Too many children are still being newly infected with HIV. The Global Plan is to eliminate new HIV infections among children by 2015 and keep their mothers alive. The rate of MTCT of HIV-1 has fallen to less than 2% in countries with the implementation of recommendations. The best documented factor that correlates to higher rates of transmission is the maternal level of plasma viremia. Therefore it is important to maximally inhibit HIV replication in order to prevent HIV-associated morbidity and mortality and to prevent MTCT. Durable viral suppression prolongs life by improving immune function and overall quality of life, lowering the risk of both AIDs-defining and non-AIDS-defining complications. Clinical data are more limited on antiretroviral drugs in pregnant women than in non-pregnant individuals due to concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. However there are sufficient data to base recommendations for drug choice for many of the available antiretroviral drugs. Preferred drugs must show durable viral suppression, increased CD4 cell count, and a favorable safety profile. In addition to the aforementioned characteristics of a preferred drug, preferred antiretroviral drugs for pregnant individuals must pay special attention to maternal toxicity, potential teratogenicity, and fetal safety, efficacy of reducing perinatal transmission, and pharmacokinetics data during the perinatal transmission of HIV. Currently the optimal initial antiretroviral regimens to treat antiretroviral-naïve patients in high resource regions consist of two nucleoside/tide reverse transcription inhibitors in combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with RTV. Continually re-evaluation is recommended to challenge current paradigms. Treatment advances may lead to safer and even superior alternatives to current first-line therapy. The WHO current first-line therapy in less developed or developing regions includes the nonnucleoside reverse transcriptase inhibitor, EFV and considerations of poorer overall efficacy compared to newer drugs, toxicity, resistance, and adverse effects suggest that EFV should be reconsidered for use in first-line therapy. Although preferred protease inhibitors are as effective as EFV with fewer adverse effects, serious issues arise when patients are on concomitant medications with drug interactions. Currently raltegravir is the only integrase strand transfer inhibitor drug (INSTI) with data during pregnancy. Raltegravir is an attractive alternative or additional drug for pregnant women requiring medications with resistance, incomplete virologic response, or significant interactions with current first-line regimen drugs. Furthermore, based on recent data, raltegravir could provide pre-exposure prophylaxis in the fetus. DTG is a newer generation INSTI with clinical trials data showing safety and efficacy in nonpregnant adults. These studies suggest great promise for DTG and justify its role as first-line therapy for the nonpregnant population with relatively few drug interactions; in addition, it offers the only single tablet regimen for patient with or at risk for renal dysfunction. Although more data must be collected to ensure the safety and efficacy of INSTI as a first-line therapy in pregnant women, current studies show promise and with increasing experience INSTI agents may become part of the recommended first-line regimen for pregnant women.

Humant immunbristvirus (HIV) tillhör gruppen retrovirus. Det finns två typer av HIV, HIV-1 och HIV-2. HIV-1 är den mest spridda typen. Viruset angriper CD4+ T-hjälparceller och använder cellerna för att replikera. När HIV förökar sig minskar antalet CD4+ T-hjälparceller vilket leder till nedsatt immunförsvar och kroppen får svårare att hantera andra infektioner. Obehandlad HIV kan leda till ”acquired immunodeficiency syndrome” (AIDS) som innebär att immunförsvaret är kraftigt nedsatt och kroppen därmed är mycket känslig mot alla sorters infektioner. Globalt uppskattas cirka 38,4 miljoner människor leva med HIV, och 40 miljoner människor har avlidit på grund av AIDS.  Det finns ingen botande behandling mot HIV, men flera olika behandlingsmöjligheter för att minska virusmängden i kroppen. HIV muterar dock frekvent vilket innebär att viruset kan utveckla resistens mot läkemedel. För att minska risken för resistensutveckling behandlas HIV med kombinationsbehandling där läkemedel med olika verkningsmekanism kombineras. Standardbehandlingen mot HIV har under en lång period varit en kombination av tre eller fler olika läkemedel. Det finns dock nackdelar med att kombinera tre eller flera olika läkemedel, till exempel läkemedel-läkemedelsinteraktioner och ökad frekvens av biverkningar. På grund av detta testas nu i olika studier om kombinationer med endast två läkemedel kan fungera lika bra.  Syftet med det här arbetet var att genomföra en litteraturstudie för att beskriva effekt och säkerhet av kombinationsbehandling mot HIV-1 med två antiretrovirala läkemedel där det ena läkemedlet var integrashämmaren dolutegravir, jämfört med tidigare godkända kombinationsbehandlingar med tre eller fyra antiretrovirala läkemedel. Dolutegravir valdes på grund av att läkemedlet har hög resistensbarriär och ingår i två rekommenderade kombinationer med två läkemedel. För att svara på syftet genomfördes sökningar efter relevanta artiklar i PubMed. Artiklarna som inkluderades skulle vara randomiserade kontrollerade studier med noninferiority studiedesign. Artiklar som redovisade sekundära eller uppföljande studier exkluderades. Utifrån inklusion- och exklusionskriterierna inkluderades fyra kliniska studier till resultatet. Resultatet visade att dubbelbehandling mot HIV-1 innehållande dolutegravir och antingen lamivudin eller rilpivirin inte gav sämre effekt än standardbehandling med tre eller fyra antiretrovirala läkemedel hos både virologiskt supprimerade och behandlingsnaiva personer med HIV-1 under 48 veckor. Dubbelbehandling var inte sämre på att behålla HIV-1 RNA <50 kopior/ml vid vecka 48 och gav inte högre risk för virologisk svikt eller resistensmutationer. Biverkningar var fler vid dubbelbehandling än standardbehandling hos redan virologiskt supprimerade personer, men färre vid dubbelbehandling än standradbehandling hos behandlingsnaiva personer under 48 veckor.  Längre studier och fler studier som inkluderar subgrupper, t.ex. gravida, barn och personer med samsjuklighet behövs för att långtidseffekter ska kunna uvärderas och göra det möjligt att använda dubbelbehandling bredare i framtiden. / Human immunodeficiency virus (HIV) belongs to the group of retroviruses. There are two types of HIV, HIV-1 and HIV-2. HIV-1 is the most widespread type. The virus attacks CD4+ helper T cells and uses the cells to replicate. When HIV replicates, the number of CD4+ helper T cells decreases, which leads to a weakened immune system which makes it harder for the body to fight other infections. Untreated HIV can lead to acquired immunodeficiency syndrome (AIDS), which means that the immune system is severely weakened, and the body is, therefore, very susceptible to many kinds of infections. Globally, it is estimated that about 38,4 million people are living with HIV, and 40 million people have died due to AIDS. There are no cure for HIV, but several different treatment options to reduce the viral load in the body. HIV has a high frequency of mutations which can make the virus resistant to a drug. To reduce the risk of resistance, HIV is normally treated with a combination of drugs with different mechanisms of action. The standard treatment for HIV has for a long time been a combination of three or more different drugs. However, there are disadvantages to combining several different drugs, such as drug-drug interactions and increased risk of side effects. Because of this, recent studies have been testing whether combinations with only two drugs can work just as well. The purpose of this study was to review the efficacy and safety of combination therapy for HIV-1 with two antiretroviral drugs, where one drug was the integrase inhibitor dolutegravir, compared to previously approved combination therapies with three or four antiretroviral drugs. Dolutegravir was chosen due to the drug's high resistance barrier and inclusion in two recommended two drug regimens. To answer the purpose,  searches for relevant articles were conducted on PubMed. The articles that were included were randomized controlled trials with a non-inferiority study design, while articles that presented secondary or follow-up studies were excluded. Based on the inclusion and exclusion criteria, four clinical studies were included in the result. The results showed that dual therapy against HIV-1 containing dolutegravir and lamivudine or rilpivirine were non-inferior in efficacy compared to standard treatment with three or four antiretroviral drugs in both virologically suppressed and antiretroviral therapy-naive individuals with HIV-1 for up to 48 weeks. Dual therapy was non-inferior in maintaining HIV-1 RNA <50 copies/mL at week 48 and did not confer a higher risk of virological failure or resistance mutations. Side effects were more frequent with dual therapy than standard treatment in individuals who were already virologically suppressed, but fewer with dual therapy than standard treatment in treatment-naive individuals over 48 weeks. Longer and more studies that include subgroups, such as pregnant women, children, and people with comorbidities, are needed to evaluate long-term effects and make it possible to use two drug regimens more widely in the future.

As HIV is now primarily a chronic condition, treatment is given life-long with changes as necessitated by alterations in tolerability and efficacy. Thus, personalized medicine may be useful in the prevention of unnecessary drug exposure and avoidable side effects. Three of the four currently available HIV integrase strand transfer inhibitors (INSTIs), raltegravir, elvitegravir, and dolutegravir, are widely utilized antiretrovirals in the USA and exhibit variations in outcomes among subjects. To interrogate differences among subjects receiving these drugs, we investigated the association of several single nucleotide polymorphisms (SNPs) with drug exposure, clinical outcomes, and subject-reported adverse events. HIV+ adults (≥18 years old) receiving an INSTI regimen were recruited (n=88). Subject genotypes were evaluated using an iPLEX PGx Panel. Genetic variations within our population, underwent multiple regression with covariates [age, sex, BMI, regimen duration, and baseline variables (as required) along with specific regimen in the comprehensive group] to detect significant (p=0.028) between abnormal dream occurrence and specific INSTI regimen with the raltegravir grouping presenting a higher frequency. This exploratory study also discovered several SNP-outcome associations when using INSTIs. Although these SNPs were found to have a role in predicting segments of adverse effect profiles, the clinical significance of these findings remains to be determined. Larger studies will be needed to confirm these exploratory findings with functional studies to understand pathogeneses. In conclusion, the associations found in this study strengthen the need for further assessment, within the HIV+ population, of factors contributing to unfavorable subject outcomes.

Objective: Evidence links initiation of integrase strand-transfer inhibitors (INSTIs) to excess weight gain in people living with HIV, potentially through changes in β-cell function. Thus, our goal was to investigate potential mechanisms that contribute to alterations in pancreatic β-cells insulin secretion by following exposure to two commonly used integrase inhibitors, Dolutegravir (DTG) and Elvitegravir (ELV). Methods: Insulin content and secretion were measured from clonal pancreatic ß-cells (INS-1) cultured in medium containing 4 mM and 11 mM glucose and were exposed to either dimethyl sulfoxide (DMSO) as a control, DTG, or ELV at physiological concentrations 72 hours. Insulin was measured by fluorescence using an HTRF insulin kit (Perkin Elmer). Changes in mitochondrial function were determined using a Seahorse mitochondrial stress test. Intracellular Ca2+ was measured in fura-2 loaded INS-1 cells as the ratio of fluorescence at 340 nm to 380 nm using a Hitachi 2000 spectrofluorometer. The data were presented as mean ± standard deviation (SD). Statistical analysis was conducted using Student's t-test or analysis of variance (ANOVA). Results: Dolutegravir treatment significantly reduced insulin secretion in cells cultured at 11G, even when normalizing for insulin content. In the 11G condition, Dolutegravir administration reduced oxygen consumption rate (OCR) compared to ELV and control, but no such difference was observed in the 4G condition. Consistent with reduced oxygen consumption, when INS-1 cells were cultured at 11 mM glucose with Dolutegravir, the glucose-stimulated increase in intracellular Ca2+ was observed to be reduced by 80% compared to the control group. Conclusion: Our study reveals that exposure to DTG leads to impaired insulin secretion, less oxygen consumption and reduced calcium influx in β-cells under high glucose conditions. These findings provide important insights into the potential effects of Dolutegravir (DTG) on β-cell function and glucose regulation regarding the weight gain observed in people living with HIV (PLWH) who started or switched to INSTI treatment. Further investigations are warranted to elucidate the underlying mechanisms responsible for the observed effects of DTG on insulin synthesis, storage, and calcium signaling pathways. Understanding these mechanisms could potentially lead to the development of strategies to mitigate the detrimental impacts of DTG on β-cell function and optimize therapeutic approaches in patients receiving DTG therapy.

Des progrès importants ont été réalisés dans la thérapie des personnes vivant avec le VIH (PVVIH) avec le développement d’antirétroviraux (ARV) de plus en plus efficaces, sûrs avec une bonne innocuité et tolérance. Cependant, des défis thérapeutiques demeurent chez les PVVIH dont le VIH pourrait être porteur de mutations génétiques conférant de la résistance aux traitements soit en raison d’une histoire d’échec thérapeutique antérieur soit en raison d’une exposition antérieure à une mono/bithérapie aux inhibiteurs nucléosidiques de la transcriptase inverse (INTI) (thérapie sous-optimale qui se faisait avant l’ère des trithérapies). Chez ces patients, les cliniciens peuvent tenter des combinaisons peu étudiées dans l’espoir de mieux contrôler la charge virale ou de réduire les effets secondaires. Ainsi, cette thèse par articles avait trois objectifs qui visaient à étudier des thérapies utilisées chez ces patients mais pour lesquelles il y a peu ou pas de données. Le premier objectif (article 1) consistait à déterminer si l'efficacité du régime ARV avec dolutégravir chez les patients stables (dont la charge virale est supprimée) variait en présence d'une histoire d’échec virologique ou d’exposition antérieure à la thérapie sous-optimale. Le deuxième objectif (article 2) visait à comparer l’issue virologique des PVVIH stables ayant un échec virologique documenté ou une exposition antérieure à la thérapie sous-optimale et qui ont maintenu leur régime inhibiteur de la protéase/ritonavir (IP/r) par rapport à ceux qui sont passés au dolutégravir. Finalement, le troisième objectif (article 3) était de comparer le risque d’échec virologique chez les PVVIH avec une histoire d’échec virologique ou de thérapie sous-optimale prenant un traitement non standard d’ARV composé d’abacavir/ténofovir disoproxil (ABC/TDF) avec un 3e ARV d’une classe différente par rapport à un régime composé d’un traitement de fond standard. Nous avons utilisé les données de la cohorte VIH du Québec qui regroupe 10 219 PVVIH suivies au niveau de quatre centres à Montréal incluant la Clinique de médecine urbaine du Quartier Latin (CMUQL), la Clinique médicale l’Actuel (CMA), le Centre hospitalier universitaire de Montréal (CHUM) et le Centre universitaire de santé McGill (CUSM). Une restriction à certains patients a été réalisée pour chacun des objectifs. Les patients avec une charge virale indétectable qui avaient reçu une thérapie avec dolutégravir + 2 INTI à partir de 2013 ont été retenus pour l’objectif 1. Le modèle de risque proportionnel de Cox avec score de propension a été utilisé afin de comparer l’issue virologique des patients sous dolutégravir en fonction de l’exposition étudiée. Pour l’objectif 2, les patients stables avec une histoire d’échec virologique documenté ou d’exposition à une thérapie sous-optimale qui étaient sous IP/r + 2 INTI à partir de 2014 ont été sélectionnés. Le modèle de Cox structurel marginal a permis de voir l’effet du changement de traitement vers le dolutégravir + 2 INTI en comparaison avec ceux qui sont restés sur IP/r + 2 INTI. Pour l’objectif 3, les patients avec une histoire d’échec virologique documenté ou d’exposition à une thérapie sous-optimale qui étaient sous traitements de fond standards (abacavir/lamivudine, ténofovir disoproxil/emtricitabine, ténofovir disoproxil/lamivudine) avec un agent autre qu’un INTI à partir du 1er janvier 2006 ont été retenus. Le modèle multivarié proportionnel de Cox a été utilisé afin de comparer l’issue virologique des patients passés à un régime de thérapie inhabituelle à base d’ABC/TDF par rapport à ceux qui sont restés sur traitement de fond standard. L’article 1 a montré une efficacité similaire du dolutégravir chez les patients stables avec ou sans histoire d’échec virologique documenté ou d’exposition à une thérapie sous-optimale (Hazard ratio ajusté (HRa)=0,84 (IC95% : 0,35 - 2,01)). Dans l’article 2, aucune preuve d'un risque accru d'échec virologique n’a été trouvée chez les patients stables ayant déjà eu un échec virologique antérieur ou une exposition à une thérapie sous-optimale qui ont eu un changement de régime vers le dolutégravir en comparaison avec ceux qui ont maintenu leur régime IP/r (HRa=0,57 (IC95% : 0,21 - 1,52)). Dans l’article 3, une réduction non significative du risque d’échec virologique avec le traitement de fond non standard à base d’ABC/TDF a été trouvée par rapport au traitement de fond standard (HRa=0,45 (IC95% : 0,06 - 3,36)). En conclusion, les résultats de cette thèse n’ont pas montré un effet de la présence d’échec virologique antérieur ou d’exposition à une thérapie sous-optimale sur l’efficacité du dolutégravir. Par ailleurs, les résultats ont permis de constater que le changement vers le dolutégravir + 2 INTI pour des patients stables sur un régime IP/r + 2 INTI peut être envisagé malgré la présence ou la suspicion de mutation de résistance aux INTI. Ces résultats sont importants puisqu’ils devraient permettre de faire changer les guides cliniques concernant le dolutégravir chez les patients stables. Par contre, nos résultats n’ont pas réussi à montrer un avantage significatif à utiliser le traitement de fond à base d’ABC/TDF en comparaison au traitement de fond standard chez des patients présentant une histoire d’échec virologique ou d’exposition à la thérapie sous-optimale. / Significant progress has been made in treatment for people living with HIV (PLHIV) with the development of increasingly effective antiretroviral (ARV) therapy, safe with good tolerability. However, clinicians can sometimes face treatment challenges related to the monitoring of PLHIV whose HIV could carry genetic mutations conferring resistance to treatments either because of a history of virologic failure or because of previous exposure to mono/bitherapy to nucleoside reverse transcriptase inhibitors (NRTIs) (suboptimal therapy that was provided before the era of triple therapy). In these patients, clinicians can sometimes try less studied combinations in the hopes to better control viral load or reduce side effects in these patients. Therefore, this thesis by articles had three objectives aiming to evaluate less studied therapies that are used in these patients. The first objective (Paper 1) was to determine whether the efficacy of ARV regimen with dolutegravir in stable patients (whose viral load is controlled) varied in the presence of a history of virologic failure or with a previous exposure to suboptimal therapy regimen. The second objective (Paper 2) was to study virologic outcome after switching to dolutegravir compared to remaining on a boosted protease inhibitor (PI/r) regimen in stables PLHIV with prior documented virologic failure or exposure to mono/dual NRTI. Finally, the third objective (Paper 3) was to compare the risk of virologic failure for PLHIV who have previous documented virologic failure or prior exposure to suboptimal therapy taking an ARV therapy composed of abacavir/tenofovor (ABC/TDF) with a third agent of a different class, versus an ARV regimen composed of a standard backbone also with a non-NRTI third agent. We used data from the Quebec HIV cohort which brings together clinical information from 10,219 PLHIV followed in four clinical care centers in Montreal including the “Clinique de médecine urbaine du Quartier Latin (CMUQL)”, “Clinique médicale l’Actuel (CMA)”, the “Centre hospitalier de l'Université de Montréal (CHUM)” and the “McGill University Health Center (MUHC)”. A restriction to some patients in the cohort was made with regards to each objective of this thesis. Patients with an undetectable viral load who had received therapy with dolutegravir +2 NRTI from 2013 were selected for the objective 1. A Cox proportional hazard model with propensity score was used to compare the virologic outcome of patients on dolutegravir according to the exposure. For objective 2, patients with an undetectable viral load with an history of documented virologic failure or exposure to suboptimal therapy who were on PI/r + 2 NRTI from 2014 were selected. A marginal structural Cox model was used to measure the effect of switching to dolutegravir +2 NRTI compared to those who remained on PI/r + 2 NRTI therapy. For objective 3, patients with a documented virologic failure or exposure to suboptimal therapy in standard backbone (abacavir/lamivudine, tenofovir disoproxil/emtricitabine, tenofovir disoproxil/lamivudine) with another agent from January 01, 2006 were selected. A Cox proportional multivariate model was used to compare the virologic outcome of patients who switched to a non-standard regimen including ABC/TDF therapy versus those who remained on standard backbone. The article 1 suggested similar virologic efficacy of dolutegravir in stables patients with or without an history of documented virologic failure or exposure to suboptimal therapy (adjusted Hazard Ratio (aHR)=0,84 (95%CI: 0,35 - 2,01)). In article 2, no evidence of an increased risk of virologic failure was found in stables patients who had a regimen switched to dolutegravir compared to those who maintained their regimen with PI/r in patients who have had previous virologic failure or exposure to suboptimal therapy (aHR=0,57 (95%CI: 0,21 - 1,52)). In article 3, a non-significant reduction in the risk of virologic failure with the non-standard backbone including ABC/TDF was found compared to standard backbone (aHR=0,45 (95%CI: 0,06 - 3,36)). In conclusion, the results of this thesis first suggested no effect of the presence of previous virologic failure or exposure to suboptimal therapy on the efficacy of dolutegravir in stables patients. In addition, the results showed that the switch to dolutegravir +2 NRTI for patients with an undetectable viral load on PI/r +2NRTI regimen can be considered despite the presence of proved or suspected NRTI resistance mutation. These results are of great importance as they should lead to changes the clinical guidelines for the use of dolutegravir in stable patients. On the other hand, our results failed to show a significant advantage to the use of the backbone ABC/TDF instead of standard backbones in patients with prior documented virologic failure or previous exposure to suboptimal therapy.