Dolutegravir + lamivudine effectiveness and tolerability in real-world cohorts with HIV-1 across Asia and South America: A systematic literature review

Abstract

Background:

Dolutegravir (DTG) + lamivudine (3TC) has demonstrated efficacy and safety in phase 3 clinical trials; however, most published data are from people with HIV-1 in North America and Europe.

Methods:

To investigate outcomes from other regions, we summarized real-world outcomes with DTG + 3TC in cohorts from Asia and South America. In this systematic literature review, relevant databases and congresses (2013–2023) were searched to identify non-interventional studies reporting DTG + 3TC use; materials reporting effectiveness, safety, or tolerability outcomes were eligible. Post hoc targeted literature searches explored newer and non-English-language materials.

Results:

From 218 publications identified, 42 representing 23,512 people using DTG + 3TC (naive to antiretroviral therapy (ART), n = 731; switching ART, n = 3159; unspecified, n = 19,622) in China, Japan, Türkiye, Brazil, Taiwan, Russia, Argentina, and South Korea were included. Most virologic effectiveness outcomes were reported at week 48, with virologic suppression rates ranging from 82% to 100% in people naive to ART and 86% to 100% in those switching ART. Among people initiating DTG + 3TC with very high (≥500,000 copies/mL) baseline viral loads, 64% to 95% achieved virologic suppression at week 48. Virologic failure was infrequent. No treatment-emergent resistance was reported. Serious adverse events (1%) and discontinuations due to adverse events (2%) were infrequent.

Conclusion:

In real-world cohorts across Asia and South America, initiating or switching to DTG + 3TC resulted in high proportions of people achieving or maintaining virologic suppression and demonstrated a good safety profile at multiple time points, consistent with clinical trial and real-world data in North America and Europe.

1. Introduction

The availability of highly effective antiretroviral therapy (ART) has transformed HIV from a terminal illness into a chronic condition requiring lifelong clinical management. Thus, enabling people with HIV to have long and healthy lives is a goal of contemporary clinical care.^[1,2] Compared with the general population, people with HIV have an increased risk of age-related comorbidities, such as chronic kidney disease, cardiovascular disease, malignancies, low bone mineral density and fracture, metabolic dysfunction-associated fatty liver disease, and type 2 diabetes.^[3–8] Choice of ART regimen is an important factor that can impact the likelihood of age-related comorbidities in populations with HIV. Renal toxicity and reduced bone mineral density have been observed with tenofovir-based regimens,^[9–11] metabolic disorders and hepatic toxicity with protease inhibitors,^[12] weight gain with tenofovir alafenamide (TAF) or integrase strand transfer inhibitors,^[13,14] increased risk of cardiovascular disease with abacavir (ABC),^[15,16] and increased risk of drug–drug interactions with pharmacokinetic boosters.^[9,12] To avoid unwanted side effects and/or drug–drug interactions, especially in the context of polypharmacy and/or multiple comorbidities, people with HIV may benefit from ART regimens with fewer components.

The use of 2-drug regimens (2DRs) has been evaluated as a strategy to reduce the number of antiretroviral agents required in a complete ART regimen.^[14,17,18] Dolutegravir (DTG) + lamivudine (3TC) demonstrated durable efficacy with a high barrier to resistance and tolerability in phase 3/3b randomized trials in both participants naive to ART (GEMINI-1/-2 through week 144 and STAT through week 48) and participants with virologic suppression (VS) who switched regimens (TANGO through week 196 and SALSA through week 48).^[19–22] In the randomized phase 3 TANGO and SALSA trials, switching to the fixed-dose combination of DTG/3TC was non-inferior to continuing 3- or 4-drug regimens for up to 3 years in TANGO and 1 year in SALSA for maintenance of VS.^[20,23]

Clinical efficacy and real-world effectiveness and safety analyses of DTG + 3TC among people with HIV-1 are primarily from North America and Europe. Among the 1336 participants randomized to DTG + 3TC across the GEMINI-1/-2, TANGO, and SALSA studies, 975 (73%) were in centers in North America or Europe. A previous systematic literature review (SLR) of primarily North American and European real-world studies of DTG + 3TC found high rates of VS and that DTG + 3TC was generally well tolerated.^[24] However, populations outside of North America and Europe can have different characteristics that may influence treatment outcomes, including ethnic, socioeconomic, geographic, and/or cultural factors unique to a region. Analyzing data from different regions can reveal the needs and challenges of a given region, which can be used to target solutions, improve communication, and improve clinician confidence in treatment decisions. Therefore, the objective of this paper is to provide more targeted insights into treatment outcomes from different geographic regions through summarizing SLR-identified real-world evidence of DTG + 3TC effectiveness and safety outcomes in people with HIV-1 from cohorts outside of North America and Europe.

2. Methods

2.1. Systematic literature review

2.1.1. Search strategy

SLRs were performed, and records were screened according to previously published methods^[24]; SLRs were not registered, and the study protocol is not publicly accessible. Briefly, Embase^®, Ovid MEDLINE^®, MEDLINE^® In-Process, and the Cochrane library databases and congresses from January 1, 2013, to November 4, 2022, were searched for publications reporting outcomes in real-world populations with HIV-1 using DTG + 3TC (Table S1, Supplemental Digital Content, https://links.lww.com/MD/P574). The SLR was updated to include records through March 8, 2023, and supplemented with a post hoc literature review as described below.

2.1.2. Eligibility criteria

Real-world non-interventional studies in countries outside of North America and Europe were included based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1). Eligibility was assessed by 2 reviewers independently screening abstracts and titles first, followed by a secondary screening of full text. Eligibility assessment discrepancies were resolved by a third independent reviewer.

Figure 1.

PRISMA flow charts for systematic literature reviews. 3TC = lamivudine, DTG = dolutegravir. ^aOthers included records not classified under key categories. ^bSearched congresses included the Asian Conference on Hepatitis and AIDS; Australasian HIV and AIDS Conference; British Association for Sexual Health and HIV; British HIV Association; Canadian Conference on HIV/AIDS Research; Conference on Retroviruses and Opportunistic Infections; European AIDS Clinical Society (EACS); Grupo de Estudio del SIDA-SEIMC; HIV Drug Therapy Glasgow; HIV and Hepatitis in the Americas; HIV Netherlands Australia Thailand Research Collaboration; IDWeek; International AIDS Society/International AIDS Conference; International Conference on AIDS and Sexually Transmitted Infections in Africa; International Conference on Antiviral Research; International Congress on Infectious Diseases; International Francophone Conference on HIV, Hepatitis, and Sexual Health (AFRAVIH; searched May 24, 2022); Japanese Society for AIDS Research (JSAR); Kenya Association of Physicians; National Conference of AIDS Society of India; and Société Française de Lutte contre le Sida. ^cPost hoc searches in July 2023 included the Wanfang Database and CNKI Database, Asia-Pacific AIDS and Co-Infections Conference (APACC; 2023), Japanese Association for Infectious Diseases, JSAR, National Academic Conference on HIV/AIDS (Chinese Association of Sexually Transmitted Disease and AIDS Prevention and Control; 2020–2023), and the National Academic Conference on AIDS and Hepatitis C (Chinese Medical Association; 2020–2023). Final post hoc searches were performed on October 18, 2023, and December 6, 2023, for records from the 2023 St Petersburg HIV Forum and 2023 EACS, respectively.

Studies reporting effectiveness, safety, and/or tolerability outcomes at any specified time point for a total of N ≥ 10 individuals using DTG + 3TC were eligible, including cohorts in which the total was divided between populations with and without prior ART experience. Potential study bias was assessed using a 26-question modified version of the Downs and Black checklist.^[25] Studies with a bias score ≤ 10 were excluded. Potentially overlapping cohorts were identified and compared to avoid double-counting populations. The lead publication chosen to represent each cohort was the publication that reported outcomes for the largest population. An abstract and its presentation were collectively considered 1 study.

2.1.3. Data extraction

All data were extracted by 1 reviewer and independently verified by a second reviewer per previously published methods.^[24] Briefly, data extracted included the number of people using DTG + 3TC, study location, baseline demographics and characteristics, effectiveness outcomes (VS, virologic failure [VF], change in CD4+ cell count), study discontinuations, biomarker outcomes (lipid, liver, renal, and inflammation), and metabolic outcomes at any time point. Data were grouped and summarized by ART status (naive or switch; effectiveness and safety outcomes were excluded unless specific to ART status); additionally, effectiveness data were grouped and summarized according to the time point of the outcome. Calculations of proportions with a given outcome pooled n/N values from only those studies reporting the outcome (at the time point of interest, if applicable) and described explicitly. Any assumptions made about unclear or missing data are explicitly described where applicable.

2.2. Post hoc targeted literature reviews

Supplemental targeted literature searches were performed post hoc to support the SLR and explore more recent and/or non-English-language materials. Wanfang Database and CNKI Database Chinese-language databases were searched for publications from January 1, 2021, to July 11, 2023, using “dolutegravir” and “lamivudine” as search terms and excluding non-human studies. Additionally, relevant non–North American or non-European congress searches were performed in July, October, and December 2023 (Fig. 1).

2.3. Ethics compliance statement

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

3. Results

3.1. Included studies and populations

The SLR identified 187 publications representing 36,313 people with HIV-1 using DTG and 3TC, from 67 unique cohorts. Of these, 11 publications representing 20,413 people using DTG and 3TC met all screening criteria and were included. The post hoc literature search included 31 publications that met all screening criteria, representing 3330 people. Together, the 42 included publications represented 33 cohorts based on overlapping study locations and/or population naive/switch status (Table S2, Supplemental Digital Content, https://links.lww.com/MD/P574), consisting of 23,512 people using DTG + 3TC (naive to ART, n = 731; switching ART, n = 3159; unspecified, n = 19,622) in China (n = 1241),^[26–45] Japan (n = 846),^[46–54] Türkiye (n = 283),^[55–60] Brazil (n = 20,005),^[61,62] Taiwan (n = 531),^[63,64] Russia (n = 269),^[65] Argentina (n = 186),^[66] and South Korea (n = 151; Fig. 1).^[67] No studies from Africa or Australia were identified.

3.2. Baseline characteristics

Baseline characteristics from lead studies are summarized in Table 1. The majority of people using DTG + 3TC were male (assumed to represent sex assigned at birth; range, 58%–100%). Median age ranged from 28 to 67 years,^{[26–30,32,42,43,46–48,52,54–57,60,62,65,67]} and mean age ranged from 38 to 53 years.^{[33,40,44,50,57,64]} The most prevalent comorbidities reported at baseline were related to metabolic health, bone health, and renal function. Individuals with baseline clinical characteristics of interest from lead studies are summarized below according to ART status at time of DTG + 3TC start.

Table 1.

Baseline characteristics of people with HIV-1 using dolutegravir + lamivudine from cohort lead studies reporting outcomes in populations naive to antiretroviral therapy or with prior antiretroviral therapy experience with N ≥ 10 individuals.

Cohort lead study	Country	Study type	People using DTG + 3TC	Inclusion criteria	VL ≥ 100,000 copies/mL, n (%)	CD4+ cell count <200 cells/mm3, n (%)	People with GRT, n (%) [RAMs]	Comorbidities in ≥ 10% of people using DTG + 3TC, n (%)
Naive to ART
Wei et al[39]	China	Prospective	200	–	≥30 (≥15)*	67 (34)	118 (59)	–
Long et al[43]	China	Prospective	145	–	14 (10)	70 (48)	–	AIDS-defining OIs: 48 (33) HTN: 34 (23) Diabetes: 15 (10)
Dou et al[26]	China	Prospective	96	24-wk follow-up after initiating DTG + 3TC	42 (44)	51 (53)	–	OI: 36 (38)
Inan et al[60]	Türkiye	Retrospective	56	Age > 18 yr, baseline VL ≥ 500,000 copies/mL, ≥24 wk of follow-up data	56 (100)	–	27 (48)	Dyslipidemia: 18 (27) HTN: 9 (16) Diabetes: 7 (13)
Hui et al[28]	China	Prospective	54†	Exclusion criteria: pregnancy, breastfeeding, HBV co-infection, grade 4 laboratory abnormalities, eGFR < 60 mL/min/1.73 m2 via MDRD	34 (77)	23 (45)	0	Co-metabolic disease: 8 (15)‡
Hou et al[33]	China	Retrospective	46	Age ≥ 18 yr	9 (20)	10 (22)	–	Syphilis: 5 (11)
Zhao et al[29]	China	Retrospective-prospective	42	–	32 (76)	32 (76)	0	OI or tumor: 33 (79) Kidney injury/high risk: 26 (62) HTN: 11 (26) CVD: 10 (24) Osteoporosis/bone disease: 9 (21) Diabetes: 6 (14) Anemia (Hb < 90): 4 (10)
Lee et al[67]	South Korea	Retrospective	20	Age > 19 yr and follow-up for > 12 mo	–	–	18 (90) [5 (25); NNRTI: 4 (20); INSTI: 2 (10)]	Osteopenia: 3 (15) Syphilis: 3 (15) HTN: 2 (10) Diabetes: 2 (10) Dyslipidemia: 2 (10) CVD: 2 (10) Psychiatric illness: 2 (10)
Cheng et al[63]	Taiwan	Prospective	19	–§	–	–	–§	–
Ling et al[27]	China	Prospective	14	No HBsAg-resistant HBV infection, no M184V	9 (64)	9 (64)	11 (79) [no M184V]	“Joint disease”: 11 (79) Other OI: 3 (21) Tuberculosis: 2 (14)
Cecchini et al[66]	Argentina	Retrospective	12	Adult	–	–	–	–
Basova et al[65]	Russia	Prospective	11	–	0	0	–	–
Cohort lead study	Country	Study type	People using DTG + 3TC	Inclusion criteria	Time on ART, median, yr	Previous ART, n (%)	People with GRT, n (%) [RAMs]	Comorbidities in ≥ 10% of people using DTG + 3TC, n (%)
Switching ART
Cheng et al[64]	Taiwan	Retrospective	512	Negative HBsAg status, no DTG- or 3TC-selective RAMs	Mean: 6.5	DTG/ABC/3TC: 72% DTG/RPV: 17% EFV/FTC/TDF: 3% RPV/FTC/TAF: 2% BIC/FTC/TAF: 2% EVG/c/FTC/TAF: 2% MTR: 2% RPV/FTC/TDF: <1%	512 (100) [48 (9); NRTI: 20 (4); NNRTI: 34 (7); PI: 5 (1); INSTI: 2 (<1)]	–
Iglessias et al[62]	Brazil	Retrospective	383‖	–	Mean: 13.5	INSTI-based: 218 (57)	–¶	Bone-related: 110 (29) Kidney-related: 95 (25)
Basova et al[65]	Russia	Prospective	258	–	–	NNRTI: 72% PI: 58% INSTI: 3%	–	–
Nagashima et al[52]	Japan	Retrospective	221	–	–	DTG/ABC/3TC: 144 (65) DTG + FTC/TAF: 38 (17) INSTI-based: >90	–	–
Cecchini et al[66]	Argentina	Retrospective	174	Adult	–	–	–	–
Watanabe et al[54]	Japan	Retrospective	157	People who started DTG/3TC at a different site excluded	–	DTG/ABC/3TC: 135 (86) DTG + ABC/3TC 9 (6)	–	–
Ikegaya et al[48]	Japan	Retrospective	149	–	–	INSTI + 2 NRTIs: 136 (91) DTG + 2 NRTIs: 109 (73)	–	–
Zhou et al[42]	China	–	146	–	2.9#	DTG-based 3DR: 45% EFV-based: 33% Other: 22%	–	AIDS-related OIs: 21% Abnormal renal function: 15% CVD: 14% Syphilis: 14%
Lee et al[67]	South Korea	Retrospective	131	Age > 19 yr, follow-up for > 12 mo	–	PI + 2 NRTIs ATV/c: 2 (2) ATV: 1 (<1) LPV/r: 1 (<1) INSTI + 2 NRTIs DTG: 102 (78) RAL: 9 (7) BIC: 8 (6) EVG/c: 2 (2) NNRTI + 2 NRTIs EFV: 5 (4) ETR: 1 (<1)	51 (39) [14 (11); NRTI: 1 (1); NNRTI: 11 (8); INSTI: 3 (2); H51H/D/N/Y]	Dyslipidemia: 52 (40) Syphilis: 45 (35) HTN: 30 (23) Diabetes: 25 (19) Osteopenia: 20 (15) Tuberculosis: 19 (15)
Yang[44]	China	Retrospective	121	Age ≥ 18 yr, VL < 50 copies/mL	–	–	4 (3) had archived M184V/I	–
Adachi et al[46]	Japan	Retrospective	119	Previous regimen of either DTG/ABC/3TC, DTG + FTC/TAF, or BIC/FTC/TAF; VL < 50 copies/mL for ≥ 6 mo; ≥2 blood tests post-switch to DTG + 3TC	–	DTG/ABC/3TC: 85 (71) DTG + FTC/TAF: 21 (18) BIC/FTC/TAF: 13 (11)	–	HTN: 37 (31) Dyslipidemia: 33 (28) Diabetes: 17 (14)
Zhong et al[30]	China	Retrospective	112	No HBV, VL < 500,000 copies/mL, completed 48-wk follow-up	2.5	INSTI + 2 NRTIs: 54 (48) NNRTI + 2 NRTIs: 39 (35) bPI + 2 NRTIs: 11 (10) Other: 8 (7)	–	–
Yağci-Çağlayik et al[55]	Türkiye	Retrospective	107	–	–	INSTI + 2 NRTIs: 73/98 (74) PI + 2 NRTIs: 10/98 (10) NNRTI + 2 NRTIs: 6/98 (6) PI + INSTI: 6/98 (6) INSTI + PI + 2 NRTIs: 3/98 (3)	37** [4 with relevant 3TC mutations: T69A/D: 1 K65R: 3 K70T/S: 2 M184V: 1]	CKD: 20/98 (20) Osteoporosis: 13/98 (13)
Xin[40]	China	Retrospective	100	VS for > 3 mo, TDF-inclusive 3DR as previous ART	–	TDF-inclusive 3DR	–	Abnormal eGFR: 20 (20) Abnormal BMD: 20 (20) CKD: 20 (20) Osteoporosis: 20 (20) Diabetes: 10 (10)
Minami et al[50]	Japan	–	91	Participants under good virologic control	–	–	–	–
Hou et al[32]	China	Retrospective	79	VS at time of switch	5	NNRTI + 2 NRTIs: 36 (46) INSTI + 2 NRTIs: 26 (33) PI + 2 NRTIs: 8 (10)	–	Dyslipidemia: 18 (23)
Ergen et al[56]	Türkiye	Retrospective	63	Age ≥ 18 yr, not pregnant, switched from a 3DR, VL < 100 IU/mL or undetectable for ≥ 6 mo, using DTG + 3TC ≥ 6 mo	3.5	PI/R + 2 NRTIs LPV: 16 (25) IDV: 1 (2) NNRTI + 2 NRTIs EFV: 6 (10) INSTI + 2 NRTIs DTG: 36 (57) EVG: 8 (13) RAL: 7 (11)	–	HTN: 10 (16)
Ling et al[27]	China	Prospective	53	No HBsAg-resistant HBV infection, no M184V	2.6	INSTI + 2 NRTIs: 18 (34) NNRTI + 2 NRTIs: 16 (30) bPIs + 2 NRTIs: 11 (21) PI + NRTI: 8 (15)	–	“Joint disease”: 22 (42) Tuberculosis: 7 (13) Other OI: 6 (11)
Tsukiji et al[53]	Japan	Retrospective	47	Switched before Mar 31, 2021, with 48-wk follow-up	–	DTG/3TC/ABC: 23 (49) DTG + TAF/FTC: 9 (19) Not specified: 3 (6)††	–	–
Hirano et al[47]	Japan	Retrospective	51	–	–	Most common: BIC/FTC/TAF: 21 (41) DTG + FTC/TAF: 6 (12) DTG/ABC/3TC: 6 (12)	–	–
Sönmezer et al[58]	Türkiye	Prospective	40	Age > 18 yr	–	–	–	–
Shiyun et al[31]	China	Retrospective	33	Aged ≥ 18 yr, negative for HBsAg	2.1	INSTI-based: 15 (45) PI + NRTI: 8 (24) NNRTI + 2 NRTIs: 7 (21) PI + 2 NRTIs: 2 (6) bPI: 1 (3)	30 (91) had GRT performed at baseline; 26 (79) had previous GRT results M184V/I: 6 (18) NRTI: 6 (18) NNRTI: 12 (36) PI: 1 (3)	Hyperlipidemia: 13 (39) HTN: 12 (36)
Konishi et al[49]	Japan	–	10	Aged ≥ 18 yr, VL < 50 copies/mL for ≥ 3 mo, switch from 3DR, no HBsAg-positive or HBV	–	For total population‡‡: DTG + FTC/TAF: 5 DTG/ABC/3TC: 4 RAL + FTC/TAF: 2	–	–
Combined (both naive to ART and switching ART)
Véras et al[61]	Brazil	Retrospective	19,622 total (naive/switch distribution not reported)	Switched to 2DR (DTG + 3TC or DRV/R + 3TC) per Ministry of Health electronic records	–	DTG-containing regimens: 72%	–	–

– = no data, 2DR = 2-drug regimen, 3DR = 3-drug regimen, 3TC = lamivudine, ABC = abacavir, ART = antiretroviral therapy, ATV = atazanavir, BIC = bictegravir, BMD = bone mineral density, bPI = boosted protease inhibitor, c = cobicistat, CKD = chronic kidney disease, CVD = cardiovascular disease, DRV = darunavir, DTG = dolutegravir, EFV = efavirenz, eGFR = estimated glomerular filtration rate, ETR = etravirine, EVG = elvitegravir, FTC = emtricitabine, GRT = genotypic resistance testing, Hb = hemoglobin, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HTN = hypertension, IDV = indinavir, INSTI = integrase strand transfer inhibitor, LPV = lopinavir, MDRD = modification of diet in renal disease, MTR = multi-tablet regimen, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleoside reverse transcriptase inhibitor, OI = opportunistic infection, PI = protease inhibitor, r = ritonavir, RAL = raltegravir, RAM = resistance-associated mutation, RPV = rilpivirine, TAF = tenofovir alafenamide, TDF = tenofovir disoproxil fumarate, VL = viral load, VS = virologic suppression.

^*Total number not reported at baseline; n = 30 individuals with wk 12 data had baseline VL ≥ 100,000 copies/mL.

^†Outcomes reported for n = 21 people using DTG + 3TC.

^‡4/21 (19%) with an OI.

^§Study population was mixed naive/switch, but information about inclusion criteria and GRT availability only mentioned switch population.

^‖Did not explicitly report that full study population was switch but reported mean duration of HIV-1 (16.9 yr) and ART exposure (13.5 yr).

^¶At least n = 1 individual had previous M184V mutation.

^#Value not specified as median or mean.

^**Denominator not specified.

^††Study did not list previous ART for the n = 3 individuals who discontinued DTG/3TC.

^‡‡Includes previous ART for n = 1 individual in the analysis who switched to DTG + RPV.

3.2.1. Populations naive to ART

Across 10 lead studies reporting baseline viral load (VL) data, at least 27% (188/684) of people had VL ≥ 100,000 copies/mL^{[26–29,33,60,65]} and 17% (113/684) had VL ≥ 500,000 copies/mL at DTG + 3TC initiation.^{[26,27,29,43,60,65]} The actual proportion with VL ≥ 100,000 copies/mL may be higher based on median (IQR) VLs reported by 2 of these studies.^[39,67] From 10 lead studies reporting baseline CD4+ cell count, median CD4+ cell counts ranged from 59 to 446 cells/mm^{3[26–29,33,39,43,60,67]} and 36% (248/684) of lead study populations initiated with < 200 cells/mm³ (Table 1).^{[26–29,33,39,43,65]}

3.2.2. Populations switching ART

Between 73% and 100% of each lead study population switched to DTG + 3TC from a 3-drug regimen^{[27,30–32,40,42,46,49,52,55,56,64,67]} after a median 2.1 to 5 years^{[27,30–32,42,56]} (mean, 6.5 or 13.5 years^[62,64]) on previous ART (Table 1). Primary reasons for switch were treatment simplification and side effects or toxicities from previous ART^{[30,31,42,44,55,56,58,67]}; other major reasons were comorbidities (including dyslipidemia, renal disease, and bone disease)^{[30,42,44,55,56,58,62]} and avoiding drug–drug interactions or preventing toxicities.^{[30,42,55,56]}

At time of switch to DTG + 3TC, 93% (1596/1707) of people had study-defined VS, 6% (97/1707) had viremia and/or VF, and < 1% (14/1707) had unknown VL among the 14 lead studies reporting baseline data.^{[27,30–32,40,42,44,46,50,55,56,58,64,67]} Overall, n = 77 people switched with known previous VF (2 consecutive VL > 200 copies/mL, n = 9; VL > 1000 copies/mL, n = 68).^[55,64] Others switched to DTG + 3TC despite presence or historical evidence of resistance-associated mutations (RAMs) selected by 3TC and DTG (n = 16^{[31,44,55,62,67]} and n = unspecified, between 1 and 3,^[67] respectively; Table 1).

3.3. Virologic and immunologic effectiveness

Virologic effectiveness outcomes for people using DTG + 3TC were most often reported as VS rates, frequently defined as either an undetectable VL or VL < 50 copies/mL.

3.3.1. Populations naive to ART

Rates of VS (VL < 50 copies/mL, unless otherwise specified) among people who initiated DTG + 3TC as first-line ART were generally high from week 4 to week 96, with lower effectiveness at early time points. Proportions of individuals achieving VS at week 4 or month 1 were 12% (5/42) or 28% to 100% in studies with undefined VS criteria,^[29,34,58] 45% (15/33) at week 8,^[38] and between 62% (26/42) and 85% (105/124) at week 12.^[29,34,39] Week 24 or month 6 VS rates ranged from 71% to 100% (Figure S1, Supplemental Digital Content, https://links.lww.com/MD/P574); of note, 2 cohorts reported VL < 20 copies/mL or undetectable VL in 95% (19/20) and 100% (8/8) of people.^[57,67] At week 36, 90% (38/42) and 100% (per-protocol population; VS undefined) achieved VS^[29,34]; week 48 VS rates ranged from 82% to 100% (Fig. 2A), where 95% (19/20) of individuals in 1 study achieved VL < 20 copies/mL or undetectable.^[67] Few individuals had data reported at week 72 (100% [3/3] of people with VL > 50 copies/mL at week 48 achieved VL < 20 copies/mL) or week 96 (86% [6/7] achieved VL < 50 copies/mL).^[27,35]

Figure 2.

Virologic response and failure rates after 48 wk of DTG + 3TC use. Reported in lead studies with N ≥ 10 people with HIV-1 who were either (A) naive to ART or (B) switched ART. 3TC = lamivudine, ART = antiretroviral therapy, c/mL = copies/mL, DTG = dolutegravir, ITT = intention to treat, MEX = missing = excluded, NR = not reported, OT = on treatment, PP = per protocol,VF = virologic failure, VL = viral load, VS = virologic suppression. ^aProportion with VL < 20 copies/mL after 12 mo. ^bStudy-defined virologic rebound, not VF. ^cThe 2 people with VL > 50 copies/mL resuppressed to < 20 copies/mL at wk 72. ^dEffectiveness reported at mo 12 (93.7%) was not specific to people using DTG + 3TC (9.5% of 127 people at baseline). ^ePeople with VL < 50 copies/mL. ^fAssumed; 0 people were reported to have VL > 200 copies/mL at wk 48. ^gEffectiveness reported at mo 12 (95.7%) was not specific to people using DTG + 3TC (32.3% of 538 people at baseline).

Individuals initiating DTG + 3TC generally had high VS rates across all baseline VL categories, including high (≥100,000 copies/mL) and very high (≥500,000 or ≥ 1,000,000 copies/mL) baseline VL (Figure S2, Supplemental Digital Content, https://links.lww.com/MD/P574). Among individual cohorts, VS rates in subgroups with very high VL ranged from 59% to 89% (vs 90% with VL < 500,000 copies/mL) at week 24 and from 64% to 95% (vs 90%–92% with VL < 500,000 copies/mL) at week 48. Data should be interpreted with caution, as some baseline VL subgroups had small sample sizes.

Overall, <1% (2/731) of people naive to ART experienced study-defined VF at any time point across all 15 lead studies (non-lead studies, 0%) reporting virologic effectiveness outcomes. Both individuals experienced VF (unknown criteria) at week 48.^[63] However, not all studies reported VF outcomes or defined VF criteria. Of note, 1 individual in a non-lead study achieved VS (VL < 50 copies/mL) at week 48 but had VL 3370 copies/mL at week 96 (attributed to suboptimal adherence).^[35] No treatment-emergent RAMs were reported at any time point.

All 13 studies (10 cohorts) with immunologic outcomes in people naive to ART reported CD4+ cell count increases at all time points from week 4 to week 96 (Table 2). Increases from baseline reached statistical significance among all studies that reported statistics at weeks 12 and 24 (P < .001 each),^[39] 48 (P < .05 to < .001),^{[27,33,34,36]} and 96 (P = .05)^[35]; additionally, 1 cohort reported significant increases via a repeated-measure analysis of variance test for months 6 and 12 (P < .001).^[67] Individuals with very high VL (≥500,000 and/or ≥ 1,000,000 copies/mL) experienced significant increases in CD4+ cell count at weeks 8, 24, and 48 in 1 cohort (P < .05).^[38] Other cohorts reported increases of ≥ 200 cells/mm³ at week 24^[26] and week 48^[29] without reporting statistics.

Table 2.

Immunologic outcomes reported in people naive to antiretroviral therapy initiating dolutegravir + lamivudine by cohort and lead study.

Cohort lead study (substudy)	People naive to ART using DTG + 3TC	Time point, wk*	Median (IQR)* baseline CD4+ cell count, cells/mm3	Median (IQR)* CD4+ cell count at time point, cells/mm3
Dou et al[26]	96	4	174 (63–346)	+82 from baseline
		12		+138 from baseline
		24		+166 from baseline
(Li et al)[34]	77	48	278 (141–453)	+149 (68–231) from baseline (P < .001)
Hou et al[33]	46	48	312 (224–257)	+455 (262–661) from baseline (P < .05)
Hui et al[28]	54†	24	249 (118–310)	+128 (85–194) from baseline (<200 cells/mm3 at baseline: +130 [46–207])
Inan et al[60]	56	24	Mean (SD): 376 (210)	Mean (SD): 624 (307)
		48		Mean (SD): 721 (340)
Long et al[43] (Tu et al)[38]	33	8	VL < 500,000 copies/mL: 237 VL ≥ 500,000 copies/mL: 106	VL < 500,000 copies/mL: 295 (P < .05) VL ≥ 500,000 copies/mL: 250 (P < .05)
		24		VL < 500,000 copies/mL: 274 (P < .05) VL ≥ 500,000 copies/mL: 219 (P < .05)
(Long et al)[36]	107	48	257 (149–302)	Significant increase from baseline (z = −2.197; P = .03)
(Long et al)[35]	11	96	─	+119 from baseline (P = .05)
Wei et al[39]	200	12	285 (141–433)	364 (210–599) (P < .001)
		24		414 (318–673) (P < .001)
Zhao et al[29]	42	48	59 (27–178)	Mean (SD) change from baseline: VL < 500,000 copies/mL: +218 (122) VL ≥ 500,000 copies/mL: +265 (127)
Basova et al[65]	11	Mo 12	─	+243 from baseline
Lee et al[67]	20	Mo 6	446 (294–561)	620 (421–888) (P < .001 via repeated-measure ANOVA)
		Mo 12		667 (508–912) (P < .001 via repeated-measure ANOVA)
Ling et al[27]	14	48	Mean (SD): 202 (191)	Mean (SD): 323 (190) (P = .01)

─ = no data, 3TC = lamivudine, ANOVA = analysis of variance, ART = antiretroviral therapy, DTG = dolutegravir, VL = viral load.

^*Unless otherwise specified.

^†n = 21 included in analysis.

3.3.2. Populations switching ART

Definitions of VS in cohorts switching ART to DTG + 3TC, when provided, included either an undetectable VL or a range from VL < 50 to < 250 copies/mL. Most studies reported VS rates at week 24 (range, 88%–100%) and/or week 48 (range, 86%–100%; Fig. 2B), with reports of undetectable VL and/or VL < 20 copies/mL (week 24, 96% [126/131] and 100% [2/2]; week 48, 95% [125/131]).^[57,67] In a cohort subgroup who switched due to VF (2 consecutive VL > 50 copies/mL [assumed]), 75% (3/4) achieved VS at week 12 and 100% (4/4) had VS at weeks 24 and 48.^[31]

Rates of VS ranged from 87% to 100% per study reporting other follow-up times (median or absolute) from month 1 to month 60 across studies totaling N = 356 people with prior ART experience.^{[27,35,46,55,58]} Of note, 1 large study (N = 19,622) reported undetectable (≤49 copies/mL) VLs in 92%, 95%, and 97% of individuals using DTG + 3TC in 2019, 2020, and 2021, respectively; however, n/N values, duration of use, and distribution by ART experience (99% overall [multiple 2DRs] switched ART) were not reported for any time point.^[61]

Immunologic outcomes were reported at any time point by 14 studies (13 cohorts), primarily as increases from baseline in mean or median CD4+ cell count. At week 24 or month 6, increases reached significance in 1 cohort (from 264 to 350 cells/mm³; P = .01)^[42] but not others.^[30,56,67] Changes from baseline at week 48 or month 12 ranged from + 11 to + 113 cells/mm³, which reached significance in 4 cohorts (P < .05)^{[27,31,32,42]} but not others^{[44,53,64,67]}; 2 did not report statistics.^[50,65] One cohort reported a 35 cells/mm³ increase from baseline at week 96 (P > .05).^[35] Only 1 study reported a decrease from baseline, after a median duration of 150 days post-switch to DTG + 3TC (614 to 595 cells/mm³; P = .55).^[46]

Across the 25 cohorts with virologic effectiveness outcomes in people switching to DTG + 3TC, 14 reported no VF, no virologic rebound, and/or 100% VS^{[27,30,31,40,44,46–50,55,65–67]}; additionally, 3 reported that VS (undefined) was achieved and/or continued.^[57,58,68] Three cohorts reported study-defined VF incidence rates: 3% (17/508) and 2% (2/86) at week 48 (VL ≥ 50 copies/mL),^[37,63] and < 1% (2/371) after a mean follow-up of 2.4 years (undefined).^[62] Low-level viremia (VL > 250 and < 500 copies/mL) and virologic non-response (2 consecutive VL ≥ 250 copies/mL after ≥ 6 months of ART) were each experienced by < 1% (2/258) of 1 cohort.^[65] Few virologic blips were reported: 3% (2/63) after a median of 10.4 months (transient VL ≥ 50 to 400 copies/mL after achieving VL < 50 copies/mL),^[56] and 1% (1/72) after a median of 19 weeks (VL > 100 copies/mL).^[51]

No treatment-emergent RAMs were reported in any study. Two people, each with a baseline RAM selected by either 3TC (M184I) or DTG (H51H/D/N/Y), maintained undetectable VLs after switch to DTG + 3TC.^[67] One study reported that having ≥ 2 VFs before switch or having an NRTI RAM were both associated with increased adjusted odds of having VL > 50 copies/mL at week 48; however, the analysis may have pooled data from people who switched to DTG/3TC (n = 512) and to bictegravir/emtricitabine/TAF (BIC/FTC/TAF; n = 506).^[64]

3.4. Safety

3.4.1. Tolerability/discontinuations

In total, 4% (140/3149) of people discontinued DTG + 3TC for any reason across 26 cohorts reporting any discontinuation outcome, for reasons including lost to follow-up, economic reasons, changing medical centers or ART, suboptimal adherence, and adverse events (AEs). At least 1 discontinuation was reported in 18 studies (1.1%–32.3% per study) at 24- to 96-week time points,^{[27–30,33–35,39,47,48,50,52–55,62,63,65]} and 0 discontinuations were reported or could be inferred across 7 cohorts^{[31,36,41,42,49,56,57,60,67]}; of these, 6 studies only reported discontinuations that were due to AEs^{[36,41,42,49,56]} or serious drug-related AEs.^[60] Drug-related AEs were grade ≤ 2 in severity,^[29,35] and serious AEs were infrequent: 1% (6/500; hepatobiliary and nervous system disorders, n = 2 each; COVID-19 and ovarian germ cell cancer, n = 1 each).^{[31,58,65,67]}

Overall, 2% (37/2242) of people discontinued DTG + 3TC due to AEs^{[27,28,30,31,33,35,41,42,47–50,52,54–57,62,63,67]} and < 1% (2/319) due to drug-related AEs^[29,52,60] across 24 cohorts reporting either outcome. The most common AEs leading to discontinuation were neuropsychiatric (n = 10^[63]; including severe insomnia,^[33] excessive irritability,^[55] and nightmares^[50]; n = 1 each), allergies (n = 5),^[63] and weight gain (n = 2).^[63] One person each discontinued due to myalgia,^[55] hair loss,^[55] nausea,^[63] and lower limb tingling.^[30] Symptoms of malaise, abdominal pain, lumbago, photophobia, and sleep disturbance were collectively reported reasons for n = 6 discontinuations.^[54]

3.4.2. Lipid outcomes

Lipid changes from baseline at 3- to 96-week time points were reported (Table 3). In populations naive to ART, total cholesterol (TC), triglycerides (TG), low-density-lipoprotein cholesterol (LDL-C), and high-density-lipoprotein cholesterol (HDL-C) all increased^[43] or remained unchanged^[33,34,67] vs baseline. One study reported individuals with grade 1 to 2 dyslipidemia up to 24 weeks.^[28] Others reported increases, decreases, or no changes vs baseline in 1 or more lipid parameters, with no consistent pattern across cohorts.^[27,39,41]

Table 3.

Lipid and renal outcomes reported in people with HIV-1 using dolutegravir + lamivudine.

Cohort lead study (substudy)	People using DTG + 3TC	Time point, wk*	Lipid outcomes with DTG + 3TC from BL to time point	Renal outcomes with DTG + 3TC from BL to time point
Dou et al[26]  (Li et al) [34]	Naive: 77	48	No significant changes in lipids	–
Yanyun et al[41]	Naive: 54	48	–†	sCr: Significant increase (70 to 81 µmol/L; P = .02); Urea: Significant increase (4.3 to 5.1 mmol/L; P = .00)
Hou et al[33]	Naive: 46	48	No significant changes in lipids	sCr: No significant changes
Hui et al[28]	Naive: 54‡	3, 12, and 24	Grade 1 to 2 dyslipidemia: BL: 0/21 (0%) Wk 3: 2/21 (9.5%) Wk 12: 2/21 (9.5%) Wk 24: 1/21 (4.8%)	–
Long et al[43]	Naive: 145	48	Adjusted change in TC: +0.5 mmol/L Adjusted change in TG: +0.2 mmol/L Adjusted change in HDL-C: +0.2 mmol/L Adjusted change in LDL-C: +0.4 mmol/L	Creatinine clearance change: −10 (−20, −3.3) mL/min
Wei et al[39]	Naive: 200	12 and 24	Wk 24: Significant increases in TC (3.97 to 4.58 mmol/L; P < .001) and HDL-C (1.03 to 1.27 mmol/L; P < .001) No significant changes in TG or LDL-C	Wk 12: eGFR§: Significant decrease (116.12 to 98.38; P < .01) sCr: Significant increase (71.45 to 84.10 µmol/L; P < .01) No significant changes between wk 12 and 24
Lee et al[67]	Naive: 20 Switch: 131	24 and 48	Naive: No significant changes in lipids Switch: Significant decreases at wk 48 in median TG (188.91 to 161.52 mg/dL; P = .03) and TC (184.62 to 177.70 mg/dL; P = .00)	Naive: sCr: Significant increase from BL (0.9 mg/dL) vs wk 24 (1.0 mg/dL) and 48 (1.1 mg/dL; P < .001) Switch: sCr: Significant increase from BL (0.99 mg/dL) to wk 24 (1.04 mg/dL) and wk 48 (1.02 mg/dL; P < .001)
Ling et al[27]	Naive: 14 Switch: 53	48	Naive: Significant increase in HDL-C (P = .03) Switch: Significant increase in HDL-C (P = .00) and LDL-C (P = .02)	Naive: eGFR: Significant decrease (P = .02)§ sCr: No significant change Switch: sCr: Significant increase (P = .00) eGFR: Significant decrease (P = .00)§ eGFR: Significant increase (P = .04)‖
Adachi et al[46]	Switch: 119	Median: 21 wk	People who switched from DTG + FTC/TAF or BIC/FTC/TAF had a significant increase in HDL-C (51 vs 52 mg/dL; P = .01) and decrease in TC/HDL (4.1 vs 3.8; P = .05) No significant changes in lipids after switch from DTG/ABC/3TC	sCr: No significant changes after switch from DTG + FTC/TAF or BIC/FTC/TAF
Cheng et al[64]	Switch: 512	48	Change in TC: −0.3 mg/dL Change in TG: −7.2 mg/dL Change in HDL-C: −1.1 mg/dL Change in LDL-C: −0.1 mg/dL	–
Ergen[56]	Switch: 63	Median: 10.4 mo	No significant changes in TC or TG	eGFR: No significant changes
Hou et al[32]	Switch: 79	48	No significant changes in lipids	sCr: No significant changes
Konishi et al[49]	Switch: 10¶	–	No significant changes in TC, HDL-C, or TG	No significant changes in eGFR, sCr, or cystatin C
Minami et al[50]	Switch: 91	48	Mean change in LDL-C (n = 56): +3.17 mg/dL	eGFR: Mean change (n = 56): +0.61 mL/min/1.73 m2 Wk 48 vs 1 yr before BL (n = 56): eGFR: Significant change (−4.2 mL/min/1.73 m2)
Nagashima et al[52] (Nagashima et al)[51]	Switch: 52	24	No significant changes in median TC, TG, LDL-C, or HDL-C	No significant changes in median eGFR or sCr
Shiyun et al[31]	Switch: 33	48	Overall: Significant increase in LDL-C (median, 2.35 to 3.12 mmol/L; P < .001) Significant decrease in TG (median, 2.21 to 1.61 mmol/L; P = .02) People who switched due to dyslipidemia (n = 6): Significant reduction in TC (P = .00) and TG (P = .00)	Overall: sCr: Significant increase (71.6 to 86.8 µmol/L; P = .00) eGFR: Significant decrease (106.4 to 88.6 mL/min/1.73 m2; P = .01) People who switched due to nephrotoxicity (n = 6): sCr: Significant decrease (113.2 to 96.1 µmol/L; P = .01) eGFR: Significant increase (77.4 to 87.1 mL/min/1.73 m2; P = .04)
Xin[40]	Switch: 100	24 and 48	–	eGFR (BL eGFR < 60 or 60 to ≤ 90 mL/min): Significant increases at wk 24 and 48 (P < .01) eGFR (BL eGFR > 90 mL/min): No significant changes at wk 48
Yağci-Çağlayik et al[55]	Switch: 107	48	–	eGFR: No significant changes Proteinuria (switch from TDF): Significant decrease (155 to 92 mg/g; P = .02)
Yağci-Çağlayik et al[59]	Switch: 32	Median: 30 wk	No significant changes in lipids	–†
Yang[44]	Switch: 121	48	Significant increase in LDL-C (2.66 to 2.82 mmol/L; P < .05)	eGFR: Significant increase (90.99 to 99.12 mL/min/1.73 m2; P < .05)#
Zhong et al[30]	Switch: 112	24	n = 1 abnormalities in lipid metabolism parameters with TG of up to 13.52 mmol/L Significant decrease in proportion with normal LDL-C (88.4% to 75%; P = .01)	No significant changes in proportions with normal sCr or eGFR levels
Zhou et al[42]	Switch: 146	24 and 48	Significant increase in LDL-C at wk 24 (2.38 to 2.69 mmol/L; P = .00) and wk 48 (P < .05) Significant decrease in TG at wk 48 (P = .04)	sCr: No significant changes at wk 24 or 48

– = no data, 3TC = lamivudine, ABC = abacavir, BIC = bictegravir, BL = baseline, CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration equation, DTG = dolutegravir, eGFR = estimated glomerular filtration rate, FTC = emtricitabine, HDL-C = high-density-lipoprotein cholesterol, LDL-C = low-density-lipoprotein cholesterol, sCr = serum creatinine, TAF = tenofovir alafenamide, TC = total cholesterol, TDF = tenofovir disoproxil fumarate, TG = triglycerides.

^*Unless otherwise specified.

^†Outcome was reported in the publication; however, the lead study or a substudy with higher N is presented to represent this outcome for this cohort.

^‡Outcomes reported for n = 21 using DTG + 3TC.

^§Using the CKD-EPI formula based on sCr.

^‖Using the CKD-EPI formula based on serum cystatin C.

^¶Eleven people were included in the study, but 1 switched to DTG + rilpivirine.

^#Assumption; values increased but were reported as a decrease.

Cohorts with prior ART experience had inconsistent lipid profile changes after switch to DTG + 3TC. A significant decrease in the proportion of people with normal LDL-C levels was observed,^[30] as were increases vs baseline in LDL-C^[50] that achieved significance (P < .05).^{[27,31,42,44]} At least 1 lipid parameter significantly improved in 5 cohorts,^{[27,31,37,42,46]} including HDL-C in those who switched from TAF-based regimens.^[46] Other cohorts reported no significant changes overall^{[32,49,51,56,59]} or in those who switched from DTG/ABC/3TC.^[46]

3.4.3. Renal outcomes

Outcomes for serum creatinine (sCr), creatinine clearance, and estimated glomerular filtration rate (eGFR) were reported at time points from 12 to 48 weeks (Table 3). In cohorts naive to ART, sCr significantly increased^[39,41,67] or did not change^[27,33] vs baseline, creatinine clearance decreased,^[43] and eGFR significantly decreased.^[27,39] In cohorts with prior ART experience, sCr significantly increased^[27,31,67] or did not change^{[32,42,46,49,51]} vs baseline; these outcomes were specific to people switching from TAF-based regimens in 1 cohort.^[46] Most cohorts with prior ART experience reported no changes in eGFR^{[49,51,55,56]}; however, individual studies reported significant increases either overall^[44] or in subpopulations with baseline eGFR ≤ 90 mL/min^[40] or who switched due to nephrotoxicity.^[31] One study reporting proportions of individuals with normal sCr and eGFR levels observed no significant changes in either parameter.^[30]

3.4.4. Liver outcomes

Liver function outcomes were reported as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assessments. No significant changes from baseline in ALT or AST were reported at weeks 24^[57] or 48,^{[27,31–33,36,37,53,67,69,70]} regardless of ART experience. Individual studies reported either a significant decrease from baseline in both ALT and AST (P = .00 each; naive to ART)^[41] or only AST (P = .02; prior ART experience)^[42] at week 48. Elevated ALT levels (4 × the upper limit of normal^[55] and 192.3 U/L^[30]) were reported in individuals with prior ART experience; in the latter group, ALT improved but remained elevated after switch to raltegravir + tenofovir disoproxil fumarate + 3TC.^[30]

3.4.5. Metabolic, weight, and body mass index outcomes

No significant changes in blood glucose or glucose control were observed in people naive to ART at weeks 24^[39] or 48^[27,67] or in those with prior ART experience at week 48.^[27,31,67] An individual naive to ART experienced a grade 1 to 2 hyperglycemia event at week 3 that resolved without study discontinuation.^[28]

Body weight and/or BMI vs baseline generally increased^{[27,34,39,43,50,64]} or did not significantly change^{[27,31–33,37,67]} with DTG + 3TC use across populations with or without prior ART experience. Of note, a cohort with prior ART experience reported an average weight loss of 0.69 kg, which was not significant.^[32] Significant weight increases were reported at week 24 (naive, +2.0 kg; P = .01)^[39] and week 48 (naive, +2.0 kg [P < .001]; prior ART, +1.1 kg [P < .05]).^[34,44] Significant increases from baseline in BMI were also reported at week 48 (naive, +0.6 kg/m² [P < .001]; prior ART, +1.1 kg/m² [P = .00]).^[27,34]

3.4.6. Inflammation biomarker outcomes

In a cohort naive to ART, elevated baseline levels of interleukin-6, interleukin-10, and tumor necrosis factor-α decreased to normal levels by week 4 or week 12 among 12 people with baseline opportunistic infections.^[45] No significant changes in C-reactive protein were observed among people who switched to DTG + 3TC from DTG/ABC/3TC or TAF-based regimens.^[46]

3.5. Quality assessment

Not all questions addressed in the modified Downs and Black bias assessment checklist were applicable to every study. As only observational studies were included, questions related to blinding or randomizing an intervention (numbers 14, 15, 23, and 24) were not applicable and effectively reduced the maximum checklist score from 27 to 23. Included studies had an overall mean (SD) score of 15.9 (3.0) out of 23 (Document S1, Supplemental Digital Content, https://links.lww.com/MD/P575). Mean (SD) scores by study type were 19.8 (1.3) for the 10 included manuscripts and 14.6 (2.2) for the 32 included congress materials (n = 16 abstracts, 13.9 [2.2]; n = 16 oral presentations and posters, 15.3 [2.1]).

4. Discussion

Real-world studies of people with HIV-1 outside of North America and Europe reported effectiveness and/or tolerability outcomes in individuals starting DTG + 3TC as a first-line or switch regimen at time points ranging from week 4 to week 96. Only countries from Asia and South America were represented. Outcomes were generally consistent with real-world analyses in North American and European cohorts, as well as results from phase 3 clinical trials, using DTG + 3TC. Rates of VS were high across cohorts regardless of prior ART experience at DTG + 3TC start. Notably, VS rates were high among people naive to ART with high baseline VL (≥100,000, ≥500,000, and/or ≥ 1,000,000 copies/mL), and VS rates shortly after treatment initiation tended to be lower than at later time points (week ≥ 48). Overall VF rates were low, and no RAMs were reported at VF. The safety profile of DTG + 3TC was mostly consistent across cohorts, with low numbers of serious AEs and discontinuations due to AEs.

The high VS rates, low VF rates, high barrier to resistance, and good safety profile observed in these real-world studies in Asia and South America are consistent with phase 3 clinical trials evaluating DTG + 3TC. In GEMINI-1/-2, DTG + 3TC demonstrated durable efficacy with a high barrier to resistance through 144 weeks in participants naive to ART.^[19] In TANGO and SALSA, the fixed-dose combination of DTG/3TC also had high efficacy and a high barrier to resistance for up to 4 years in participants with VS who switched from 3- or 4-drug regimens.^[20,22] GEMINI-1/-2, TANGO, and SALSA predominantly recruited participants from North America and Europe. In real-world settings, high rates of VS were observed in populations naive to ART and with prior ART experience at week 48. Although data at later time points were limited, high VS rates were observed in people naive to ART initiating DTG + 3TC (86% [6/7]) up to week 96^[35] and those switching to DTG + 3TC (100% [5/5]) up to month 60 (~5 years).^[55] No studies reported DTG + 3TC treatment-emergent resistance in this review, consistent with the high barrier to resistance observed in clinical trials.

Biomarker changes in this analysis were generally neutral or minimal and mostly consistent with phase 3 clinical trials evaluating DTG + 3TC or other real-world cohorts from North America and Europe. The minimal or positive effect of DTG + 3TC on lipid profiles vs baseline in most populations was consistent with a previous SLR reporting outcomes from 30 weeks through 5 years.^[71] Increases in sCr were expected, as DTG inhibits creatinine tubular secretion via the organic cation transporter 2 (OCT2); however, this effect does not alter eGFR.^[72] More studies in populations naive to ART vs with prior ART experience reported sCr increases from baseline, consistent with observations in participants naive to ART from GEMINI-1/-2 at week 48.^[73] The cohort naive to ART that reported significant decreases in eGFR at week 12 reported no explanation for this observation.^[43] Though many cohorts with prior ART experience reported improvements in renal function, 1 study^[31] reported sCr decreases in people who switched to DTG + 3TC due to nephrotoxicity. Most studies reported no change in liver parameters regardless of ART status at DTG + 3TC start. Inflammation biomarker levels decreased in a population naive to ART with opportunistic infections at baseline,^[45] consistent with observations after 6 months of DTG/3TC use in an Italian prospective cohort and with expected decreases in inflammation that accompany VS.^[74] No inflammation biomarker changes were observed in a population switching ART, similar to week 48 SALSA results.^[20]

Weight increased or remained the same among populations naive to ART, consistent with observations in GEMINI-1/-2 at weeks 96 and 144^[19] and studies of individuals initiating ART with an integrase strand transfer inhibitor.^[14] Reported weight changes were inconsistent across cohorts with prior ART experience; not all studies reported detailed ART history to discern whether these differences were due to antiretrovirals associated with weight gain, such as TAF.^[14]

Few serious AEs and drug-related AEs leading to discontinuation were reported in the present analysis, indicating an overall good safety and tolerability profile in ART-naive and switch populations using DTG + 3TC in clinical practice. Neuropsychiatric AEs were typically mild and infrequently led to study discontinuation, similar to observations in people using DTG + 3TC in North American and European cohorts.^[75]

The strengths of this study include the use of robust SLR searches supplemented with targeted literature reviews of non-English-language literature. Reviewing real-world evidence included people with baseline characteristics that would have excluded them from randomized clinical trials, such as very high VL, RAMs, and various co-infections. Data from people with these characteristics can provide additional reassurance for DTG + 3TC effectiveness and safety in situations where these characteristics may not be known and support use as initial therapy in individuals with very high VL. Of note, other populations of interest (e.g., women, people with tuberculosis or hepatitis co-infection) were sparsely or not at all represented, which is not unique to the results of this review and highlights that data gaps exist for these populations. Though the SLR screened publications from 2013 to 2023, all included studies except 1 were published in 2020 or later.

Outcomes summarized here are limited to what studies reported. Abstracts and congress presentations represented 76% (32/42) of the included studies, which may not be peer-reviewed and generally have limited space to report results; at minimum, abstracts were reviewed and approved by a congress abstract committee. Bias assessment scores were lower for congress materials overall compared with manuscripts; however, those with low (≤10) bias scores were excluded entirely. Translations of non-English materials may have introduced errors. Steps were taken to avoid double-counting study populations (e.g., comparing study sites, authors, and data windows) using previously established methods,^[24] although overlap cannot be ruled out completely. Outcomes were reported by study-defined VS and VF, which were not standardized. Some studies reported virologic outcomes as rates without corresponding n/N values, including 1 large study (N = 19,622) that reported VS rates ranging from 92% to 97%^[61]; as such, it was not possible to report overall percentages with VS or VF for a given time point. Studies that included VF events reported either no resistance testing at failure or that tests were not available, which may underestimate true RAM incidence. Effectiveness data are summarized descriptively, as the high variability of outcome definitions and time points precludes using a pooled meta-analysis approach to estimate treatment effects. Outcomes by subgroup (i.e., time point, VL) were presented together when possible. Few studies reported outcomes later than 48 weeks of follow-up; however, DTG + 3TC real-world evidence for outcomes up to week 96^[76–79] or later are also sparsely available in European and North American cohorts.^[80,81] Thus, long-term observation of DTG + 3TC use is a global data gap that requires additional study. Cohorts from Africa and Australia were not identified in this review, even though DTG + 3TC was approved at the same time in Australia and the United States; however, the body of evidence for DTG + 3TC effectiveness from Asian and South American cohorts may indicate that the benefits of this 2-drug regimen could extend to other geographic regions.

5. Conclusion

The complete 2DR DTG + 3TC reduces the number of prescribed antiretrovirals for the treatment of HIV-1 without compromising virologic or immunologic outcomes. VS was achieved and maintained with DTG + 3TC in people with HIV-1 in countries outside of North America and Europe, and safety and tolerability was good. Overall, findings were generally consistent with data from DTG + 3TC randomized controlled trials and reports from real-world cohorts in North America and Europe. Along with results from a previous SLR of observational studies,^[24] our findings reinforce the real-world effectiveness and safety of DTG + 3TC across international cohorts, including underrepresented groups such as Asian people with HIV-1 and those with diverse clinical characteristics (very high baseline VL, previous VF, and/or RAMs).

Acknowledgments

Editorial assistance was provided under the direction of the authors by Lindsay Walton, PhD, and Jennifer Rossi, MA, ELS, MedThink SciCom, and funded by ViiV Healthcare. Data included in this manuscript have previously been presented in part at the Asia-Pacific AIDS and Co-Infections Conference (APACC) 2024; June 27–29, 2024; Hong Kong, Hong Kong; Poster 57.

Author contributions

Conceptualization: Andrés Doblado-Maldonado.

Formal analysis: Andrés Doblado-Maldonado, Adrian Yit Reen Ooi, Emilio Letang, Michelle Moorhouse, Bryn Jones.

Investigation: Andrés Doblado-Maldonado, Adrian Yit Reen Ooi.

Methodology: Andrés Doblado-Maldonado, Adrian Yit Reen Ooi.

Writing – review & editing: Andrés Doblado-Maldonado, Adrian Yit Reen Ooi, Chien-Yu Cheng, Wei Sun, Emilio Letang, Michelle Moorhouse, Bryn Jones.