Abstract
Background
The World Health Organization recommended dolutegravir (DTG)-based antiretroviral therapy (ART) as first- and second-line treatment for people living with HIV (PLHIV) in 2018. Given its widespread use across diverse patient populations, ongoing evaluation of the real-world effectiveness and tolerability of DTG-based ART particularly across treatment-naïve (TN) and treatment-experienced (TE) patients remains essential to inform routine clinical practice.
Materials and Methods
This retrospective cohort study included PLHIV receiving tenofovir, lamivudine, and dolutegravir (TLD) at a tertiary referral hospital. Patients were classified as TN or TE. Outcomes at 12 months included virological response, immunological status, weight change, and toxicity/adverse events. Statistical analyses included descriptive statistics, chi-square tests for categorical variables, multivariable Poisson regression was performed for the immunological status to estimate adjusted relative risks (aRR), and Mann–Whitney U tests for comparison of continuous weight change, which was summarized as median.
Results
A total of 147 participants were included in the analysis. The mean age was 37.9±10.5 years in the TN group and 41.2±9.1 years in the TE group, with males predominating in both groups (75.0% vs. 63.5%). After 12 months of TLD therapy, virological suppression was achieved in nearly all patients, with detectable viral load observed in 1 TN patient (1.2%) and 3 TE patients (4.8%). The median CD4 count at 12 months was 313 (interquartile range [IQR], 207–432) cells/mm3 in the TN group and 371 (IQR, 252–475) cells/mm3 in the TE group. Bivariate analyses showed no significant differences between TN and TE groups in virological response (P=0.314), immunological status (P=0.151), or incidence of toxicity/adverse events (P=0.320). Weight change differed significantly between groups, with greater median weight gain observed in TN patients compared with TE patients (6 [IQR, 2–11] vs. 3 [IQR, 1–6] kg; P<0.001). In multivariable analysis, advanced clinical stage (stage 3–4) was independently associated with an increased risk of CD4 <200 cells/mm3 at 12 months (aRR, 4.655; 95% confidence interval, 1.438–15.073; P=0.010).
Conclusion
After 12 months of TLD therapy, no significant differences were observed between TN and TE HIV patients in virological response, immunological status, or toxicity/adverse events. A significant difference was observed in weight change, with greater weight gain among TN patients.
Keywords: HIV, Antiretroviral therapy, Dolutegravir, Clinical outcomes
Graphical Abstract
Introduction
The human immunodeficiency virus (HIV) continues to be a major global health challenge, with millions of people living with HIV (PLHIV) worldwide. Antiretroviral therapy (ART) remains the cornerstone of HIV treatment and new drugs such as dolutegravir (DTG) have significantly improved treatment outcomes. DTG-based ART, a fixed-dose combination containing a single integrase strand transfer inhibitor, is widely recommended for both treatment-naïve (TN) and treatment-experienced (TE) individuals due to its high efficacy, low resistance profile, and favorable safety profile [1]. However, while DTG-based ART show high virological suppression rates, they also present new challenges, such as an increased risk of weight gain among patients [2]. This weight gain, especially among TN individuals, can lead to metabolic complications, including a higher risk of cardiovascular disease, diabetes and hypertension [3]. Furthermore, HIV co-infections, such as with hepatitis B or C, can complicate the management of PLHIV, impacting ART effectiveness.
Although DTG has a strong resistance barrier, the possibility of resistance mutations, particularly in TE individuals, remains a concern. Even though DTG is highly effective, previous exposure to ART and the development of resistance mutations may reduce its efficacy. Several studies have shown that while the risk of resistance mutations in TN individuals is extremely low, it can be higher in patients who have previously failed ART regimens. This highlights the importance of monitoring resistance profiles and ensuring high adherence to therapy, particularly for TE patients [4,5]. Understanding these dynamics is crucial to maintaining the long-term effectiveness of DTG-based regimens in diverse patient populations.
Materials and Methods
1. Study method
This observational analytical study used a retrospective cohort design to compare clinical outcomes among HIV patients receiving DTG-based ART, administered as a fixed-dose combination of tenofovir, lamivudine, and dolutegravir (TLD). Patients were classified as TN or TE. TE patients were defined as those with documented prior ART exposure for at least 6 months before switching to TLD.
Data were collected from medical records at the Voluntary Counseling and Testing Clinic of RS Ngoerah Denpasar, Bali, Indonesia, between January 2021 and December 2023. Patients were enrolled using consecutive sampling. Inclusion criteria were HIV-positive individuals aged ≥18 years who had received TLD for at least 12 months with good adherence (≥95%), assessed through self-report and pharmacy refill records. Patients with incomplete medical records or those receiving rifampicin-containing tuberculosis regimens were excluded.
Patients were stratified by age into two groups (18–35 years and >35 years) for descriptive and analytical purposes, consistent with age categorization commonly used in epidemiological HIV studies to distinguish younger and older adult populations [6,7]. Disease stage was classified using the World Health Organization (WHO) clinical staging system, with stages 1–2 defined as early disease and stages 3–4 as advanced disease [8].
The study outcomes included virological response, immunological status, weight change, and adverse events. Virological suppression was defined as plasma HIV-1 RNA <40 copies/mL at 12 months. Baseline viral load data were not consistently available. Therefore, virological outcomes were assessed based on follow-up measurements.
Immunological status was categorized using a CD4 threshold of 200 cells/mm3 at 12 months. This reflects immune status at follow-up due to incomplete baseline data. Weight change was analyzed as a continuous variable. Adverse events were defined as documented clinical or laboratory abnormalities, including neuropsychiatric, gastrointestinal, renal, or hepatic manifestations during TLD therapy.
2. Ethics statement
This study was approved by the Research Ethics Committee of the Faculty of Medicine, Udayana University, under ethical eligibility number 0003/UN14.2.2.VII.14/LT/2025. Informed consent was waived due to the retrospective nature of the study, in accordance with institutional ethics committee approval. All patient data were anonymized prior to analysis to ensure confidentiality.
3. Statistical analysis
Data were analyzed using SPSS (version 30.0, IBM Corp., Armonk, NY, USA) and STATA (version 14, StataCorp LLC, College Station, TX, USA). Categorical variables were compared between groups using chi-square tests, as appropriate.
For outcomes with a small number of events (virological response and toxicity/adverse events), analyses were limited to descriptive and bivariate analyses, and no multivariable modeling was performed. In addition, analyses were restricted to a limited number of clinically relevant variables to avoid unstable estimates and improve interpretability.
For the immunological status, variables with P<0.250 in bivariate analyses were included in multivariable Poisson regression models with robust variance to estimate adjusted relative risks (aRR).
Weight change was analyzed as a continuous variable and compared between groups using the Mann–Whitney U test. Statistical significance was defined as a two-sided P-value <0.050 with 95% confidence intervals (CI).
Results
A total of 147 HIV patients receiving TLD therapy were included in the analysis, comprising 84 TN and 63 TE patients. Table 1 summarizes the baseline demographic and clinical characteristics of both groups. The mean age was 39.3±10.0 years, and most participants were male (70.1%). A higher proportion of patients aged 18–35 years was observed in the TN group compared with the TE group (42.9% vs. 25.4%). TN patients also had a higher proportion of advanced HIV disease (WHO clinical stage 4) than TE patients (66.7% vs. 31.7%). The prevalence of co-infections was low, with most patients in both groups without tuberculosis, hepatitis B, or hepatitis C.
Table 1. Baseline characteristics of the study subjects.
| Characteristic | ARV use status | Total (n=147) | ||
|---|---|---|---|---|
| TE (n=63) | TN (n=84) | |||
| Age, years | ||||
| 18–35 | 16 (25.4) | 36 (42.9) | 52 (35.4) | |
| >35 | 47 (74.6) | 48 (57.1) | 95 (64.6) | |
| Mean±SD | 41.2±9.1 | 37.9±10.5 | 39.3±10.0 | |
| Sex | ||||
| Female | 23 (36.5) | 21 (25.0) | 44 (29.9) | |
| Male | 40 (63.5) | 63 (75.0) | 103 (70.1) | |
| HIV clinical stage | ||||
| Stage 1 | 35 (55.6) | 18 (21.4) | 53 (36.1) | |
| Stage 2 | 3 (4.8) | 5 (6.0) | 8 (5.4) | |
| Stage 3 | 5 (7.9) | 5 (6.0) | 10 (6.8) | |
| Stage 4 | 20 (31.7) | 56 (66.7) | 76 (51.7) | |
| TB coinfection | ||||
| Present | 4 (6.3) | 3 (3.6) | 7 (4.8) | |
| Absent | 59 (93.7) | 81 (96.4) | 140 (95.2) | |
| Hepatitis B coinfection | ||||
| Present | 2 (3.2) | 4 (4.8) | 6 (4.1) | |
| Absent | 61 (96.8) | 80 (95.2) | 141 (95.9) | |
| Hepatitis C coinfection | ||||
| Present | 4 (6.3) | 0 | 4 (2.7) | |
| Absent | 59 (93.7) | 84 (100) | 143 (97.3) | |
| Opportunistic infection | ||||
| Present | 15 (23.8) | 36 (42.9) | 51 (34.7) | |
| Absent | 48 (76.2) | 48 (57.1) | 96 (65.3) | |
| Transmission route | ||||
| MSM | 4 (6.3) | 34 (40.5) | 38 (25.8) | |
| Heterosexual | 58 (92.1) | 50 (59.5) | 108 (73.5) | |
| IDU | 1 (1.6) | 0 | 1 (0.7) | |
| Immunological status | ||||
| CD4 <200 | 9 (14.3) | 20 (23.8) | 29 (19.7) | |
| CD4 ≥200 | 54 (85.7) | 64 (76.2) | 118 (80.3) | |
| Median (IQR) | 371 (252–475) | 313 (207–432) | 321 (224–457) | |
| Body weight, kg | ||||
| Before treatment, mean±SD | 58.4±12.7 | 59.8±13.4 | 59.2±13.1 | |
| After treatment, mean±SD | 62.4±12.5 | 67.1±14.1 | 65.1±13.6 | |
| Weight change | ||||
| <5 kg | 40 (63.5) | 33 (39.3) | 73 (49.7) | |
| ≥5 kg | 23 (36.5) | 51 (60.7) | 74 (50.3) | |
| Median (IQR) | 3 (1–6) | 6 (2–11) | 5 (2–9) | |
| Toxicity/adverse events | ||||
| Present | 5 (7.9) | 11 (13.1) | 16 (10.9) | |
| Absent | 58 (92.1) | 73 (86.9) | 131 (89.1) | |
Values are presented as n (%) unless otherwise indicated.
ARV, antiretroviral; TE, treatment-experienced; TN, treatment-naïve; SD, standard deviation; HIV, human immunodeficiency virus; TB, tuberculosis; MSM, men who have sex with men; IDU, injecting drug use; CD4, cluster of differentiation 4; IQR, interquartile range.
Among TE patients, the majority had previously received non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, while a smaller proportion had protease inhibitor (PI)-based regimens. The reasons for switching to TLD are summarized in Table 2, with treatment simplification being the most common, followed by drug-related toxicity and programmatic transition.
Table 2. Previous antiretroviral regimens and reasons for switching among treatment-experienced patients.
| Previous ARV regimen | Reason for switching | n (%) |
|---|---|---|
| ZDV/3TC/NVP | Availability of new ARV regimen (programmatic transition) | 8 (12.7) |
| ZDV/3TC/NVP | Poor adherence to previous ARV (treatment interruption) | 5 (7.9) |
| ZDV/3TC/NVP | Treatment failure | 6 (9.5) |
| ZDV/3TC/NVP | Pill burden reduction | 6 (9.5) |
| ZDV/3TC/NVP | Adverse effects of previous ARV | 2 (3.2) |
| TDF/3TC/EFV | Availability of new ARV regimen (programmatic transition) | 19 (30.2) |
| TDF/3TC/EFV | Poor adherence to previous ARV (treatment interruption) | 8 (12.7) |
| TDF/3TC/EFV | Adverse effects of previous ARV | 1 (1.6) |
| TDF/3TC/EFV | Treatment failure | 5 (7.9) |
| ZDV/3TC/EFV | Availability of new ARV regimen (programmatic transition) | 2 (3,2) |
| TDF/3TC/LPV/r | Availability of new ARV regimen (programmatic transition) | 1 (1.6) |
| Total | 63 (100) |
ARV, antiretroviral; ZDV, zidovudine; 3TC, lamivudine; NVP, nevirapine; TDF, tenofovir; EFV, efavirenz; PI, protease inhibitor; DTG, dolutegravir; LPV/r, lopinavir/ ritonavir.
1. Virological response
Table 3 summarizes the virological response in both groups. After 12 months of TLD therapy, viral suppression was achieved in 98.8% of TN patients and 95.2% of TE patients.
Table 3. Simplified analysis of virological response.
| Parameter | Detected n (%) | Undetected n (%) | RR (95% CI) | P-value | |
|---|---|---|---|---|---|
| ARV use status | |||||
| TE (n=63) | 3 (4.8) | 60 (95.2) | 4.000 (0.426–37.554) | 0.314 | |
| TN (n=84) | 1 (1.2) | 83 (98.8) | Reference | ||
| Age | |||||
| 18–35 years | 3 (5.8) | 49 (94.2) | 5.481 (0.585–51.368) | 0.127 | |
| >35 years | 1 (1.1) | 94 (98.9) | Reference | ||
| Clinical stage | |||||
| Stage 3–4 | 4 (4.7) | 82 (95.3) | - | ||
| Stage 1–2 | 0 | 61 (100) | - | ||
P-values are from bivariate comparisons and should be interpreted cautiously due to the small number of detectable viral load events (n=4).
RR, relative risk; CI, confidence interval; ARV, antiretroviral; TE, treatment-experienced; TN, treatment-naïve; Ref., reference category.
Only four patients had detectable viral load (3 TE, 1 TN). In the TE group, individual viral load values were 1.30×102, 6.22×104, and 6.9×10 copies/mL, while the TN group had a single value of 1.28×102 copies/mL.
Given the very small number of patients with detectable viral load, the findings are presented descriptively. Bivariate analyses of selected clinically relevant variables did not show statistically significant associations with detectable viral load.
2. Immunological status
As shown in Table 4, the majority of patients in both groups achieved a CD4 count ≥200 cells/mm3 at 12 months of TLD therapy. In the TN group, 76.2% of patients had CD4 ≥200 cells/mm3, compared with 85.7% in the TE group. In multivariable analysis, treatment status was not independently associated with immunological status at 12 months. However, advanced clinical stage was independently associated with poor immunological status, defined as CD4 <200 cells/mm3 (aRR, 4.66; 95% CI, 1.44–15.07; P=0.010).
Table 4. Analysis of immunological status.
| Parameter | Immunological status | Bivariate | Multivariate | ||||
|---|---|---|---|---|---|---|---|
| CD4<200, n (%) | CD4≥200, n (%) | RR (95% CI) | P-value | aRR (95% CI) | P-value | ||
| ARV use status | |||||||
| TE | 9 (14.3) | 54 (85.7) | 0.600 (0.293–1.227) | 0.151 | 0.774 (0.344–1.742) | 0.536 | |
| TN | 20 (23.8) | 64 (76.2) | Reference | Reference | |||
| Age | |||||||
| 18–35 years | 6 (11.5) | 46 (88.5) | 0.477 (0.207–1.096) | 0.065 | 0.444 (0.179–1.100) | 0.079 | |
| >35 years | 23 (24.2) | 72 (75.8) | Reference | Reference | |||
| Sex | |||||||
| Female | 7 (15.9) | 37 (84.1) | 1.343 (0.619–2.911) | 0.447 | Not estimable | Not estimable | |
| Male | 22 (21.4) | 81 (78.6) | Reference | Reference | |||
| Stage | |||||||
| 3–4 | 26 (30.2) | 60 (69.8) | 6.147 (1.948–19.398) | 0.001 | 4.655 (1.438–15.073) | 0.010 | |
| 1–2 | 3 (4.9) | 58 (95.1) | Reference | Reference | |||
| TB Coinfection | |||||||
| Present | 1 (14.3) | 6 (85.7) | 0.714 (0.113–4.518) | >0.999 | Not estimable | Not estimable | |
| Absent | 28 (20.0) | 112 (80.0) | Reference | Reference | |||
| Hepatitis B | |||||||
| Present | 2 (33.3) | 4 (66.7) | 1.741 (0.534–5.673) | 0.338 | Not estimable | Not estimable | |
| Absent | 27 (19.1) | 114 (80.9) | Reference | Reference | |||
| Hepatitis C | |||||||
| Present | 0 | 4 (100) | Not estimable | 0.585 | Not estimable | Not estimable | |
| Absent | 29 (20.3) | 114 (79.7) | Reference | Reference | |||
| Opportunistic Infection | |||||||
| Present | 15 (29.4) | 36 (70.6) | 2.017 (1.059–3.841) | 0.032 | 1.008 (0.455–2.234) | 0.984 | |
| Absent | 14 (14.6) | 82 (85.4) | Reference | Reference | |||
| Transmission Route | |||||||
| MSM | 7 (18.4) | 31 (81.6) | Not estimable | 0.775 | Not estimable | Not estimable | |
| Heterosexual | 22 (20.4) | 86 (79.6) | Reference | Reference | |||
| IDU | 0 | 1 (100) | Not estimable | Not estimable | Not estimable | ||
“Not estimable” indicates the parameter could not be estimated due to sparse data or model instability.
CD4, cluster of differentiation 4; RR, relative risk; CI, confidence interval; aRR, adjusted relative risk; ARV, antiretroviral; TE, treatment-experienced; TN, treatment-naïve; Ref., reference category; TB, tuberculosis; MSM, men who have sex with men; IDU, injecting drug use.
3. Weight change
Table 5 illustrates weight change after 12 months of treatment as continuous variables. The median weight gain was significantly greater in the TN group than in the TE group (6 [interquartile range (IQR), 2–11] kg vs. 3 [IQR, 1–6] kg; P<0.001).
Table 5. Weight change after 12 months of treatment.
| Characteristic | TE (n=63) | TN (n=84) | P-value |
|---|---|---|---|
| Weight change, kg, median (IQR) | 3 (1–6) | 6 (2.25–11) | <0.001 |
P-value is from the Mann–Whitney U test comparing TN vs. TE.
IQR, interquartile range; TE, treatment-experienced; TN, treatment-naïve.
4. Toxicity/adverse events
Table 6 summarizes the incidence of adverse events during 12 months of TLD therapy. Adverse events occurred in 13.1% of patients in the TN group and 7.9% in the TE group, with most events being mild in severity. Renal dysfunction was the most common adverse event in both groups. In the TN group, adverse events included kidney disorders (n=6), nausea (n=3), vomiting (n=3), transaminitis (n=3), tingling (n=1), and vertigo (n=1). In contrast, the TE group showed kidney disorders (n=3) and headache (n=2), with no cases of nausea, vomiting, transaminitis, or vertigo observed.
Table 6. Simplified analysis of toxicity/adverse events.
| Parameter | Present, n (%) | Absent, n (%) | RR (95% CI) | P-value | |
|---|---|---|---|---|---|
| ARV use status | |||||
| TE | 5 (7.9) | 58 (92.1) | 0.606 (0.222–1.656) | 0.320 | |
| TN | 11 (13.1) | 73 (86.9) | Reference | ||
| Clinical stage | |||||
| 3–4 | 13 (15.1) | 73 (84.9) | 3.074 (0.915–10.325) | 0.050 | |
| 1–2 | 3 (4.9) | 58 (95.1) | Reference | ||
| Opportunistic infection | |||||
| Present | 8 (15.7) | 43 (84.3) | 1.882 (0.751–4.720) | 0.173 | |
| Absent | 8 (8.3) | 88 (91.7) | Reference | ||
P-values are from bivariate analysis.
RR, relative risk; CI, confidence interval; ARV, antiretroviral; TE, treatment-experienced; TN, treatment-naïve; Ref., reference category.
Given the small number of adverse events, the findings are presented descriptively. Bivariate analyses of selected clinically relevant variables did not show statistically significant associations with toxicity/adverse events.
Discussion
In this study, age distribution was primarily descriptive, and age was not identified as an independent predictor of virological or immunological outcomes. In contrast, a higher proportion of men who have sex with men (MSM) was observed in the TN group (40.5%) compared to the TE group (6.3%), consistent with previous reports identifying MSM as a key population in the HIV epidemic [9].
The higher burden of opportunistic infections observed in the TN group may reflect later clinical presentation and more advanced disease at diagnosis, rather than confirmed delays in ART initiation. However, data on the interval between HIV diagnosis and ART initiation were not available, precluding causal inference regarding treatment delay. Advanced HIV disease is strongly associated with an increased risk of opportunistic infections and mortality, and early ART initiation is therefore recommended by the WHO for these patients [8,10]. Consistent with this, studies from Nigeria and Lesotho reported a high prevalence of advanced HIV disease and emphasized the importance of early ART initiation in improving clinical outcomes [11,12].
Co-infection rates for tuberculosis (4.8%), hepatitis B (4.1%), and hepatitis C (2.7%) were lower than reported global averages [13,14,15]. This study did not assess vaccination coverage or national TB control indicators, and therefore causal explanations for these findings cannot be established.
Consequently, direct comparisons between TN and TE groups should be interpreted with caution, as baseline differences in disease severity may introduce selection bias. This study was not designed or powered to demonstrate equivalence between TN and TE populations, but rather to describe real-world clinical outcomes following initiation of TLD in two clinically distinct groups.
No significant difference in virological response was observed between TN and TE patients after 12 months of TLD therapy, suggesting similar effectiveness across both groups. Given the very small number of patients with detectable viral load, these findings should be interpreted with caution, as the limited number of events precluded more extensive analyses and restricted the evaluation to descriptive and bivariate approaches.
These results are consistent with existing evidence supporting the high efficacy of DTG-based ART regimens in both TN and TE populations. Mondi et al. in a cohort of 1,679 patients (932 TN and 747 TE), reported virological failure rates of 1.2% in TN and 2.2% in TE patients after one year, with comparable cumulative failure rates (2.6% vs. 2.8%), indicating that DTG maintains robust virological suppression whether used as initial therapy or as a switch strategy. Current international guidelines also recommend DTG as a preferred component of first-line and switch ART regimens due to its high genetic barrier to resistance and favorable long-term virological outcomes [16,17].
Evidence from programmatic settings further supports the effectiveness of switching to TLD among TE patients. Esber et al. reported that 94.3% of participants who transitioned to TLD across four African countries maintained viral suppression, compared with 82.1% among non-switch participants, with a significantly lower risk of viral rebound among those who switched. Similarly, Luwaya et al. demonstrated that 90.4% of patients in Zambia achieved viral suppression (<50 copies/mL) after switching to TLD, although poor adherence defined as missing two or more doses in the preceding 30 days was strongly associated with virological failure (adjusted odds ratio, 0.047; 95% confidence interval, 0.016–0.136; P<0.001) [18,19].
In the present study, the high virological suppression observed in the TE group should be interpreted in the context of baseline clinical characteristics and reasons for switching. Most TE patients transitioned from NNRTI-based regimens for programmatic or simplification reasons rather than documented virological failure, which may have contributed to the favorable outcomes. However, residual confounding related to prior treatment exposure cannot be excluded.
A key limitation of this study is the absence of routine genotypic resistance testing. Antiretroviral susceptibility to TLD was inferred from clinical records, and resistance patterns could not be assessed. Therefore, virological outcomes should be interpreted with caution.
Both TN and TE patients achieved median CD4 counts above 200 cells/mm3 at 12 months, with no significant difference between groups, suggesting generally favorable immunological status. These findings are consistent with previous studies demonstrating immunological benefits of DTG-based ART. Fiseha et al. reported that among 566 HIV patients initiating DTG-based regimens in Ethiopia, median CD4 count increased from 264 cells/mm3 at baseline to 472 cells/mm3 after 12 months, with older age, male sex, and higher baseline CD4 counts associated with lower CD4 recovery. Similarly, Gebremedhin et al. observed a significant increase in CD4 counts among 109 HIV patients, with median levels rising from 209 cells/mm3 at baseline to 378 cells/mm3 after 6 months of DTG-based ART. In contrast, Carriquiry et al. reported more modest median CD4 increases ranging from 105 to 156 cells/mm3 after 48 weeks of DTG-based ART among TE patients [20,21,22].
A phase III/IIIb study by Spinelli et al. comparing immunological responses between TN and TE patients demonstrated significantly greater median CD4 increases in TN patients (234–251 cells/mm3) compared with TE patients (105–156 cells/mm3), reflecting a more robust immune reconstitution in individuals initiating ART. The potent antiviral activity of DTG, as an integrase strand transfer inhibitor, facilitates rapid viral suppression, which in turn supports immune recovery [23].
Patients with advanced clinical stage had a higher risk of persistent immunosuppression at 12 months compared with those in earlier stages. This finding is consistent with previous evidence from a meta-analysis by Endalamaw et al. demonstrating that advanced clinical stage is strongly associated with suboptimal immunological recovery [24]. In addition, opportunistic infections and poor adherence have been identified as important contributors to impaired CD4 recovery, highlighting that immunological outcomes are influenced not only by ART regimen potency but also by baseline clinical status.
The absence of a statistically significant difference in CD4 status between TN and TE groups in this study may be influenced by baseline clinical differences and incomplete availability of baseline CD4 data, and should not be interpreted as evidence of equivalent immunological recovery. Due to these data limitations, immunological outcomes in this study reflect CD4 status at 12 months rather than true immunological response defined by changes from baseline CD4 counts.
Greater weight gain was observed in TN patients compared with TE patients after 12 months of TLD use, with a significantly higher median increase in the TN group. As a secondary analysis, weight gain ≥5 kg was also more frequently observed among TN patients. The association between DTG-based ART and weight gain has been consistently reported in previous studies. Bourgi et al. demonstrated that TN patients receiving DTG experienced a mean weight gain of approximately 6.0 kg over 18 months, exceeding that observed with NNRTI or elvitegravir-based regimens. Similarly, Mukuna et al. reported a greater increase in body mass index (BMI) among TN patients on DTG compared with those on efavirenz, with a mean BMI increase of 1.09 kg/m2 over 24 months. Chanie et al. further reported a mean weight gain of 3.76 kg over 72 months among TN patients receiving DTG [2,25,26].
In contrast, weight gain among TE patients switching to DTG-based ART was more modest. Data from the African Cohort Study by Esber et al. showed an average weight gain of 1.46 kg per year following transition to TLD, compared with 0.35 kg per year prior to switching, with more pronounced changes observed among women and individuals with lower baseline BMI. These findings align with previously reported differences in weight trajectories between individuals initiating ART and those with prior treatment exposure [27].
The greater weight gain observed among TN patients in this study should be interpreted descriptively. In the absence of consistent baseline BMI and nutritional status data, no inference regarding underlying mechanisms can be drawn, and the observed differences between TN and TE groups may reflect variations in baseline characteristics and clinical profiles that could not be fully evaluated. From a clinical perspective, the magnitude of weight gain, particularly in TN patients, may have implications for long-term metabolic health. Previous studies have reported associations between weight gain following initiation of DTG-based regimens and an increased risk of metabolic complications, including insulin resistance, dyslipidemia, and potential long-term cardiovascular risk [3]. These findings underscore the importance of routine clinical monitoring, although causal relationships cannot be established based on the present data.
Although weight change was not independently associated with treatment status, the observed pattern is consistent with previous reports on DTG-based regimens. As baseline BMI and nutritional data were not consistently available, residual confounding cannot be excluded. Further prospective studies with standardized nutritional and metabolic assessment are warranted.
Adverse events were infrequent and comparable between TN and TE patients after 12 months of TLD therapy, consistent with the established safety profile of DTG-based regimens. Most events were mild in severity, and no treatment discontinuation due to toxicity/adverse events was observed. Serum creatinine elevation was the most commonly reported adverse event, consistent with the known pharmacological effects of DTG and tenofovir disoproxil fumarate (TDF) rather than true renal impairment.
The favorable safety profile observed in this study aligns with findings from large randomized trials evaluating DTG-based ART, including SPRING-1, SPRING-2, SINGLE, and FLAMINGO in TN patients, as well as SAILING in TE populations. Although up to 90% of participants in these studies reported adverse events, the majority were mild, transient, and not directly attributable to DTG. Severe adverse events (grade III or IV) were uncommon, occurring in approximately 1% of patients. Commonly reported symptoms included headache, nausea, diarrhea, and insomnia, the latter being more frequently noted in the SINGLE study [1,28].
In the present study, serum creatinine elevation was the most common adverse event, particularly among TN patients. Existing evidence suggests that renal toxicity observed in patients receiving TLD is more commonly related to TDF than to DTG. A systematic review and meta-analysis by Yazie et al. reported a chronic kidney disease prevalence of approximately 7% among HIV patients receiving TDF-based regimens, with higher risk observed in women and individuals with low CD4 counts. DTG itself has a favorable renal safety profile but is known to cause a benign increase in serum creatinine by inhibiting renal tubular transporters (OCT2 and MATE1), leading to reduced creatinine secretion without a true decline in glomerular filtration rate [29,30].
Discontinuation due to DTG-related adverse events is rare, reported in fewer than 2% of patients, comparable to raltegravir and lower than efavirenz- or PI-based regimens [14]. DTG has also not been associated with an increased risk of cardiovascular events, supporting its suitability for long-term use.
Overall, the findings of this study are consistent with global data indicating that TLD is associated with minimal adverse events and good tolerability. Nevertheless, routine monitoring of renal and hepatic function remains essential to identify rare but clinically significant adverse effects, particularly in patients with additional risk factors such as older age, pre-existing kidney disease, or concomitant use of nephrotoxic medications.
This study has several limitations. Its retrospective, single-center design limits generalizability. Baseline viral load and CD4 data were incompletely available due to limited access to testing during early TLD implementation. This restricted assessment of longitudinal virological and immunological changes. Antiretroviral resistance testing was also not routinely performed.
TN and TE patients represent clinically distinct populations with baseline imbalances in disease severity, introducing potential selection bias and residual confounding. The relatively small sample size and low frequency of detectable viral load and adverse events limited statistical power, increasing the risk of Type II error. In addition, the small number of events restricted the scope of statistical analyses and limited the ability to explore potential associations more comprehensively. Therefore, these findings should be interpreted with caution.
Adherence assessment relied in part on self-reported measures, which are subject to recall and social desirability bias and may overestimate true adherence. Pharmacy refill records were used to complement self-reported data. However, both methods have inherent limitations and may not fully reflect actual medication-taking behavior. Despite these limitations, this study provides relevant real-world data on the effectiveness and safety of TLD in routine clinical practice.
In conclusion, this study demonstrates favorable virological and immunological outcomes in both TN and TE patients after 12 months of TLD therapy. Although no statistically significant differences were observed between groups, these findings should be interpreted cautiously due to baseline imbalances, limited sample size, and the retrospective, single-center design, and should not be considered evidence of clinical equivalence.
High virological suppression rates in both groups support the effectiveness of DTG-based regimens regardless of prior treatment history. Immunological status at 12 months were comparable between groups, although advanced clinical stage was associated with poorer CD4 recovery. TN patients demonstrated greater median weight gain over 12 months of TLD use compared with TE patients. This finding should be interpreted in the context of limited baseline BMI and nutritional data. TLD was well tolerated, with predominantly mild adverse events and no significant differences in adverse events between groups.
Overall, these findings provide real-world evidence supporting the effectiveness and tolerability of TLD in routine clinical practice, highlighting the importance of ongoing monitoring of immunological and metabolic outcomes.
ACKNOWLEDGMENTS
The authors thank the staff of the Department of Internal Medicine of the Division of Tropical and Infectious Diseases at Udayana University. The authors would also like to thank all the nurses and volunteers at the outpatient clinic at Ngoerah Hospital, Bali, Indonesia.
Footnotes
Funding: None.
Conflict of Interest: No conflict of interest.
- Conceptualization: IPYS, IKAS, AAYG.
- Data curation: IPYS, IKAS, AAYG.
- Formal analysis: IPYS, IKAS, AAYG.
- Investigation: NMDD, IMSU, CAWP.
- Methodology: IKAS, AAYG, IMSU, NMDD, CAWP, KTPM.
- Project administration: IPYS, IKAS, AAYG.
- Resources: NMDD, IMSU, AAYG, KTPM.
- Software: IPYS, CAWP.
- Supervision: IKAS, AAYG.
- Validation: NMDD, IMSU, CAWP, KTPM.
- Writing - original draft: IPYS, IKAS, AAYG.
- Writing - review & editing: IPYS, IKAS, AAYG, IMSU, NMDD, CAWP, KTPM.
References
- 1.Kandel CE, Walmsley SL. Dolutegravir - a review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug Des Devel Ther. 2015;9:3547–3555. doi: 10.2147/DDDT.S84850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bourgi K, Rebeiro PF, Turner M, Castilho JL, Hulgan T, Raffanti SP, Koethe JR, Sterling TR. Greater weight gain in treatment-naive persons starting dolutegravir-based antiretroviral therapy. Clin Infect Dis. 2020;70:1267–1274. doi: 10.1093/cid/ciz407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Valenzuela-Rodriguez G, Diaz-Arocutipa C, Collins JA, Hernandez AV. Weight and metabolic outcomes in naïve HIV patients treated with integrase inhibitor-based antiretroviral therapy: a systematic review and meta-analysis. J Clin Med. 2023;12:3644. doi: 10.3390/jcm12113644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chu C, Tao K, Kouamou V, Avalos A, Scott J, Grant PM, Rhee SY, McCluskey SM, Jordan MR, Morgan RL, Shafer RW. Prevalence of emergent dolutegravir resistance mutations in people living with HIV: a rapid scoping review. Viruses. 2024;16:399. doi: 10.3390/v16030399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.World Health Organization (WHO) New report documents increase in HIV drug resistance to dolutegravir. [Accessed 15 September 2025]. Available at: https://www.who.int/news/item/05-03-2024-new-report-documents-increase-in-hiv-drug-resistance-to-dolutegravir.
- 6.Carriquiry G, Giganti MJ, Castilho JL, Jayathilake K, Cahn P, Grinsztejn B, Cortes C, Pape JW, Padgett D, Sierra-Madero J, McGowan CC, Shepherd BE, Gotuzzo E. Virologic failure and mortality in older ART initiators in a multisite Latin American and Caribbean Cohort. J Int AIDS Soc. 2018;21:e25088. doi: 10.1002/jia2.25088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Meshesha HM, Nigussie ZM, Asrat A, Mulatu K. Determinants of virological failure among adults on first-line highly active antiretroviral therapy at public health facilities in Kombolcha town, Northeast, Ethiopia: a case-control study. BMJ Open. 2020;10:e036223. doi: 10.1136/bmjopen-2019-036223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.World Health Organization (WHO) Advanced HIV disease. [Accessed 15 September 2025]. Available at: https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/treatment/advanced-hiv-disease.
- 9.Joint United Nations Programme on HIV/AIDS (UNAIDS) HIV and gay men and other men who have sex with men. [Accessed 15 September 2025]. Available at: https://thepath.unaids.org/wp-content/themes/unaids2023/assets/files/thematic_fs_hiv_gay_men.pdf.
- 10.de Waal R, Wools-Kaloustian K, Brazier E, Althoff KN, Jaquet A, Duda SN, Kumarasamy N, Savory T, Byakwaga H, Murenzi G, Justice A, Ekouevi DK, Cesar C, Pasayan MKU, Thawani A, Kasozi C, Babakazo P, Karris M, Messou E, Cortes CP, Kunzekwenyika C, Choi JY, Owarwo NC, Niyongabo A, Marconi VC, Ezechi O, Castilho JL, Petoumenos K, Johnson LF, Ford N, Kassanjee R. Global trends in CD4 count measurement and distribution at first antiretroviral treatment initiation. Clin Infect Dis. 2025;80:1332–1336. doi: 10.1093/cid/ciae548. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ikpe G, Enukeme J, Amuta C, Nwakanma I, Agomoh O, Chukwudinma O, Ukanwa C, Nwaokenneya P. Advanced HIV disease among persons newly diagnosed with HIV: a hospital-based study in Abia State, Nigeria. Int J Transl Med Res Public Health. 2025;9:e003 [Google Scholar]
- 12.Tiam A, Paulin H, Machekano R, Oboho I, Agyemang E, Mugyenyi FA, Maama-Maime L, Mengistu Y, Chatora T, Mungati M, Mokone M, Mots’oane T, Masheane A, Tukei V. Rapid antiretroviral therapy initiation in patients with advanced HIV disease: 6-month outcomes of an observational cohort evaluation in Lesotho. PLoS One. 2023;18:e0292660. doi: 10.1371/journal.pone.0292660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.World Health Organization (WHO) HIV data and statistics: global data. [Accessed 15 September 2025]. Available at: https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/strategic-information/hiv-data-and-statistics.
- 14.Platt L, French CE, McGowan CR, Sabin K, Gower E, Trickey A, McDonald B, Ong J, Stone J, Easterbrook P, Vickerman P. Prevalence and burden of HBV co-infection among people living with HIV: a global systematic review and meta-analysis. J Viral Hepat. 2020;27:294–315. doi: 10.1111/jvh.13217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Platt L, Easterbrook P, Gower E, McDonald B, Sabin K, McGowan C, Yanny I, Razavi H, Vickerman P. Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Lancet Infect Dis. 2016;16:797–808. doi: 10.1016/S1473-3099(15)00485-5. [DOI] [PubMed] [Google Scholar]
- 16.Mondi A, Cozzi-Lepri A, Tavelli A, Rusconi S, Vichi F, Ceccherini-Silberstein F, Calcagno A, De Luca A, Maggiolo F, Marchetti G, Antinori A, d’Arminio Monforte A Icona Foundation Study Group. Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort. J Int AIDS Soc. 2019;22:e25227. doi: 10.1002/jia2.25227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Günthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, Hoy JF, Mugavero MJ, Sax PE, Thompson MA, Gandhi RT, Landovitz RJ, Smith DM, Jacobsen DM, Volberding PA. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA panel. JAMA. 2016;316:191–210. doi: 10.1001/jama.2016.8900. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Allahna E, Nicole D, Neha S, Hannah K, Jonah M, John O, Valentine S, Emmanuel B, Michael I, Trevor A C, Christina S P, Joseph S C, Julie A A AFRICOS Study Group. Brief report: virologic impact of the dolutegravir transition: prospective results from the multinational African cohort study. J Acquir Immune Defic Syndr. 2022;91:285–289. doi: 10.1097/QAI.0000000000003065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Luwaya EL, Mwape L, Bwalya K, Siakabanze C, Hamooya BM, Masenga SK. Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia. PLoS One. 2024;19:e0308869. doi: 10.1371/journal.pone.0308869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Fiseha T, Ebrahim H, Ebrahim E, Gebreweld A. CD4+ cell count recovery after initiation of antiretroviral therapy in HIV-infected Ethiopian adults. PLoS One. 2022;17:e0265740. doi: 10.1371/journal.pone.0265740. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gebremedhin T, Aynalem M, Adem M, Geremew D, Aleka Y, Kiflie A. Dolutegravir based therapy showed CD4+ T cell count recovery and viral load suppression among ART naïve people living with HIV AIDS: a pilot evaluation. Sci Rep. 2024;14:3297. doi: 10.1038/s41598-024-53282-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Carriquiry G, Giganti MJ, Castilho JL, Jayathilake K, Cahn P, Grinsztejn B, Cortes C, Pape JW, Padgett D, Sierra-Madero J, McGowan CC, Shepherd BE, Gotuzzo E. Virologic failure and mortality in older ART initiators in a multisite Latin American and Caribbean Cohort. J Int AIDS Soc. 2018;21:e25088. doi: 10.1002/jia2.25088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Spinelli F, Prakash M, Slater J, van der Kolk M, Bassani N, Grove R, Wynne B, van Wyk J, Clark A. Dolutegravir-based regimens in treatment-naive and treatment-experienced aging populations: analyses of 6 phase III clinical trials. HIV Res Clin Pract. 2021;22:46–54. doi: 10.1080/25787489.2021.1941672. [DOI] [PubMed] [Google Scholar]
- 24.Endalamaw A, Mekonnen M, Geremew D, Yehualashet FA, Tesera H, Habtewold TD. HIV/AIDS treatment failure and associated factors in Ethiopia: meta-analysis. BMC Public Health. 2020;20:82. doi: 10.1186/s12889-020-8160-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Chanie GS, Atalay W, Zeleke TK, Bayleyegn ZW, Aragie YS, Bizuneh GK, Melese M, Abebe RB. Incidence and determinants of excessive weight gain in people living with HIV initiating tenofovir, lamivudine, and dolutegravir-based therapy: a multicenter retrospective study in northwest Ethiopia. Front Pharmacol. 2025;16:1394458. doi: 10.3389/fphar.2025.1394458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Mukuna DM, Decroo T, Nyapokoto CM. Effect of dolutegravir-based versus efavirenz-based antiretroviral therapy on excessive weight gain in adult treatment-naïve HIV patients at Matsanjeni health center, Eswatini: a retrospective cohort study. AIDS Res Ther. 2024;21:4. doi: 10.1186/s12981-023-00591-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Esber AL, Chang D, Iroezindu M, Bahemana E, Kibuuka H, Owuoth J, Singoei V, Maswai J, Dear NF, Crowell TA, Polyak CS, Ake JA AFRICOS Study Group. Weight gain during the dolutegravir transition in the African Cohort Study. J Int AIDS Soc. 2022;25:e25899. doi: 10.1002/jia2.25899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Curtis L, Nichols G, Stainsby C, Lim J, Aylott A, Wynne B, Clark A, Bloch M, Maechler G, Martin-Carpenter L, Raffi F, Min S. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients. HIV Clin Trials. 2014;15:199–208. doi: 10.1310/hct1505-199. [DOI] [PubMed] [Google Scholar]
- 29.Koishikawa T, Fujiwara K, Taskar K, Zamek-Gliszczynski MJ, Yoshida K, Chu X, Hirabayashi H, Mao J, Rockich K, Takashima T, Yamaura Y, Lai Y, Tomoda Y, Kito T, Maeda K, Furihata K, Sugiyama Y, Kusuhara H. Effects of cimetidine and dolutegravir on the endogenous drug-drug interaction biomarkers for organic cation transporter 2 and multidrug and toxin extrusion protein 1 in healthy volunteers. Clin Pharmacol Ther. 2025;117:523–533. doi: 10.1002/cpt.3482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Yazie TS, Shiferaw WS, Gebeyehu AA, Teshome AA, Addisu ZD, Belete AM. Chronic kidney disease among people living with HIV on TDF based regimen: a systematic review and meta-analysis. PLoS One. 2025;20:e0318068. doi: 10.1371/journal.pone.0318068. [DOI] [PMC free article] [PubMed] [Google Scholar]