Mortality in KPC-producing Klebsiella pneumoniae bloodstream infections: a changing landscape.

OBJECTIVES: To assess the impact of carbapenem resistance on mortality in Klebsiella pneumoniae bloodstream infection (BSI) in the era of novel ß-lactam/ß-lactamase inhibitor combinations. MATERIAL AND METHODS: Retrospective study of patients with K. pneumoniae BSI between January and August 2020 in 16 centres (CARBANEW study within the MULTI-SITA project). RESULTS: Overall, 426 patients were included: 107/426 (25%) had carbapenem-resistant K. pneumoniae (CR-Kp) BSI and 319/426 (75%) had carbapenem-susceptible K. pneumoniae (CS-Kp) BSI. Crude cumulative 30 day mortality was 33.8% and 20.7% in patients with, respectively, CR-Kp BSI and CS-Kp BSI (P = 0.027). Carbapenemase production or carbapenemase-encoding genes were detected in 84/98 tested CR-Kp isolates (85.7%), mainly KPC (78/84; 92.9%). Ceftazidime/avibactam was the most frequently used appropriate therapy for CR-Kp BSI (80/107; 74.7%). In multivariable analyses, variables showing an unfavourable association with mortality after correction for multiple testing were age-adjusted Charlson comorbidity index (HR 1.20; 95% CI 1.10-1.31, P < 0.001) and Pitt score (HR 1.33; 95% CI 1.15-1.55, P < 0.001), but not carbapenem resistance (HR 1.28, 95% CI 0.74-2.22, P = 0.410). In a propensity score-matched analysis, there was no difference in mortality between patients appropriately treated with ceftazidime/avibactam for CR-Kp BSI and patients appropriately treated with other agents (mainly meropenem monotherapy or piperacillin/tazobactam monotherapy) for CS-Kp BSI (HR 1.07; 95% CI 0.50-2.29, P = 0.866). CONCLUSIONS: Our results suggest that the increased mortality in CR-Kp BSI compared with CS-Kp BSI is not (or no longer) dependent on the type of therapy in areas where ceftazidime/avibactam-susceptible KPC-producing isolates are the most prevalent type of CR-Kp.

Epidemiology, aetiology and treatment of skin and soft tissue infections: final report of a prospective multicentre national registry.

Skin and soft tissue infections (SSTIs) represent a heterogenous group of pathological conditions involving the skin or the underlying subcutaneous tissues, fascia and muscle, characterised by a considerable variety of clinical presentations, severity and possible aetiological pathogens. Although previous analyses on restricted types of SSTIs and population have already been published, we conducted a large nationwide surveillance program on behalf of the Italian Society of Infectious and Tropical Diseases to assess the clinical and microbiological characteristics of the whole SSTI spectrum, from mild to severe life-threatening infections, in both inpatients and outpatients and their management. Twenty-nine Infectious Diseases (ID) Centres throughout Italy collected prospectively data concerning both the clinical and microbiological diagnosis of patients affected by SSTIs via an electronic case report form. We included in our database all cases managed by ID specialists participating to the study, independently from their severity or the setting of consultation. Here, we integrated previous preliminary results analysing and reporting data referring to a 3-year period (October 2016-October 2019). During this period, the study population included 478 adult patients with diagnosis of SSTI. The type of infection diagnosed, the aetiological agent involved and some notes on antimicrobial susceptibilities were collected and reported herein. We also analysed the most common co-morbidities, the type and duration of therapy executed, before and after ID intervention and the length of stay. The results of our study provide information to better understand the national epidemiologic data and the current clinical management of SSTIs in Italy.

Epidemiology and Microbiology of Skin and Soft Tissue Infections: Preliminary Results of a National Registry.

Skin and soft tissue infections (SSTIs) represent a wide range of clinical conditions characterized by a considerable variety of clinical presentations and severity. Their aetiology can also vary, with numerous possible causative pathogens. While other authors previously published analyses on several types of SSTI and on restricted types of patients, we conducted a large nationwide surveillance programme on behalf of the Italian Society of Infectious and Tropical Diseases to assess the clinical and microbiological characteristics of the whole SSTI spectrum, from mild to severe life-threatening infections, in both inpatients and outpatients. Twenty-five Infectious Diseases (ID) Centres throughout Italy collected prospectively data concerning both the clinical and microbiological diagnosis of patients affected by SSTIs via an electronic case report form. All the cases included in our database, independently from their severity, have been managed by ID specialists joining the study while SSTIs from other wards/clinics have been excluded from this analysis. Here, we report the preliminary results of our study, referring to a 12-month period (October 2016-September 2017). During this period, the study population included 254 adult patients and a total of 291 SSTI diagnoses were posed, with 36 patients presenting more than one SSTIs. The type of infection diagnosed, the aetiological micro-organisms involved and some notes on their antimicrobial susceptibilities were collected and are reported herein. The enrichment of our registry is ongoing, but these preliminary results suggest that further analysis could soon provide useful information to better understand the national epidemiologic data and the current clinical management of SSTIs in Italy.

Prospective study of the clinical performance of three BACTEC media in a modern emergency department: Plus Aerobic/F, Plus Anaerobic/F, and Anaerobic Lytic/F.

The performance of 3 blood culture bottles (BACTEC Plus Aerobic/F, Plus Anaerobic/F, and Anaerobic Lytic/F) were analyzed with clinical specimens collected from 688 Emergency Department patients. A total of 270 strains belonging to 33 species were identified, with E. coli and S. aureus as the most frequently detected. Overall recovery rate (RR) of bacteria and yeast was equivalent in the Plus Aerobic/F vials (208 of 270 isolates; 77.0%) and Anaerobic Lytic/F vials (206 isolates; 76.3%) and significantly better than in the Plus Anaerobic/F vials (189 isolates; 70.0%). Median time to detection (TTD) was earliest with the Anaerobic Lytic/F vials (12.0h) compared with the Plus Aerobic/F (14.6h) and Plus Anaerobic/F vials (15.4h). Positivity rate (PR) was similar for Anaerobic Lytic/F vials (76.9%) and Plus Aerobic/F vials (76.5%), but better if compared with Plus Anaerobic/F vials (69.4%). The PR and TTD for the combination of Plus Aerobic/F with Anaerobic Lytic/F (94.5% and 12.3h, respectively) was significantly better than with Plus Aerobic/F with Plus Anaerobic/F (87.8% and 14.1h).

Usefulness of suPAR in the risk stratification of patients with sepsis admitted to the emergency department.

To investigate the role of suPAR in patients with sepsis admitted to the Emergency Department (ED). We performed multicentre prospective trial including patients admitted to the ED of three different Italian hospitals. Patients were studied upon admission on day 1, 2, 4 and 7. They were subdivided into two groups: sepsis (group 1) and severe sepsis or septic shock (group 2). The two groups were comparable for age, gender and CRP level on day 1. Patients with severe sepsis or septic shock displayed significantly higher baseline levels of suPAR, PCT and lactate. In both groups, suPAR decreased across the time (p < 0.0005). Group 1 was not different from group 2 (p = 0.545) in mortality at 7 days, while group 2 had higher mortality at 30 days than group 1 (p = 0.022). At the multivariate analysis, lactate1 (p = 0.012) and age (p = 0.019) were independent predictors of mortality at 7 days, whereas suPAR1 (p = 0.023) and age (p = 0.032) were independent predictors of mortality at 30 days. Lactate and suPAR resulted the most predictive biomarkers in the risk stratification of patients with suspected infection initially admitted to the ED, according to their role in predicting 7- and 30-day mortality, respectively.

[A population-based database to study malignancies in HIV-infected patients in the Local Health Unit of Brescia (Northern Italy), period 1999-2009]. / Creazione di un database integrato per lo studio dei tumori maligni nei pazienti con infezione da HIV nell'ASL di Brescia nel periodo 1999-2009.

OBJECTIVE: to complete the database of all patients infected by the human immunodeficiency virus (HIV) who lives in the area belonging to the Local Health Unit (ASL) of Brescia, Northern Italy,with all the cancers diagnosed in the period 1999-2009. DESIGN: diagnoses of cancer between 1999 and 2009 registered in the electronic database in use in the Clinic of Infectious and Tropical Diseases (source A) for the clinic follow-up of HIV-infected patients were checked. Then, the cases were integrated with the data recorded in the ASL database (source B) and in the Cancer Registry of Brescia (source C). SETTING AND PARTICIPANTS: all HIV-infected patients belonging to the ASL of Brescia followed-up in the Clinic of Infectious and Tropical Diseases of Brescia. MAIN OUTCOME MEASURES: in the database were included all HIV-positive patients who had a diagnosis of cancer between 1999 and 2009. The diagnosis of cancer had to be present at least in two of the three sources considered; if it was recorded only in one of them, the source had to be an histological document or confirmed directly by the patient him/herself. RESULTS: from the sourceA, 339 diagnoses of cancer were recorded, then other 82 records from the sources B and C were added, achieving a total of 421 cancers, belonging to 391 different patients. Half of the diagnoses was present in all the three sources considered. Among the AIDS-defining cancers (No. 200; 47.5%), Kaposi's sarcoma and non-Hodgkin lymphoma were the most frequent diagnosed tumours (22.8% and 22.33%, respectively). Among the non-AIDS-defining cancers (No. 221; 52.5%), malignancies of the skin other than melanoma (No. 41; 9.74%), tumours of the liver (No. 34; 8.08%) and Hodgkin lymphoma (No. 31; 7.36%) were the most frequent tumours. CONCLUSIONS: the database of all HIVpositive patients, including the diagnoses of cancer between 1999 and 2009, represents an important instrument, not only for the clinical practice: collecting clinical and sociodemographics characteristics of these patients, it would be possible to perform clinical and epidemiological studies.

Burden of non-AIDS-defining and non-virus-related cancers among HIV-infected patients in the combined antiretroviral therapy era.

The risk of cancer is substantially increased in HIV-infected patients. However, little is known about non-AIDS-defining cancers (NADCs) without an infectious etiology. A total of 5,090 HIV-infected patients registered in the Local Health Authority (LHA) of Brescia and receiving primary care at our clinic were included in a retrospective (1999-2009) analysis. The cancer diagnoses were obtained through a record-linkage procedure between our database and the LHA general database and population-based Cancer Registry of LHA. We compared risks of these malignancies with those of the general population living in the same health area by using age-standardized incidence ratios (SIRs). Poisson regression analysis was used to assess factors associated with non-virus-related NADCs. We recorded an increase in the SIR of non-virus-related NADCs over time, with 138 cancers diagnosed in 131 patients. The mean incidence rate was 42.6/10,000 person years and the median age at the diagnosis was 49 (range, 28-78) years old. Stratifying for gender, only HIV-infected males had an increased risk of non-virus-related NADCs [SIR=1.86; 95% confidence interval (CI), 1.55-2.26]. Risk was higher for lung (SIR=3.59; 95% CI, 2.36-5.45) and testis cancer (SIR=3.11; 95% CI, 1.48-6.52). However,, cancers of the prostate and breast in HIV-positive men and women were null (SIR=1.10; 95% CI, 0.53-2.32 and SIR=0.91; 95% CI, 0.47-1.74, respectively). The only predictors of non-virus-related NADCs included older age [incidence rate ratio (IRR)=1.10; 95% CI, 1.08-1.12 per each additional year, p<0.001] and a shorter or no exposition to combined antiretroviral therapy (cART) (IRR=2.31; 95% CI, 1.38-3.89, p=0.002). A CD4⁺ count lower than 50/mm³ was significantly associated with cancers only in the univariate model (IRR=1.40; 95% CI, 0.99-1.98, p=0.057). HIV-infected men showed a 2-fold increased risk of non-virus-related NADCs compared to the general population. However, the use of cART appeared to be beneficial in protecting against the development of these malignancies.

Clinical characteristics, incidence, and risk factors of HIV-related Hodgkin lymphoma in the era of combination antiretroviral therapy.

HIV-infected patients are at increased risk for developing HIV-related Hodgkin lymphoma (HIV-HL) despite the success of combination antiretroviral therapy (cART). To study the incidence of HIV-HL in HIV-patients with respect to the general population of Brescia, Italy, we conducted a single-center cohort study of HIV-patients followed from 1999 to 2009. The incidence of HIV-HL was compared to the incidence in the general population of Brescia using standardized incidence ratios (SIRs). Poisson analysis was used to study the association between covariates and HL. A total of 5085 HIV-patients were observed among 30,946 person-years; 30 patients developed HIV-HL. The incidence rate was 9.9 (95% confidence interval [CI], 6.7-14.1) per 10,000 person-years of follow-up. HL was substantially more frequent in HIV-patients than in the general population living in the same district area [standardized incidence rate, SIR=21.8 (95% CI, 15.33-31)]. The risk of HIV-HL tended to increase with lowering CD4+ cell counts at time of HL diagnosis [adjusted incidence relative risk (IRR) for CD4 cell count<50 cells/µL: 41.70, p<0.001]. HL risk had been elevated during the 6 months after combination antiretroviral therapy (cART) initiation (IRR: 26.65, p<0.001). Twenty-two HIV-HL cases were matched to 3280 controls. In the year preceding HIV-HL diagnosis the mean change in CD4+ cell counts between cases and controls was significantly different (-99 cells/µL for cases vs. +37 cells/µL for controls, p<0.0001). Compared with the general population, HIV-infected patients showed an increased risk for developing HL. The risk of HIV-HL increased significantly in the first months after cART initiation.

Increase in standard cholesterol and large HDL particle subclasses in antiretroviral-naïve patients prescribed efavirenz compared to atazanavir/ritonavir.

BACKGROUND: Cardiovascular risk in HIV-infected patients is related, at least in part, to serum lipid alterations before and after HAART. Lipoprotein-particle subclasses may also have an effect, but comparative data after standard HAART regimens are limited. METHODS: This was a substudy of a trial in 91 antiretroviral-naïve patients randomized to tenofovir + emtricitabine + atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Over-time trends from baseline to week 48 in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL particles (HDLp), and TC:HDL-C and TG:HDL-C ratios were analyzed by analysis of covariance (ANCOVA). Furthermore, confidence intervals for differences between the 2 groups at week 48 were calculated. Indications for lipid-lowering interventions and low HDL-C were also studied. RESULTS: ANCOVA showed that, with respect to patients receiving ATV/r, those prescribed efavirenz (EFV) had greater increases reported as mean differences in lipid values at week 48: 14 mg/dL (95% CI, 0.2 to 27) for TC, 14 mg/dL (95% CI, 4 to 25) for LDL-C, 5 mg/dL (95% CI, 2 to 9) for HDL-C, and 2.2 mg/dL (95% CI, 0.4 to 4) for large HDLp. Proportions of subjects with indications for lipid-lowering interventions and with HDL-C <40 mg/dL did not differ significantly. CONCLUSIONS: Patients prescribed EFV had greater increases in TC, LDL-C, and HDL-C. Although no significant differences were detected between the 2 groups for the TC:HDL ratio and for indications to start lipid-lowering interventions, large HDLp increased more in the EFV group compared to the ATV/r group, suggesting a protective effect associated with EFV use.

Lopinavir pharmacokinetic profiles in HIV-infected patients during rifabutin-based anti-mycobacterial therapy.

OBJECTIVES: To evaluate the pharmacokinetic profile of ritonavir-boosted lopinavir in HIV-infected patients during rifabutin-based anti-mycobacterial therapy. PATIENTS AND METHODS: A longitudinal, cross-over pharmacokinetic evaluation of lopinavir with and without rifabutin in HIV-infected subjects with mycobacterial disease was done. All received lopinavir/ritonavir (400/100 mg twice a day) + an adjusted rifabutin dose of 150 mg every other day. Twelve-hour lopinavir pharmacokinetic sampling occurred at 2 weeks (T1) and 6 weeks (T2) after starting combined therapy and 10 weeks after completion of adjusted rifabutin (T3). Plasma was assayed using an HPLC method; lopinavir plasma concentration-time data were analysed using non-compartmental methods. RESULTS: In 10 patients with complete lopinavir curves at T1, T2 and T3 pharmacokinetic values were, respectively: AUC(0-12), 187.5, 161.8 and 121.1 µg ·â€Šh/mL; C(trough), 13.2, 10.0 and 7.7 µg/mL; C(max), 18.7, 15.9 and 13.3 µg/mL; and apparent oral clearance (CL/F), 0.035, 0.037 and 0.045 L/h/kg. Lopinavir C(trough) and AUC(0-12) were significantly higher at T1 compared with T3 while CL/F remained unchanged throughout. Combined treatment was well tolerated and none of the patients experienced moderate to severe lopinavir-related adverse events. CONCLUSIONS: Lopinavir serum concentrations are not reduced when the drug is administered together with an adjusted dose of 150 mg of rifabutin every other day.

Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz.

BACKGROUND: Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain. METHODS: We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated. RESULTS: Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated. CONCLUSIONS: These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.

A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naive HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/ritonavir or efavirenz.

BACKGROUND: Glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on creatinine or cystatine C may be more accurate methods especially in patients without chronic kidney disease. There is lack of data on GFR estimated by these methods in patients on highly active antiretroviral therapy. METHODS: Antiretroviral-naive HIV-infected patients were randomized to tenofovir/emtricitabine in association with atazanavir/ritonavir (ATV/r) or efavirenz (EFV) Patients had to have an actual creatinine clearance >50 mL/minute (24-hour urine collection) and were followed for 48 weeks. RESULTS: Ninety-one patients (48 ATV/r, 43 EFV) were recruited. Using the CKD-EPI creatinine formula, there was a significant decrease in GFR up to week 48 in patients receiving ATV/r (4.9 mL/minute/m(2), P = 0.02) compared with a not statistically significant increment in patients prescribed EFV. Using the cystatin C-based equation, we found greater decrease in GFR in both arms, although, in the EFV arm, the decrease was not statistically significant (5.8 mL/minute/m(2), P = 0.92). At multivariable analysis, ATV/r was a significant predictor of greater decrease in estimated glomerular filtration rate (eGFR) (P = 0.0046) only with CKD-EPI creatinine. CONCLUSIONS: ATV/r plus tenofovir caused greater GFR decreases compared with EFV. The evaluation of eGFR by cystatin C confirmed this result, but this method seemed to be more stringent, probably precluding the possibility to detect a significant difference in the pattern of eGFR evolution between the two arms over time. More studies are needed to understand the clinical relevance of these alterations and whether cystatin C is a more appropriate method for monitoring GFR in clinical practice.

Male breast cancer in an HIV-infected patient: a case report.

Male breast cancer is rare and few cases of breast cancer in human immunodeficiency virus (HIV)-infected patients are reported. We describe the case of breast cancer in a 65-year-old HIV-positive man who presented a nodule near the nipple of his left breast. He did not report risk factors for breast cancer, but he had liver cirrhosis. Biopsy of the lesion revealed a ductal carcinoma and he was submitted to mastectomy and axillary dissection. Staging resulted in pT1c/pN1a/M0; it was positive for the presence of oestrogen/progesterone receptors, negative for the human epidermal growth factor receptor-22. He was also treated with local radiotherapy and tamoxifen. At cancer diagnosis, he received highly active antiretroviral therapy (HAART) with undetectable HIV viral load, and his CD4+ T-cell count was 445 cells/mm(3). Patients with HIV infection have a higher cancer risk due to immunosuppression: it concerns not only malignancies related to human acquired immunodeficiency syndrome (AIDS), but also other cancers. A heightened awareness of male breast cancer by HIV specialists is needed, especially for particular risk categories, such as trans-sexuals who take oestrogen therapies, and for the presence of breast conditions, such as gynecomastia, usually considered as part of the lipodystrophy syndrome.

Prevalence and risk factors for etravirine resistance among patients failing on non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Prevalence and factors associated with etravirine (EW) resistance mutations among patients failing on first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI) merit investigation. METHODS: The study comprised an analysis of all sequential patients attending the Institute of Infectious Diseases (Brescia, northern Italy) who performed a genotypic resistance testing (GRT) after > or =3 months of a stable NNRTI-based regimen between 2001 and 2006. Multivariable ordinal logistic regression analysis was performed to assess predictors of ETV resistance mutations. RESULTS: Out of 248 strains, 153 (61.7%) harboured > or =1 ETV resistance mutations. In particular, 88 (35.5%), 53 (21.4%) and 12 (4.8%) harboured one, two and three mutations, respectively. The most frequent mutations were G190A (230%), Y181C (23%) and K101E (14.1%). Use of nevirapine (odds ratio [OR] 2.73; 95% confidence level [CI] 1.62-4.62; P<0.001) and a longer time frame between first HIV RNA >500 copies/ml and GRT (per month, OR 1.05; 95% CI 1.01-1.09; P=0.012) were associated with a greater number of ETV resistance mutations. Conversely, higher CD4+ T-cell counts at nadir (per 100 cells/mm3, OR 0.81; 95% CI 0.67-0.98; P=0.029) and use of lamivudine/emtricitabine (OR 0.57; 95% CI 0.37-0.87; P=0.009) were protective. Accumulation of ETV resistance-associated mutations was demonstrated by sequential GRT in 4/35 patients (all treated with nevirapine). CONCLUSIONS: Mutations associated with ETW resistance were common among patients failing on NNRTI, but prevalence of viral strains harbouring three mutations was low. Use of efavirenz and co-administration of lamivudine reduced the risk of ETW resistance. The continued use of the current NNRTI in a failing regimen may select for additional resistant variants.

Evidence of long-term suppression of hepatitis B virus DNA by tenofovir as rescue treatment in patients coinfected by HIV.

BACKGROUND: The efficacy of long-term hepatitis B virus (HBV) treatment with tenofovir (TDF) in relation to lamivudine (LMV) resistance in HIV patients failing on LMV deserves further investigations. METHODS: HIV-HBV coinfected patients were selected, provided that LMV was included in the first highly active antiretroviral therapy regimen and TDF was subsequently introduced. RESULTS: Forty HIV-HBV patients were included, 25 had undetectable HBV DNA on LMV and 15 were failing on LMV treatment. Three cases of triple 173V + 180M + 204V HBV reverse transcriptase (rt) mutants were identified, as well as several mutations or polymorphisms in the surface antigen gene at positions possibly correlating with vaccine escape. A new mutation (rtl233V) was found in one adefovir-naive patient. In 10 patients, uninterrupted TDF treatment led to a sustained treatment response for a median of 160 (interquartile range 111-189) weeks. Two patients underwent intermittent treatment with TDF and LMV, responding any time TDF was reintroduced. In one patient, TDF without LMV provided treatment response. One patient did not respond to TDF because of low treatment adherence. One patient infected with the triple rt mutant did not respond to entecavir, but TDF was successful as rescue. CONCLUSIONS: Combination therapy with TDF was effective against HBV mutant viruses resistant to LMV and provided sustained control of HBV replication over long-term follow-up, even after entecavir failure. Moreover, suppression of HBV vaccine escape variants could provide important benefits from a public health perspective.