Bridging the gap: addressing real-life challenges to the implementation of DTG/3TC in treatment-naive people living with HIV

Dolutegravir/lamivudine (DTG/3TC), used as a two-drug regimen (2DR), has demonstrated non-inferiority to traditional three-drug regimens (3DRs) in treatment-naive people with HIV (PWH), with sustained virological efficacy, favorable tolerability, and a good safety profile. However, its implementation in routine clinical practice raises several questions, particularly in populations underrepresented in registration trials. This review critically appraises current evidence supporting DTG/3TC as first-line antiretroviral therapy, drawing from randomized clinical trials and real-world studies. Available data indicate that DTG/3TC maintains high virological suppression rates even in individuals with high baseline viral load (>500,000 copies/mL), with no emergent resistance. Evidence from test-and-treat settings suggests comparable efficacy to triple therapy, provided that hepatitis B coinfection and transmitted resistance are adequately excluded. Preliminary data in late presenters and those with advanced disease support its effectiveness, although confirmatory trials are warranted. Beyond viro-immunological outcomes, DTG/3TC appears equivalent to triple regimens in reducing viral reservoirs, immune activation, and systemic inflammation. Evidence in women living with HIV, including during pregnancy, remains limited but reassuring, with no major safety concerns identified. Overall, the body of clinical and real-world evidence supports DTG/3TC as a simplified and durable first-line regimen for most treatment-naive PWH. Ongoing research should further define its role in acute infection, advanced HIV disease, and specific subpopulations such as women and individuals from regions with high prevalence of non-B subtypes.

Introduction

Dolutegravir (DTG) plus lamivudine (3TC), used as a two-drug regimen (2DR), has demonstrated non-inferiority compared to the three-drug regimen (3DR) of DTG plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the pivotal GEMINI-1 and GEMINI-2 trials (1). In these studies, DTG/3TC showed high virologic efficacy, favorable tolerability, and a good safety profile, benefits that were sustained up to 144 weeks (2). These positive outcomes have led to the inclusion of DTG/3TC as a recommended first-line regimen in major international guidelines (3, 4).

Nevertheless, some caveats remain regarding the use of DTG/3TC in treatment-naive people with HIV (PWH), as highlighted by current guidelines. The regimen is not indicated for individuals with positive hepatitis B surface antigen (HBsAg) (3) or for those who acquire HIV infection while on pre-exposure prophylaxis (PrEP), either oral, due to the risk of M184V resistance selection, or long-acting, owing to concerns about potential integrase strand transfer inhibitor (INSTI) resistance (5–7). Additionally, the GEMINI trials excluded individuals with baseline HIV-RNA >500,000 copies/mL, and therefore, the regimen is not actually recommended in this population (1, 3) (Figure 1).

Figure 1

Figure 1. Indication of dolutegravir/lamivudine (DTG/3TC) in treatment-naive people living with HIV according to major guidelines; caveats and challenges faced in everyday clinical practice.

Implementing DTG/3TC in real-world clinical settings is further challenged by the high proportion of PWH presenting late at diagnosis—52% across the WHO European Region—who are underrepresented in registration trials, especially those with CD4 counts <200 cells/mm³ or AIDS-defining conditions, and who are known to experience worse clinical outcomes (8, 9).

Moreover, in many clinical scenarios, including acute HIV infection, pregnancy, and late presentation, rapid or immediate initiation of antiretroviral therapy is recommended (10). This may pose a limitation for the use of DTG/3TC, which ideally requires baseline resistance testing before initiation. This consideration is especially relevant in patients with high viremia (>500,000 copies/mL) or in pregnant women, for whom data are still limited.

In this opinion piece, we review the current evidence and explore the main challenges associated with the implementation of DTG/3TC as a treatment strategy for treatment-naive PWH in routine clinical practice.

Challenge #1: DTG/3TC in PWH with high baseline HIV viral load and acute infection

Major international guidelines (3) have specified that DTG/3TC should not be used in antiretroviral therapy (ART)-naive PWH with HIV-RNA >500,000 copies/mL, due to lack of data on the efficacy of this strategy in this subset of PWH. However, several studies have tried to address the matter (Table 1). Firstly, the 144-week update from the GEMINI 1–2 trials shows that 82% of PWH with a baseline HIV-RNA over 100,000 copies/mL, as well as 77% of PWH with over 500,000 copies/mL, achieved virological suppression (2). Similarly, data from the STAT study, a single-arm study conducted in a US test-and-treat setting, show that 82% of PWH with over 100,000 copies/mL and 89% of those with over 500,000 copies/mL were virologically suppressed at week 48 (11). More recently, the DOLCE study explored the efficacy of a first-line regimen of DTG/3TC in treatment-naive PWH with CD4 counts ≤200 cells/mm³ compared to DTG+TDF/XTC. The results from this study show that virological suppression at week 48 was achieved with DTG/3TC by 81% of PWH with a baseline HIV-RNA over 100,000 copies/mL, 74% of PWH with over 500,000 copies/mL, and 63% of individuals with a baseline HIV-RNA over 1,000,000 copies/mL with comparable results when compared to DTG+TDF/FTC (12). Importantly, real-world evidence seemingly supports these findings; in the study by Zhao et al., 96% of individuals with over 500,000 copies/mL at baseline were found to be virologically suppressed after 48 weeks (13). Data from Hou et al. also show that 94% of PWH with over 100,000 copies/mL achieved virological suppression after 48 weeks of follow-up (14), while Pulido et al. observed that, in their cohort, 87% of those with over 100,000 copies/mL achieved virological suppression by week 96 (15). In a multicenter real-world study conducted by Schuettfort et al., DTG/3TC showed a similar virological suppression rate at 48 weeks when compared to TAF/FTC/BIC in late-presenter PWH (97.1% vs 94.2%; p = 0.206) with a mean baseline HIV-RNA of 275,320 ± 45,600 copies/mL (16).

Table 1

Table 1. Randomized clinical studies of DTG/3TC in treatment-naive PWH.

Finally, in a study by Calza et al., enrolling 58 individuals with baseline HIV-RNA between 100,000 and 500,000 copies/mL, 91.4% of PWH on DTG/3TC were virologically suppressed after 48 weeks (17). As shown, recent evidence supports the use of DTG/3TC as a first-line treatment option for HIV-1 infection, including in PWH with high (or very-high) baseline viral loads. One limitation, however, is that none of the analyzed studies specifically enrolled PWH with acute HIV infection (acute HIV infection was indeed one of the exclusion criteria in GEMINI (1)); therefore, data on the efficacy of DTG/3TC as initial regimen in the setting of acute HIV infection remain lacking, with further studies needed to properly assess the matter.

Challenge #2: DTG/3TC in test-and-treat strategies

The test-and-treat approach presents unique challenges, particularly due to the absence of baseline genotypic resistance testing, potentially high or very high levels of HIV-RNA, and a lack of information regarding HBsAg status at treatment initiation. Nevertheless, several studies have assessed the efficacy of DTG/3TC in this setting.

In the aforementioned STAT study, most non-responses in the intention-to-treat (ITT) analysis were attributable to loss to follow-up or early discontinuation rather than virologic failure or documented resistance to the study drugs (11). In particular, those who required a regimen modification due to HBsAg positivity (n = 5) or M184V (n = 1) documented post baseline showed good virological efficacy.

The D2ARLING randomized trial, which simulated the absence of baseline resistance testing, demonstrated that DTG/3TC was non-inferior to 3DR, achieving 92% virologic suppression at week 48 without any emergent resistance (18). Similarly, a Spanish real-life cohort (REDOLA) reported an 85% suppression rate at week 48 among treatment-naive patients initiating therapy without resistance data (which was missing in 71.4% of individuals), with only 2 of 135 individuals discontinuing the regimen following detection of a baseline M184V mutation (19). In the same study, consistent results were observed at 96 weeks: 83.8% suppression by intention to treat and 95.7% per protocol at 96 weeks (15). The URBAN German cohort, although with a limited sample size, showed long-term suppression in 77.8% of 27 treatment-naive individuals at 3 years (20). The TANDEM study, conducted in the US, found that 94% of 126 treatment-naive patients achieved suppression on DTG/3TC, with 83% maintaining suppression over a median follow-up of 65 weeks (21). Results were also consistent in a subanalysis, in which highly viremic individuals (>100,000 copies/mL) and the test-and-treat strategy were analyzed [14/16 (88%) and 57/61 (93%) individuals, respectively, achieved virologic suppression] (21).

In the CoRIS cohort (n = 472), nearly half of the participants initiated treatment within 7 days of diagnosis, highlighting the real-world feasibility of test-and-treat DTG/3TC, even in the absence of baseline resistance testing (22) (Table 2).

Table 2

Table 2. Observational clinical studies of DTG/3TC in treatment-naive PWH.

Despite this robust body of evidence, initiating DTG/3TC without baseline data raises three key clinical concerns: transmitted drug resistance (TDR); HBV coinfection, especially in individuals from highly prevalent regions; and efficacy in non-B HIV subtypes, which are predominant in low- and middle-income countries (LMICs).

Recent European data support the use of DTG/3TC in treatment-naive individuals even without resistance testing, due to the extremely low prevalence of clinically significant TDR. In the SPREAD and MeditRes cohorts (2008–2021), the M184V mutation was found in only 0.27%–0.85% of cases, and dual resistance to both DTG and 3TC was virtually absent. INSTI-associated TDR was ≤0.3%, and resistance to second-generation INSTIs like dolutegravir remained below 1%. These findings align with recent WHO surveillance reports (23–25).

Although HBV coinfection could appear as a major obstacle to the test-and-treat strategy, in the GEMINI-1 and GEMINI-2 trials, no cases of lamivudine-associated HBV resistance were observed since individuals testing HBsAg-positive were promptly switched to tenofovir-based regimens. In addition, in the STAT study, chronic HBV infection was detected in seven participants, five of whom had their ART regimen modified; the remaining two had unquantifiable repeat HBV-DNA tests. Successful resistance testing in three of the five participants with HBV coinfection showed no treatment-emergent resistance in HBV at the time of ART modification (26).

In LMICs, where non-B subtypes dominate, DTG/3TC is expected to retain good effectiveness because the prevalence of M184V remains low (26). However, emerging DTG resistance in viremic individuals, particularly in sub-Saharan Africa, calls for increased vigilance. In the DTG RESIST study, conducted in seven sub-Saharan countries, 59 of 227 viremic individuals (26.0%) infected with non-B subtypes had at least one major integrase resistance mutation. Of these, 49 (21.6%) were predicted to have high-level resistance to dolutegravir (27, 28). Most resistance cases emerged among people with adherence issues, and half of the resistance cases involved the R263K substitution, which did not always preclude re-suppression with dolutegravir (28).

While high baseline viremia and unknown HBsAg status do not appear to undermine the test-and-treat strategy with DTG/3TC, caution is warranted in regions where baseline integrase resistance may be more common, and the use is discouraged in case of PrEP failure, both oral and long-acting.

Challenge #3: DTG/3TC in PWH with late HIV presentation and AIDS

Worse immunologic and clinical outcomes have been long established in late presenters compared with patients diagnosed earlier, regardless of the treatment regimen studied (9, 29, 30). Several studies investigated the use of DTG/3TC as a first-line regimen irrespective of CD4 cell counts; however, the inclusion of PWH with counts <200 cells/mm³ remained limited. In particular, in the 3-year pooled analysis of the GEMINI 1–2 trials, participants randomized to DTG/3TC or DTG+FTC/TDF with baseline CD4 ≤200 cells/µL represented 17% of the population; 9% were treated with DTG/3TC (2). Among PWH with CD4 <200 cells/mm³, 67% of patients achieved HIV-1 RNA <50 copies/mL by week 144, compared to 76% in the DTG + TDF/FTC arm, a finding which initially claimed caution in this setting (31). Nevertheless, the number of participants in this subgroup analysis was small, and non-response was unrelated to efficacy (1).

Some evidence now supports the use of DTG/3TC also in this difficult clinical scenario. In the abovementioned DOLCE study, which enrolled treatment-naive adults with nadir CD4 counts <200 cells/µL in South America, 32% of participants presented an AIDS-defining condition at diagnosis, with 43.4% displaying a CD4 count ≤100 cells/mm³. At week 48, DTG/3TC demonstrated high efficacy in a population with low CD4 counts and high viral load with non-inferiority of DTG/3TC compared to DTG+TDF/FTC as documented in a post hoc analysis (12).

The results from the DOLCE study, although preliminary and requiring confirmation in large controlled studies, could be pivotal in addressing current knowledge gaps and guiding clinical implementation of DTG/3TC in such a setting that is usually excluded from clinical trials.

Data from real-world context are actually limited as evidenced by the CoRIS cohort, in which 50% of PWH who started DTG/3TC had baseline CD4 counts between 200 and 500 cells/mm³ but only 3.6% below 200 cells/mm³ (22). These findings are in line with the data from the ICONA cohort, in which only 6% of PWH treated with DTG/3TC as a first-line regimen had a CD4 ≤200 cells/mm³ and <1% presented an AIDS-defining condition at baseline (32).

Challenge #4: beyond viro-immunological outcomes: the role of DTG/3TC on HIV reservoir and inflammation

The DOLCE study provided important evidence that DTG/3TC ensures meaningful CD4 recovery even in treatment-naive late presenters, with a median increase of +200 cells/µL (IQR 127–316) at week 48, compared to +177 cells/µL (IQR 128–267) in the triple therapy arm (12).

Beyond achieving virological suppression and immunological recovery, the impact of DTG/3TC on HIV reservoirs and systemic inflammation has garnered increasing interest, particularly among PWH initiating dual therapy as a first-line regimen.

Importantly, a randomized clinical trial showed that first-line DTG/3TC achieves HIV-1 reservoir control and modulation of systemic inflammation comparable to triple therapy with DTG+TAF/FTC, reinforcing the concept that dual therapy does not compromise long-term viral persistence or immune homeostasis (33).

A substudy of a phase IV trial compared DTG/3TC with DTG plus tenofovir alafenamide/emtricitabine (DTG+TAF/FTC) in terms of viral suppression in the male genital tract. Both regimens showed similar kinetics over 24 weeks, with all participants reaching undetectable or low-level (<200 copies/mL) seminal plasma HIV-RNA by week 12 (34). This confirms that DTG/3TC is as effective as triple therapy in clearing viral reservoirs in sanctuary sites like the genital tract, an important factor for reducing transmission risk (34).

In line with these findings, a multicenter pilot study evaluated HIV-RNA decay in blood plasma (BP), seminal plasma (SP), and rectal fluid (RF) in treatment-naive PWH receiving DTG/3TC or bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). While both regimens showed comparable efficacy overall, DTG/3TC led to notably faster viral decay in SP and RF, compared to BP (35). The data highlight the efficacy of DTG/3TC in achieving rapid viral control in mucosal compartments that play a central role in HIV transmission and reservoir maintenance, equaling triple regimens (35).

The DUALITY study also investigated HIV persistence, inflammation, and immune activation over 48 weeks in treatment-naive PWH treated with DTG/3TC or DTG+FTC/TAF. Total and intact HIV-DNA, cell-associated RNA, and HIV-inducible cells (VIP-SPOT) were consistently comparable between the two treatment groups (36). Likewise, inflammatory markers showed comparable trends in both regimens. Additionally, CD4⁺ and CD8⁺ T cells exhibited significant decreases in activation and exhaustion markers over time, with no meaningful differences between the groups. These results would altogether support the adjunctive efficacy of DTG/3TC in reducing limiting reservoir size and chronic immune activation (36).

Further insights come from the ICONA cohort in Italy, where treatment-naive PWH starting first-line DTG/3TC or BIC/FTC/TAF were followed for 48 weeks to assess systemic inflammation, microbial translocation, and endothelial function. While both groups showed declines in sCD14 and VCAM levels, markers of microbial translocation (LBP) and gut barrier damage (I-FABP, E-cadherin) remained unchanged, suggesting ongoing epithelial disruption (37). Interestingly, IL-6 levels were stable in the 2DR group and declined in the 3DR group, reflecting an overall favorable inflammatory profile (37).

Collectively, these lines of evidence from clinical trials and real-world cohorts show that DTG/3TC ensures durable virological control while matching triple therapy in its effects on HIV reservoirs, mucosal viral suppression, and systemic inflammation.

Challenge #5: DGT/3TC in women living with HIV

Women represent over half of new HIV diagnoses globally and one-third in Europe (38), and compared to men, women are more likely to be diagnosed late, with lower CD4 counts and higher viral loads at presentation (39, 40). Among younger women living with HIV (WoWH), early ART initiation may enhance care engagement, especially in light of psychosocial barriers that affect adherence. DTG/3TC has demonstrated effectiveness in test-and-treat settings, with good tolerability and no emergence of resistance (11) even with suboptimal adherence (41). In women aged 25–45, pregnancy planning becomes central. Surveillance studies such as Tsepamo and Eswatini (42, 43) have reported no increased risk of neural tube defects with incidental DTG exposure from conception, supporting its use during pregnancy (3). Recent findings from observational studies on pregnant ART-naive WoWH also indicate that DTG/3TC may be an effective and safe first-line ART option in such setting, with no vertical transmissions observed although the number of PWH treated with DTG/3TC is extremely limited (44, 45).

With aging, menopause brings hormonal and metabolic changes that worsen cardiovascular risk in WoWH such as alteration in bone mineral density (BMD) homeostasis (46). Regarding metabolic profile, DTG/3TC showed a neutral effect on lipids when compared to baseline or other ART regimens (mainly ABC-, TAF- and TDF-based (15, 37, 47–49)). No studies have directly assessed BMD outcomes with DTG/3TC in WoWH. However, GEMINI trials suggest potential stability or improvement in bone health compared to TDF-based regimens (1).

Given the current lack of sex-specific data to guide the selection of the most appropriate ART regimen, observational studies involving ART-naive WoWH are needed.

Discussion and conclusions

Evidence supporting the implementation of DTG/3TC as a treatment strategy for treatment-naive PWH in routine clinical practice comes from both RCTs and observational studies across different clinical settings (Table 3).

Table 3

Table 3. Challenges addressed by RCTs and observational studies.

Resistance to DTG/3TC is rare and should not be considered a major limitation when prescribing this regimen in the context of a test-and-treat strategy. In particular, the prevalence of transmitted drug resistance to NRTIs, and specifically to 3TC, is expected to be low (50, 51). This is due to the reduced viral fitness associated with the M184V/I mutation (52) and the fact that most current first-line regimens have a high genetic barrier to resistance, which prevents the selection of mutations in the vast majority of virological failures (53). With regard to potential resistance selected by prior oral PrEP exposure, failures are extremely rare and resistance selection has been uncommon; therefore, no meaningful epidemiological impact at the population level is expected (54, 55). For long-acting cabotegravir PrEP, failures are also very limited; however, when they occur, resistance selection is more frequent. In such cases, the use of DTG/3TC should be avoided in the absence of a baseline resistance test, which may limit the possibility of rapid ART initiation as recommended by major international guidelines (56).

HBV coinfection remains a contraindication to DTG/3TC use; however, short-term exposure does not appear to select for HBV resistance to 3TC (26, 53). In addition, the prevalence of chronic HBV coinfection is relatively low in European and US settings (57, 58), whereas in other regions, such as China and sub-Saharan Africa, a high proportion of individuals are expected to have HBV coinfection (58). In these contexts, tenofovir-based regimens are warranted unless HBV infection is excluded, and widespread HBV vaccination programs are in place.

Data in highly viremic individuals demonstrate high effectiveness of DTG/3TC even in PWH with baseline HIV-RNA >500,000 copies/mL, although evidence in the context of acute/primary HIV infection remains limited. Indeed, a very limited body of evidence in the context of acute/primary infection is provided by randomized controlled studies comparing antiretroviral efficacy (59). This gap is mainly due to the challenges associated with identifying individuals during this early phase of infection, as well as the fact that most historical clinical trials compared 3DR with other complex regimens (i.e., 4DR), providing no direct information on the use of two-drug strategies in this setting (60).

Findings in advanced treatment-naive patients also suggest high effectiveness of DTG/3TC, although definitive non-inferiority data compared with DTG-based 3DRs are not yet available, and real-world evidence is still scarce.

One potential advantage of TAF-sparing 2DR regimens may lie in their allegedly safer metabolic profile, although current evidence comparing TAF-sparing and TAF-containing regimens remains conflicting, with some studies showing no significant differences (61).

Preliminary data on viral reservoir and inflammation indicate no relevant differences compared with 3DRs. No RCTs are currently available in pregnancy, and observational evidence is extremely limited.

Beyond clinical considerations, DTG/3TC has consistently demonstrated cost-effectiveness compared with three-drug regimens. Economic models conducted in the US setting, informed by the GEMINI trials, show that DTG/3TC is cost-saving in treatment-naive individuals. In treatment-naive patients, DTG/3TC generated higher QALYs at markedly lower costs than all comparators (62, 63).

In conclusion, the body of evidence supporting DTG/3TC as a first-line regimen in treatment-naive PWH is steadily expanding, reinforcing its role in several challenging clinical scenarios.

Author contributions

AG: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. GB: Conceptualization, Writing – original draft, Writing – review & editing. VB: Methodology, Writing – original draft, Writing – review & editing. AC: Writing – original draft, Writing – review & editing. MM: Writing – original draft, Writing – review & editing. MP: Writing – original draft, Writing – review & editing. MR: Writing – original draft, Writing – review & editing. FS: Writing – original draft, Writing – review & editing. ET: Writing – original draft, Writing – review & editing. GM: Conceptualization, Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. The authors acknowledge support from: PRIN 2022 (Cod progetto 2022B3SXZE) dal titolo “Project study: Dynamics of residual peripheral inflammation in virally suppressed cART-treated persons living with HIV (PLWH) switching to an INSTI-based oral dual daily or injectable Long-Acting regimen”. PRIN 2022 Cod progetto G53C24001070006 Titolo: Reciprocal Interactions among VIrological, Inflammatory SIgnatures and Translocating microbiome composition in dictating the long-term immune-virological outcome in virologically suppressed HIV+ patients with known duration of infection (RIVISITHIV) UNIVERSITY OF MILAN - APC INITIATIVE.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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