Virological Effectiveness of Dolutegravir-based Second-line ART in the Context of NRTI Resistance Among HIV-Positive Patients in India

Advances and challenges in antiretroviral therapy for acquired immunodeficiency syndrome.

Factors Associated With Coronavirus Disease 2019 Morbidity in a Cohort of People Living With Human Immunodeficiency Virus.

BackgroundHIV infection and antiretroviral therapy (ART) are associated with bone loss of people living with HIV (PLWH), but limited studies exist on the impacts of ART regimens on bone mineral density (BMD) in China. This study evaluated BMD changes with three common ART regimens: tenofovir disoproxil fumarate (TDF) + lamivudine (3TC) + efavirenz (EFV), tenofovir alafenamide (TAF)-containing, and dolutegravir (DTG)-containing (non-TDF/non-TAF) therapies.MethodsIn this retrospective study, the prevalence of low BMD was analyzed in PLWH who underwent dual-energy X-ray absorptiometry (DXA) before ART initiation. BMD changes were assessed in participants who had follow-up DXA scans after ≥ 1 year of ART with TDF + 3TC + EFV, TAF-containing, or DTG-containing regimens. We used multivariate logistic regression to evaluate the impact of different ART regimens on > 3% BMD reduction, adjusting for demographic and clinical variables that were significant in univariate analysis (P < 0.10).Results22.99% (630/2740) of PLWH before ART initiation had low BMD. Among 571 individuals followed up for over 1 year, BMD at the femoral neck (FN) and total hip (TH) decreased significantly in the TDF + 3TC + EFV [FN: -0.03(-0.07, 0.00) g/cm2, TH: -0.02(-0.05, 0.00) g/cm2, P < 0.001 for both] and TAF-containing regimens [FN: -0.02(-0.05, 0.01) g/cm2, TH: -0.02(-0.04, 0.01) g/cm2, P < 0.001 for both]. Lumbar spine (LS) BMD decreased significantly only with TDF + 3TC + EFV [-0.02(-0.05, 0.01) g/cm2, P < 0.001]. TDF + 3TC + EFV caused greater BMD loss at the FN and LS than the TAF-containing regimen[FN: -3.66% (-8.05%, 0.34%) vs. -2.38% (-5.44%, 1.12%), P = 0.044; LS: -2.11% (-4.50%, 0.62%) vs.-0.06% (-2.05%, 2.57%), P < 0.001]. Compared to TDF + 3TC + EFV, DTG-containing regimens showed smaller BMD reductions across all sites [FN: -1.49% (-4.65%, 3.83%), TH: 0.00% (-3.98%, 3.18%), LS: 0.59% (-2.73%, 3.09%), P = 0.004, 0.008 and 0.004, respectively]. TAF-containing and DTG-containing regimens showed no significant differences in BMD changes. Multivariable logistic regression showed that TDF + 3TC + EFV, compared to DTG-containing regimens, had higher odds of > 3% FN and LS BMD reduction (FN: OR 2.91, 95% CI: 1.33 to 6.37, P = 0.009; LS: OR 2.93, 95% CI: 1.17 to 7.32, P = 0.022), while TAF-containing regimens were not independently linked to > 3% BMD loss (P > 0.05).ConclusionsTAF-containing and DTG-containing regimens caused less bone loss than TDF + 3TC + EFV, offering safer options for preserving bone health in Chinese PLWH.

Objective: To evaluate the lipid profile and body mass index (BMI) in antiretroviral-experienced people living with HIV (PLWH) starting therapy with two doravirine (DOR)-based regimens (dolutegravir (DTG)/DOR or lamivudine (3TC)/tenofovir disoproxil fumarate (TDF)/DOR).Methods: Data from the Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) prospective database, including all experienced PLWH who started treatment with DTG/DOR and 3TC/TDF/DOR. To obtain a comparable sample, subjects on emtricitabine (FTC)/tenofovir alafenamide (TAF)/bictegravir (BIC) were matched 1:1 (by sex, age (±1 year), at least one between dyslipidemia and statin use) with those on 3TC/TDF/DOR.Results: Among 355 PLWH on viral suppression, the median age was 53 years; men represented 74.9% of the sample. At baseline, 147 people treated with FTC/TAF/BIC had a better lipid profile and lower CD4 cell count than 147 people treated with 3TC/TDF/DOR; diabetes was less frequent in the latter group. After 6 and 12 months, the BMI did not significantly change in any of the groups. Total cholesterol (TC) level significantly declined in PLWH on 3TC/TDF/DOR but not in FTC/TAF/BIC and remained unchanged in DTG/DOR. LDL-C showed a similar trend, with the most marked decline in the 3TC/TDF/DOR group and no difference in FTC/TAF/BIC. The TC/HDL-C ratio declined significantly in 3TC/TDF/DOR and DTG/DOR but not in FTC/TAF/BIC. Over the entire observation period (median 18 months, interquartile range 10–30), 43 (12.1%) PLWH interrupted the cohort drug, mainly because of adverse events (n = 15), with 12 lost to follow-up and 12 simplifications.Conclusions: The regimens were well tolerated in terms of lipid profile and BMI. Persons treated with 3TC/TDF/DOR triple regimen showed a better lipid profile, as expected, whereas those on DTG/DOR did not show any significant changes.

Background: Integrase inhibitor (INSTI) based antiretroviral therapy is the mainstay for people living with HIV (PLHIV). Due to its favorable efficacy and safety profile, dolutegravir (DTG) is widely used in combination with nucleoside reverse transcriptase inhibitors (NRTIs). TLD, a fixed-dose combination of tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and DTG, is the first-line treatment for PLHIV in Thailand. However, data on metabolic complications from DTG-based regimens in the Thai population have not been thoroughly investigated. Materials and Methods: A cohort study non-randomized trial was conducted at Buddhachinaraj Hospital, Phitsanulok, Thailand. Data on demographics, baseline antiretroviral regimens, and metabolic profiles such as triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting blood sugar, and aminotransferases, were collected at baseline and six months after switching to a DTG-based regimen in virologically suppressed PLHIV between November 1, 2022 and August 31, 2023. Informed consents were obtained from all participants. Results: One hundred thirty-eight PLHIV were enrolled, with a majority being men, at 59%, and a median age of 47.5 years (IQR 36.2, 55.1). Median CD4 count was 608 cells/mm³ (IQR 452, 805) and median duration of antiretroviral treatment was 13 years (IQR 8, 18). Underlying conditions included dyslipidemia with 44.2%, hypertension for 29.7%, and type II diabetes for 14.5%. Of the participants, 107 out of 138 (77.5%) were on TDF, 3TC, or emtricitabine (FTC) combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (EFV) or rilpivirine (RPV) as their baseline regimen. After six months, significant changes were observed in median triglycerides, from 138.5 to 97.5 mg/dL (p&lt;0.001), total cholesterol from 201 to 173 mg/dL (p&lt;0.001), and LDL cholesterol from 117 to 103 mg/dL (p&lt;0.001). Median body weight increased from 63.2 to 63.35 kg (p&lt;0.001). Conclusion: DTG, a second-generation INSTI, is widely used as a key antiretroviral therapy in Thailand. While it demonstrates favorable effects on lipid profiles, body weight gain, which is a crucial factor for cardiovascular outcomes, should be monitored closely. Keywords: Integrase inhibitor; People living with HIV (PLHIV); Dolutegravir (DTG); Triglyceride; Total cholesterol; LDL-cholesterol; HDL-cholesterol; Fasting blood sugar; Aminotransferase

Introduction:According to 2021 UNAIDS report, there were approximately 99,159 adolescents living with human immunodeficiency virus (HIV) in Kenya, with a viral suppression rate of 67% [1].There are limited studies in Kenya on the types of regimens associated with viral suppression among adolescents.Therefore, this study aimed to determine the antiretroviral therapy (ART) regimens associated with viral load suppression in adolescents on ART. Material and methods:A retrospective cross-sectional analysis of 38,503 HIV-infected adolescents (age range, 10-19 years) receiving ART for at least 6 months with a documented viral load, was conducted.Data analyzed were Kenyan HIV program data obtained from electronic medical records of HIV-positive patients from January 2018 till December 2022. Results:The viral suppression rate was 81.2%, distinctly higher than the 2021 UNAIDS estimate of 67% and the national suppression rate of 75% (2022).The highest viral suppression was found in the lamivudine (3TC) + dolutegravir (DTG) + tenofovir disoproxil fumarate (TDF) regimen (86.4%), followed by lamivudine (3TC) + abacavir (ABC) + dolutegravir (DTG) (81.6%) (AOR = 0.57, 95% CI: -0.52 to 1.65).Lamivudine (3TC) + atazanavir/ritonavir (ATV/r) + tenofovir (TDF) exhibited a viral suppression of 70.1% (AOR = 0.4, 95% CI: -0.34 to 0.45), lamivudine (3TC) + ritonavir/atazanavir (ATV/r) + zidovudine (AZT) had viral suppression of 62.7% (AOR = 0.28, 95% CI: -0.24 to 0.32), while lamivudine (3TC) + zidovudine (AZT)+ lopinavir/ritonavir (LPV/r) was found with 62.2% rate (AOR = 0.23, 95% CI: -0.21 to 0.26), lamivudine (3TC) + zidovudine (AZT) + dolutegravir (DTG) with 58.7% (AOR = 0.2, 95% CI: -0.17 to 0.22), and lamivudine (3TC) + abacavir (ABC) + lopinavir (LPV/r) with 56.4% (AOR = 0.18, 95% CI: -0.16 to 0.20). Conclusions:The viral suppression rate for adolescents was 81.2%.It is crucial to expedite treatment optimization for youths with non-optimal regimens to prevent treatment failure and ensure achieving the UNAIDS target of 95%.A comprehensive examination of viral suppression rates for adolescents on protease inhibitors is essential with consideration of shifting to optimal regimens, thereby improving treatment outcomes.

Tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/dolutegravir (DTG) (TLD) is the preferred first-line therapy for all people living with HIV (PWH) per WHO 2019 and Thai HIV guidelines. This has prompted switches from TDF + FTC or 3TC + EFV to TLD in Thailand. We conducted a randomized trial among virologically suppressed PWH aged ≥18 years on TDF + FTC or 3TC + EFV who were switched to either TLD or DTG + 3TC. The primary outcome was the change in estimated glomerular filtration rate (eGFR) calculated by cystatin C at 24 weeks. Sixteen participants (eight per group), 69% male with a mean age of 41 years and a median duration of HIV diagnosis of 7.1 years, were enrolled. A greater, though not statistically significant, decline in eGFR was observed in the TLD group. The mean differences were 5.15 mL/ min/1.73 m² (95% CI: -12.06 to 22.35; p = 0.532) for cystatin C and 4.01 mL/min/1.73 m² (95% CI: -3.58 to 11.59; p = 0.277) for creatinine. All participants maintained virological suppression. No significant differences were observed in BMI, LDL, or CD4 counts. Although not statistically significant, TLD was associated with a trend toward greater eGFR decline. This finding warrants attention, particularly in patients at risk for renal dysfunction. Dual therapy with DTG + 3TC may be a preferable switch option over TLD for virologically suppressed PWH with renal safety concerns.

With great interest, we read the review by Shafran et al. 1 on the advantages of tenofovir alafenamide (TAF) over tenofovir disoproxil fumarate (TDF) in clinical practice. Based on the pharmacological profile of TAF, similar or even superior virological efficacy is considered to be an intrinsic feature of TAF, whereas the overall favourable effects on kidney and bone are attributable to the absence of TDF rather than the use of TAF per se and have been reproduced in other TDF-free antiretroviral therapy (ART) regimens 2-5. However, as the article by Shafran et al. focuses on possible advantages for prevention of comorbidities in an aging population of people living with HIV (PLWH), as stated in both the title and the main text of the paper, we feel it is lacking a critical discussion about the increasing evidence of TAF promoting relevant weight gain, at least in a subset of patients with a potentially unidentified predisposition. This was first reported by Gomez et al. 6, in a study that was limited by the retrospective character of the cohort data, but recent findings from randomized controlled trials support the observation of TAF use being associated with excess weight gain when compared to TAF-free regimens. In the Gilead 380-4030 trial, 565 patients were randomized to switch from dolutegravir (DTG) and TDF/emtricitabine (FTC) or TAF/FTC to either bictegravir (BIC) or DTG in combination with TAF/FTC. Those switching from TDF/FTC to TAF/FTC experienced a higher weight gain compared to patients who were already on TAF/FTC at baseline (median 2.2 versus 0.6 kg, respectively; P-value not reported), while the weight gains in the DTG and BIC groups were comparable (median 1.1 versus 1.3 kg, respectively; P = 0.46) 7. Similarly, in another trial in which patients without ART for at least 6 months were randomized to receive efavirenz (EFV)/TDF/FTC or DTG/TDF/FTC or DTG/TAF/FTC, again the highest increase in body weight was found in the DTG + TAF/FTC group (mean increase 6.4 kg), followed by DTG + TDF/FTC (mean increase 3.2 kg) and the EFV/TDF/FTC group (mean 1.7 kg) 8. Moreover, in HIV-negative individuals taking TAF or TDF for pre-exposure prophylaxis, weight gain was again more pronounced in the TAF group (median 1.0 versus 0.0 kg, respectively; P < 0.05), although the difference was smaller than in PLWH 9. The more pronounced weight gains in clinical trials with PLWH may be attributed to an additive or synergistic effect of TAF in combination with other currently used third agents with potentially obesogenic properties. And even more evidence might have arisen between submission and publication of this comment due to the high interest on this phenomenon. As weight gain – unless occurring in underweight and potentially low-normal weight people – might contribute to cardiovascular risk in a population that is already at higher risk than uninfected controls, even after adjustment for traditional risk factors 10, we need a deeper understanding of the underlying pathomechanisms and clinical implications before we can postulate that TAF use will generally prevent comorbidities.

BackgroundFollowing the World Health Organization’s (WHO) 2015 guidelines recommending initiation of antiretroviral therapy (ART) irrespective of CD4 count for all people living with HIV (PLHIV), many countries in sub-Saharan Africa have adopted this strategy to reach epidemic control. As the number of PLHIV on ART rises, maintenance of viral suppression on ART for over 90% of PLHIV remains a challenge to government health systems in resource-limited high HIV burden settings. Non facility-based antiretroviral therapy (ART) delivery for stable HIV+ patients may increase sustainable ART coverage in resource-limited settings. Within the HPTN 071 (PopART) trial, two models, home-based delivery (HBD) or adherence clubs (AC), were offered to assess whether they achieved similar viral load suppression (VLS) to standard of care (SoC). In this paper, we describe the trial design and discuss the methodological issues and challenges.MethodsA three-arm cluster randomized non-inferiority trial, nested in two urban HPTN 071 trial communities in Zambia, randomly allocated 104 zones to SoC (35), HBD (35), or AC (34). ART and adherence support were delivered 3-monthly at home (HBD), adherence clubs (AC), or clinic (SoC). Adult HIV+ patients defined as “stable” on ART were eligible for inclusion. The primary endpoint was the proportion of PLHIV with virological suppression (≤ 1000 copies HIV RNA/ml) at 12 months (± 3months) after study entry across all three arms. Viral load measurement was done at the routine government laboratories in accordance with national guidelines, annually. The study was powered to determine if either of the community-based interventions would yield a viral suppression rate drop compared to SoC of no more than 5% in its absolute value. Both community-based interventions were delivered by community HIV providers (CHiPs). An additional qualitative study using observations, interviews with PLHIV, and FGDs with community HIV providers was nested in this study to complement the quantitative data.DiscussionThis trial was designed to provide rigorous randomized evidence of safety and efficacy of non-facility-based delivery of ART for stable PLHIV in high-burden resource-limited settings. This trial will inform policy regarding best practices and what is needed to strengthen scale-up of differentiated models of ART delivery in resource-limited settings.Trial registrationClinicalTrials.gov NCT03025165. Registered on 19 January 2017

There is limited evidence on how the rollout of dolutegravir (DTG) has affected retention in care, tuberculosis (TB) disease risk, and viral load suppression (VLS) among people living with HIV (PLHIV) in routine program settings. This study evaluated associations between DTG rollout and VLS, risk of developing TB disease, and retention in care in rural KwaZulu-Natal (KZN), South Africa. We employed a retrospective cohort study of PLHIV aged 15 and above, followed up from 1 October 2019 to 31 December 2023 in a rural sub-district of KZN. We grouped antiretroviral therapy (ART) regimens into DTG-containing and non-DTG-containing regimens. We classified PLHIV as virally suppressed or non-suppressed based on a VLS threshold of <400 copies/mL. We used Kaplan-Meier survival curves to describe the transition to DTG over time. We applied Cox proportional-hazards models to evaluate associations between DTG rollout and VLS, the risk of developing TB, and retention in care. Of the 69 919 PLHIV included in the DTG rollout cohort, approximately 70% (n = 48 598) transitioned to DTG-containing regimens during the 4-year follow-up period. Compared with non-DTG regimens, DTG use was associated with a greater likelihood of VLS (aHR 1.24, 95% CI 1.10-1.29), retention in care (aHR 1.20, 95% CI 1.11-1.30), and lower risk of TB disease (aHR 0.68, 95% CI .54-.87). These findings support the sustained rollout of DTG-based regimens and emphasize the importance of continuous monitoring to assess their long-term associations and programmatic performance in comparable settings.

Weight and metabolic changes among virally suppressed people with HIV who switched to co-formulated bictegravir/emtricitabine/tenofovir alafenamide

Pujari, Sanjay; Gugale, Piyush; Shah, Darshan; Patel, Divya; Gaikwad, Sunil; Desouza, Clyde; Atre, Ashish Author Information

Millions of people living with HIV (PLWH) take oral antiretroviral therapy (ART), which requires a lifetime of consistent medication adherence. The relationship between adherence and poor HIV outcomes is well documented. Newer ART regimens that include dolutegravir (DTG) could be more forgiving, but empirical evidence on the relationship between adherence and viral suppression under DTG is only emerging. In this observational cohort study (secondary analysis of data from a randomized trial), we used data from 313 ART clients from a large HIV clinic in Kampala, Uganda. Over the 4-year study period (January 2018-January 2022), 91% switched from non-DTG regimens to DTG regimens. We measured adherence using Medication Event Monitoring Systems-caps and extracted prescription information and viral load measures from electronic health records. We estimated unadjusted linear regressions and adjusted models that included individual and time fixed-effects. Under non-DTG regimens, 96% of participants were virally suppressed (defined as viral load < 200 copies/ml) when adherence was 90% or higher in the 3 months before viral load measurement. Viral suppression was 32 percentage points lower when adherence was between 0% and 49% (95% CI -0.44, -0.20, p < 0.01), 12 percentage points lower when adherence was between 50% and 79% (95% CI -0.23, -0.02, p < 0.01), and not significantly different when adherence was between 80% and 89% (effect of 0.00, 95% CI -0.06, 0.07, p = 0.81). In contrast, for participants taking DTG, there was no statistically significant difference in viral suppression among any of the four adherence levels; more than 95% were virally suppressed at each adherence level. On average, switching to DTG increased viral suppression by 6 percentage points in our adjusted models (95% CI 0.00, 0.13, p = 0.03). There was no significant association between adherence levels and viral suppression among PLWH taking DTG regimens, suggesting a high degree of forgiveness for missed doses. The use of DTG should be prioritized over older regimens, particularly for those with low adherence. NCT03494777.

Objectives:Evaluate long-term rates of virological failure and treatment interruption for people living with HIV (PLWHIV) with viral suppression on first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine/lamivudine (EFV + TDF + FTC/3TC), and compare these according to patient characteristics.Methods:PLWHIV enrolled in the Collaboration of Observational HIV Epidemiological Research Europe cohort collaboration, who started first-line EFV + TDF + FTC/3TC at age at least 16 years and had viral suppression (<200 copies/ml) within 9 months were included. Rates of virological failure (≥200 copies/ml) and (complete) treatment interruption were estimated according to years since initial suppression. We used Poisson regression to examine associations of baseline characteristics with rates of virological failure or treatment interruption.Results:Among 19 527 eligible PLWHIV with median (interquartile range) follow-up 3.7 (2.0–5.6) years after initial viral suppression, the estimated rate of the combined incidence of virological failure or treatment interruption fell from 9.0/100 person-years in the first year to less than 4/100 person-years beyond 3 years from suppression; considering only those remaining on EFV + TDF + FTC/3TC, the combined rate dropped from 8.2/100 person-years in the first year to less than 3.5/100 person-years beyond 3 years. PLWHIV with injecting drug-related or heterosexual transmission were at higher risk of virological failure or treatment interruption, as were those of Black ethnicity. PLWHIV aged less than 35 years were at higher risk of virological failure and treatment interruption.Conclusion:PLWHIV starting first-line EFV + TDF + FTC/3TC had low rates of virological failure and treatment interruption up to 10 years from initial suppression. Demographic characteristics can be used to identify subpopulations with higher risks of these outcomes.

Low HIV reservoirs may be associated with viral suppression under a lower number of antiretroviral drugs. We investigated tenofovir disoproxil fumarate/emtricitabine as a maintenance strategy in people living with HIV (PLHIV) with low HIV-DNA. TRULIGHT (NCT02302547) was a multicentre, open-label, randomized trial comparing a simplification to tenofovir disoproxil fumarate/emtricitabine versus a triple regimen continuation (tenofovir disoproxil fumarate/emtricitabine with a third agent, control arm) in virologically suppressed adults with HIV-DNA <2.7 log10 copies/106 PBMCs and no prior virological failure (VF). The primary endpoint (non-inferiority margin 12%) was the percentage of participants with a plasma viral load (pVL) <50 copies/mL in ITT (Snapshot approach) and PP analyses at Week 48 (W48). Of the 326 participants screened, 223 (68%) were randomized to the tenofovir disoproxil fumarate/emtricitabine arm (n = 113) or control arm (n = 110). At W48, the tenofovir disoproxil fumarate/emtricitabine and control arms maintained a pVL < 50 copies/mL in 100/113 (88.5%) and 100/110 (90.9%) participants, respectively (ITT difference 2.4%, 95% CI -5.9 to 10.7; PP difference 3.4%, 95% CI -4.2 to 11.0). Six VFs occurred in the tenofovir disoproxil fumarate/emtricitabine arm (two with emerging mutations M184V and K65R) versus two in the control arm (ITT difference 3.5%, 95% CI -1.9 to 9.4). All VFs were resuppressed after treatment modification. Although non-inferiority was shown, simplification to tenofovir disoproxil fumarate/emtricitabine should not be used for most PLHIV because of a low risk of VF with resistance.