DTG-based Regimen Research Articles

“It’s only fatness, it doesn’t kill”: a qualitative study on perceptions of weight gain from use of dolutegravir-based regimens in women living with HIV in Uganda

BackgroundDolutegravir (DTG)-based regimens have been recommended by the WHO as the preferred first-line and second-line HIV treatment in all populations. Evidence suggests an association with weight gain, particularly among black women. Our study investigated perceptions of weight gain from DTG-based regimen use on body image and adherence of antiretroviral therapy in women living with HIV (WLHIV) in Uganda.MethodsBetween April and June 2021, we conducted semi-structured interviews involving 25 WLHIV (adolescents, women of reproductive potential and post-menopausal women) and 19 healthcare professionals (clinicians, nurses, ART managers and counsellors) purposively selected from HIV clinics in Kampala. The interviews explored perceptions of body weight and image; experiences and management of weight related side effects associated with DTG; and knowledge and communication of DTG-related risks. Data was analysed thematically in NVivo 12 software.ResultsOur findings indicate WLHIV in Uganda commonly disliked thin body size and aspired to gain moderate to high level body weight to improve their body image, social standing and hide their sero-positive status. Both WLHIV and healthcare professionals widely associated weight gain with DTG use, although it was rarely perceived as an adverse event and was unlikely to be reported or to alter medication adherence. Clinical management and pharmacovigilance of DTG-related weight gain were hampered by the limited knowledge of WLHIV of the health risks of being over-weight and obesity; lack of diagnostic equipment and resources; and limited clinical guidance for managing weight gain and associated cardiovascular and metabolic comorbidities.ConclusionsThe study highlights the significance of large body-size in promoting psychosocial wellbeing in WLHIV in Uganda. Although weight gain is recognized as a side effect of DTG, it may be welcomed by some WLHIV. Healthcare professionals should actively talk about and monitor for weight gain and occurrence of associated comorbidities to facilitate timely interventions. Improved supply of diagnostic equipment and support with sufficient guidance for managing weight gain for healthcare professionals in Uganda are recommended.

Evidence synthesis evaluating body weight gain among people treating HIV with antiretroviral therapy - a systematic literature review and network meta-analysis

SummaryBackgroundThis systematic review aimed to compare body weight gain associated outcomes over time between dolutegravir (DTG)-based antiretroviral (ART) regimens to other ART regimens, to compare tenofovir alafenamide (TAF)-based regimens, and to evaluate the associated prognostic factors.MethodsSystematic searches of MEDLINE, Embase, and CENTRAL for RCTs and observational studies comparing ART regimens were conducted on 13 September 2021. Outcomes of interest included: change in body weight, body mass index (BMI), waist circumference; and risk of hyperglycaemia and diabetes. Network meta-analyses were conducted at 12, 24, 48, 96 and 144 weeks using two networks differentiated by 3rd agents and backbone agents.FindingsThe review identified 113 publications reporting on 73 studies. DTG-based regimens led to statistically higher weight gains than efavirenz-based regimens at all time points (mean difference: 1·99 kg at 96 weeks; 95% credible interval: 0·85–3·09) and was higher over time than low-dose efavirenz-, elvitegravir-, and rilpivirine-based regimens. They were comparable to raltegravir-, bictegravir- and atazanavir-based regimens. For backbones, TAF led to higher weight gain relative to tenofovir disoproxil fumarate (TDF), abacavir, and zidovudine. Prognostic factor analysis showed both low CD4 cell count and high HIV RNA viral load at baseline were consistently associated with higher weight gain, while sex was an effect modifier to African origins.InterpretationDTG-based regimens lead to larger average weight gains than some other ART regimens and TAF leads to larger average weight gains than all other backbone antiretrovirals. Further research is needed to better understand long-term outcomes and their relationship to other metabolic outcomes.FundingThe WHO Global HIV, Hepatitis and Sexually Transmitted Infections Programmes.

Patient satisfaction with anti-retroviral services at General Hospital, Ogoja, Cross River State, Nigeria: a cross-sectional study

Background: Patients have explicit desires for services when visiting hospitals and inadequate inquiries of their needs may result in dissatisfaction. This study aimed to assess the level of satisfaction and its correlates amongst clients receiving ART care and treatment at the General Hospital, Ogoja, Cross River State, Nigeria.Methods: A cross sectional study was conducted among PLHIV age ≥18 years from June 2020 to August 2020 at RISE supported ART clinic of GH Ogoja and satisfaction level was assessed using the PSQ18 instrument. Data was collected using a structured interviewer administered questionnaire and was analyzed for descriptive and inferential statistics using IBM SPSS version 23.Results: Out of the 365 participants enrolled into the study, 60.5% were females. The mean score of PSQ-18 domain was 40.8±2.52 with the highest scores reported in accessibility/convenience (9.4±0.76) and technical quality (9.4±0.74) domains while the lowest was in time spent with doctors/case managers (3.0±0.0). The correlates of patient satisfaction were respondents involved in businesses, earning above the minimum wage, on TLD and no reported missed doses of ART and the only determinant was being on TLD.Conclusions: Access, convenience and technical quality were perceived satisfied by patients receiving care. However, they were dissatisfied with the time spent with them and being on TLD was a determinant of patient satisfaction. Client-centric interventions should include health caregivers spending quality time with their patients and all clients weighing 20kg and above are on DTG-based regimen for their care and treatment.

Prevalence and factors associated with adverse drug events among patients on dolutegravir-based regimen at the Immune Suppression Syndrome Clinic of Mbarara Regional Referral Hospital, Uganda: a mixed design study

BackgroundIn low income countries such as Uganda progress has been made towards achieving the United Nations AIDS programme 95-95-95 target however efforts are still impeded by pretreatment drug resistance and adverse drug events (ADEs) hence introduction of dolutegravir-based antiretroviral therapy as first-line treatment due to a higher genetic barrier to resistance, better tolerability and safety profile. However, recent studies have raised concerns regarding its safety in real-clinical settings due to ADEs and being a recently introduced drug there is need to actively monitor for ADEs, hence this study aimed to establish the prevalence and factors associated with ADEs among patients on dolutegravir-based regimen at the Immune Suppression Syndrome (ISS) Clinic- Mbarara Regional Referral Hospital (MRRH).MethodsA mixed design study was conducted at ISS Clinic-MRRH among 375 randomly selected patients who had been exposed to DTG-based regimen for at-least 12 weeks. These were interviewed to obtain data on socio-demographics, dietary habits and their files reviewed for ADEs. Data entry was done using Epi-data 3.0 and exported to SPSS 25.0 for analysis. Prevalence was determined as a percentage, and ADE associated factors assessed using bivariate analysis, those found significant were further subjected to multivariate analysis and considered significant at P < 0.05.ResultsThe prevalence of ADEs among patients on DTG-based regimen was found to be 33.1% (124/375) with 5.6% (7/124) participants discontinued from treatment due ADEs, 4 due to hyperglycemia and 3 liver toxicity. The commonly experienced ADE was allergy at 36.3%. Male sex (AOR 1.571, 95% CI 1.433–1.984), WHO stage one at entry to care (AOR 4.586, 95% CI 1.649–12.754), stage two (AOR 4.536, 95% CI 1.611–12.776), stage three (AOR 3.638, 95% CI 1.262–10.488), were significantly associated with ADEs. Patients with undetectable viral load at initiation of DTG-based regimen were 67.6% less likely to experience ADEs (AOR = 0.324, 95% CI 0.1167–0.629).ConclusionThis study reports a prevalence of 33.1% of ADEs among patients on DTG-based regimen. The most commonly experienced ADE was allergy. Male sex, early HIV disease stage at entry into care and detectable viral load at initiation of DTG-based regimen were significantly associated with ADEs. It is crucial to actively monitor patients with these characteristics for ADEs.

Incidence and factors associated with adverse drug reactions in a cohort of individuals starting dolutegravir or efavirenz

Prospective cohort of people living with HIV who started combination antiretroviral therapy (cART) with regimens containing efavirenz (EFV) or dolutegravir (DTG) in three specialized HIV/AIDS care services in Belo Horizonte, Brazil, with the objective of analyzing incidence, time to development and factors associated with the first adverse drug reaction (ADR). Data were collected from September 2015 to October 2018 through face-to-face interviews, clinical records, and information systems. The ADR-associated factors were evaluated with Cox regression and the time to the first ADR with Kaplan-Meier survival curves. Among the 433 individuals included, 217 (50.1%) had ADR in 12 months of follow-up. Among the 695 registered ADRs, 604 (86.9%) occurred in individuals using the EFV-based regimen, and gastrointestinal, psychiatric, and nervous system disorders were the most frequent. The mean time to develop the first ADR was 210.6 days (95% CI: 195.5-225.8). The concomitant use of other medications was associated with a higher risk of ADR (HR: 2.00; 95% CI: 1.38-2.89). The use of alcohol (HR: 0.64; 95% CI: 0.49-0.85) and the DTG-based regimen (HR: 0.40; 95% CI: 0.28-0.58) were factors associated with a lower risk of ADRs. We conclude that the DTG-based regimen had a better safety profile than the EFV-based regimen at 12 months of follow-up. Clinical and behavioral characteristics were associated with higher ADR risks and should be monitored when managing the treatment of HIV.

Pretreatment Human Immunodeficiency Virus (HIV) Drug Resistance Among Treatment-Naive Infants Newly Diagnosed With HIV in 2016 in Namibia: Results of a Nationally Representative Study.

BackgroundThe World Health Organization (WHO) recommends routine surveillance of pretreatment human immunodeficiency virus (HIV) drug resistance (HIVDR) in children <18 months of age diagnosed with HIV through early infant diagnosis (EID). In 2016, 262 children <18 months of age were diagnosed with HIV in Namibia through EID. Levels of HIVDR in this population are unknown.MethodsIn 2016, Namibia surveyed pretreatment HIVDR among children aged <18 months following WHO guidance. Reverse transcriptase, protease, and integrase regions of HIV-1 were genotyped from remnant dried blood spot specimens from all infants diagnosed with HIV in Namibia in 2016. HIVDR was predicted using the Stanford HIVdb algorithm.ResultsOf 262 specimens genotyped, 198 HIV-1 protease and reverse transcriptase sequences and 118 HIV-1 integrase sequences were successfully amplified and analyzed. The prevalence of efavirenz/nevirapine (EFV/NVP), abacavir (ABC), zidovudine, lamivudine/emtricitabine (3TC/FTC), and tenofovir (TDF) resistance was 62.6%, 17.7%, 5.6%, 15.7%, and 10.1%, respectively. No integrase inhibitor resistance was detected.ConclusionsThe high level of EFV/NVP resistance is unsurprising; however, levels of ABC and TDF resistance are among the highest observed to date in infants in sub-Saharan Africa. The absence of resistance to dolutegravir (DTG) is reassuring but underscores the need to further study the impact of ABC and 3TC/FTC resistance on pediatric protease inhibitor– and DTG-based regimens and accelerate access to other antiretroviral drugs. Results underscore the need for antiretroviral therapy optimization and prompt management of high viral loads in infants and pregnant and breastfeeding women.

Predictors of Viral Non-Suppression among Patients Living with HIV under Dolutegravir in Bunia, Democratic Republic of Congo: A Prospective Cohort Study.

The Democratic Republic of the Congo adopted the integrase inhibitor dolutegravir (DTG) as part of its preferred first-line HIV treatment regimen in 2019. This study aimed to identify predictors of viral non-suppression among HIV-infected patients under a DTG-based regimen in the context of ongoing armed conflict since 2017 in the city of Bunia in the DRC. We conducted a cohort study of 468 patients living with HIV under DTG in all health facilities in Bunia. We calculated the proportion of participants with an HIV RNA of below 50 copies per milliliter. About three in four patients (72.8%) in this cohort had a viral load (VL) of <50 copies/mL after 6–12 months. After controlling for the effect of other covariates, the likelihood of having non-suppression remained significantly lower among the 25–34 age group and self-reported naïve patients with a baseline VL of ≥50 copies/mL. The likelihood of having non-suppression remained significantly higher among those who were at advanced stages of the disease, those with abnormal serum creatinine, those with high baseline HIV viremia over 1000 copies/mL, and the Sudanese ethnic group compared to the reference groups. This study suggests that we should better evaluate adherence, especially among adolescents and economically vulnerable populations, such as the Sudanese ethnic group in the city of Bunia. This suggests that an awareness of the potential effects of DTG and tenofovir is important for providers who take care of HIV-positive patients using antiretroviral therapy (ART), especially those with abnormal serum creatinine levels before starting treatment.

Adherence, Effectiveness and Safety of Dolutegravir Based Antiretroviral Regimens among HIV Infected Children and Adolescents in Tanzania.

Objectives:This study aimed at assessing adherence, effectiveness, and safety of DTG-based HAART regimens among HIV-infected children and adolescents in Tanzania. Methods: This was a single-center prospective cohort study, conducted at the pediatric HIV Clinic in Mbeya, Tanzania. A binary logistic regression model was used to determine predictors of undetectable viral load at week 24. The results were significant when P-value was <0.05. Results: A total of 200 patients were enrolled with the majority (85.5%) being treatment experienced. High adherence levels (71%) were observed using the pharmacy refill method. At week 24, the overall proportion of patients with undetectable viral load was 70.2%. The predictors of undetectable viral load were age, World Health Organization (WHO) clinical stage, baseline VL and adherence to pharmacy refill. Conclusion: The majority of patients attained undetectable viral load 6 months after using DTG based regimen. DTG-based regimens were generally safe with few ADEs reported.

Adherence, resistance, and viral suppression on dolutegravir in sub-Saharan Africa: implications for the TLD era.

Dolutegravir (DTG) is now a component of preferred first-line antiretroviral therapy (ART) worldwide. ADVANCE and NAMSAL were two landmark clinical trials conducted exclusively in sub-Saharan Africa, which studied the effectiveness of DTG-based first-line regimens for ART-naive individuals. In this review, we examine the data from these studies to consider the contributions of adherence and HIV drug resistance to treatment failure on DTG-based ART, as compared with efavirenz (EFV)-based ART, which has a lower genetic barrier to resistance. We also discuss the implications of virologic failure on DTG and consolidate currently available data to conclude with recommendations for virologic monitoring on DTG-based ART.

Provider perspectives on the acceptability and tolerability of dolutegravir-based anti-retroviral therapy after national roll-out in Uganda: a qualitative study

BackgroundThe World Health Organization recommends dolutegravir (DTG) as the for first-line and second-line antiretroviral therapy (ART) worldwide. However, little is known about the acceptability and tolerability of DTG-based ART at routine points-of-care in Uganda. We set out to explore the perceptions of clinicians in ART clinics regarding the acceptability and tolerability of DTG-based ART since national roll-out in March 2018 in Uganda.MethodsWe adopted a qualitative exploratory design involving 49 participants. Between September 2020 and February 2021, we conducted 22 in-depth interviews with clinicians in the ART clinics of 12 purposively selected health facilities across Uganda. The selection of study sites ensured diversity in facility ownership-type (public/private), level of service delivery (tertiary/secondary/primary) and the four major geographic sub-regions of Uganda. We conducted three focus group discussions with 27 clinicians in the participating facilities. Data were analyzed by thematic approach.ResultsClinicians in ART clinics acknowledged that DTG-based ART is well tolerated by the majority of their patients who appreciate the reduced pill burden, perceived less side effects and superior viral load suppression. However, they reported that a number of their patients experience adverse drug reactions (ADRs) after being transitioned to DTG. Hyperglycemia is, by far, the most commonly reported suspected ADR associated with DTG-based regimens and was cited in all but two participating facilities. Insomnia, weight gain and reduced libido are among the other frequently cited suspected ADRs. In addition, clinicians in ART clinics perceived some of the suspected ADRs as resulting from drug interactions between dolutegravir and isoniazid. Weak diagnostic capacities and shortage of associated commodities (e.g. glucometers and test kits) were reported as impediments to understanding the full extent of ADRs associated DTG-based ART.ConclusionWhile DTG-based regimens were perceived by clinicians in ART clinics to be well tolerated by the majority of their patients, they also reported that a number of patients experience suspected ADRs key among which were hyperglycemia, insomnia and reduced libido. Based on the perspectives of clinicians, we recommend that future studies examine the prevalence of dolutegravir-induced hyperglycemia in patients in Uganda.

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme’s catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.

Cost-Utility Analysis of Dolutegravir- Versus Efavirenz-Based Regimens as a First-Line Treatment in Adult HIV/AIDS Patients in Ethiopia.

BackgroundIn several countries, the dolutegravir (DTG)-based regimen is generally preferred as first-line antiretroviral therapy (ART) over the efavirenz (EFV)-based regimen, but the evidence in low-income countries is limited.ObjectiveOur study aimed to evaluate the cost effectiveness of DTG- versus EFV-based first-line human immunodeficiency virus (HIV) treatment in Ethiopia.MethodsWe developed a microsimulation model for the progression of HIV/acquired immune deficiency syndrome (AIDS) to examine the cost effectiveness of DTG-based first-line ART compared with an EFV-based regimen from a healthcare payer perspective. We used a lifetime horizon with a 1-month cycle length and a 3% annual discount rate. The primary outcomes were a lifetime cost in US dollars ($), quality-adjusted life-months (QALMs) that converted to QALYs using the formula QALY = QALM/12, and incremental cost-effectiveness ratio (ICER). Deterministic sensitivity analysis was conducted to account for parameter uncertainty.ResultsCompared with the EFV-based regimen, the DTG-based regimen was associated with an expected lifetime cost of $12,709 (vs. $12,701) and expected QALYs of 15.3 (vs. 14.7 QALYs) per patient, resulting in an ICER value of $13.33 per QALY. From an alternative analysis with a 5-year time horizon, DTG-based ART was found to be dominant, with expected gains of 0.17 QALYs at a lower cost of $1 per patient. The deterministic sensitivity analysis depicted that the maximum increase in ICER value was $72 per QALY, and all ICER values were below the estimated threshold value.ConclusionsThe DTG-based first-line regimen appears to be cost effective compared with the EFV-based regimen for the treatment of HIV/AIDS patients in an Ethiopian setting.

Dolutegravir response in antiretroviral therapy naïve and experienced patients with M184V/I: Impact in low-and middle-income settings

BackgroundDolutegravir (DTG) is now recommended to all HIV infected adults, adolescents, and children of right age by WHO. The low cost of $75 per year for generic DTG-based combination, has allowed 3.9 million people living with HIV (PLWH) in low and middle-income countries (LMICs) access to DTG. Lamivudine and emtricitabine associated M184V/I mutation is highly prevalent in PLWH and the majority of HIV infected individuals receiving DTG regimens may already be carrying M184V/I mutation. DiscussionDespite high prevalence of M184V/I in antiretroviral therapy (ART) experienced patients, DTG treatment outcomes will likely not be adversely affected by this mutation. The use of DTG in ART naïve has been largely characterised by rare emergence of resistance and virological failure. DTG-based regimens have to great extent been effective at maintaining viral suppression in treatment experienced PLWH carrying M184V/I. ConclusionsInitiating patients on DTG may help preserve more treatment options for HIV infected individuals living in LMICs. High genetic barrier to the development of resistance associated with DTG and progressive viral suppression in patients switched to DTG-based therapy with M184V/I, may encourage better DTG outcomes and help in curbing increasing levels of HIV drug resistance in LMICs.

Dolutegravir-Based Regimen for Maintenance of Viral Suppression in People Living with HIV: 48-Week Results in Real-Life Setting.

To evaluate the efficacy, safety, and tolerability of switching to a dolutegravir (DTG)-based regimen in a cohort of virological suppressed HIV-infected patients who have previously been treated with different antiretroviral combination. The dynamics of total HIV-DNA and levels of high-sensitivity c-reactive protein, interleukin-6, soluble-CD14, and D-Dimer were also analyzed. Ninety-six individuals who switched to a DTG-containing regimen were followed up for 48 weeks. HIV RNA, CD4+ T cell count, weight, and levels of laboratory parameters were recorded at baseline, after 24 and 48 weeks of treatment for all study participants. In a subgroup of patients, HIV DNA and inflammation/coagulation marker levels were also analyzed until week 24. Ninety-three out of 96 patients maintained virological suppression, including patients who switched to dual-therapy from triple-drug combination. Eighteen out of 96 patients had residual viremia at baseline, of which 13 reached the maximal viral suppression at W48. Serum creatinine levels showed a significant increase at weeks 24 and 48. A progressive reduction of total cholesterol was observed from week 24 and up to week 48. No variation in body mass index was detected. HIV DNA, inflammation, and coagulation marker levels did not significantly change during follow-up. Switching to a DTG-based regimen may be a key option for achieving and maintaining maximal virological suppression, even in patients showing residual viremia at baseline. Furthermore, the improvement in blood lipid profile and the overall tolerability observed in this study strongly support the use of these regimens in the aging HIV population.

Participants on Dolutegravir Resuppress Human Immunodeficiency Virus RNA After Virologic Failure: Updated Data from the ADVANCE Trial.

Following evidence of HIV RNA re-suppression on DTG-based regimens, we assess the re-suppressive capacity of ADVANCE participants on TAF/FTC+DTG, TDF/FTC+DTG, and TDF/FTC/EFV. Viraemic participants were able to re-suppress within 3 follow-up visits of protocol-defined virological failure (PDVF) in 77/121 (64%), 85/126 (67%), and 44/138 (32%) cases respectively (DTG regimens vs. TDF/FTC/EFV; P < 0.001).

Cost-Utility Analysis of a Dolutegravir-Based Versus Low-Dose Efavirenz-Based Regimen for the Initial Treatment of HIV-Infected Patients in Cameroon (NAMSAL ANRS 12313 Trial).

ObjectivesEvidence comparing the economic and patient values of the World Health Organization’s preferred (dolutegravir 50 mg [DTG]-based) and alternative (low-dose [400 mg] efavirenz [EFV400]-based) first-line antiretroviral regimens is limited. We compared patient-reported outcomes (PROs), costs, and the cost-utility of DTG- versus EFV400-based regimens in treatment-naive HIV-1 adults in the randomised NAMSAL ANRS 12313 trial in Yaoundé, Cameroon.MethodsWe used clinical data, PROs, and health resource use data collected in the trial’s first 96 weeks (2016–2019). Quality-adjusted life-years (QALYs) were computed using utility scores obtained from the 12-item Short Form (SF-12) generic health scale. Other PROs included perceived symptoms, depression, anxiety, and stress. In the 96-week base-case analysis, we estimated the unadjusted and multivariate-adjusted (1) mean costs (in US$, 2016 values) and QALYs/patient, (2) incremental costs and QALYs/patient, and (3) net health benefit (NHB). Outcomes were extrapolated over 5 and 10 years. Uncertainty was assessed using the cost-effectiveness acceptability curve and scenario and cost-effective price threshold analyses.ResultsIn the base-case analysis, the NHB (95% confidence interval) for the DTG-based regimen relative to the EFV400-based regimen was 0.056 (− 0.037 to 0.153), corresponding to an 88% probability of DTG being cost-effective. A 10% decrease in this regimen’s price (from $5.2 to $4.7/month) would increase its cost-effectiveness probability to 95%. When extrapolating outcomes over 5 and 10 years, the DTG-based regimen had a 100% probability of being cost-effective for a large range of cost-effectiveness thresholds.ConclusionsAt 2020 antiretroviral drug prices, a DTG-based first-line regimen should be preferred over an EFV400-based regimen in sub-Saharan Africa.Trial RegistrationClinicalTrials.gov Identifier: NCT02777229.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-020-00987-3.

Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study.

Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG's high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.

Discontinuation due to neuropsychiatric adverse events with efavirenz- and dolutegravir-based antiretroviral therapy: a comparative real-life study

ObjectivesDespite the high efficacy of antiretroviral treatment, no drug is free from adverse events (AEs). Efavirenz (EFV) and dolutegravir (DTG) are antiretroviral drugs for which neuropsychiatric adverse events (NPAEs) have...

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV.

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.

High acceptability and viral suppression of patients on Dolutegravir-based first-line regimens in pilot sites in Uganda: A mixed-methods prospective cohort study.

Uganda adopted the integrase inhibitor dolutegravir (DTG) as part its preferred first-line HIV treatment regimen in 2018. Prior to the national rollout, the Uganda Ministry of Health and Clinton Health Access Initiative (CHAI) launched a pilot study in July 2017 aimed at better understanding patients’ and prescribers’ experience and acceptability of DTG. Patients were enrolled in the study if they were newly initiating treatment or switched from an NNRTI regimen due to intolerance. Patients were followed up for 6 months after initiation onto DTG and acceptability and experiences were assessed through questionnaires at one-month and six-month follow-up visits. In addition to acceptability side effects of patients on DTG regimens were assessed. Analysis was conducted using MS Excel and SAS 9.4 and confidence intervals were adjusted for facility level clustering. A total of 365 patients from 6 study sites were enrolled in the study, of whom 50% were treatment-experienced and 50% treatment naïve. 325 patients completed the 6 months of follow-up. Survey results showed a high level of acceptability (more than 90%) of DTG-containing regimens for both categories of patients during the from one-month and six-months interviews. The rate of self-reported side effects amongst patients was 33% overall and higher for experienced (37%) than naïve (29%) patients at 6 months. Although frequencies declined between month-1 and month-6, the changes were not statistically significant. Almost all patients (94%) were virally suppressed at 6 months. Overall, the study findings showed a very high level of acceptability of Dolutegravir-based regimens across both experienced and naïve patients. The overall viral suppression rate in this cohort was 94% at six months of taking DTG-based regimen.