Second-Line Switch to Dolutegravir for Treatment of HIV Infection.

BACKGROUND: Data to inform the switch from a ritonavir-boosted protease inhibitor (PI) to dolutegravir in patients living with human immunodeficiency virus (HIV) infection who do not have genotype information and who have viral suppression with second-line therapy containing a ritonavir-boosted PI have been limited. METHODS: In a prospective, multicenter, open-label trial conducted at four sites in Kenya, we randomly assigned, in a 1:1 ratio, previously treated patients without genotype information who had viral suppression while receiving treatment containing a ritonavir-boosted PI to either switch to dolutegravir or continue the current regimen. The primary end point was a plasma HIV type 1 RNA level of at least 50 copies per milliliter at week 48, assessed on the basis of the Food and Drug Administration snapshot algorithm. The noninferiority margin for the between-group difference in the percentage of participants who met the primary end point was 4 percentage points. Safety up to week 48 was assessed. RESULTS: A total of 795 participants were enrolled, with 398 assigned to switch to dolutegravir and 397 assigned to continue taking their ritonavir-boosted PI; 791 participants (397 in the dolutegravir group and 394 in the ritonavir-boosted PI group) were included in the intention-to-treat exposed population. At week 48, a total of 20 participants (5.0%) in the dolutegravir group and 20 (5.1%) in the ritonavir-boosted PI group met the primary end point (difference, -0.04 percentage points; 95% confidence interval, -3.1 to 3.0), a result that met the criterion for noninferiority. No mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure. The incidence of treatment-related grade 3 or 4 adverse events was similar in the dolutegravir group and the ritonavir-boosted PI group (5.7% and 6.9%, respectively). CONCLUSIONS: In previously treated patients with viral suppression for whom there were no data regarding the presence of drug-resistance mutations, dolutegravir treatment was noninferior to a regimen containing a ritonavir-boosted PI when the patients were switched from a ritonavir-boosted PI-based regimen. (Funded by ViiV Healthcare; 2SD ClinicalTrials.gov number, NCT04229290.).

HIV pre-exposure prophylaxis services, provision, and delivery in the European treatment network of HIV, hepatitis and global emerging infectious diseases (NEAT ID).

OBJECTIVES: We conducted a survey to evaluate HIV pre-exposure prophylaxis (PrEP) practices in a European clinical research network on HIV, hepatitis, and global infectious diseases (NEAT ID). METHODS: An online survey comprising 22 questions was sent via a secure electronic tool to the investigating physician of each of the 342 NEAT ID study centres across 15 European countries in November 2020. RESULTS: In total, 50 sites from 12 countries responded (15% response rate). Most sites were in Western Europe, two were in Poland, and one was in Hungary. Of the responding sites, 45 provided PrEP services for a total of 27 416 PrEP users, with 1361 new PrEP initiators each month. These centres supplied PrEP for men who have sex with men (100%), people who inject drugs (84%), sex workers (84%), women (62%), and transgender women (31%). PrEP persistence after 1 year was >90%, 75%-90%, and 40%-75% in 17, 24, and 4 centres, respectively. In total, 32/45 (71%) centres reported strong community-based organization commitment at their site, and 15/45 (33%) centres developed task-shifting processes to deliver PrEP through nurses (11/15), pharmacists (5/15), and key-population peers (2/15). The biggest barriers to implementation of PrEP were low awareness of and knowledge about PrEP (47%), unwillingness to disclose sexual identity or at-risk behaviour (36%), and lack of administrative support (29%). Of the 45 centres, 32 (71%) have already been involved in PrEP research and 43 (96%) were interested in participating in such studies. CONCLUSIONS: The few NEAT ID centres that responded to the survey showed disparities in PrEP deployment and practices despite a common interest in participating in research in this field.

Stability in care and risk of loss to follow-up among clients receiving community health worker-led differentiated HIV care: Results from a prospective cohort study in northern Tanzania.

BACKGROUND: HIV services in Tanzania are facility-based but facilities are often overcrowded. Differentiated care models (DCM) have been introduced into the National Guidelines. We piloted a Community Health Worker (CHW)-led HIV treatment club model (CHW-DCM) in an urban region, and assessed its effectiveness in comparison to the standard of care (SoC, facility-based model), in terms of stability in care, loss to follow-up (LTFU) and treatment adherence. METHODS: In two clinics in the Shinyanga region, clients established on ART (defined as stable clients by national guidelines as on first-line ART >6 months, undetectable viral load, no opportunistic infections or pregnancy, and good adherence) were offered CHW-DCM. This prospective cohort study included all stable clients who enrolled in CHW-DCM between July 2018 and March 2020 (CHW-DCM) and compared them to stable clients who remained in SoC during that period. Multivariable Cox regression models were used to analyse factors associated with continued stability in care and the risk of LTFU during 18 months of follow-up; treatment adherence was assessed by pill count and compared using Chi-square tests. RESULTS: Of 2472 stable clients, 24.5% received CHW-DCM and 75.5% SoC. CHW-DCM clients were slightly older (mean 42.8 vs. 37.9 years) and more likely to be female (36.2% vs. 32.2%). Treatment adherence was better among CHW-DCM than SoC: 96.6% versus 91.9% and 98.5% versus 92.2%, respectively (both p = 0.001). SoC clients were more likely to not remain stable over time than CHW-DCM (adjusted Hazard ratio [AHR] = 2.68; 95% CI: 1.86-3.90). There was no difference in LTFU (adjusted hazard ratio [AHR] = 1.54; 95%CI: 0.82-2.93). CONCLUSION: Clients attending CHW-DCM demonstrated better stability in care and treatment adherence than SoC, and the risk of LTFU was not increased. These findings demonstrate the potential of CHW in delivering community-based HIV services in the local Tanzanian context. These results could be used to extend this CHW-DCM model to similar settings.

Limited Weight Impact After Switching From Boosted Protease Inhibitors to Dolutegravir in Persons With Human Immunodeficiency Virus With High Cardiovascular Risk: A Post Hoc Analysis of the 96-Week NEAT-022 Randomized Trial.

BACKGROUND: In the NEAT022 trial, virologically suppressed persons with human immunodeficiency virus (HIV) at high cardiovascular risk switching from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D) showed noninferior virological suppression and significant lipid and cardiovascular disease risk reductions on switching to dolutegravir relative to continuing protease inhibitors. METHODS: In post hoc analysis, major endpoints were 48-week and 96-week weight and body mass index (BMI) changes. Factors associated with weight/BMI changes within the first 48 weeks of DTG exposure, proportion of participants by category of percentage weight change, proportions of BMI categories over time, and impact on metabolic outcomes were also assessed. RESULTS: Between May 2014 and November 2015, 204 (DTG-I) and 208 (DTG-D) participants were included. Weight significantly increased (mean, +0.810 kg DTG-I arm, and +0.979 kg DTG-D arm) in the first 48 weeks postswitch, but remained stable from 48 to 96 weeks in DTG-I arm. Switching from darunavir, White race, total to high-density lipoprotein cholesterol ratio <3.7, and normal/underweight BMI were independently associated with higher weight/BMI gains. The proportion of participants with ≥5% weight change increased similarly in both arms over time. The proportions of BMI categories, use of lipid-lowering drugs, diabetes and/or use of antidiabetic agents, and hypertension and/or use of antihypertensive agents did not change within or between arms at 48 and 96 weeks. CONCLUSIONS: Switching from protease inhibitors to dolutegravir in persons with HIV with high cardiovascular risk led to modest weight gain limited to the first 48 weeks, which involved preferentially normal-weight or underweight persons and was not associated with negative metabolic outcomes. CLINICAL TRIALS REGISTRATION: NCT02098837 and EudraCT 2013-003704-39.

Incidence of Hypertension and Blood Pressure Changes in Persons With Human Immunodeficiency Virus at High Risk for Cardiovascular Disease Switching From Boosted Protease Inhibitors to Dolutegravir: A Post-hoc Analysis of the 96-week Randomised NEAT-022 Trial.

BACKGROUND: Integrase inhibitors have been recently linked to a higher risk for hypertension. In NEAT022 randomized trial, virologically suppressed persons with human immunodeficiency virus (HIV, PWH) with high cardiovascular risk switched from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D). METHODS: Primary endpoint was incident hypertension at 48 weeks. Secondary endpoints were changes in systolic (SBP) and diastolic (DBP) blood pressure; adverse events and discontinuations associated with high blood pressure; and factors associated with incident hypertension. RESULTS: At baseline, 191 (46.4%) participants had hypertension and 24 persons without hypertension were receiving antihypertensive medications for other reasons. In the 197 PWH (n = 98, DTG-I arm; n = 99, DTG-D arm) without hypertension or antihypertensive agents at baseline, incidence rates per 100 person-years were 40.3 and 36.3 (DTG-I) and 34.7 and 52.0 (DTG-D) at 48 (P = .5755) and 96 (P = .2347) weeks. SBP or DBP changes did not differed between arms. DBP (mean, 95% confidence interval) significantly increased in both DTG-I (+2.78 mmHg [1.07-4.50], P = .0016) and DTG-D (+2.29 mmHg [0.35-4.23], P = .0211) arms in the first 48 weeks of exposure to dolutegravir. Four (3 under dolutegravir, 1 under protease inhibitors) participants discontinued study drugs due to adverse events associated with high blood pressure. Classical factors, but not treatment arm, were independently associated with incident hypertension. CONCLUSIONS: PWH at high risk for cardiovascular disease showed high rates of hypertension at baseline and after 96 weeks. Switching to dolutegravir did not negatively impact on the incidence of hypertension or blood pressure changes relative to continuing protease inhibitors.

Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir.

BACKGROUND: In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. METHODS: PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. RESULTS: Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. DISCUSSION: After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.

Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study.

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.

Effectiveness of provider-initiated versus client-initiated HIV testing by different health facility departments in Northern Tanzania.

BACKGROUND: HIV prevalence in Tanzania is still high at 4.7% among adults. Regular HIV testing is consistently advocated in the country to increase the level of awareness of HIV status, thus contributing to national HIV prevention. We report findings from three years of implementation of an HIV Test and Treat project utilizing provider-initiated and client-initiated testing and counselling (PITC and CITC). This study compared the effectiveness of PITC versus CITC in HIV case detection by the different departments of health facilities. METHOD: This retrospective cross-sectional study used health facility-based HIV testing data collected from adults aged 18 years and above between June 2017 - July 2019 in the Shinyanga region, Tanzania. Chi-square and logistic regression analysis were used to assess determinants of yield (HIV positivity). RESULTS: A total of 24,802 HIV tests were performed of which 15,814 (63.8%) were by PITC and 8,987 (36.2%) by CITC. Overall HIV positivity was 5.7%, higher among CITC at 6.6% than PITC at 5.2%. TB and IPD departments had the highest HIV positivity 11.8% and 7.8% respectively. Factors associated with a positive test were testing at a department in the facility compared to CITC, first-time test, and being or having been married compared to being single. CONCLUSION: Success in identifying HIV + patients was highest among people visiting the clinic for HIV testing (CITC) and first-time testers. With PITC, HIV + patient detection differed between departments, suggesting divergent risk profiles of respective clients and/or divergent HIV alertness of staff. This underscores the importance of increased targeting for PITC to identify HIV + patients.

Call to action: how can the US Ending the HIV Epidemic initiative succeed?

With more than 1·2 million people living with HIV in the USA, a complex epidemic across the large and diverse country, and a fragmented health-care system marked by widening health disparities, the US HIV epidemic requires sustained scientific and public health attention. The epidemic has been stubbornly persistent; high incidence densities have been sustained over decades and the epidemic is increasingly concentrated among racial, ethnic, and sexual and gender minority communities. This fact remains true despite extraordinary scientific advances in prevention, treatment, and care-advances that have been led, to a substantial degree, by US-supported science and researchers. In this watershed year of 2021 and in the face of the COVID-19 pandemic, it is clear that the USA will not meet the stated goals of the National HIV/AIDS Strategy, particularly those goals relating to reductions in new infections, decreases in morbidity, and reductions in HIV stigma. The six papers in the Lancet Series on HIV in the USA have each examined the underlying causes of these challenges and laid out paths forward for an invigorated, sustained, and more equitable response to the US HIV epidemic than has been seen to date. The sciences of HIV surveillance, prevention, treatment, and implementation all suggest that the visionary goals of the Ending the HIV Epidemic initiative in the USA might be achievable. However, fundamental barriers and challenges need to be addressed and the research effort sustained if we are to succeed.

Atherogenicity of low-density lipoproteins after switching from a protease inhibitor to dolutegravir: a substudy of the NEAT022 study.

BACKGROUND: The aim of this study was to investigate whether switching from a ritonavir-boosted PI-based regimen to a dolutegravir-based regimen improved the atherogenic properties of LDL particles in patients with HIV. METHODS: This was a substudy of the NEAT022 study (ClinicalTrials.gov NCT02098837). Adults with HIV with a Framingham score >10% or aged >50 years and being treated with a stable boosted PI-based regimen were randomized to either switch to dolutegravir or continue with boosted PI. At baseline and Week 48, we assessed atherogenic LDL properties: LDL particle size and phenotype (A, intermediate, B), oxidized LDL (ox-LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. RESULTS: Eighty-six participants (dolutegravir 44; PI 42) were included. Participants had a median (IQR) age of 54 (51-57) years and 79.1% were male. In the dolutegravir arm, after 48 weeks, we observed: (1) an increase in LDL size [median 1.65 Š(IQR -0.60 to 4.20); P = 0.007], correlated with the decrease in triglyceride concentration [Spearman correlation = -0.352 (P = 0.001)], with a corresponding decrease of subjects with atherogenic LDL phenotype B (36.4% to 20.5%; P = 0.039); (2) a decrease in Lp-PLA2 activity [median 1.39 µmol/min/mL (IQR -2.3 to 0.54); P = 0.002]; and (3) a decrease in ox-LDL [median 14 U/L (IQR -102 to 13); P = 0.006]. In the PI arm, none of these favourable lipid modifications was observed. CONCLUSIONS: Forty-eight weeks after switching from a PI-based to a dolutegravir-based regimen, patients with Framingham score >10% or aged >50 years showed improvement of several atherogenic lipid features, including LDL particle phenotype, ox-LDL and Lp-PLA2.

Factors associated with overweight/obesity in a cohort of people living with HIV over 50 years of age.

Changes in body weight in people living with HIV vary by regimen components, timing of therapy introduction (naive, switch) and demographic factors. Our objective was to evaluate weight change and factors associated in an ageing cohort of treated subjects with HIV at Chelsea and Westminster Hospital. We found that the prevalence of obesity was similar to general population and was associated with a number of health conditions, which increase metabolic risk.

Beyond viral suppression: Quality of life among stable ART clients in a differentiated service delivery intervention in Tanzania.

BACKGROUND: With antiretroviral therapy, more people living with HIV (PLHIV) in resource-limited settings are virally suppressed and living longer. WHO recommends differentiated service delivery (DSD) as an alternative, less resource-demanding way of expanding HIV services access. Monitoring client's health-related quality of life (HRQoL) is necessary to understand patients' perceptions of treatment and services but is understudied in sub-Saharan Africa. We assessed HRQoL among ART clients in Tanzania accessing two service models. METHODS: Cross-sectional survey from May-August 2019 among stable ART clients randomly sampled from clinics and clubs in the Shinyanga region providing DSD and clinic-based care. HRQoL data were collected using a validated HIV-specific instrument-Functional Assessment of HIV infection (FAHI), in addition to socio-demographic, HIV care, and service accessibility data. Descriptive analysis of HRQoL, logistic regression and a stepwise multiple linear regression were performed to examine HRQoL determinants. RESULTS: 629 participants were enrolled, of which 40% accessed DSD. Similar HRQoL scores [mean (SD), p-value]; FAHI total [152.2 (22.2) vs 153.8 (20.6), p 0.687] were observed among DSD and clinic-based care participants. Accessibility factors contributed more to emotional wellbeing among DSD participants compared to the clinic-based care participants (53.4% vs 18.5%, p = < 0.001). Satisfactory (> 80% of maximum score) HRQoL scoring was associated with (OR [95% CI], p-value) being male (2.59 [1.36-4.92], p 0.004) among clinic participants and with urban residence (4.72 [1.70-13.1], p 0.001) among DSD participants. CONCLUSIONS: Similar HRQoL was observed in DSD and clinic-based care. Our research highlights focus areas to identify supporting interventions, ultimately optimizing HRQoL among PLHIV.

Human Immunodeficiency Virus (HIV) Care Models During the Coronavirus Disease 2019 (COVID-19) Era.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global challenge that substantially risks reversing the progress in ending human immunodeficiency virus (HIV). At the same time, it may offer the opportunity for a new era of HIV management. This viewpoint presents the impact of COVID-19 on HIV care, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) "three 90s" targets. It outlines how to enhance a patient-centered care approach, now known as the "fourth 90," by integrating face-to-face patient-physician and telemedicine encounters. It suggests a framework for prevention and treatment of multimorbidity and frailty, to achieve a good health-related quality of life, and to preserve intrinsic capacity in all people living with HIV.

Switching from boosted PIs to dolutegravir decreases soluble CD14 and adiponectin in high cardiovascular risk people living with HIV.

BACKGROUND: Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. METHODS: We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. RESULTS: Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (-11%, P < 0.001) and adiponectin (-11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (-13%, P = 0.069) and oxidized LDL (-13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). CONCLUSIONS: Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.

Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy.

BACKGROUND: The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs. METHODS: Four pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class "congenital or familial disorders" were searched for NTDs. RESULTS: NTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators. CONCLUSIONS: Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

Five-year follow-up of patients enrolled in the NEAT 001/ANRS 143 randomized clinical trial: NEAT 001/ANRS 143 LONG TERM study.

BACKGROUND: Few long-term data are available in subjects having initiated ART with an NRTI-sparing regimen. OBJECTIVES: Outcomes of subjects enrolled in the NEAT 001/ANRS 143 randomized clinical trial (comparing ritonavir-boosted darunavir + raltegravir versus ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were retrospectively collected, through anonymized electronic case report forms, up to 6 years post-enrolment. METHODS: The last NEAT 001 visit (Week 96) was conducted in 745/805 randomized subjects (363/401 ritonavir-boosted darunavir + raltegravir and 382/404 ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine). Of these, 430 were enrolled in NEAT 001/ANRS 143 LONG TERM (NLT) study (201 raltegravir, 229 tenofovir disoproxil fumarate/emtricitabine), with a median follow-up of 44.4 months. RESULTS: During NLT follow-up, the proportion of AIDS, non-AIDS events, virological rebound and serious adverse events, discontinuation for virological failure and for adverse events did not differ between groups; discontinuations for virological failure since NEAT 001 inclusion were more frequent in subjects with baseline CD4 <200 cells/mm3 (11.9% versus 5.3%; P = 0.077). At last follow-up, a quarter of subjects (22.2% for ritonavir-boosted darunavir + raltegravir and 29.7% for ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were still receiving their initial regimen. Integrase inhibitor exposure was not associated with weight gain (P = 0.48), while tenofovir disoproxil fumarate exposure was associated with a trend to higher creatinine increase (P = 0.067). CONCLUSIONS: After a median of 5.6 years, subjects initiating ritonavir-boosted darunavir + raltegravir or ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine experienced few serious clinical adverse events. Most discontinuations were for reasons unrelated to adverse events or virological failure.

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.

OBJECTIVES: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. METHODS: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression. RESULTS: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively]. CONCLUSIONS: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

Switching from boosted PIs to dolutegravir in HIV-infected patients with high cardiovascular risk: 48 week effects on subclinical cardiovascular disease.

BACKGROUND: Switching from boosted PIs to dolutegravir in virologically suppressed HIV-infected patients with high cardiovascular risk significantly decreased total cholesterol and other proatherogenic lipid fractions at 48 weeks. The impact of this strategy on subclinical cardiovascular disease is unknown. METHODS: NEAT022 is a European, multicentre, open-label, randomized, non-inferiority trial. HIV-infected adults aged >50 years or with a Framingham score >10% were eligible if plasma HIV RNA was <50 copies/mL for >24 weeks on a boosted PI-based regimen. Patients were randomized 1:1 to switch from boosted PIs to dolutegravir or to continue on boosted PIs. Common carotid arteries intima-media thickness (CIMT) and pulse wave velocity (PWV) were measured following a standardized protocol in a subgroup of NEAT022 study participants at baseline and at Week 48. RESULTS: One hundred and fifty-six patients participated in the ultrasonography and arterial stiffness substudies, respectively. In each substudy, population characteristics did not differ between arms and matched those of the main study. At 48 weeks, patients who switched to dolutegravir had lower mean progression of both right (+4 versus +14.6 µm) and left (-6.1 versus +1.6 µm) CIMT and also a smaller increase in mean PWV (+0.18 versus +0.39 m/s) than patients continuing on boosted PIs, although differences were not statistically significant. CIMT trends were consistent across Framingham score, age and country. Inconsistent effects were seen in arterial stiffness. CONCLUSIONS: Relative to continuing on boosted PIs, switching to dolutegravir in virologically suppressed patients with high cardiovascular risk showed consistent favourable although non-significant trends on CIMT progression at 48 weeks.

Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction.

BACKGROUND: Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. METHODS: Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. RESULTS: Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P < .00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P < .00001). CONCLUSIONS: Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.

Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age ≥50 Years: Final 96-Week Results of the NEAT022 Study.

Background: Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to a dolutegravir (DTG)-based regimen may improve lipid profile. Methods: European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)-infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results: Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, -.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile. Clinical Trials Registration: NCT02098837 and EudraCT: 2013-003704-39.