Search

Background The impact of low levels of human immunodeficiency virus (HIV) RNA (low-level viremia [LLV]) during combination antiretroviral therapy (cART) on clinical outcomes is unclear. We explored the associations between LLV and all-cause mortality, AIDS, and serious non-AIDS events (SNAEs). Methods We grouped individuals starting cART 1996–2017 (identified from the Swedish InfCare HIV register) as virologic suppression (VS; <50 copies/mL), LLV (repeated viral load, 50–999 copies/mL), and nonsuppressed viremia (NSV; ≥1000 copies/mL). Separately, LLV was subdivided into 50–199 and 200–999 copies/mL (reflecting different definitions of virologic failure). Proportional-hazard models (including sex, age, pre-ART CD4 count and viral load, country of birth, injection drug use, treatment experience and interruptions, and an interaction term between viremia and time) were fitted for the study outcomes. Results A total of 6956 participants were followed for a median of 5.7 years. At the end of follow-up, 60% were categorized as VS, 9% as LLV, and 31% as NSV. Compared with VS, LLV was associated with increased mortality (adjusted hazard ratio [aHR], 2.2; 95% confidence interval [CI], 1.3–3.6). This association was also observed for LLV 50–199 copies/mL (aHR, 2.2; 95% CI, 1.3–3.8), but was not statistically significant for LLV 200–999 copies/mL (aHR, 2.1; 95% CI,.96–4.7). LLV 50–999 copies/mL was not linked to increased risk of AIDS or SNAEs, but in subanalysis, LLV 200–999 copies/mL was associated with SNAEs (aHR, 2.0; 95% CI, 1.2–3.6). Conclusions In this population-based cohort, LLV during cART was associated with adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Effective antiretroviral treatment of HIV-1, defined as continuously undetectable virus in blood, has substantial effects on the infectiousness and spread of HIV. This paper outlines the assessment of the Swedish Reference Group for Antiviral Therapy (RAV) and Public Health Agency of Sweden regarding contagiousness of HIV-infected persons on antiretroviral therapy (ART). Results and Conclusion: The expert group concludes that there is no risk of transmission of HIV during vaginal or anal intercourse if the HIV-infected person fulfils the criteria for effective ART. Summary: The effective antiretroviral therapy (ART) for HIV-1 infection has dramatically reduced the morbidity and mortality among people who live with HIV. ART also has a noticeable effect on the infectiousness and on the spread of the disease in society. Knowledge about this has grown gradually. For ART to be regarded effective, the level of the HIV RNA in the plasma should be repeatedly and continuously undetectable and the patient should be assessed as continually having high adherence to treatment. Based on available knowledge the Swedish Reference Group for Antiviral Therapy (RAV) and the Public Health Agency of Sweden make the following assessment: There is no risk of HIV transmission during vaginal or anal intercourse if the HIV positive person fulfils the criteria for effective treatment. This includes intercourse where a condom is not used. However, there are a number of other reasons for recommending the use of condoms, primarily to protect against the transmission of other STIs (sexually transmitted infections) and hepatitis, as well as unwanted pregnancy. The occurrence of other STIs does not affect the risk of HIV transmission in persons on effective ART. It is plausible that the risk for transmission of HIV infection between people who inject drugs and share injection equipment is reduced if the individual with HIV is on effective ART, but there are no studies that directly show this. The risk of transmission from mother to child during pregnancy, labour and delivery is very low if the mother's treatment is initiated well before delivery and if the treatment aim of undetectable virus levels is attained. This is dependent on healthcare services being aware of the mother's HIV infection at an early stage. In most contacts with health and medical care, including dental care, the risk of transmission is not significant if the patient is on effective treatment, but the risk may remain, although considerably reduced, in more advanced interventions such as surgery. When an incident with risk of transmission occurs, the patient must always inform those potentially exposed about his or her HIV infection. [ABSTRACT FROM AUTHOR]

The Swedish Reference Group for Antiviral Therapy (RAV) published recommendations for the treatment of HIV infection in this journal most recently in 2017. An expert group under the guidance of RAV here provides updated recommendations. The most important updates in the present guidelines are the following: (a) The risk of HIV transmission through condomless sex from individuals with fully suppressed HIV viral load is effectively zero. (b) Pre-exposure prophylaxis (PrEP) is recommended for groups with a high risk of HIV infection. (c) Since the last update, two new substances have been registered: bictegravir and doravirine. (d) Dual treatment may be an alternative in selected patients, using lamivudine + dolutegravir or lamivudine + boosted darunavir/atazanavir. As with previous publications, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine. This document does not cover treatment of opportunistic infections and tumours. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Describe trends in antiretroviral treatments and drug resistance mutations among Swedish HIV-patients over time 1997–2011. Methods: Treatment histories, viral sequences, and demographic and clinical data were retrieved from the national database InfCareHIV. All ART-experienced patients were included (N = 6537), while resistance tests were restricted to those obtained ≥90 days after ART start. This cohort is fully representative for Sweden since the database covers virtually all diagnosed HIV-patients since the start of the epidemic. Patients were grouped according to the year of first ART, and treatments and mutations were analyzed by calendar year. Results: The prevalence of major drug resistance mutations decreased dramatically over time, most rapidly between 2003 and 2007. Since then there has been a continued slow decrease for NRTI- and PI-associated mutations with an overall prevalence among all ART-experienced patients at 1.1% (NRTI) and 0.3% (PI) in 2011. NNRTI resistance reached the lowest level in 2007–2009 (0.6%), but is now increasing (0.9% in 2011). Patients with first ART exposure before 2001 are still highly overrepresented among those with PI and, to a lesser extent, NRTI resistance. In contrast, almost half of the patients with NNRTI mutations in 2011 initiated their first ART after 2007. Conclusions: Tremendous improvements in ART options and knowledge have resulted in rapidly declining levels of resistance, and most of the current NRTI and PI mutations are found among patients with a history of suboptimal treatments. However, NNRTI resistance is increasing and is primarily found in patients infected in low- and middle-income countries who initiated ART in recent years. It is plausible that these patients were infected with resistant strains and it is therefore suggested that resource-rich countries like Sweden should test for resistance in minor quasispecies or use PI-based first-line regimens in patients who are at increased risk of carrying resistant virus. [ABSTRACT FROM AUTHOR]

Transmitted drug resistance (TDR) is a clinical and epidemiological problem because it may contribute to failure of antiretroviral treatment. The prevalence of TDR varies geographically, and its prevalence in Sweden during the last decade has not been reported. Plasma samples from 1,463 patients newly diagnosed with HIV-1 infection between 2003 and 2010, representing 44% of all patients diagnosed in Sweden during this period, were analyzed using the WHO 2009 list of mutations for surveillance of TDR. Maximum likelihood phylogenetic analyses were used to determine genetic subtype and to investigate the relatedness of the sequences. Eighty-two patients showed evidence of TDR, representing a prevalence of 5.6% (95% CI: 4.5%-6.9%) without any significant time trends or differences between patients infected in Sweden or abroad. Multivariable logistic regression showed that TDR was positively associated with men who have sex with men (MSM) and subtype B infection and negatively associated with CD4 cell counts. Among patients with TDR, 54 (68%) had single resistance mutations, whereas five patients had multi-drug resistant HIV-1. Phylogenetic analyses identified nine significantly supported clusters involving 29 of the patients with TDR, including 23 of 42 (55%) of the patients with TDR acquired in Sweden. One cluster contained 18 viruses with a M41L resistance mutation, which had spread among MSM in Stockholm over a period of at least 16 years (1994-2010). Another cluster, which contained the five multidrug resistant viruses, also involved MSM from Stockholm. The prevalence of TDR in Sweden 2003-2010 was lower than in many other European countries. TDR was concentrated among MSM, where clustering of TDR strains was observed, which highlights the need for continued and improved measures for targeted interventions. [ABSTRACT FROM AUTHOR]

Prophylaxis and treatment with antiretroviral drugs and the use of elective caesarean section have resulted in a very low mother-to-child transmission of human immunodeficiency virus (HIV) during recent years. The availability of new antiretroviral drugs, updated general treatment guidelines and increasing knowledge of the importance of drug resistance, have necessitated regular revisions of the ''Prophylaxis and treatment of HIV-1 infection in pregnancy'' recommendations. For these reasons, The Swedish Reference Group for Antiviral Therapy (RAV) updated the 2007 recommendations at an expert meeting that took place on 25 March 2010. The most important revisions from the previous recommendations are: (1) it is recommended that treatment during pregnancy starts at the latest at gestational week 14--18; (2) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (3) lopinavir/r and atazanavir/r are equally recommended protease inhibitors; (4) if maternal HIV RNA is >50 copies/ml close to delivery, a planned caesarean section, intravenous zidovudine, oral nevirapine for the mother and post-exposure prophylaxis for the infant with 3 antiretroviral drugs are recommended; (5) for delivery at <34 gestational weeks, intravenous zidovudine and oral nevirapine for the mother and at 48--72 h for the infant is recommended, in addition to other prophylaxis; (6) intravenous zidovudine is not recommended when HIV RNA is <50 copies/ml and a caesarean section is performed; (7) it is recommended that prophylaxis for the infant is started within 4 h; (8) prophylactic zidovudine for the infant may be administered twice daily instead of 4 times a day, as was the case previously; and (9) the number of sampling occasions for the infant has been decreased. [ABSTRACT FROM AUTHOR]

Prophylaxis and treatment with antiretroviral drugs, a consequent low viral load, and the use of elective Caesarean section, are factors that radically decrease the risk of HIV transmission from mother to child during pregnancy and delivery. The availability of new antiretroviral drugs, updated general treatment guidelines and increasing knowledge of the importance of drug resistance, have necessitated recurrent revisions of the recommendations for 'Prophylaxis and treatment of HIV-1 infection in pregnancy'. For these reasons, The Swedish Reference Group for Antiviral Therapy (RAV) has, at an expert meeting on May 4, 2007, once more updated the treatment recommendations of 1999, 2002 and 2005, which were defined in cooperation with the Swedish Medical Products Agency (Lakemedelsverket). This new text takes the recently updated general HIV treatment recommendations into account. Furthermore, the very low risk of HIV transmission when the mother is treated with combination antiretroviral therapy, has undetectable levels of viraemia and no obstetric risk factors, has been considered in the recommendations concerning the mode of delivery. Finally, the recommendations for monitoring of infants born to HIV-infected mothers have been modified. The recommendations are evidence graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels). [ABSTRACT FROM AUTHOR]

On 3 previous occasions, in 2002, 2003 and 2005, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. An expert group, under the guidance of RAV, has now revised the text again. Since the publication of the previous treatment recommendations, 1 new drug for the treatment of HIV has been approved - the protease inhibitor (PI) darunavir (Prezista®). Furthermore, 3 new drugs have become available: the integrase inhibitor raltegravir (MK-0518), the CCR5-inhibitor maraviroc (Celsentri®), both of which have novel mechanisms of action, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC-125). The new guidelines differ from the previous ones in several respects. The most important of these are that abacavir is now preferred to tenofovir and zidovudine, as a first line drug in treatment-naïve patients, and that initiation of antiretroviral treatment is now recommended before the CD4 cell count falls below 250/µl, rather than 200/µl. Furthermore, recommendations on the treatment of HIV infection in children have been added to the document. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels). [ABSTRACT FROM AUTHOR]

On 2 earlier occasions, in 2002 and 2003, the Swedish Medical Products Agency (MPA) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly publicized recommendations for the treatment of HIV infection. A working group from the same expert team that produced the 2002 report has now revised the text again. Since the publication of the last treatment recommendations, 4 new medicines have become available: emtricitabine, atazanavir, fosamprenavir, and enfuvirtid. The last-mentioned belongs to a new class of HIV medications called fusion inhibitors (Box 1). It is likely that tipranavir will also be on the market soon. Simultaneously, the drug zalcitabin has been deregistered. The following updated recommendations parallel the earlier ones, but increased knowledge allows us to be more specific in our recommendations. Thus, it is now suggested that the initial treatment for HIV infection consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI); or 2 NRTIs and 1 protease inhibitor (PI). In the group of the NRTIs, stavudine is no longer recommended for this purpose. In the NNRTI group, efavirenz should be preferred to nevirapine, except under special circumstances. Finally, PIs ought to be boosted with ritonavir (PI/r). Also new are recommendations regarding treatment choices for patients co-infected with hepatitis B virus (HBV) or tuberculosis (TB). As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels), and have been supplemented with references to newly-added sections and data not referred to in earlier background documentation. [ABSTRACT FROM AUTHOR]

Discusses guidelines for antiretroviral treatment of HIV infections in Sweden. Comparison with other treatment standards; Indications for initiation of treatment; Drug regimen components.

BackgroundSweden reached the UNAIDS 90-90-90 target in 2015. It is important to reassess the HIV epidemiological situation due to ever-changing migration patterns, the roll-out of PrEP and the impact of the COVID-19 pandemic.AimWe aimed to assess the progress towards the UNAIDS 95-95-95 targets in Sweden by estimating the proportion of undiagnosed people with HIV (PWHIV) and HIV incidence trends.MethodsWe used routine laboratory data to inform a biomarker model of time since infection. When available, we used previous negative test dates, arrival dates for PWHIV from abroad and transmission modes to inform our incidence model. We also used data collected from the Swedish InfCareHIV register on antiretroviral therapy (ART).ResultsThe yearly incidence of HIV in Sweden decreased after 2014. In part, this was because the fraction of undiagnosed PWHIV had decreased almost twofold since 2006. After 2015, three of four PWHIV in Sweden were diagnosed within 1.9 and 3.2 years after infection among men who have sex with men and in heterosexual groups, respectively. While 80% of new PWHIV in Sweden acquired HIV before immigration, they make up 50% of the current PWHIV in Sweden. By 2022, 96% of all PWHIV in Sweden had been diagnosed, and 99% of them were on ART, with 98% virally suppressed.ConclusionsBy 2022, about half of all PWHIV in Sweden acquired HIV abroad. Using our new biomarker model, we assess that Sweden has reached the UNAIDS goal at 96-99-98.

In May 2024, the Swedish Reference Group on Antiviral Therapy updated the guidelines on management of HIV infection in pregnancy. The most important recommendations and revisions were: (i) ART during pregnancy should be started as early as possible and continue after delivery; (ii) Suppressive ART should normally not be modified; (iii) The treatment target of HIV RNA <20 copies/ml remains; (iv) Dolutegravir/emtricitabine/tenofovir DF is the first-line drug combination also in pregnant women and women planning pregnancy; (v) There is no evidence of an increased risk of neural tube defects associated with dolutegravir; (vi) Mode of delivery for women with effective ART and HIV RNA <200 copies/ml should follow standard obstetric procedures; (vii) Caesarean section is recommended if HIV RNA ≥200 copies/ml; (viii) Scalp electrode, foetal blood sampling and/or vacuum delivery should be used on strict indications, but does not necessitate intensified infant prophylaxis; (ix) Management and mode of delivery in case of premature or full-term rupture of membranes should follow standard obstetric procedures; (x) Recommended infant antiretroviral prophylaxis has been updated; (xi) The duration of infant antiretroviral prophylaxis (gestational age ≥35 weeks and mother on effective ART and HIV RNA <200 copies/ml) has been changed from 4 to 2 weeks; (xii) Infants born to women with HIV RNA ≥200 copies/ml should receive 4 weeks of combination prophylaxis; (xiii) Fertility evaluation and assisted reproduction should be offered to women on suppressive ART according to the same principles as for other women; (xiv) Women living with HIV should still be advised against breastfeeding; (xv) Women who nevertheless opt to breastfeed should be offered intensified support and follow-up.

BackgroundThe global distribution of HIV-1 subtypes is evolving, which is reflected in the Swedish HIV cohort. The subtype HIV-1A6, which may be prone to developing resistance to cabotegravir, is the most common subtype in Ukraine.AimWe aimed to examine trends in HIV-1 subtype distribution in Sweden, with a special focus on HIV-1A6, and to describe the virology, demography and treatment of Ukrainian people living with HIV (PLWH) who migrated to Sweden in 2022.MethodsData about PLWH in Sweden are included in a national database (InfCareHIV). We used the online tool COMET to establish HIV-1 subtypes and the Stanford database to define drug resistance mutations. We investigated the relation between virological characteristics and demographic data.ResultsThe early epidemic was predominated by HIV-1 subtype B infections in people born in Sweden. After 1990, the majority of new PLWH in Sweden were PLWH migrating to Sweden, resulting in an increasingly diverse epidemic. In 2022, HIV-1A6 had become the sixth most common subtype in Sweden and 98 of the 431 new PLWH that were registered in Sweden came from Ukraine. We detected HIV RNA in plasma of 32 Ukrainian patients (34%), of whom 17 were previously undiagnosed, 10 had interrupted therapy and five were previously diagnosed but not treated. We found HIV-1A6 in 23 of 24 sequenced patients.ConclusionThe molecular HIV epidemiology in Sweden continues to diversify and PLWH unaware of their HIV status and predominance of HIV-1A6 should be considered when arranging care directed at PLWH from Ukraine.

Purpose: The Swedish InfCareHIV cohort was established in 2003 to ensure equal and effective care of people living with HIV (PLHIV) and enable long-term follow-up. InfCareHIV functions equally as a decision support system as a quality registry, ensuring up-to-date data reported in real time., Participants: InfCareHIV includes data on >99% of all people with diagnosed HIV in Sweden and up to now 13 029 have been included in the cohort. InfCareHIV includes data on HIV-related biomarkers and antiretroviral therapies (ART) and also on demographics, patient-reported outcome measures and patient-reported experience measures., Findings to Date: Sweden was in 2015 the first country to reach the UNAIDS (United Nations Programme on HIV/AIDS)/WHO's 90-90-90 goals. Late diagnosis of HIV infection was identified as a key problem in the Swedish HIV-epidemic, and low-level HIV viraemia while on ART associated with all-cause mortality. Increased HIV RNA load in the cerebrospinal fluid (CSF) despite suppression of the plasma viral load was found in 5% of PLHIV, a phenomenon referred to as 'CSF viral escape'. Dolutegravir-based treatment in PLHIV with pre-existing nucleoside reverse transcriptase inhibitor-mutations was non-inferior to protease inhibitor-based regimens. An increase of transmitted drug resistance was observed in the InfCareHIV cohort. Lower efficacy for protease inhibitors was not due to lower adherence to treatment. Incidence of type 2 diabetes and insulin resistance was high in the ageing HIV population. Despite ART, the risk of infection-related cancer as well as lung cancer was increased in PLHIV compared with HIV-negative. PLHIV were less likely successfully treated for cervical precancer and more likely to have human papillomavirus types not included in current HPV vaccines. Self-reported sexual satisfaction in PLHIV is improving and is higher in women than men., Future Plans: InfCareHIV provides a unique base to study and further improve long-term treatment outcomes, comorbidity management and health-related quality of life in people with HIV in Sweden., Competing Interests: Competing interests: CC has received lecture, moderator and advisory board fees from GSK/ViiV, Gilead Sciences and MSD and an unrestricted Nordic Fellowship Grant from Gilead Sciences Nordic. JB has received lecture and advisory board fees from GSK/ViiV and Gilead. FM has received lecture and advisory board fees from GSK/ViiV, AstraZeneca and Gilead Sciences. OE has received a grant to his institution from Pfizer and honoraria as speaker from Gilead Sciences. HN has received advisory board fees from Gilead and AbbVie. AM has received lecture and advisory board fees from GSK/ViiV, Gilead Sciences and Pfizer. MG has received research grants from Gilead Sciences and Janssen-Cilag and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi. AS has received research grants from Gilead Sciences and honoraria as speaker, DSMB committee member and/or scientific advisor from AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV and MSD. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

People living with HIV (PLHIV) have an increased risk of hematologic malignancies (HMs). We aimed to characterize HMs among PLHIV at Karolinska University Hospital, Stockholm, Sweden. We studied all PLHIV receiving care at our center between 2004 and 2018. Data were retrieved retrospectively from InfCareHIV database and medical records. Around 3,484 patients received HIV care for a total of 22,903 person-years (py) with median follow-up of 7.6 years. HMs were identified in 43 patients with 30 cases of non-Hodgkin lymphoma (NHL), 9 cases of Hodgkin lymphoma (HL), 2 multicentric Castleman's disease, and 1 case each of myeloma and myelodysplastic syndrome. The incidence rate of NHL was 88/10 5 py and HL 39.6/10 5 py. The incidence of NHL declined 2004-2010 versus 2011-2018 (180.8 vs. 40.1/10 5 py; p  = .001). Median time from HIV diagnosis to malignancy was shorter in NHL compared with HL (1.2 years vs. 8.9 years; p  = .01) and effective HIV treatment was less common in NHL (33% vs. 100%; p  < .001). The 5-year survival rate of NHL was 59% and HL 43%, significantly lower compared with lymphoma survival in the general population in Sweden. In the era of effective antiretroviral therapy (ART), the incidence rate of lymphoma was more than five times higher in PLHIV and 5-year survival significantly inferior. Efforts for earlier identification of HIV-infected individuals are likely to affect the incidence of NHL. Additionally, an effective screening for clinical and laboratory signs of HL in PLHIV on ART should be introduced to improve identification and survival of HL in this population.

Objectives: HIV-1 pretreatment drug resistance (PDR) is a global concern. Our aim was to evaluate high-throughput sequencing (HTS) for HIV-1 resistance testing and describe PDR in Sweden, where 75% of diagnosed individuals are foreign-born., Design: Cross-sectional study., Methods: Individuals entering HIV-1 care in Sweden 2017 to March 2019 (n = 400) were included if a viremic sample was available (n = 220). HTS was performed using an in-house assay. Drug resistance mutations (DRMs) (based on Stanford HIV DB vs. 8.7) at levels 1-5%, 5-19% and at least 20% of the viral population were described. Results from HTS and routine Sanger sequencing were compared., Results: HTS was successful in 88% of patients, 92% when viral load was at least 1000 copies/ml. DRMs at any level in protease and/or reverse transcriptase were detected in 95 individuals (49%), whereas DRMs at least 20% in 35 (18%) individuals. DRMs at least 20% correlated well to findings in routine Sanger sequencing. Protease/reverse transcriptase (PR/RT) DRMs at least 20% were predicted by treatment exposure; adjusted OR 9.28 (95% CI 2.24-38.43; P = 0.002) and origin in Asia; adjusted OR 20.65 (95% CI 1.66-256.24; P = 0.02). Nonnucleoside reverse transcriptase inhibitor (NNRTI) DRMs at least 20% were common (16%) and over-represented in individuals originating from sub-Saharan Africa or Asia. Low-level integrase strand transfer inhibitor (INSTI) DRMs less than 20% were detected in 15 individuals (8%) with no association with INSTI exposure., Conclusion: Our HTS can efficiently detect PDR and findings of DRMs at least 20% compare well to routine Sanger sequencing. The high prevalence of PDR was because of NNRTI DRMs and associated with migration from areas with emerging PDR., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Marginal structural Cox models have been used to estimate the causal effect of a time-varying treatment on a survival outcome in the presence of time-dependent confounders. These methods rely on the positivity assumption, which states that the propensity scores are bounded away from zero and one. Practical violations of this assumption are common in longitudinal studies, resulting in extreme weights that may yield erroneous inferences. Truncation, which consists of replacing outlying weights with less extreme ones, is the most common approach to control for extreme weights to date. While truncation reduces the variability in the weights and the consequent sampling variability of the estimator, it can also introduce bias. Instead of truncated weights, we propose using optimal probability weights, defined as those that have a specified variance and the smallest Euclidean distance from the original, untruncated weights. The set of optimal weights is obtained by solving a constrained quadratic optimization problem. The proposed weights are evaluated in a simulation study and applied to the assessment of the effect of treatment on time to death among people in Sweden who live with human immunodeficiency virus and inject drugs., (© 2018 John Wiley & Sons, Ltd.)

BackgroundSweden has a low HIV prevalence. However, among new HIV diagnoses in 2016, the proportion of late presenters and migrants was high (59% and 81%, respectively). This poses challenges in estimating the proportion of undiagnosed persons living with HIV (PLHIV).AimTo estimate the proportion of undiagnosed PLHIV in Sweden comparing two models with different demands on data availability and modelling expertise.MethodsAn individual-based stochastic simulation model of HIV positive populations (SSOPHIE) and the incidence method of the European Centre for Disease Prevention and Control (ECDC) HIV Modelling Tool were applied to clinical, surveillance and migration data from Sweden 1980-2016.ResultsSSOPHIE estimated that the proportion of undiagnosed PLHIV in 2013 was 26% (n = 2,100; 90% plausibility range (PR): 900-5,000) for all PLHIV, 17% (n = 600; 90% PR: 100-2,000) for men who have sex with men (MSM), 35% in male (n = 300; 90% PR: 200-700) and 34% in female (n = 400; 90% PR: 200-800) migrants from sub-Saharan Africa (SSA). The estimates for the ECDC model in 2013 were 21% (n = 2,013; 95% confidence interval (CI): 1,831-2,189) for all PLHIV, 15% (n = 369; 95% CI: 299-434) for MSM and 21% (n = 530; 95% CI: 436-632) for migrants from SSA.ConclusionsThe proportion of undiagnosed PLHIV in Sweden is uncertain. SSOPHIE estimates had wide PR. The ECDC model estimates were unreliable because migration was not accounted for. Better migration data and estimation methods are required to obtain reliable estimates of proportions of undiagnosed PLHIV in similar settings.

Objectives: To assess if women living with HIV (WLWH) have poorer outcome after treatment of cervical intraepithelial neoplasia grade 2, grade 3, adenocarcinoma in situ or cervical cancer (CIN2+) than HIV-negative women (HNW) and to identify predictors of CIN2+ treatment failure and recurrence in WLWH., Design: Population-based cohort study with follow-up between 1983 and 2015., Methods: The Swedish National HIV Registry, the Swedish Population Registry and the Swedish National Cervical Screening Registry were linked to identify all women in Stockholm and Gothenburg counties (Sweden) living with HIV and diagnosed with CIN2+ (n = 179) sometime between 1983 and 2014. For each WLWH, two HNW resident in the same counties and matched for country of birth, diagnosed with CIN2+, were chosen as controls. Treatment failure was defined as the presence of CIN2+ at initial follow-up. Recurrence was defined as the presence of CIN1+ subsequent to an initial normal follow-up., Results: WLWH were three times more likely to have treatment failure (odds ratio (OR) 3.7 [95% confidence interval (CI) 2.0-6.8]) and five times more likely to recur (hazard ratio 5.0 [95% CI 2.1-11.6]) than HNW. Suppressive antiretroviral therapy (ART) at time of treatment of CIN2+ was associated with reduced OR of treatment failure (OR 0.3 [95% CI 0.1-0.8]). Immunosuppression (CD4 cell count <200 cells/μl) associated strongly with treatment failure (OR compared with CD4 cell count ≥500: 8.5 [95% CI 2.3-30.7])., Conclusion: Suppressive ART is associated with effective treatment of CIN2+. Early HIV diagnosis and ART are essential for successful CIN2+ treatment.

Objective: To study the trends of transmitted drug resistance (TDR) in HIV-1 patients newly diagnosed in Sweden, 2010-2016., Design: Register-based study including all antiretroviral therapy-naive patients ≥18 years diagnosed with HIV-1 in Sweden 2010-2016., Methods: Patient data and viral pol sequences were extracted from the national InfCareHIV database. TDR was defined as the presence of surveillance drug resistance mutations (SDRMs). A CD4 T-cell decline trajectory model estimated time of infection. Phylogenetic inference was used for cluster analysis. Chi-square tests and logistic regressions were used to investigate relations between TDR, epidemiological and viral factors., Results: One thousand, seven hundred and thirteen pol sequences were analyzed, corresponding to 71% of patients with a new HIV-1 diagnosis (heterosexuals: 53%; MSM: 34%). The overall prevalence of TDR was 7.1% (95% CI 5.8-8.3%). Nonnucleoside reverse transcriptase inhibitor (NNRTI) TDR increased significantly from 1.5% in 2010 to 6.2% in 2016, and was associated to infection and/or origin in sub-Saharan Africa (SSA). An MSM transmission cluster dating back to the 1990s with the M41L SDRM was identified. Twenty-five (1.5%) patients exhibited TDR to tenofovir (TDF; n = 8), emtricitabine/lamivudine (n = 9) or both (n = 8)., Conclusion: NNRTI TDR has increased from 2010 to 2016 in HIV-1-infected migrants from SSA diagnosed in Sweden, mirroring the situation in SSA. TDR to tenofovir/emtricitabine, used in preexposure prophylaxis, confirms the clinical and epidemiological need for resistance testing in newly diagnosed patients.

A temporal increase in non-B subtypes has earlier been described in Sweden by us and we hypothesized that this increased viral heterogeneity may become a hotspot for the development of more complex and unique recombinant forms (URFs) if the epidemics converge. In the present study, we performed subtyping using four automated tools and phylogenetic analysis by RAxML of pol gene sequences (n = 5246) and HIV-1 near full-length genome (HIV-NFLG) sequences (n = 104). A CD4 + T-cell decline trajectory algorithm was used to estimate time of HIV infection. Transmission clusters were identified using the family-joining method. The analysis of HIV-NFLG and pol gene described 10.6% (11/104) and 2.6% (137/5246) of the strains as URFs, respectively. An increasing trend of URFs was observed in recent years by both approaches (p = 0·0082; p < 0·0001). Transmission cluster analysis using the pol gene of all URFs identified 14 clusters with two to eight sequences. Larger transmission clusters of URFs (BF1 and 01B) were observed among MSM who mostly were sero-diagnosed in recent time. Understanding the increased appearance and transmission of URFs in recent years could have importance for public health interventions and the use of HIV-NFLG would provide better statistical support for such assessments.

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].

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.

Objective: To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naïve HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR)., Methods: Treatment naïve adults (n=191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N., Results: The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East- African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naïve patient groups by population sequencing., Conclusions: Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naïve HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naïve patients should be topic for future large scale studies.

The IL28B genotype has been found to have a strong influence on spontaneous clearance of acute HCV both in HCV mono- and HIV/ the HCV co-infected patients. Spontaneous clearance of chronic HCV without HCV treatment is rare. Here, we report on three chronic HCV cases co-infected with HIV with spontaneous clearance of their HCV infection, all with the IL28B CC genotype. These cases were derived from a surveillance of the total HIV/HCV co-infected cohort in Sweden (n =4 66). The estimated frequency of spontaneous clearance of chronic HCV infection in our cohort was calculated to be 0.6-4.7%. Our cases lend some support to the initiation of ART prior to HCV treatment in HIV/HCV co-infected patients. Furthermore, HCV-RNA testing should be recommended immediately before initiation of HCV treatment, to find the subset of HIV/HCV co-infected patients with IL28B CC that may have cleared their chronic infection spontaneously., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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.

Prophylaxis and treatment with antiretroviral drugs and elective caesarean section delivery have resulted in very low mother-to-child transmission of HIV during recent years. Updated general treatment guidelines and increasing knowledge about mother-to-child transmission have necessitated regular revisions of the recommendations for the prophylaxis and treatment of HIV-1 infection in pregnancy. The Swedish Reference Group for Antiviral Therapy (RAV) updated the recommendations from 2010 at an expert meeting on 11 September 2013. The most important revisions are the following: (1) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (2) if treatment is initiated during pregnancy, the recommended first-line therapy is essentially the same as for non-pregnant women; (3) raltegravir may be added to achieve rapid reduction in HIV RNA; (4) vaginal delivery is recommended if at > 34 gestational weeks and HIV RNA is < 50 copies/ml and no obstetric contraindications exist; (5) if HIV RNA is < 50 copies/ml and delivery is at > 34 gestational weeks, intravenous zidovudine is not recommended regardless of the delivery mode; (6) if HIV RNA is > 50 copies/ml close to delivery, it is recommended that the mother should undergo a planned caesarean section, intravenous zidovudine, and oral nevirapine, and the infant should receive single-dose nevirapine at 48-72 h of age and post-exposure prophylaxis with 2 drugs; (7) if delivery is preterm at < 34 gestational weeks, a caesarean section delivery should if possible be performed, with intravenous zidovudine and oral nevirapine given to the mother, and single-dose nevirapine given to the infant at 48-72 h of age, as well as post-exposure prophylaxis with 2 additional drugs.

Background: Successful treatment reduces morbidity, mortality and transmission of HIV. We evaluated trends in the treatment status of HIV infected individuals enrolled in care in Sweden and Denmark during the years 1995-2010. Our aim was to assess the proportion of HIV-infected individuals who received services along the continuum of care in Denmark in 2010, and to discuss the findings in relation to the organization of the health care system., Methods: We analyzed CD4 counts and viral loads (VL) among all HIV patients enrolled in the cohort. For each month of the study period we estimated the proportions of patients who 1) had initiated highly active antiretroviral treatment (HAART) and had VL<500 copies/mL, 2) were not eligible for HAART, 3) had initiated HAART but had VL≥500 copies/mL, 4) were eligible for, but had not initiated HAART and 5) had initiated HAART but no VL monitoring for >13 months or 6) no HAART or monitoring of CD4 for >13 months. Patients fulfilling criteria 1 or 2 were considered successfully managed., Results: The proportion of successfully managed patients continued to increase throughout the study period and reached 83% in 2010, 92% of Swedish/Danish men who have sex with men and heterosexual patients, but only 74% of immigrants and 78% of injection drug users were successfully managed due to higher rates of inadequate monitoring in the latter two groups. In 2010, 70% of all individuals diagnosed with HIV in Denmark were virally suppressed., Conclusion: In a public health care system with free access to specialized care, successful management of the majority of HIV patients is achievable. Interventions tailored to retain immigrants and injection drug users in care are needed to further reduce the proportion of sub-optimally treated HIV patients.

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.

On 4 previous occasions, in 2002, 2003, 2005 and 2007, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. In November 2008, an expert group under the guidance of RAV once more revised the guidelines, of which this is a translation into English. The most important updates in the present guidelines include the following: (a) treatment initiation is now recommended at a CD4 cell count of approximately 350/microl; (b) new recommendations for first-line therapy: abacavir/lamivudine or tenofovir/emtricitabine in combination with efavirenz or a boosted protease inhibitor (PI/r); (c) an increased focus on reducing the use of antiretroviral drugs that may cause lipoatrophy; (d) an emphasis on quality assurance of HIV care through the use of InfCare HIV; (e) considerably altered recommendations for the initiation of antiretroviral therapy in children. All infants (<1 y) should start antiretroviral therapy, regardless of immune status. Also, absolute CD4+ cell counts, rather than percentage, may be used to guide treatment initiation in children above the age of 5 y.

Objective: The objective of this secondary analysis of data from a cross-sectional, nation-wide survey, was to test a hypothesized model with two latent concepts (readiness and adherence), based on the theory of trigger events. A secondary objective was to compare this model with two simpler models, without the concept of readiness., Methods: Data consisted of a consecutive sample of 828 HIV patients > or = 18 years on antiretroviral treatment at 30 out of 32 HIV Clinics in Sweden (response rate 97.5%). Structural equation modeling (SEM) was used to test the models against the empirical data. Chi2 test was used to compare fit between models., Results: The hypothesized model, with two latent concepts (readiness and adherence), fitted the data best (chi(2)=223.508, d.f.=129, p-value<0.0001, GFI=0.970, CFI=0.913, RMSEA=0.030), and significantly better than the models with adherence as the only latent concept., Conclusion: Although the SEM technique could not rule out that other models might also fit the data equally well, the hypothesized model, where readiness and adherence were two separate latent concepts, fitted data the best. This supports readiness as a distinct factor that influences adherence and hence treatment outcome. Increased attention should therefore be attached to interventions that focus on the individual' readiness for behavioural change, i.e. factors amendable to change and that can be addressed by the patients themselves., Practice Implications: Based on these results it seems necessary to shift focus from adherence to readiness, especially in conditions where treatment can be postponed such as antiretroviral treatment.

Objective: The aim of this study was to compare the level of adherence and motivation in two independent cross-sectional samples of HIV-infected patients conducted in 1998 and 2002, and to investigate the relationship between adherence and motivation., Method: Consecutive HIV-infected patients on treatment at a Swedish clinic were asked to complete an anonymous questionnaire. In 1998, 60 patients participated and in 2002, 53 participated. In 2002, the 9-item Morisky Medication Adherence Scale (MMAS) was added to the questionnaire set., Main Outcome Measure: Self-reported adherence and motivation., Results: In 1998, 28.1% of the respondents were considered adherent, while the corresponding proportion was 57.4% in 2002 (P = 0.002). The mean summary score for MMAS was 10.7 in 2002 (13 = perfect adherence). The proportion considered motivated were 22.4% in the 1998 survey and 41.3% in 2002 (P = 0.038). Of the respondents considered motivated in the 2002 survey, 46.7% scored the maximum summary score on the MMAS, while 8.7% of the non-motivated respondents did so (P = 0.016)., Conclusion: The respondents in 2002 were more adherent and motivated than the respondents in 1998 and a relationship between motivation and adherence was found. The difference in adherence and motivation might be due to a new treatment model at the clinic.

The non-nucleoside reverse transcriptase inhibitor efavirenz is mainly metabolised by the polymorphic cytochrome P450 enzyme CYP2B6. Genomic DNA from four subjects in a group of 51 patients being treated with efavirenz and having surprisingly high plasma concentrations were screened by direct sequencing for mutations in the CYP2B6 gene. Four exonic single nucleotide polymorphisms (SNPs), 516G > T, 714G > A, 785A > G and 983T > C, and eight intronic SNPs were identified. Haplotype analysis revealed that 983T > C was linked with 785A > G defining a novel allele, CYP2B6*16. This allele was present in totally five of the patients. The CYP2B6.16 cDNA was expressed in yeast and HEK293 cells and significantly less protein was formed compared to the wild-type cDNA, in both heterologous systems. By contrast, the catalytic activity of the enzyme variant was not different from the CYP2B6.1 enzyme, using bupropion as a probe substrate. The CYP2B6*16 allele was not found in Swedes, was present at 4% frequency among Turks, but was common among Africans. The steady-state level of efavirenz was significantly higher in the five carriers of CYP2B6*16, being of African origin, compared to the other patients. Higher efavirenz concentrations were also seen in carriers of 516G>T (CYP2B6*6 and CYP2B6*9). In conclusion, a novel CYP2B6*16 allele causing less expression of the corresponding enzyme was identified and found to influence the metabolism of efavirenz in vivo, a finding that is of potential impact for anti-HIV therapy in black populations.

A selective real-time PCR (SPCR) method was developed and evaluated for discrimination of resistance mutations in minor human immunodeficiency virus type 1 (HIV-1) populations, using the M184 mutation site as a model system due to its high clinical importance and the low genetic barrier to its development. The method enabled detection of minor viral populations down to 0.1%, and the relative proportions of different quasispecies could be easily displayed using cycle threshold (C(t)) values. An excellent concordance was found when the assay was compared with direct sequencing and cloning results. The impact of mismatch between virus and primer/probe sequences was evaluated, showing that 3' end mutations in the selective downstream primers were very disruptive and that 5' end polymorphisms in the probe area were directly fatal, while mutations in the middle or the 3' end of the probe were less disruptive. These effects were compensated by introducing wobble bases to accommodate the mutations. This sensitive and reliable point-mutation assay, analyzing M184I/V and other important mutations, will be fruitful in gaining new scientific knowledge about the kinetics of resistance mutations in minor viral populations of HIV-1 infected patients at failure of antiretroviral therapy.

Antiretroviral combination therapy has markedly decreased the mortality and morbidity in HIV-disease during the last years. An increasing number of new antiretroviral agents has been introduced and there has been a rapid evolution of new information regarding treatment of HIV. Physicians and patients have to deal with medical associated side-effects, problems with adherence, and viral resistance. Recently a national expert group has prepared guidelines for antiretroviral treatment in HIV-infected adults and adolescents which are summarized in this report. The Swedish guidelines recommend initiation of treatment when the CD4-cell-count is in the range between 200 and 350 x 10(6)/l in asymptomatic HIV-infection. They emphasize that the patient should be carefully prepared before treatment initiation to avoid adherence difficulties which regularly leads to viral failure. As first line is suggested a therapy with 2 NRTIs (nucleoside reverse transcriptase inhibitors) in combination with either a NNRTI (non-nucleoside RTI) or a protease inhibitor. When protease inhibitors are chosen, ritonavir-boosted combinations are most often to prefer. The virological treatment goal is to achieve a decrease in HIV-RNA with 1.5-2 log after 4 weeks and to below 50 copies/ml after 3-4 months of therapy. If a therapy fails, the causes should be carefully investigated for adherence difficulties, medicine interactions, and viral resistance. Treatment change should be guided by a thorough drug treatment history and the results of resistance testing. Treatment of HIV is complex and it is recommended that it should be conducted by an expert in the field.

Objective: To study the appearance of drug-induced mutations at low viraemia in treated HIV-1-infected patients., Design and Methods: Fourteen patients, who received their first (n = 5), second (n = 7) or third (n = 2) line antiretroviral combination therapy, developed a persistent low-grade viraemia after an initial decrease of the viral load (VL) to less than 500 copies/ml. The amount of HIV-1 RNA (n = 71) and reverse transcriptase (RT)/protease sequences (n = 56) were determined in longitudinally obtained plasma samples during a mean period of 16.6 months., Results: In the vast majority (93%) of patients, new primary resistance mutations were found in the RT and/or protease genes at virological failure at a median VL of 500 and 200 copies/ml, respectively. Drug-experienced patients developed mutations at a lower VL than naive patients. In one previously protease inhibitor-naive patient, primary RT and protease mutations were detected, although the VL was less than 50 copies/ml. A serial accumulation of drug resistance mutations was seen despite the VL increase being mostly modest, reaching a median of 1450 copies/ml at the end of the study, and the CD4 T cell counts continued to increase. One patient still had a VL of 300 copies/ml after 28 months, despite the presence of the multidrug-resistance Q151M mutation., Conclusion: Low viraemia after virological treatment failure can select for virus with several new drug resistance mutations, despite a concomitant increase in CD4 T cell counts. This serial accumulation of mutations is likely to exhaust future drug options