cancer (100%), non-Hodgkin's lymphoma (88%), cryptococcosis (82%), and cryptosporidiosis (80%) and was lowest for HIV encephalopathy (25%), HIV wasting syndrome (33%), and multidermatomal herpes zoster (35%). 25% of cases required adjudication between reviewers before diagnostic certainty was assigned.Important requirements for HIV trials using clinical endpoints include objective definitions of "confirmed" and "probable," a formal reporting process with adequate information and supporting source documentation, evaluation by independent blinded reviewers, and procedures for adjudication.

The ability of Plasmodium vivax to relapse is a challenge to its management. Primaquine is the only drug licensed for the eradication of hypnozoites. We report the case of a non-immune traveller, who required high dosage primaquine treatment to obtain radical cure of vivax malaria, emphasizing the importance of country-specific and weight-based dosing of primaquine.

Limited information exists on the prognostic value of genotypic interpretation systems (GISs) for ritonavir-boosted protease inhibitors (PI/rs). We compared PI/r resistance levels ascribed by four GIS and examined their abilities to predict HIV-RNA reductions after starting a PI/r-based regimen (baseline).: Data on viraemic (HIV-RNA500 copies/ml) patients starting a PI/r with a baseline resistance test were combined from an observational cohort study (EuroSIDA) and three randomized trials (MaxCmin1; MaxCmin2 and COLATE). The GIS surveyed were ANRS, DMC, REGA and Stanford. Factors associated with HIV-RNA change were identified through censored regression analysis.: We included 744 patients, of whom 67% were PI experienced. At baseline 12-28% (depending on the GIS) patients had a virus with predicted resistance/intermediate resistance to the PI/r initiated. Concordance between GISs on ascribed PI/r resistance levels was moderate: kappa values ranged from 0.01 to 1.00, with the lowest kappas seen for amprenavir. The median (interquartile range) baseline HIV-RNA was 4.4 (3.5-5.1) log10 and was reduced by 2.2 (2.1-2.3) log10 12 (9-13) weeks after baseline. GIS consistently showed greater HIV-RNA reductions as the ascribed level of sensitivity to the PI/r increased. Conversely, the number of other active drugs in the rest of the regimen, according to each GIS did not predict HIV-RNA reductions consistently.: Despite large variations in how GIS classify HIV susceptibility to PI/r, all GIS predicted HIV-RNA reductions of a similar magnitude. The ascribed level of susceptibility to other drugs in the regimen did not predict HIV-RNA decline.

BACKGROUND Factors that determine the immunological response to highly active antiretroviral therapy (HAART) are poorly defined. OBJECTIVE Our aim was to investigate predictors of immunological failure after initial CD4(+) response. METHODS Data were from EuroSIDA, a prospective, international, observational human immunodeficiency virus (HIV) type 1 cohort. RESULTS Of 2347 patients with an increase in CD4(+) cell count >or=100 cells/microL within 6-12 months of the initiation of HAART, 550 (23%) subsequently experienced immunological failure (CD4(+) count less than or equal to the pre-HAART value). The incidence of failure was 11.6 incidences/100 person-years of follow-up (95% confidence interval [CI], 10.2-13.4) during the first 12 months and decreased significantly over time (P

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/ Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/ Rtv arms, respectively. The time to virological failure did not differ between study arms (P = .76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/ Rtv arm (P = .009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P = .013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/ Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

Denmark is an area of low incidence of HIV and tuberculosis (TB). The number of newly reported cases of HIV has been stable during the 1990s, whereas the number of TB cases has doubled in Denmark in the past decade, mainly due to immigration. However, among native Danes the incidence of TB has increased in the younger age groups, indicating more newly infected persons. This study was performed in order to assess the impact of the HIV epidemic and immigration on TB incidence among native Danes. The study was also designed to reveal transmission patterns of TB among HIV-positive patients. Data from HIV-TB co-infected patients identified in the national registers of TB and AIDS from 1992-95 were collected retrospectively from medical records. Restriction fragment length polymorphism (RFLP) analyses of TB isolates from co-infected patients were compared with all patterns registered in the nationwide Danish RFLP database (approximately 1,700 patients). Sixty-seven co-infected patients were identified, 26 Danes and 41 immigrants, representing only 4% of all TB cases during the study period. Danish co-infected patients were part of a cluster, i.e. they had a RFLP-pattern identical to a pattern in the national RFLP database, more often than immigrants (83% vs. 45%, p < 0.005). In only 2 cases were co-infected Danes and immigrants part of the same cluster. Danish HIV-TB co-infected patients were more often intravenous drug users than were co-infected immigrants (p < 0.0005). In conclusion, we found no evidence to suggest that the increase in TB incidence among young Danes was caused by the HIV-epidemic or transmission from immigrants. TB among HIV-positive Danes is most often due to recent infection. The patients often belong to a subpopulation living in Copenhagen characterized by intravenous drug use.

ObjectiveTo assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r).DesignOpen-label, prospective, randomized (1:1), international multi-centre trial.MethodsAdult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks.ResultsOf 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P=0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation=failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment ( P=0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (30%) in the SAQ/r-treated group (ITT/e; P=0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients’ choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms ( P=0.27, log rank test).ConclusionLPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients’ preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.