Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe.

OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

Deficiencies in the health care system contribute to a high rate of late HIV diagnosis in Sweden.

OBJECTIVES: The aim of the study was to identify factors in HIV-infected patients and the health care system which contribute to late diagnosis. METHODS: All patients who were newly diagnosed with HIV infection at 12 clinics in Sweden over a period of 2.5 years (n = 575) were included in the study, corresponding to three-quarters of newly diagnosed HIV infections in the country. The patients were classified as non-late presenters or late presenters (LPs), defined as those with a CD4 count < 350 cells/µL or AIDS. LPs were subdivided into those without and those with advanced HIV disease, which was defined as a CD4 count < 200 cells/µL or AIDS. Demographics, missed AIDS and HIV-associated symptoms in the preceding 3 years, immigration date, and health examination at immigration were recorded. RESULTS: Fifty-eight per cent of the patients were LPs, of whom 66% had advanced disease. Age > 30 years, origin in sub-Saharan Africa or Eastern Europe/Asia/the Pacific region, and country of transmission being in sub-Saharan Africa or unknown were associated with late presentation. Half of the patients of non-Swedish origin had lived for more than 1 year in Sweden at diagnosis and 66% had a missed HIV testing opportunity at immigration. Twenty-seven per cent of all patients had presented for health care with AIDS- and/or HIV-associated conditions without having an HIV test. Sixteen per cent had a history of symptoms without seeking care. CONCLUSIONS: Deficiencies in the health care system with missed HIV testing opportunities contribute to the high proportion of late presenters in Sweden, especially among migrants. With increased testing at immigration and further incorporation of "indicator-guided" testing in general practice, most patients could be diagnosed earlier.

Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART.

OBJECTIVES: To describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir). METHODS: Genotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32. RESULTS: A resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of <100,000 copies/mL, 25.0% for a VL of ≥100,000 copies/mL and <500,000 copies/mL and 53.8% for a VL of ≥500,000 copies/mL (PTREND = 0.007). Of note, 4/15 participants with IN RAM had a VL < 200 copies/mL at time of testing. CONCLUSIONS: In the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.

Limited spread of hepatitis C among HIV-negative men who have sex with men in Stockholm, Sweden.

Reported cases of hepatitis C (HCV) have been increasing among HIV-positive men who have sex with men (MSM) in many cities worldwide, including Stockholm, Sweden. This study was performed in order to see whether there is also an increase of HCV among HIV-negative MSM. A total number of 1008 MSM attending a clinic for sexually transmitted infections (STI) were screened for HCV. A confirmed positive HCV antibody screening test was found in five cases. Two of these also tested positive for HCV-RNA. We conclude that there is limited spread of HCV among MSM in Stockholm, and the prevalence of HCV among HIV-negative MSM is similar to that found in the general population.

The spread of Mycoplasma genitalium among men who have sex with men.

We report two instances of urethral-to-rectal transmission of Mycoplasma genitalium (MG) in men who have sex with men (MSM) couples. Such clear epidemiological correlation has to our knowledge not been published before. The urethral infections led to clinical symptoms, but the rectal infections did not. The rectum might serve as a reservoir for MG in MSM, but there is also some evidence from the literature that MG can cause proctitis. Our finding raises important questions about the role of MG as a pathogen among MSM. Any correlation with HIV transmission risk is currently unknown and needs further research.

The burden of hepatitis C in Sweden: a national study of inpatient care.

The spread of hepatitis C virus (HCV) in Sweden in the 1970s indicated that serious liver complications (SLC) would increase in the 2000s. The aim of this study was to analyse the burden of HCV-associated inpatient care in Sweden, to demonstrate the changes over time and to compare the findings with a noninfected population. The HCV-cohort (n: 43,000) was identified from the national surveillance database 1990-2006, and then linked to national registers to produce an age-, sex-, and region-matched noninfected comparison population (n: 215,000) and to obtain information on demographics, cancers, inpatient care and prescriptions. Cox regression was used to estimate the likelihood (hazard ratios) for admission to hospital in the HCV compared with the noninfected cohort. The hazard ratios were 4.03 (95% CI: 3.98-4.08) for all care, 77.52 (71.02-84.60) for liver-related care and 40.74 (30.58-54.27) for liver cancer care. The admission rate in the HCV-cohort compared with the noninfected cohort, the rate ratio (age- and sex-adjusted) for all inpatient care was 5.91 (95% CI: 5.87-5.94), and the rate ratio for liver-related care was 70.05 (66.06-74.28). In the HCV-cohort, 45% of all episodes were for psychiatric, mostly drug-related, care. Inpatient care for SLC increased in the 2000s. To conclude, drug-related care was common in the HCV-infected cohort, the demand for liver-related care was very high, and SLC increased notably in the 2000s, indicating that the burden of inpatient care from serious liver disease in HCV-infected individuals in Sweden is an increasing problem.

Syphilis epidemiology in Sweden: re-emergence since 2000 primarily due to spread among men who have sex with men.

Syphilis has re-emerged in western Europe since 2000. Changes in sexual behaviour have facilitated the spread of syphilis especially among men who have sex with men (MSM) and improved surveillance systems and case detection have lead to an increase in the reported numbers of cases. This report describes recent trends (2000-2007) of syphilis in Sweden, where the spread among MSM, particularly in the big cities, has been a major contributor to an increase in cases. Estimated syphilis incidence among MSM was up to twenty-eight times higher than in the general Swedish male population. The most affected age group among males was 25-44 years of age. The majority of infections in men and women through heterosexual contacts were acquired abroad whereas the majority of infections attributed to sex between men were acquired in Sweden. Appropriate prevention activities are needed to reach vulnerable populations in Sweden.

The epidemiology of hepatitis C virus infection in Sweden.

In Sweden, infection with hepatitis C virus (HCV) has been a notifiable disease since 1990, when diagnostic methods became available. Blood donor screening indicated that about 0.5% of the Swedish population (9 millions) had been HCV infected. Here we present the Swedish hepatitis C epidemic based on data from all the HCV notifications 1990-2006. During this time about 42,000 individuals (70% men) were diagnosed and reported as HCV infected. The majority (80%) were born in 1950 or later, with a high percentage (60%) born in the 1950s and 1960s. Younger people, 15-24 years old at notification, were reported on the same level each year. The main reported routes of HCV transmission were intravenous drug use in 65%, blood transfusions/products in 6%, and sexual in 2%, though unknown or not stated in 26%. Approximately 6,000 of all notified individuals have died during the study period. To conclude, the Swedish HCV epidemic is highly related to the increase of intravenous drug use in the late 1960s and 1970s, with a high proportion of people now chronically infected for more than 25 years, resulting in an increase of severe liver complications in form of cirrhosis and hepatocellular carcinoma. Furthermore the unchanged number of notifications of newly infected younger people indicates an ongoing HCV epidemic.

Loss to follow-up in an international, multicentre observational study.

OBJECTIVE: The aim of this work was to assess loss to follow-up (LTFU) in EuroSIDA, an international multicentre observational cohort study. METHODS: LTFU was defined as no follow-up visit, CD4 cell count measurement or viral load measurement after 1 January 2006. Poisson regression was used to describe factors related to LTFU. RESULTS: The incidence of LTFU in 12 304 patients was 3.72 per 100 person-years of follow-up [95% confidence interval (CI) 3.58-3.86; 2712 LTFU] and varied among countries from 0.67 to 13.35. After adjustment, older patients, those with higher CD4 cell counts, and those who had started combination antiretroviral therapy all had lower incidences of LTFU, while injecting drug users had a higher incidence of LTFU. Compared with patients from Southern Europe and Argentina, patients from Eastern Europe had over a twofold increased incidence of LTFU after adjustment (incidence rate ratio 2.16; 95% CI 1.84-2.53; P<0.0001). A total of 2743 patients had a period of >1 year with no CD4 cell count or viral load measured during the year; 743 (27.1%) subsequently returned to follow-up. CONCLUSIONS: Some patients thought to be LTFU may have died, and efforts should be made to ascertain vital status wherever possible. A significant proportion of patients who have a year with no follow-up visit, CD4 cell count measurement or viral load measurement subsequently return to follow-up.

Reasons for the sharp increase of genital chlamydia infections reported in the first months of 2007 in Sweden.

After a continuous increase in the reported chlamydia incidence over the past 10 years in Sweden, the incidence decreased by 2% in 2006. A new genetic variant of Chlamydia trachomatis (nvCT) was discovered in Sweden in October 2006 that could not be detected by some of the commonly used diagnostic tests, which led to underreporting of chlamydia cases. This variant has also been called "swCT" by some authors. After the switch at the end of 2006 to other diagnostic tests that can detect nvCT, the reported incidence rose considerably (75 per 100,000 population) in the beginning of 2007. The objective of this study was to explore alternative explanations for this increase and to propose further action if needed. A data quality check was done in order to exclude double reporting and delayed reporting. To compare the incidence of chlamydia and the proportion of the population that was tested, we divided the Swedish counties into two groups, according to the diagnostic test used. We estimated the chlamydia incidence trend for January and February in the years from 2000 to 2005 by regression model, and predict the chlamydia incidence for the same period in 2006 and 2007. The age and sex distribution of the cases in January and February did not differ between the years 2000 to 2007. The proportion of tested people increased on average by 5% every year. If we assume that the percentage of the population that was tested had been 20% higher in 2007 than in 2006, the incidence predicted by the model for January and February 2007 is exactly the same as the incidence that was actually observed. The change of diagnostic test and an increase in the number of people tested, as well as the increase in the prevalence of CT have probably all contributed to the increased numbers of reported chlamydia cases in January and February 2007. These findings support the need for enhanced prevention campaigns in order to control spread of CT.

Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death.

OBJECTIVES: The aim of the study was to compare incidence rates (IRs) of AIDS/death in patients with and without treatment interruption (TI) of combination antiretroviral therapy (cART) for periods of 3 months or more for different categories of CD4 cell count and viral load, and to determine risk factors for clinical progression to AIDS/death. METHODS: Patients starting cART with a CD4 cell count and a viral load available within 6 months of starting cART were included in the study. The IR and risk factors of TI were determined. We assessed the incidence rate ratios (IRRs) for TI and AIDS/death events using Poisson regression models. RESULTS: Of 3811 patients included in the study, 26% were ART-naïve prior to cART. The median date of starting cART was July 1997, the median CD4 cell count was 226 cells/microL and the median viral load was 4.36 log(10) HIV-1 RNA copies/mL. We observed 1243 interruptions and 403 AIDS-events/deaths. The IR of AIDS/death was higher in patients with lower CD4 cell counts or higher viral loads, regardless of TI. After adjusting for baseline factors, the IR of AIDS/death was significantly higher in the TI group than in the non-TI group [IRR 2.63; 95% confidence interval (CI) 2.01-3.44; P<0.0001]; this could be explained by current CD4 cell counts and viral loads, as the CD4 cell count- and viral load-adjusted IRR was 1.14 (95% CI 0.86-1.51; P=0.37). Within the TI group, patients with a current CD4 cell count of <200 cells/microL had a 3-fold higher risk of AIDS/death than those with a CD4 cell count of 200-350 cells/microL, whereas patients with a current CD4 cell count of >350 cells/microL had a 4-fold lower risk of disease progression. CONCLUSIONS: TI is common in clinical practice. The risk of AIDS/death increased more than 2-fold for patients stopping all cART regimen drugs for 3 months or more. Among patients experiencing a TI, those with low CD4 cell counts, high viral loads or prior AIDS had an increased risk of AIDS/death. Hence, TI should be discouraged and closely monitored if it occurs.

Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection.

Low adherence and toxicities among HIV-positive patients starting highly active antiretroviral therapy (HAART) can lead to discontinuation of therapy and treatment failure. Little is known about hepatitis C (HCV) status and discontinuation of HAART. Poisson regression was used to determine factors related to discontinuation of any part of an initial HAART regimen due to treatment failure (TF) or toxicities and patient/physician choice (TOX), and to investigate the relationship between HCV and discontinuation of a HAART regimen in 1198 patients staring HAART after 1999 from the EuroSIDA study. At 1 year after starting HAART, 70% of patients remained on their original regimen, 24% had changed, and 6% were off all treatment. The most frequent reason for discontinuation was toxicities (30.4%). There was no change over time in the proportion of patients discontinuing after stratification by reason for discontinuation (p = 0.18). Of patients 190 stopped at least one antiretroviral drug used in their initial HAART regimen due to toxicities; the toxicity reported did not vary according to HCV status (p = 0.90). Anti-HCV seropositive patients had a higher incidence of discontinuation due to TOX (IRR 1.46, 95% CI 1.13-1.88, p = 0.0042) compared to patients without HCV. Patients with HCV were more likely to discontinue all or part of their HAART regimens due to toxicity or patient/physician choice. Managing adverse events must remain a key intervention in maintaining HAART. There is a need for further studies to describe the relationship between HCV, specific antiretrovirals, and different treatment strategies.

Patients unaware of their HIV infection until AIDS diagnosis in Sweden 1996-2002--a remaining problem in the highly active antiretroviral therapy era.

Our objective was to analyse the characteristics of patients who were unaware of their HIV infection until they developed AIDS, in the period after introduction of highly active antiretroviral therapy. The complete national register of HIV and AIDS cases reported to the Department of Epidemiology at the Swedish Institute for Infectious Disease Control 1996-2002 was searched for cases diagnosed with HIV less than three months before AIDS diagnosis (so-called "late testers"). Of a total of 487 patients with AIDS, reported during the seven-year period, 219 (45%) were late testers. Their proportion of all AIDS cases increased from 22% in 1996 to 58% in 2002. Heterosexual route of transmission, age greater than 40 years, and foreign origin were all significant risk factors for being a late tester. Intravenous drug users were associated with a highly significant reduced risk. The group without previously known HIV infection represents an increasing part of all cases of AIDS. From a disease control and from a medical perspective, it is important to study this group further and discover what measures are needed for earlier identification and access to medical care.

Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection.

Low adherence and toxicities among HIV-positive patients starting highly active antiretroviral therapy (HAART) can lead to discontinuation of therapy and treatment failure. Little is known about hepatitis C (HCV) status and discontinuation of HAART. Poisson regression was used to determine factors related to discontinuation of any part of an initial HAART regimen due to treatment failure (TF) or toxicities and patient/ physician choice (TOX), and to investigate the relationship between HCV and discontinuation of a HAART regimen in 1198 patients staring HAART after 1999 from the EuroSIDA study. At 1 year after starting HAART, 70% of patients remained on their original regimen, 24% had changed, and 6% were off all treatment. The most frequent reason for discontinuation was toxicities (30.4%). The incidence of any discontinuation was significantly lower after 1999 compared to before [incidence rate ratio (IRR) 0.43; 95% CI 0.35-0.53, p < 0.0001], this pattern was most marked for toxicities (IRR 0.28; 95% CI 0.20-0.39, p < 0.0001) and patient/physician choice (IRR 0.49; 95% CI 0.33-0.73, p < 0.0001). Patients with HCV had a higher incidence of discontinuation due to TOX (IRR 1.46, 95% CI 1.13-1.88, p = 0.0042) compared to patients without HCV. Patients with HCV were more likely to discontinue all or part of their HAART regimens due to toxicity or patient/physician choice. Managing adverse events must remain a key intervention in maintaining HAART. There is a need for further studies to describe the relationship between HCV, specific antiretrovirals, and different treatment strategies.

Antigen-specific beta-chemokine production and CD8 T-cell noncytotoxic antiviral activity in HIV-2-infected individuals.

Human immunodeficiency virus-2 (HIV-2) is less pathogenic than HIV-1, and the disease progression in HIV-2-infected individuals seems to be similar to that seen in HIV-1-infected long-term nonprogressors. Cell-mediated immune responses and the production of noncytotoxic CD8+ T-cell antiviral factors (CAF) and beta-chemokines have been correlated to protection against HIV-1 and associated with asymptomatic infection and slower disease progression. We investigated the antigen-induced beta-chemokine production in HIV-2-infected patients living in Sweden and in Guinea-Bissau. We also compared in vitro CD8+ T-cell-mediated noncytotoxic antiviral activity against beta-chemokine-sensitive R5 virus (HIV-1Bal) and beta-chemokine-insensitive X4 virus (HIV-1IIIB) in HIV-2-infected patients with that in HIV-1-infected patients. HIV-2-specific beta-chemokine production was demonstrated in a majority of the HIV-2-infected subjects. CD8+ T cells of both HIV-1 and HIV-2-infected individuals suppressed R5 virus replication in vitro in a similar manner, while the inhibition of X4 virus replication seemed to be more frequent and of a higher magnitude among HIV-2-infected patients compared to HIV-1-infected subjects. Taken together, our results indicate that the production of CD8+ T-cell noncytotoxic antiviral factors may contribute to the low transmission of the virus and slower disease progression in HIV-2-infected patients.

Changes in hospital admissions across Europe: 1995-2003. Results from the EuroSIDA study.

OBJECTIVES: To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan-European, observational cohort study. METHODS: Generalized estimating equations were used to determine changes over time in the proportion of patients admitted and the median duration of admission. Logistic regression was used to determine factors related to admission in March 1995, March 1998 and March 2001. RESULTS: The proportion of patients admitted during March declined from 7.4% in 1995 to 2.6% in 2003. After adjustment, the estimated reduction in the proportion of patients admitted was 5.5% per year [95% confidence interval (CI) 2.5-8.5%; P=0.0004], a 26% reduction. The median duration of hospital admission declined by 58% from 12 days in 1995 [interquartile range (IQR) 5-19 days] to 5 days in 2003 (IQR 3-12 days), a significant decline of 0.7 days per year after adjustment (95% CI 0.5-0.9 days; P=0.031). Patients with a lower CD4 lymphocyte count, and with an AIDS diagnosis made within the 3 months prior to March, all had increased odds of admission during March 1995, 1998 or 2001. In March 2001, patients whose treatment regimen was changed as a consequence of toxicities had increased odds of admission [odds ratio (OR) 2.34; 95% CI 1.26-4.37; P=0.0074]. In addition, patients who were hepatitis C virus-positive during March 2001 (OR 1.66; 95% CI 1.02-2.68; P=0.041) had increased odds of admission. CONCLUSIONS: There has been a considerable decline in both the proportion of patients admitted to hospital and the median duration of the stay. Patients with hepatitis C had increased odds of admission, but there was little evidence of an increase in admissions among patients taking highly active antiretroviral therapy (HAART) associated with serious adverse events, although longer follow up is required.