Will the European Union reach the United Nations Millennium declaration target of a 50% reduction of tuberculosis mortality between 1990 and 2015?

BACKGROUND: The Millennium Development Goals (MDG) provide targets for 2015. MDG 6 includes a target to reduce the tuberculosis (TB) death rate by 50% compared with 1990. We aimed to assess whether this target was reached by the European Union (EU) and European Economic Area countries. METHODS: We used Eurostat causes of death data to assess whether the target was reached in the EU. We calculated the reduction in reported and adjusted death rates and the annual average percentage decline based on the available data. RESULTS: Between 1999 and 2014, the TB death rate decreased by 50%, the adjusted death rate by 56% and the annual average percentage decline was 5.43% (95% confidence interval 4.94-6.74) for the EU. Twenty of 26 countries reporting >5 TB deaths in the first reporting year reached the target of 50% reduction in adjusted death rate. CONCLUSIONS: The EU reached the MDG target of a 50% reduction of the TB death rate and also the annual average percentage decline was larger than the 2.73% needed to reach the target. The World Health Organization 'End TB Strategy' requires a further reduction of the number of TB deaths of 35% by 2020 compared to 2015, which will challenge TB prevention and care services in the EU.

Seroprevalence and susceptibility to hepatitis A in the European Union and European Economic Area: a systematic review.

Most of the European Union (EU) and European Economic Area (EEA) is considered a region of very low hepatitis A virus (HAV) endemicity; however, geographical differences exist. We did a systematic review with the aim of describing seroprevalence and susceptibility in the general population or special groups in the EU and EEA. We searched databases and public health national institutes websites for HAV seroprevalence records published between Jan 1, 1975, and June 30, 2014, with no language restrictions. An updated search was done on Aug 10, 2016. We defined seroprevalence profiles (very low, low, and intermediate) as the proportion of the population with age-specific anti-HAV antibodies at age 15 and 30 years, and susceptibility profiles (low, moderate, high, and very high) as the proportion of susceptible individuals at age 30 and 50 years. We included 228 studies from 28 of 31 EU and EEA countries. For the period 2000-14, 24 countries had a very low seroprevalence profile, compared with five in 1975-89. The susceptibility among adults ranged between low and very high and had a geographical gradient, with three countries in the low susceptibility category. Since 1975, EU and EEA countries have shown decreasing seropositivity; however, considerable regional variability exists. The main limitations of this study are that the studies retrieved for analysis might not be representative of all EU and EEA publications about HAV and might have poor national representativeness. A large proportion of EU and EEA residents are now susceptible to HAV infection. Our Review supports the need to reconsider specific prevention and control measures, to further decrease HAV circulation while providing protection against the infection in the EU and EEA, and could be used to inform susceptible travellers visiting EU and EEA countries with different HAV endemicity levels.

Drug-class-wide resistance to antiretrovirals in HIV-infected patients failing therapy: prevalence, risk factors and virological outcome.

BACKGROUND: Drug-class-wide resistance (DCWR) to antiretrovirals substantially reduces treatment options. METHODS: A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens. RESULTS: NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (< 1 year) to 35.3% (> 4 years) and from 1.2% (< 1 year) to 34.8% (> 4 years), respectively (P < 0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%-51.3%) and by 53% (20.5%-94.3%) for each year of treatment, and by 17% (95% CI: 5.6%-29.3%) and by 32% (17.7%-50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (< 1 year) to 32.6% (> 4 years; P < 0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load < 500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574-0.979), NNRTI (OR: 0.746; 95% CI: 0.572-0.975), PI (OR: 0.655; 95% CI: 0.456-0.941), three-class (OR: 0.220; 95% CI: 0.082-0.593) resistance. CONCLUSIONS: The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.

Clinical and genotypic correlates of mutation K65R in HIV-infected patients failing regimens not including tenofovir.

The mutation RT-K65R confers resistance to tenofovir (TDF). Although its prevalence is increasing with the use of this drug, clinical and genotypic correlates of K65R occurrence have yet to be fully identified. Clinical, virological and immunological and genotypic data of patients naïve for TDF who failed HAART regimens and underwent genotypic resistance test (GRT) during 1999-2003 were collected in a database and analyzed retrospectively. Out of 1392 GRT performed for 771 patients, 12 TDF-naïve patients had the K65R mutation with an overall prevalence of 1.6%. Previous AIDS, the use of abacavir, and treatment with efavirenz at GRT were independently associated with a greater risk of expressing K65R, while patients with longer exposure to lamivudine were less likely to present the mutation. Among genotypic correlates, the presence of M184V and NAMs seems to be protective for the emergence of K65R, while a strong positive correlation was found with the Q151M complex mutation. Moreover, the L100I mutation was independently associated with a higher probability of presenting K65R. The selection of mutation K65R in patients failing without TDF is rare. However, exposure to abacavir and/or efavirenz, presence of Q151M and/or L100I, and prior AIDS may favor the selection of this mutation. Conversely, long 3TC exposure, and the presence of M184V or NAMs seem to be protective.

Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort.

BACKGROUND: Hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was described in association with reverse-transcriptase (RT) mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs). We evaluated the effect of RT mutations associated with hypersusceptibility to NNRTIs on the response to efavirenz-based therapy. METHODS: We analyzed an observational database of patients for whom highly active antiretroviral therapy failed and who received genotypic resistance testing-guided therapy, either efavirenz or protease inhibitor (PI) based. Study end points were achievement of virus load <80 copies/mL, achievement of virus load <80 copies/mL without rebound to >500 copies/mL, and changes in CD4 cell counts. RESULTS: The baseline RT mutations M41L, M184V, L210W, and T215Y and the M41L/T215Y and M41L/T215Y/M184V combinations were associated with virological suppression for efavirenz-treated patients, whereas, for PI-treated patients, only the M184V mutation was associated with virological suppression, and the L210W mutation showed a negative correlation; no correlation was found between any mutation and virological response without rebound. CONCLUSIONS: The M41L, M184V, L210W, and T215Y mutations were associated with a better, although transient, virological outcome in patients treated with efavirenz-based regimens.

Q151M-mediated multinucleoside resistance: prevalence, risk factors, and response to salvage therapy.

Among 470 patients with acquired immune deficiency syndrome and/or human immunodeficiency virus infection (HIV/AIDS) who underwent genotype resistance testing (GRT) after the failure of therapy, 17 (3.6%) harbored the Q151M mutation. The Q151M mutation was associated with younger age, lower CD4(+) lymphocyte count, higher HIV RNA level, and treatment with >2 pre-GRT regimens. By contrast, the Q151M mutation was inversely associated with lamivudine administration. A full reversion of the Q151M mutation was observed in 5 of 5 patients who underwent treatment interruption after GRT. The reversion was followed by a response to salvage therapy in 4 (80%) of 5 patients.

The effect of number of mutations and of drug-class sparing on virological response to salvage genotype-guided antiretroviral therapy.

OBJECTIVE: To assess on longitudinal data the impact of number of drug-associated mutations at genotype resistance testing (GRT) and history of previous exposure to antiretrovirals on the virological response to genotype-guided antiretroviral therapy. METHODS: Subjects that failed HAART who underwent GRT between June 1999 and March 2002 were enrolled. GRT was performed by Viroseq-2 with expert advice offered to physicians. Main outcome was reaching undetectable (< 80 copies/ml) HIV-1 RNA level after GRT and maintaining undetectable viraemia for at least 6 months. The number of mutations conferring resistance to each class of antiretrovirals was categorized and their effect on virological outcome investigated. Mutations considered in the analysis were those reported by the IAS-USA in 2002. Multivariate analysis was performed by Cox proportional hazard model. RESULTS: Four-hundred-and-seventy consecutive subjects were enrolled and followed-up for a median of 14 (IQR 9-19) months after GRT. Sustained undetectable viraemia was reached by 80 of 449 subjects (18%). Using as end-point reaching and maintaining for at least 6 months < 400 copies/ml after GRT, 103 out of 447 subjects (23%) reached the outcome. For each single protease inhibitor (PI)-, nucleoside reverse transcriptase inhibitor (NRTI)-and non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutation, there was a reduction of, respectively, 11% (P = 0.008), 12% (P = 0.001) and 39% (P = 0.005) in the likelihood of reaching virological outcome. Subjects carrying > or = 6 mutations to NRTIs, > or = 7 mutations to PIs and > or = 2 mutations to NNRTIs were less likely to reach the virological success compared with those carrying 0-1 (NRTI and PI) or 0 (NNRTI) mutations [HR = 0.25 (95% CI: 0.10-0.65); HR = 0.33 (950% CI: 0.16-0.67); HR = 0.33 (95% CI: 0.14-0.77)], respectively. However, at multivariate analysis the probability of reaching a favourable virological outcome in patients with > or = 7 mutations to PIs, if naive for NNRTIs [HR = 1.74 (0.69-4.36)], and in subjects with > or = 2 mutations for NNRTIs if naive for PIs [HR = 1.23 (0.22-6.80)], was comparable to those observed in patients with none or one mutation. CONCLUSIONS: Our data showed a non-linear association between resistance-conferring mutations and virological outcome. GRT-guided therapy still provided remarkable chances of durable virological success even in subjects with > or = 7 mutations to PIs and in subjects with > or = 2 mutations to NNRTIs, when the subjects did not have a three-class exposure or if GRT showed no evidence of mutations for a drug class. GRT and as-long-as-possible sparing of a drug class could be a convenient strategy for long-term management of drug-failing patients.