Re-evaluating the relationship between youth with HIV and BMI in an age of increasing rates of overweight and obese youth.

BACKGROUND: Newer antiretrivirals (ART) have shifted the metabolic experiences of people with HIV (PWH) from those of wasting syndrome to increases in body mass index (BMI). This study sought to examine the relationship between BMI and ART use among youth with HIV (YWH). METHODS: Charts from YWH ages 10-24 with at least two documented BMIs at least 6 months apart between 2017 and 2020 were included (N = 44). Statistical analyses were conducted in SAS 9.4. RESULTS: Clients were predominately African American (66%) males (73%) aged 19-24 years (64%), with men having sex with men (48%) being the most common mode of transmission. YWH on non-integrase inhibitor (INSTI) regimens had greater absolute increases in BMI compared to those on INSTI regimens (p = 0.03). Fourteen percent of clients using INSTI experienced an increase in BMI class from normal to overweight or overweight to obese; no non-INSTI users changed BMI class. Time since diagnosis and BMI change due to weight gain were positively associated (p = 0.03) among behaviorally-acquired YWH. CONCLUSIONS: Increasing BMI and changing BMI classes may be more likely among YWH using INSTI. More longitudinal studies inclusive of diet and exercise profiles are needed to understand the relationship between INSTI and YWH BMI.

Glycemic Control in Patients Living With HIV Initiated on Integrase Inhibitor-Based Three-Drug Antiretroviral Therapy.

Background: The increased risk of cardio-metabolic disorders associated with people living with human immunodeficiency virus (HIV) is of growing importance. Given the broad adoption of integrase strand-transfer inhibitor (INSTI)-based antiretroviral therapy (ART) as first-line therapy for HIV, additional data are needed regarding the metabolic effects of these regimens. Objective: The purpose of this study is to assess glycemic control in patients started on INSTI-based 3-drug regimens over a 2-year period. Methods: A retrospective study was conducted on patients seen in the Brooklyn Hospital Center. Men and nonpregnant, nonlactating women aged 18 years or older with a diagnosis of HIV who were initiated on or switched to an ART consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an INSTI were included in the analysis. The primary endpoint is change in A1C from baseline (pre-INSTI initiation) to 2 years after initiation. Results: Two hundred fifty-one patients were eligible based on specified inclusion and exclusion criteria. Overall, a statistically significant increase in A1C was seen in all patients started on INSTI-based regimen (95% CI, 0.10-0.36; P < 0.001). Primarily patients on both elvitegravir-based and bictegravir-based regimens saw the most significant increase in A1C: 0.16% (95% CI, 0.04-0.27; P = 0.006) and 0.39% (95% CI, 0.02-0.76; P = 0.038), respectively. Conclusion and Relevance: Integrase strand-transfer inhibitor-based 3-drug ART was associated with a small but statistically significant increase in A1C over a 2-year period, requiring additional monitoring by clinicians.

Bictegravir/Tenofovir Alafenamide/Emtricitabine: A Real-Life Experience in People Living with HIV (PLWH).

BACKGROUND: Bictegravir (BIC), a recently introduced integrase inhibitor, is available in a single tablet regimen with tenofovir alafenamide (TAF) and emtricitabine (FTC) (BIC-STR). This study aimed to describe a real-life experience with BIC-STR. METHODS: We retrospectively analyzed the data of people living with HIV (PLWH) on antiretroviral therapy (ART) with BIC-STR followed by the Clinic of Infectious Diseases of Perugia (Perugia, Italy) from September 2019 to February 2023. RESULTS: 270 PLWH were enrolled with a median follow-up time on BIC-STR of 2.2 years (IQR 1.2-2.7). In the overall population, in treatment-experienced (N = 242), in treatment-naïve (N = 28), and in population with age > 60 years old (N = 86), we observed that CD4 cell count improved in absolute number, percentage and CD4/CD8 ratio, under BIC-STR. Patients with viremia < 50 cp/mL increased in all groups. In the overall population, previous ART with TAF and nadir CD4 cell count favored immunological recovery. In the ART-experienced group, time in therapy with BIC-STR was associated with HIV-RNA undetectability. In the older group, previous opportunistic infection and advanced age were associated with lower CD4 count. CONCLUSIONS: BIC-STR was demonstrated, in real-life, to be a valid option for a switch, such as initial ART.

Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? a case report.

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization due to its favorable side effect profile, high efficacy and genetic barrier to resistance.Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, DTG as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes.Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated.We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on DTG. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.

Integrase inhibitors: current protagonists in antiretroviral therapy.

Since HIV was identified as the etiological agent of AIDS, there have been significant advances in antiretroviral therapy (ART) that has reduced morbidity/mortality. Still, the viral genome's high mutation rate, suboptimal ART regimens, incomplete adherence to therapy and poor control of the viral load generate variants resistant to multiple drugs. Licensing over 30 anti-HIV drugs worldwide, including integrase inhibitors, has marked a milestone since they are potent and well-tolerated drugs. In addition, they favor a faster recovery of CD4+ T cells. They also increase the diversity profile of the gut microbiota and reduce inflammatory markers. All of these highlight the importance of including them in different ART regimens.

Research on HIV/AIDS has been focused on finding ways to prevent or cure the disease. One important class of drugs called integrase inhibitors has gained attention. These drugs are effective and have been widely used in the past decade to treat HIV. Integrase inhibitors help in the recovery of immune cells and improve the diversity of gut bacteria while reducing inflammation. It is important to include these drugs in treatment regimens for people living with HIV.

Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? A case report.

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization. This followed widespread reports of primary resistance to non-nucleoside reverse transcriptase inhibitors. Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, dolutegravir as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes. Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated. We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on dolutegravir. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.

Convenience, efficacy, safety, and durability of INSTI-based antiretroviral therapies: evidence from the Italian MaSTER cohort.

BACKGROUND: Integrase strand transferase inhibitors (INSTI), including raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), have demonstrated better efficacy and tolerability than other combination antiretroviral therapy (cART) classes in clinical trials; however, studies of sustainability of INSTI-containing therapy in the long-term are sparse. The purpose of this study was to provide an epidemiological overview comparing the outcome performance of different INSTI-based regimens longitudinally, including the metrics of efficacy, safety, convenience, and durability among a large, nationally representative cohort of persons living with HIV in Italy. METHODS: We selected subjects in the MaSTER cohort (an Italian multicenter, hospital-based cohort established in the mid-1990s that currently has enrolled over 24,000 PLWH) who initiated an INSTI-based regimen either when naïve or following a regimen switch. Cox proportional hazards regression models were fitted to evaluate associations between therapy interruptions and age, sex, nationality, transmission risk group, viral suppression status, CD4 + T-cell count, diagnosis year, cART status (naïve or experienced), and hepatitis coinfection. Results were stratified by cART INSTI type. RESULTS: There were 8173 participants who initiated an INSTI-based cART regimen in the MaSTER cohort between 2009 and 2017. The population was majority male (72.6%), of Italian nationality (88.6%), and cART-experienced (83.0%). Mean age was 49.7 (standard deviation: 13.9) years. In total, interruptions of the 1st INSTI-based treatment were recorded in 34% of cases. The most frequently cited reason for interruption among all three drug types was safety problems. In the survival analysis, past history of cART use was associated with higher hazards of interruption due to poor efficacy for all three drug types when compared to persons who were cART naïve. Non-viral suppression and CD4 + T-cell count < 200/mm3 at baseline were associated with higher hazards of interruption due to efficacy, safety, and durability reasons. Non-Italian nationality was linked to higher hazards of efficacy interruption for RAL and EVG. Age was negatively associated with interruption due to convenience and positively associated with interruption due to safety reasons. People who injects drugs (PWID) were associated with higher hazards of interruption due to convenience problems. Hepatitis coinfection was linked to higher hazards of interruption due to safety concerns for people receiving RAL. CONCLUSION: One-third of the population experienced an interruption of any drugs included in INSTI therapy in this study. The most frequent reason for interruption was safety concerns which accounted for one-fifth of interruptions among the full study population, mainly switched to DTG. The hazard for interruption was higher for low baseline CD4 + T-cell counts, higher baseline HIV-RNA, non-Italian nationality, older age, PWID and possible co-infections with hepatitis viruses. The risk ratio was higher for past history of cART use compared to persons who were cART naive, use of regimens containing 3 drugs compared to regimens containing 2 drugs. Durability worked in favor of DTG which appeared to perform better in this cohort compared to RAL and EVG, though length of follow-up was significantly shorter for DTG. These observational results need to be confirmed in further perspective studies with longer follow-up.

Blood glucose outcomes of anti-retroviral therapy naïve Ugandan people with HIV with pre-diabetes mellitus initiated on dolutegravir for 48 weeks.

Background: The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose. Methods: In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups. Results: There was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) = < 0.0001) and decrease in those with pre-DM (FBG: -6.1mg/dl, 95%CI (-9.1, -3.2), p = < 0.0001) at 48 weeks. 2hBG at 36 weeks was significantly lower than at baseline in both groups with the magnitude of reduction larger in those with pre-DM at 12 weeks (adjusted differences in mean drop in 2hBG (a2hBG): -19.69mg/dl, 95%CI (-30.19, -9.19), p = < 0.0001) and 36 weeks (a2hBG: -19.97mg/dl, 95%CI (-30.56, -9.39), p = < 0.0001). Conclusion: We demonstrated that Ugandan ART naïve PWH with pre-diabetes at enrollment have consistent improvement in both fasting blood glucose and glucose tolerance over 48 weeks on dolutegravir. Intensified blood glucose monitoring of these patients in the first six months of dolutegravir may be unnecessary.

Factors Associated With Viral Suppression and Drug Resistance in Children and Adolescents Living With HIV in Care and Treatment Programs in Southern Tanzania.

BACKGROUND: Achieving viral suppression (VS) for persons living with HIV is key to reaching epidemic control. We assessed the prevalence of VS and the frequency of HIV drug resistance mutations (HIVDRM) among children and adolescents living with HIV (CALHIV) in the Southern Highland zone of Tanzania. METHODS: From 2019 to 2021, we enrolled CALHIV aged 1-19 years on ART for >6 months in a cross-sectional study. Participants had viral load (VL) testing; those with VL ≥ 1000 copies/mL underwent HIVDRM testing. VS (<1000 copies/mL) prevalence estimates were calculated and robust Poisson regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations with potential predictors of VS. RESULTS: Of 707 participants, 595 had VS (PR: 0.84, 95% CI: 0.81-0.87). Use of an integrase strand transfer inhibitor-containing regimen (aPR 1.15, 95% CI: 0.99-1.34), age 5-9 years (aPR 1.16, 95% CI: 1.07-1.26), and seeking care at a referral center (aPR 1.12, 95% CI: 1.04-1.21) were associated with VS. Factors inversely associated with VS included having one (aPR 0.82, 95% CI: 0.72-0.92) or two or more (aPR 0.79, 95% CI: 0.66-0.94) referrals for adherence counselling, and self-reporting missing one to two (aPR 0.88, 95% CI: 0.78-0.99) or three or more (aPR 0.77, 95% CI: 0.63-0.92) doses of ART in the past month. Of 74 participants with PRRT and INT sequencing done, 60 (81.1%) had HIVDRMs at the following frequencies: 71.6%, 67.6%, 1.4%, and 4.1% for major NNRTI, NRTI, PI, and INSTI respectively. CONCLUSIONS: Higher rates of VS were observed in this cohort, and HIVDRMs were common in those without VS. This evidence supports ART optimization using dolutegravir-based regimens. However, better strategies to improve adherence are needed.

Weight gain after antiretroviral therapy initiation in people living with HIV in the United States: analyses of electronic medical records and prescription claims.

BACKGROUND: Treatment guidelines recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimens for treatment naïve people living with HIV (PLWH) in the United States (US). This retrospective database study compared weight changes following initiation of INSTI-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based ART in treatment-naïve PLWH. METHODS: Adult (≥18 years) PLWH initiated on INSTI, NNRTI, or PI plus ≥2 nucleoside reverse transcriptase inhibitors (NRTI) between 1 January 2014 to 31 August 2019 were identified in IQVIA's Ambulatory Electronic Medical Records (AEMR) linked to prescription drug claims (LRx). Weight changes over up to 36 months (M) of follow-up were compared among PLWH on INSTI- vs. NNRTI- and PI-based ART separately using non-linear mixed effect models, adjusting for demographics and baseline clinical characteristics. RESULTS: The INSTI, NNRTI, and PI cohorts included 931, 245, and 124 PLWH, respectively. For all three cohorts, the majority were male (78.2-81.2%) and overweight/obese (53.6-61.6%) at baseline; 40.8-45.2% of the groups were African American. The INSTI vs. NNRTI/PI cohorts were younger (median age: 38 years vs. 44 years/46 years), had lower weight at ART initiation (mean: 80.9 kg vs. 85.7 kg/85.0 kg), and had higher TAF usage during follow-up (55.6% vs. 24.1%/25.8%; all p < .05). Multivariate models showed higher weight gain among PLWH in INSTI vs. NNRTI and PI cohorts during treated follow-up (estimated weight gain after 36 M: 7.1 kg vs. 3.8 kg and 3.8 kg, both p < .05). CONCLUSION: Study findings highlight the need to monitor an increase in weight and potential metabolic complications among PLWH starting ART with INSTI.

Two-Year Outcomes of Treatment-Experienced Adults After Programmatic Transitioning to Dolutegravir: Longitudinal Data From the VICONEL Human Immunodeficiency Virus Cohort in Lesotho.

In the Viral Load Cohort North-East Lesotho (VICONEL) human immunodeficiency virus cohort, 14 242 adults had transitioned from efavirenz- or nevirapine-based antiretroviral therapy (ART) to dolutegravir-based ART by October 2021. Rates of viral suppression to <50 copies/mL were 84.8%, 93.9%, and 95.4% before, 12 months after, and 24 months after transition, respectively. Sex, age, pretransition viral load, and treatment backbone correlated with 24-month viremia.

Weight and Metabolic Outcomes in Naïve HIV Patients Treated with Integrase Inhibitor-Based Antiretroviral Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of integrase inhibitor-based antiretroviral therapy could be associated with worse weight and metabolic outcomes in patients with HIV infection. METHODS: PubMed, EMBASE, and Scopus were searched from inception to March 2022. We selected randomized controlled trials (RCTs) comparing integrase inhibitors with other antiretroviral classes (efavirenz-based or protease inhibitor-based therapies) in naïve HIV patients. Random effects meta-analysis was used to assess the effects of integrase inhibitors vs. controls on weight and lipid outcomes. Effects were described as mean differences (MD) and their 95% confidence intervals (CI). Certain pieces of evidence (CoE) were evaluated using the GRADE methodology. RESULTS: Six RCTs (n = 3521) were included, with patients followed up between 48 and 96 weeks. The use of integrase inhibitors in comparison with other antiretroviral classes was associated with an increase in weight (MD 2.15 kg, 95%CI 1.40 to 2.90, I2 = 0%, moderate CoE), and decreases in total cholesterol (MD -13.44 mg/dL, 95%CI -23.49 to -3.39, I2 = 96%, low CoE), LDL cholesterol (MD -1.37 mg/dL, 95%CI -19.24 to -3.50, I2 = 83%, low CoE), HDL cholesterol (MD -5.03 mg/dL, 95%CI -10.61 to 0.54, I2 = 95%, low CoE), and triglycerides (MD -20.70 mg/dL, 95%CI -37.25 to -4.15, I2 = 92%, low CoE). There was a high risk of bias in two RCTs and some concerns about bias in two RCTs. CONCLUSIONS: In HIV patients, the use of integrase inhibitor-based therapy in comparison with protease inhibitor- or NNRTI-based therapy was associated with a small increase in weight and small decreases in lipid serum levels.

Alkaloids as Potential Anti-HIV Agents.

BACKGROUND: Alkaloids are nitrogen-containing compounds that are naturally occurring and have a variety of biological activities, including antimicrobial properties. In this study, the authors used a molecular docking approach to evaluate the anti-HIV potential of 64 alkaloids. METHODS: The authors used the Molegro Virtual Docker software to dock the alkaloids into the active sites of three HIV enzymes: protease, integrase, and non-nucleoside reverse transcriptase (NNRT). The docking scores were used to assess the potential of the alkaloids to inhibit the enzymes. RESULTS: The results showed the alkaloids to have good potential to inhibit the enzymes. Tubocurarine and reserpine were found to be the most potent alkaloids, with docking scores of -123.776 and - 114.956, respectively. CONCLUSION: The authors concluded that tubocurarine and reserpine could be further promoted as potential lead molecules for the development of new anti-HIV drugs.

Obesity Modifies the Relationship Between Raltegravir and Dolutegravir Hair Concentrations and Body Weight Gain in Women Living with HIV.

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in women living with HIV (WLH). Relationships between drug exposure, baseline obesity, and INSTI-associated weight gain remain unclear. Data from 2006 to 2016 were analyzed from virally suppressed WLH enrolled in the Women's Interagency HIV Study, who switched/added an INSTI to antiretroviral therapy: [raltegravir (RAL), dolutegravir (DTG), or elvitegravir (EVG)]. Percent body weight change was calculated from weights obtained a median 6 months pre-INSTI and 14 months post-INSTI initiation. Hair concentrations were measured with validated liquid chromatography-mass spectrometry (MS)/MS assays. Baseline (preswitch) weight status evaluated obese (body mass index, BMI, ≥30 kg/m2) versus nonobese (BMI <30 kg/m2). Mixed models examined the drug hair concentration*baseline obesity status interaction for each INSTI. There were 169 WLH included: 53 (31%) switched to RAL, 72 (43%) to DTG, and 44 (26%) to EVG. Women were median age 47-52 years, predominantly Non-Hispanic Black, median CD4 counts >500 cells/mm3, >75% with undetectable HIV-1 RNA. Over ∼1 year, women experienced median increases in body weight: 1.71% (-1.78, 5.00) with RAL; 2.40% (-2.82, 6.50) with EVG; and 2.48% (-3.60, 7.88) with DTG. Baseline obesity status modified the relationship between hair concentrations and percent weight change for DTG and RAL (p's < 0.05): higher DTG, yet lower RAL concentrations were associated with greater weight gain among nonobese women. Additional pharmacologic assessments are needed to understand the role of drug exposure in INSTI-associated weight gain.

Impact of weight gain with dolutegravir on antiretroviral adherence and viral suppression in four African countries.

OBJECTIVE: We hypothesized that total body weight (TBW) gain after switching antiretroviral therapy (ART) regimen to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) may negatively impact ART adherence and viral load (VL) and therefore sought to examine these associations. METHODS: The ongoing African Cohort Study (AFRICOS) enrols people with HIV at 12 facilities in Kenya, Nigeria, Tanzania and Uganda supported by The US President's Emergency Plan for AIDS Relief. Among ART-experienced participants who switched to TLD, we used multivariable multinomial logistic regression to examine associations between pre-/post-TLD changes in percentage TBW (≥5% gain, <5% change, ≥5% loss) and changes in self-reported ART adherence (0, 1-2, ≥3 days missed doses in past 30 days) and VL [(<50 copies/mL (undetectable), 50-999 copies/mL (detectable, but suppressed), ≥1000 copies/mL (unsuppressed)]. RESULTS: Among 1508 participants, median time from starting TLD to follow-up was 9 months (interquartile range: 7-11). Overall, 438 (29.1%) participants experienced a TBW gain ≥5%, which was more common among females than among males (32.2% vs 25.2%, p = 0.005) and participants switching from efavirenz [32.0% vs nevirapine (19.9%) and boosted protease inhibitor (20.0%); p < 0.001]. Compared with a TBW change <5% [950 (63.0%) participants], TBW gain ≥5% was not significantly associated with more days with missed ART doses [adjusted odds ratio (aOR) = 0.77, 95% confidence interval (CI): 0.48-1.23] or VL becoming detectable and/or unsuppressed (aOR = 0.69, 95% CI: 0.41-1.16). CONCLUSIONS: Although a substantial proportion of participants experienced weight gain after switching to TLD, we did not identify a significant impact on adherence or virological outcomes.

Efficacy and Durability of Dolutegravir- or Darunavir-Based Regimens in ART-Naïve AIDS- or Late-Presenting HIV-Infected Patients.

BACKGROUND: Since limited data are available, we aimed to compare the efficacy and durability of dolutegravir and darunavir in advanced naïve patients. METHODS: Retrospective multicenter study including AIDS- or late-presenting (def. CD4 ≤ 200/µL) HIV-infected patients starting dolutegravir or ritonavir/cobicistat-boosted darunavir+2NRTIs. Patients were followed from the date of first-line therapy initiation (baseline, BL) to the discontinuation of darunavir or dolutegravir, or for a maximum of 36 months of follow-up. RESULTS: Overall 308 patients (79.2% males, median age 43 years, 40.3% AIDS-presenters, median CD4 66 cells/µL) were enrolled; 181 (58.8%) and 127 (41.2%) were treated with dolutegravir and darunavir, respectively. Incidence of treatment discontinuation (TD), virological failure (VF, defined as a single HIV-RNA > 1000 cp/mL or two consecutive HIV-RNA > 50 cp/mL after 6 months of therapy or after virological suppression had been achieved), treatment failure (the first of TD or VF), and optimal immunological recovery (defined as CD4 ≥ 500/µL + CD4 ≥ 30% + CD4/CD8 ≥ 1) were 21.9, 5.2, 25.6 and 1.4 per 100 person-years of follow-up, respectively, without significant differences between dolutegravir and darunavir (p > 0.05 for all outcomes). However, a higher estimated probability of TD for central nervous system (CNS) toxicity (at 36 months: 11.7% vs. 0%, p = 0.002) was observed for dolutegravir, whereas darunavir showed a higher probability of TD for simplification (at 36 months: 21.3% vs. 5.7%, p = 0.046). CONCLUSIONS: Dolutegravir and darunavir showed similar efficacy in AIDS- and late-presenting patients. A higher risk of TD due to CNS toxicity was observed with dolutegravir, and a higher probability of treatment simplification with darunavir.

The G118R plus R263K Combination of Integrase Mutations Associated with Dolutegravir-Based Treatment Failure Reduces HIV-1 Replicative Capacity and Integration.

Human immunodeficiency virus (HIV) treatment with antiretroviral regimens containing integrase strand transfer inhibitors such as dolutegravir (DTG) and bictegravir (BIC) offers high levels of protection against the development of drug resistance mutations. Despite this, resistance to DTG and BIC can occur through the development of the R263K integrase substitution. Failure with DTG has also been associated with the emergence of the G118R substitution. G118R and R263K are usually found separately but have been reported together in highly treatment-experienced persons who experienced treatment failure with DTG. We used cell-free strand transfer and DNA binding assays and cell-based infectivity, replicative capacity, and resistance assays to characterize the G118R plus R263K combination of integrase mutations. R263K reduced DTG and BIC susceptibility ~2-fold, in agreement with our previous work. Single-cycle infectivity assays showed that G118R and G118R plus R263K conferred ~10-fold resistance to DTG. G118R alone conferred low levels of resistance to BIC (3.9-fold). However, the G118R plus R263K combination conferred high levels of resistance to BIC (33.7-fold), likely precluding the use of BIC after DTG failure with the G118R plus R263K combination. DNA binding, viral infectivity, and replicative capacity of the double mutant were further impaired, compared to single mutants. We propose that impaired fitness helps to explain the scarcity of the G118R plus R263K combination of integrase substitutions in clinical settings and that immunodeficiency likely contributes to its development.

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

BACKGROUND: There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. METHODS: We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. RESULTS: Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. CONCLUSIONS: Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.