Short Communication: Efficacy and Safety of Dolutegravir Plus Lamivudine as a First-Line Regimen in Clinical Practice

Abstract

The GEMINI trials have showed that the two drugs regimen of dolutegravir+lamivudine (DTG +3TC) was noninferior to a three-drug regimen as a first line regimen for treatment-naive people living with HIV. The aim of our study was to confirm, in a real-life setting, the efficacy of this regimen. We conducted a retrospective, observational study enrolling treatment-naive patients starting a first-line regimen with lamivudine plus dolutegravir. We evaluated the virological efficacy and the immunological and metabolic profiles. Changes from baseline were evaluated through linear-mixed models for repeated measures. Linear regression analyses were performed to explore variables associated to significant changes in laboratory parameters. We analyzed a total of 20 patients: 15 (75%) were men with a median age of 34.5 years. During a cumulative time of 15.4 patients years of follow up (PYFU), we did not observe any adverse event or treatment discontinuation and all patients achieved virological suppression in the first 6 months from treatment initiation. Increase in CD4⁺ cells was significant at both week 24 (p = .003) and week 48 (p = .007) of follow-up. Moreover, CD4/CD8 ratio also significantly improved [median increase of +0.22 (p = .028) after 48 weeks of follow-up]. As to metabolic parameters, we observed no significant changes in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. In a subgroup of 11 patients, we further investigate HIV-1 DNA variations. Our results are in line with the findings of the GEMINI trials, confirming the efficacy and safety of DTG +3TC in treatment-naive patients.

Introduction

For years, three-drug regimens (3DR) have represented the foundation for the treatment of people living with HIV (PLWHIV), leading to significant improvements in morbidity and mortality.¹ However, several antiretroviral drugs have been associated with long-term effects, such as, among others, cardiovascular events, renal toxicity, and osteopenia/osteoporosis.²

Although the most recently introduced molecules present fewer toxicities compared with older ones, long-term effects still represent a concern for clinicians and patients worldwide. For treatment-experienced, virologically suppressed PLWHIV, guidelines have begun to recommend the switch to so-called “less-drug regimens.” This simplified regimen, while removing a molecule, has shown the capability of maintaining virological suppression and reducing the toxicity.³ Meanwhile, the majority of two-drug regimens (2DR) based on protease inhibitors studied as first-line regimens have shown mixed results and have been not suggested by guidelines as credible alternatives to 3DR.

Recently, the GEMINI trials have shown evidence that the 2DR of dolutegravir+lamivudine (DTG +3TC) was noninferior to a 3DR as a first-line regimen for treatment-naive PLWHIV.⁴ We previously reported preliminary results from our cohort, to provide the first real-life experience with DTG +3TC as initial treatment of HIV infection.⁵ Goal of this study was to confirm our preliminary findings in a multicenter cohort of adult HIV-1-infected, treatment-naive patients.

Materials and Methods

We conducted a retrospective, observational study in which we enrolled HIV-1-infected, treatment-naive patients from two Italian clinical centers. All patients started a first-line regimen with lamivudine plus dolutegravir. We evaluated the proportion of patients reaching virological suppression (defined as HIV-RNA <50 copies/mL) during follow-up time. Changes from baseline in immunological parameters (absolute and percentage CD4⁺ T cell counts), HIV-DNA, estimated glomerular filtration rate (eGFR) (by the modification diet renal disease study equation), and blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides] were evaluated using linear-mixed models for repeated measures. Linear regression analyses were performed to explore variables associated with significant changes in laboratory parameters.

The study received the approval by each independent local Ethics Committee (study coordination site protocol number 5284/15), with all patients signing informed consent for data collection.

Results

We analyzed a total of 20 patients: 15 (75%) were men with a median age of 34.5 years [interquartile range (IQR) = 25.2–53.5]. None of the patients had HCV coinfection and the main risk factor for HIV infection was men who have sex with men (MSM) intercourse (55%). At baseline, median HIV-RNA was 4.78 log10 copies/mL (IQR = 4.01–5.00), whereas median CD4⁺ cell count was 342 cell/mm³ (IQR = 239–472). All patients' characteristics at baseline are given in Table 1.

Table 1.

Patients' Characteristics at Baseline (n = 20)

Variables
Age (years), median (IQR)	34.5 (25.2–53.5)
Female, n (%)	5 (25.0)
Risk factor for HIV infection, n (%)
Heterosexual	6 (30.0)
MSM	11 (55.0)
IDU	2 (10.0)
Others	1 (5.0)
Anti-HCV antibodies positive, n (%)	0
Time from HIV diagnosis (days), median (IQR)	23.5 (7.0–29.5)
CDC stage C, n (%)	0
CD4⁺ count (cell/μL), median (IQR)	342 (239–472)
CD4⁺ %, median (IQR)	21.5 (18.5–25.7)
HIV-RNA (log10 copies/mL), median (IQR)	4.78 (4.01–5.00)
Patients with a HIV-RNA >100,000 copies/mL, n (%)	5 (25.0)
HIV-DNA (log/10⁶ CD4), median (IQR), n = 11	3.85 (3.50–4.04)

CDC, Centers for Disease Control and Prevention; IDU, intravenous drug users; IQR, interquartile range; MSM, men who have sex with men.

During a cumulative time of 15.4 patient-years of follow-up, we did not observe any adverse event or treatment discontinuation in our cohort. All patients achieved virological suppression in the first 6 months from treatment initiation and maintained viral suppression during follow-up time with no viral blips registered.

Increase in CD4⁺ cells was significant at both week 24 (p = .003) and week 48 (p = .007) of follow-up. In particular, we observed a median increase of +96.5 cell/mm³ (IQR = 59.5–183.5) after 24 weeks and a median increase of +125.5 cell/mm³ (IQR = 87.7–230.2) after 48 weeks. Although we failed to identify any predictive factor for CD4⁺ changes at 24 weeks, we observed that, at a multivariate analysis, a lower age was associated with a greater increase in CD4⁺ cells after 48 weeks (per 10 years younger, B = −63.8, 95% confidence interval = −122.7 to −4.9, p = .039). Moreover, CD4/CD8 ratio also significantly improved during follow-up: we registered a median increase of +0.12 (p = .005) after 24 weeks and +0.22 (p = .028) after 48 weeks of follow-up.

As to metabolic parameters, we observed no significant changes in total cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol during follow-up. Of interest, we also did not observe significant changes in eGFR in our cohort.

We further investigated patients' virological status by evaluating total HIV-1 DNA levels at baseline and at virological suppression in 11 patients (55% of our population). In this subgroup, viral suppression was achieved after a median time of 68.2 days with a median HIV-1 DNA at baseline of 3.85 log/10⁶ CD4 and a median HIV-1 DNA decrease of 0.47 log/10⁶ CD4 between baseline and viral suppression.

Discussion

Our results show high efficacy in reducing HIV-RNA and reaching virological suppression in treatment-naive PLWHIV starting DTG +3TC. In our cohort, no patient experienced virological failure after starting the study regimen; moreover, no patients reported adverse events and no treatment discontinuation was registered.

As previously described,⁶ our cohort includes one patient with transmitted Y188C and D232N resistance mutations who reached virological suppression, with undetectable HIV-RNA, after eight from treatment initiation, in line with what we observed in individuals without resistance mutations. Having followed the patient for a longer period of time, we observed that his HIV-RNA remained undetectable at week 48, confirming the efficacy of the regimen even in the presence of resistance mutations to first-generation INI.

Regarding immunological parameters, we observed a significant improvement in absolute CD4⁺ cell count and CD4/CD8 ratio. The increase in CD4⁺ cells was more marked in younger patients, a finding in line with other works from the literature.⁷ Of interest, three of the analyzed patients had a baseline CD4⁺ cell count <200 cell/mm³ and all of them were able to reach a count >300/mm³ in the first 6 months of treatment. As to metabolic parameters, we observed a neutral effect of DTG +3TC on lipid profile; interestingly, we did not observe any significant change in eGFR after 48 weeks of treatment. Dolutegravir, given its effect on inhibiting the organic cation transporter 2 (OCT2), thus reducing the excretion at the tubular level of creatinine, has been associated with an apparent worsening of renal function. The fact that we were unable to observe significant changes in eGFR is likely to be related to the limited sample size.

We conducted a subanalysis on HIV-1-DNA levels; HIV-DNA is a known biomarker of inflammation and previous studies on virologically suppressed PLWHIV have shown no differences in HIV-1-DNA levels between a 3DR and a 2DR.^8,9 In our subanalysis, we registered a median decrease of 0.47 log/10⁶ CD4 after a median time of 68 days; the observed decline rate was similar to the ones observed in PLWHIV starting a three-drug-based first-line regimen,¹⁰ suggesting that DTG +3TC may be equally effective in reducing proviral HIV-DNA and, thus, inflammation levels.

Main limitations of our study are represented by its retrospective nature and the limited sample size; however, the study represents one of the first reports of the real-life experience of a first-line strategy with DTG +3TC.

Conclusions

Our results are in line with the findings of the GEMINI trials, confirming the efficacy and safety of DTG +3TC in treatment-naive patients.

Footnotes

Authors' Contributions

A.Ci., G.B., A.B., and S.D.G. contributed to the conception and design of the study. A.Ci. and G.B. contributed to the draft of the article. G.B., A.D., M.V.C., and A.Ca. contributed to the acquisition of the data. A.Ci., G.B., and A.B. contributed to the analysis and interpretation of data. A.Ci., G.B., A.D., M.V.C., A.B., and A.Ca. contributed to the critical revision of the article for important intellectual content. All authors approved the final version of the article.

Author Disclosure Statement

A.Ca. has received a personal grant from A.B., Gilead and ViiV. A.B. has received nonfinancial support from Bristol-Myers Squibb and ViiV Healthcare, and personal fees from Gilead Sciences. S.D.G. was a paid consultant or member of advisory boards for Gilead, ViiV Healthcare, Janssen-Cilag, Merck Sharp & Dohme and Bristol-Myers Squibb. All other authors: none to declare.

Funding Information

This study was supported by a grant (ID616) from ViiV Healthcare.

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