Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study.

BACKGROUND: The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships. METHODS: The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA <200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods. FINDINGS: Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1-3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33-46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4-2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up). INTERPRETATION: Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. FUNDING: National Institute for Health Research.

Excess costs of non-infectious comorbidities among people living with HIV - estimates from Denmark and Sweden.

People living with HIV have an increased risk of comorbidities with non-communicable diseases such as cardiovascular disease, chronic kidney disease and osteoporotic fractures, compared to the general population. The burden of these comorbidities is expected to rise as the HIV-infected population ages. This development may require additional health care resources and it is relevant to ascertain the costs associated with these comorbidities. The population attributed risk approach was applied to estimate excess costs associated with the higher rates of comorbidities among HIV patients in Denmark and Sweden compared to their respective general populations. Excess direct and indirect costs for one year were calculated for myocardial infarction, stroke, osteoporotic fractures and chronic kidney disease. Cost estimates were presented in age and sex subgroups. In the course of one year the excess costs for myocardial infarction, stroke, osteoporotic fractures and chronic kidney disease attributable to HIV was estimated to €3.4 million for Denmark and €2.6 million for Sweden. Chronic kidney disease accounted for the majority of the total excess costs, followed by osteoporotic fractures, myocardial infarction and stroke. The high prevalence of comorbidities in the HIV-infected population is associated with substantial excess costs. Focus on primary and secondary prophylactic interventions is warranted. Additional studies, preferably large-scale case-control studies, may give further insights on the extent and the predictors of these excess costs.

Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.

BACKGROUND: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. AIM: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends. METHODS: In three cross-sectional analyses in 2004-05, 2009-10 and 2014-15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression. RESULTS: Overall, the percentage of people on ART increased from 2004-05 (67.8%) to 2014-15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004-05, 87.7% in 2014-15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014-15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014-15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13-0.21) in Eastern Europe. CONCLUSIONS: Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.

Antiretroviral treatment for HIV infection: Swedish recommendations 2016.

The Swedish Medical Products Agency and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection on seven previous occasions (2002, 2003, 2005, 2007, 2009, 2011 and 2014). In February 2016, an expert group under the guidance of RAV once more revised the guidelines. The most important updates in the present guidelines are as follows: Tenofovir alafenamide (TAF) has recently been registered. TAF has several advantages over tenofovir disoproxilfumarate (TDF) and is recommended instead of TDF in most cases. First-line treatment for previously untreated individuals includes dolutegravir, boosted darunavir or efavirenz with either abacavir/lamivudine or tenofovir (TDF/TAF)/emtricitabine. Pre-exposure prophylaxis (PrEP) is recommended for high-risk individuals. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine ( http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/ ) ( Table 1 ). This document does not cover treatment of opportunistic infections and tumours. [Table: see text].

Symptomatic Patients without Epidemiological Indicators of HIV Have a High Risk of Missed Diagnosis: A Multi-Centre Cross Sectional Study.

OBJECTIVES: One quarter of HIV-1 positive individuals in Sweden present for care with HIV or AIDS associated conditions without an HIV test (missed presentations) and 16% report neglect of such symptoms. The objective of this study was to identify risk factors for these missed opportunities of HIV-1 diagnosis. METHODS: A national study, recruiting 409 newly diagnosed HIV-1 infected adults over a 2.5-year period, was performed. Logistic regression models tested the relationship between missed presentation and patient's neglect versus socio-demographic and behavioural risk factors. Additionally the initiator of the HIV test was assessed. RESULTS: The odds for a missed presentation was lower for migrants (from East Europe, Asia, and Pacific (East): OR 0.4 (0.2-0.8); Sub-Saharan Africa (SSA): 0.3 (0.2-0.6); other: 0.5 (0.2-1.0)), compared to patients born in Sweden, just as symptoms neglected by the patient (East (0.3 (0.1-1.0); SSA (0.4 (0.2-0.8)). The latter was also lower for men who have sex with men (0.5 (0.2-1.0)), compared to patients infected heterosexually. Patients infected in the East, with present/previous substance use or a previous negative HIV test were more likely to take the initiative to test on their own, whereas those >50 years and with a previously missed presentation had significantly reduced odds, p<0.05. CONCLUSIONS: Individuals without epidemiological indicators of HIV are more likely to have a history of missed presentations, to neglect symptoms and are less prone to take an initiative to test for HIV themselves. It is important to further implement testing to include all patients with symptoms and conditions indicative of HIV.

Viral blips during suppressive antiretroviral treatment are associated with high baseline HIV-1 RNA levels.

BACKGROUND: Many HIV-1-infected patients on suppressive antiretroviral therapy (ART) have transiently elevated HIV RNA levels. The clinical significance of these viral blips is uncertain. We have determined the incidence of blips and investigated important associations in the Swedish HIV-cohort. METHODS: HIV-1-infected ART naïve adults who commenced ART 2007-2013 were retrospectively included. Viral blips were defined as a transient viral load between 50 and 500 copies/mL Subjects not suppressed after six months on ART were excluded. RESULTS: Viral blips were found in 76/735 included subjects (10.3 %) and in 90/4449 samples (2.0 %). Median blip viral load was 76 copies/mL (range 56-138). Median follow-up time was 170 weeks (range 97-240). Baseline viral load was higher in subjects with viral blips (median log10 4.85 copies/mL) compared with subjects without blips (median log10 4.55 copies/mL) (p < 0.01). There was a significant association between viral blips and risk for subsequent virological failure (p < 0.001). CONCLUSIONS: The Swedish national HIV-cohort has a low incidence of viral blips (10 %). Blips were associated with high baseline viral load and an increased risk of subsequent virological failure.

Six-week follow-up after HIV-1 exposure: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

In 2014 the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy (RAV) conducted a review and analysis of the state of knowledge on the duration of follow-up after exposure to human immunodeficiency virus (HIV). Up until then a follow-up of 12 weeks after exposure had been recommended, but improved tests and new information on early diagnosis motivated a re-evaluation of the national recommendations by experts representing infectious diseases and microbiology, county medical officers, the RAV, the Public Health Agency, and other national authorities. Based on the current state of knowledge the Public Health Agency of Sweden and the RAV recommend, starting in April 2015, a follow-up period of 6 weeks after possible HIV-1 exposure, if HIV testing is performed using laboratory-based combination tests detecting both HIV antibody and antigen. If point-of-care rapid HIV tests are used, a follow-up period of 8 weeks is recommended, because currently available rapid tests have insufficient sensitivity for detection of HIV-1 antigen. A follow-up period of 12 weeks is recommended after a possible exposure for HIV-2, since presently used assays do not include HIV-2 antigens and only limited information is available on the development of HIV antibodies during early HIV-2 infection. If pre- or post-exposure prophylaxis is administered, the follow-up period is recommended to begin after completion of prophylaxis. Even if infection cannot be reliably excluded before the end of the recommended follow-up period, HIV testing should be performed at first contact for persons who seek such testing.

The prevalence and predictive value of dipstick urine protein in HIV-positive persons in Europe.

INTRODUCTION: Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m(2). PATIENTS AND METHODS: Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR <60 at either DPU measurement were excluded. Logistic regression investigated factors associated with PTU. RESULTS: A total of 1,640 persons were included, participants were mainly white (n=1,517, 92.5%), male (n=1296, 79.0%) and men having sex with men (n=809; 49.3%). Median age at baseline was 45 (IQR 37-52 years), and CD4 was 570 (IQR 406-760/mm(3)). The median baseline date was 2/12 (IQR 11/11-6/12), and median eGFR was 99 (IQR 88-109 mL/min/1.73 m(2)). Sixty-nine persons had PTU (4.2%, 95% CI 3.2-4.7%). Persons with diabetes had increased odds of PTU, as were those with a prior non-AIDS (1) or AIDS event and those with prior exposure to indinavir. Among females, those with a normal eGFR (>90) and those with prior abacavir use had lower odds of PTU (Figure 1). CONCLUSIONS: One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.

Risk of HIV transmission from patients on antiretroviral therapy: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.

High HCV treatment uptake in the Swedish HIV/HCV co-infected cohort.

BACKGROUND: HCV co-infection is a leading cause of death in HIV-positive patients. Despite a strong indication for the treatment of HCV, treatment uptake is generally lower than in HCV mono-infected patients. The aim of this study was to determine the HCV treatment uptake and to define factors associated with initiation or deferral of HCV treatment in Swedish HIV/HCV co-infected patients. METHODS: All 5315 adult HIV-positive patients in Sweden are included in the InfCare HIV database. Demographic, virologic, and treatment data for 652 HIV/HCV co-infected patients were extracted from this database in September 2010. Factors associated with initiation of interferon-based HCV treatment were analysed. Patient- and physician-reported reasons for deferring HCV treatment were investigated in a subgroup. RESULTS: The anti-HCV prevalence was 14% and the chronic HCV infection rate 11%. In total, 25% of HIV/HCV co-infected patients had initiated HCV treatment. HCV genotype 2 or 3, HIV transmission route other than intravenous drug use, and ongoing HIV treatment were factors associated with a higher HCV treatment rate. The main reason for not having initiated HCV treatment was intravenous drug use or alcohol abuse. CONCLUSIONS: The 14% prevalence of anti-HCV noted in Swedish HIV-infected patients was low by international comparisons. The 25% HCV treatment rate noted in our HIV/HCV co-infected patients was high and of the same magnitude as that published for HCV mono-infected patients in Sweden. People who inject drugs had the lowest HCV treatment uptake.

Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons.

BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers. METHODS: Prospective 1-1 case-control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n = 50 matched pairs), non-AIDS-defining (n = 63) events and death (n = 41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers. RESULTS: In sum, 250 patients were included. Median time between first and last sample and last sample and event was 44.6(interquartile range [IQR]: 22.7-72.3) and 3.1(IQR: 1.4-6.4) months. Odds of death decreased by 46.0%(95% confidence interval [CI], 2.0-70.0, P = .04) for a 2-fold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P > .05). In patients with current 25(OH)D <10 ng/mL, hsIL-6 concentration increased by 4.7%(95% CI, .2,9.4, P = .04) annually after adjustment for immunological/inflammatory markers, and no change in hsCRP rate was observed (P = .76). CONCLUSIONS: Low Vitamin D predicts short term mortality in HIV-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated.

Thrombocytopenia is associated with an increased risk of cancer during treated HIV disease.

OBJECTIVE: To assess the relationship between platelet counts and risk of AIDS and non-AIDS-defining events. DESIGN: Prospective cohort. METHODS: EuroSIDA patients with at least one platelet count were followed from baseline (first platelet ≥ 1 January 2005) until last visit or death. Multivariate Poisson regression was used to assess the relationship between current platelet counts and the incidence of non-AIDS-defining (pancreatitis, end-stage liver/renal disease, cancer, cardiovascular disease) and AIDS-defining events. RESULTS: There were 62 898 person-years of follow-up (PYFU) among 12 279 patients, including 1168 non-AIDS-defining events [crude incidence 18.6/1000 PYFU, 95% confidence interval (CI) 17.5-19.6] and 735 AIDS-defining events (crude incidence 11.7/1000 PYFU, 95% CI 10.8-12.5). Patients with thrombocytopenia (platelet count ≤100 × 10/l) had a slightly increased incidence of AIDS-defining events [adjusted incidence rate ratio (aIRR) 1.42, 95% CI 1.07-1.86], when compared to those with platelet counts 101-200 × 10/l, whereas the incidence of non-AIDS-defining events was more than two-fold higher (aIRR 2.66, 95% CI 2.17-3.26). Among non-AIDS-defining events, the adjusted incidence of cancer (aIRR 2.20, 95% CI 1.61-3.01), but not cardiovascular disease (aIRR 0.66, 95% CI 0.32-1.34), was significantly higher in patients with thrombocytopenia. The association between thrombocytopenia and cancer remained unaltered in sensitivity analyses requiring repeated platelet counts to confirm thrombocytopenia and lagging platelets by 1 year prior to clinical events. CONCLUSION: Patients with thrombocytopenia had increased incidence of AIDS-defining and non-AIDS-defining events, but the association with the latter, in particular cancer, was stronger. Future studies should investigate whether the pathophysiological processes underlying thrombocytopenia are associated with the development of cancer during treated HIV disease.

Lopinavir/ritonavir, atazanavir/ritonavir, and efavirenz in antiretroviral-naïve HIV-1-infected individuals over 144 weeks: an open-label randomized controlled trial.

BACKGROUND: The objective of this study was to compare the efficacy of ritonavir boosted atazanavir versus ritonavir boosted lopinavir or efavirenz, all in combination with 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs), over 144 weeks in antiretroviral-naïve HIV-1-infected individuals. METHODS: A prospective open-label randomized controlled trial was conducted at 29 sites in Sweden and Norway between April 2004 and December 2009. Patients were randomized to receive either efavirenz 600 mg once daily (EFV), or atazanavir 300 mg and ritonavir 100 mg once daily (AZV/r), or lopinavir 400 mg and ritonavir 100 mg twice daily (LPV/r). The primary endpoints were the proportion of patients with HIV-1 RNA < 50 copies/ml at 48 and 144 weeks. RESULTS: Of 245 patients enrolled, 243 were randomized and 239 received the allocated intervention: 77 EFV, 81 AZV/r, and 81 LPV/r. Median (interquartile range) CD4 cell counts at baseline were 150 (80-200), 170 (80-220), and 150 (90-216) per microlitre, respectively. At week 48 the proportion (95% confidence interval (CI)) of patients achieving HIV-1 RNA < 50 copies/ml was 86 (78-94)% in the EFV arm, 78 (69-87)% in the AZV/r arm and, 69 (59-78)% in the LPV/r arm in the intention-to-treat analysis. There was a significant difference between the EFV and LPV/r arm (p = 0.014). At week 144, the proportion (95% CI) of patients achieving HIV-1 RNA < 50 copies/ml was 61 (50-72)%, 58 (47-69)%, 51 (41-63)%, respectively (p = 0.8). Patients with CD4 cell counts of ≤ 200/µl or HIV-1 RNA > 100,000 copies/ml at baseline had similar response rates in all arms. CONCLUSION: EFV was superior to LPV/r at week 48, but there were no significant differences between the 3 arms in the long-term (144 weeks) follow-up.

Hepatocellular carcinoma in individuals with HBV infection or HBV-HCV co-infection in a low endemic country.

OBJECTIVE: The aim of this nationwide cohort study was to assess the risk for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection or HBV and hepatitis C virus (HCV) co-infection in Sweden, a low endemic country. MATERIAL AND METHODS: A total of 12,080 patients with HBV and 3238 patients with HBV-HCV co-infection were notified to the Swedish institute for Infectious Disease Control between 1990 and 2004. After excluding 1850 patients with acute HBV and 584 patients infected in adult life, we analyzed the cohort of 9646 subjects with chronic HBV infection. In the co-infection cohort, 1697 patients were analyzed after excluding 1541 cases with acute HBV. The Swedish national cancer registry was used for follow-up. The HCC incidence rate in the cohorts was compared with the HCC incidence rate in the general population and the standardized incidence ratio (SIR) was calculated for different strata according to estimated infection period. RESULTS: HCC was found in 45 patients in the HBV cohort. In the stratum of 40-49 years of infection we found a SIR of 47 and in stratum 50-59 years the SIR was 54. In the co-infected cohort 10 HCCs were found. The SIR in the stratum 20-29 years of infection was 34 and the SIR in the stratum 30 years and over was 91. CONCLUSIONS: This national cohort study of HBV infected and HBV-HCV co-infected subjects in a low endemic country confirms a highly increased risk of liver cancer compared to the general population.