Antiretroviral drug resistance and treatment outcomes of human immunodeficiency virus type-1, implications for low and middle income countries

My thesis contains comprehensive studies of antiretroviral treatment (ART) naïve and experienced patients from the beginning of the Swedish HIV-1 epidemic. Paper I was the first study to describe the ART usage and occurrence acquired drug resistance mutations (DRM) at a population level in Sweden over time and we used data derived between 1997-2011. We showed that there was a general decrease of DRM to PIs and NRTIs, while an increase of DRM towards NNRTIs was found in patients from low-and middle-income countries (LMICs) with ART initiation after 2007. We therefore suggest that treatment regiments without NNRTI and their effectiveness tested for non-B-subtypes should be considered as first-line choice for patients from LMICs. In Papers II, III and IV I focused on the impact of different subtypes. At the start of the epidemic HIV-1B dominated in high-income countries and due to migration and traveling changes occurred in the global subtype distribution. Temporal trends of various subtypes in Sweden were unknown until analyzes presented in Paper II were preformed. In that study we showed an increasing trend of HIV-1C and recombinant forms and a decline of HIV-1B in newly diagnosed patients. Our results suggest that this is partly due to spread of non-B subtypes among heterosexuals and MSM within the country. Papers III, IV and V analyzed treatment outcomes with special focus on subtype HIV-1C (III and IV) and consequences of reasons for treatment switch (V). In Paper III we demonstrated a significantly higher risk of viral failure for patients infected with HIV-1C using PI-based ART compared to HIV-1B. In Paper IV we analyzed drug resistance to second-generation NNRTI rilpivirine (RPV) among patients failing NNRTIs in Europe and in ART-naive HIV-1C infected patients from Ethiopia and India. RPV-inhibition and binding affinity assays on HIV-1C reverse transcriptase was also performed. Our findings indicate that the use of RPV has limitations in HIV-1C dominated countries where laboratory monitoring is not standard of care. In Paper V we studied the effects of different reasons for therapy switch and found that higher viral load (VL) at switch from first-line ART had a negative effect on time to second line ART failure, nevertheless no effect of VL-level and DRM on the CD4+ T-cell gain, AIDS or death was found. In conclusion, the treatment outcome of HIV-1 infected patients in Sweden has shown remarkable improvements and is now very good. Prevalence of DRM is low and once viral failure with or without DRM occurs patients are managed effectively. Nonetheless the virus and the epidemic are highly heterogeneous and constantly changing, requiring close surveillance. Also our studies reveal new future challenges for the optimization of ART in patients infected in LMICs in terms of effectiveness on non-B subtypes

"Vi väljer inte att vara tysta, det är vår ångest som tvingar oss till det." : en kvalitativ netnografisk studie om hur det är att leva med selektiv mutism

Det blir allt vanligare med psykisk ohälsa, speciellt bland barn och unga. Selektiv mutism är en form av psykisk ohälsa där personen i fråga, på grund av ångest, inte kan kommunicera normalt utanför hemmet och med andra personer än nära familjemedlemmar. Syftet med denna studie var att öka förståelsen för hur det är att leva med selektiv mutism genom att ta reda på hur det påverkar de drabbade samt vilka utmaningar de kan ställas inför. Detta för att jag som blivande sjukskötare och annan vårdpersonal rätt ska kunna bemöta och vårda personer med selektiv mutism. För att besvara frågeställningarna användes en kvalitativ netnografisk insamlingsmetod med material från sju vloggar och en blogg. Alla informanter var kvinnor med diverse nationaliteter. Som teoretisk utgångspunkt valdes Erikssons (1994) teori om lidande. Resultatet visar att personer med selektiv mutism påverkas på många sätt, både positivt och negativt. De påverkas främst av ångest och social fobi, men de utvecklar också goda egenskaper och andra kommunikationsmetoder. Det är framför allt kommunikationen, andras bemötande och bemötandet inom vården som gör sjukdomstillståndet utmanande.Mielenterveysongelmat yleistyvät erityisesti lasten ja nuorten keskuudessa. Selektiivinen mutismi on mielenterveysongelmien muoto, jossa kyseinen henkilö ei ahdistuneisuutensa vuoksi pysty kommunikoimaan normaalisti kodin ulkopuolella ja muiden kuin läheisten perheenjäsenten kanssa. Tämän tutkimuksen tarkoituksena oli saada lisää ymmärrystä siitä, millaista on elää valikoivan mutismin kanssa, selvittämällä, miten se vaikuttaa asianomaisiin ja millaisia haasteita he voivat kohdata. Näin minä tulevana sairaanhoitajana ja muut terveydenhuollon ammattilaiset pystyvät hoitamaan ja hoivaamaan asianmukaisesti ihmisiä, joilla on selektiivinen mutismi. Tässä tutkimuksessa käytettiin kvalitatiivista netnografista aineistonkeruumenetelmää kysymyksiin vastaamiseksi, ja aineisto koostui seitsemästä vlogista ja yhdestä blogista. Kaikki informantit olivat eri kansallisuuksia edustavia naisia. Teoreettiseksi lähtökohdaksi valittiin Erikssonin (1994) kärsimysteoria. Tulokset osoittavat, että valikoivaa mutismia sairastavat ihmiset vaikutetaan monin tavoin, sekä myönteisesti että kielteisesti. Heihin vaikuttavat pääasiassa ahdistus ja sosiaalinen fobia, mutta he kehittävät myös hyviä ominaisuuksia ja muita kommunikointitapoja. Tämä koskee erityisesti viestintää, toisten kohteluun ja hoitoon terveydenhuoltojärjestelmässä, joka tekee tilasta haastavan.It´s becoming more common with mental illness, especially among children and young people. Selective mutism is a form of mental illness in which the person in question, due to anxiety, cannot communicate normally outside the home and with people other than close family members. The aim of this study was to gain an increased understanding of what it is like to live with selective mutism. It was done by finding out how people with selective mutism are affected as well as what challenges they may face. In this way, I as a prospective nurse and other health professional, will be able to properly respond to and care for people with selective mutism. To answer the questions, a qualitative netnographic collection method was used with material from seven vlogs and one blog. All the informants were women of various nationalities. As a theoretical framework, Eriksson's (1994) theory of suffering was chosen. The result shows that people with selective mutism are affected in many ways, both positively and negatively. They are mainly affected by anxiety and social phobia, but they also develop good characteristics and other methods of communication. It is, above all, communication, the treatment of others and the treatment in care that make the disease challenging

Marknadens reaktion på omvända vinstvarningar : En eventstudie om hur tillkännagivandet omvända vinstvarningar påverkar aktiekursen hos svenska börsnoterade bolag

En vinstvarning är när ett företag går ut med information till allmänheten om att resultatet kommer att bli väsentligt lägre än förväntat. Denna studie undersöker marknadens reaktion vid omvända vinstvarningar, som är precis vad namnet antyder, när företag går ut med information om att resultatet kommer bli väsentligt högre än förväntat. Marknadens reaktion vid vinstvarningar tenderar att vara mer negativ då företag väljer att inte dela med sig av detaljerad information och mindre negativ då företaget väljer att vara mer transparenta och dela med sig av detaljerad information (Bulkley & Herrerias, 2005; Church & Donker, 2010). Tidigare studier har också visat att reaktionen vid vinstvarningar är mer negativa hos små företag än stora (Jackson & Madura, 2003; Bulkley & Herrerias, 2005; Church & Donker, 2010). Om resultat från tidigare studier som har studerat negativa vinstvarningar skulle stämma överens även vid omvända vinstvarningar betyder det att aktiekursen stiger mer hos små företag än hos stora företag vid tidpunkten för tillkännagivandet och att minskad transparens har en positiv effekt. Studien försöker därför svara på frågeställningen; Hur reagerar den svenska marknaden när företag tillkännager omvända vinstvarningar? Undersökningen genomförs med hjälp av en eventstudie med kvantitativ ansats. Urvalet av omvända vinstvarningar är de som har hittats med hjälp av databasen Retriever Media Archive under åren 2004 – 2019. Resultaten visar att företagens storlek och vilken typ av information som finns i de omvända vinstvarningarna har betydelse för hur stark marknadsreaktionen blir. Studien undersöker även om det förekommer abnormal avkastning redan tiden innan dagen för tillkännagivandet, vilket kan tyda på informationsläckage, men detta kan inte påvisas med statistisk signifikans. Då regelverken kring huruvida företag måste vinstvarna är diffusa och öppna för tolkning kan det också diskuteras kring vilka konsekvenser det får för företagen att vara så transparenta som möjligt. Resultaten tyder på att den positiva kumulativa abnormala avkastningen är signifikant avvikande vid tillkännagivandet av omvända vinstvarningar från svenska börsnoterade bolag. Även fast så hög transparens som möjligt bör eftersträvas ur ett moraliskt perspektiv, så kan resultaten från denna studie användas till att förstå hur marknaden tar emot informationen vid tillkännagivandet av omvända vinstvarningar och därmed ge inblick i hur olika utformningar av denna information kan leda till olika marknadsreaktioner. Om en stark positiv reaktion eftersträvas så visar studiens resultat att det ger en starkare marknadsreaktion att inkludera mer detaljerad information. Små företag har också större chans att få aktiekursen att stiga vid en omvänd vinstvarning än vad stora företag har (Jackson & Madura, 2003; Bulkley & Herrerias, 2005; Church & Donker, 2010)

HIV Care in the Swedish-Danish HIV Cohort 1995-2010:Closing the Gaps

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

Trends in antiretroviral therapy and prevalence of HIV drug resistance mutations in Sweden 1997-2011.

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

Treatment status of patients in the Swedish-Danish HIV cohort in the period 1995-2010.

<p>The panels represent all patients in the cohort (A) and stratified by origin (B: Swedish/Danish origin and C: Immigrants) and by route of HIV transmission (D: MSM, E: Heterosexuals and F: Injection drug users).</p

Treatment status of HIV patients in Denmark in 2010 by origin and route of HIV transmission.

<div><p>Successful management is defined as viral load <500 copies/mL or non-eligibility to HAART, but monitoring of CD4 within 13 months.</p> <p>DK: Denmark, HAART: highly active antiretroviral therapy, IDU: injection drug user, S: Sweden, VL: viral load.</p></div

Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients.

Switch from first line antiretroviral therapy (ART) to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART.Data from 869 patients with 14601 clinical visits between 1999-2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL) levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF).Most patients (n = 495; 57.0%) switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2%) or without drug resistance mutations (DRM) (n = 250; 28.8%) experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90-3.96) and 3.20 (95% 2.65-3.75), respectively) compared with those who switched without VF (4.53 years). Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART.In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch

Temporal trends in the Swedish HIV-1 epidemic: increase in non-B subtypes and recombinant forms over three decades.

BACKGROUND: HIV-1 subtype B (HIV-1B) still dominates in resource-rich countries but increased migration contributes to changes in the global subtype distribution. Also, spread of non-B subtypes within such countries occurs. The trend of the subtype distribution from the beginning of the epidemic in the country has earlier not been reported in detail. Thus the primary objective of this study is to describe the temporal trend of the subtype distribution from the beginning of the HIV-1 epidemic in Sweden over three decades. METHODS: HIV-1 pol sequences from patients (n = 3967) diagnosed in Sweden 1983-2012, corresponding to >40% of patients ever diagnosed, were re-subtyped using several automated bioinformatics tools. The temporal trends of subtypes and recombinants during three decades were described by a multinomial logistic regression model. RESULTS: All eleven group M HIV-1 subtypes and sub-subtypes (78%), 17 circulating recombinant forms (CRFs) (19%) and 32 unique recombinants forms (URF) (3%) were identified. When all patients were analysed, there was an increase of newly diagnosed HIV-1C (RR, 95%CI: 1.10, 1.06-1.14), recombinants (1.20, 1.17-1.24) and other pure subtypes (1.11, 1.07-1.16) over time compared to HIV-1B. The same pattern was found when all patients infected in Sweden (n = 1165) were analysed. Also, for MSM patients infected in Sweden (n = 921), recombinant forms and other pure subtypes increased. SIGNIFICANCE: Sweden exhibits one of the most diverse subtype epidemics outside Africa. The increase of non-B subtypes is due to migration and to a spread among heterosexually infected patients and MSM within the country. This viral heterogeneity may become a hotspot for development of more diverse and complex recombinant forms if the epidemics converge