Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS

Figures & data

Table 1 Key drug interactions of dolutegravir

Interacting drug class	Interacting drug	Effect on dolutegravir or interacting drug concentration	Dose recommendation
Antiretrovirals
NRTIs	TDF	No significant effect was observed	No change in dose
NNRTIs	EFV	Significant reduction in DTG plasma concentration	Increase dose of DTG to 50 mg twice daily
	ETR	Significant reduction in DTG plasma concentration	Do not administer DTG with ETR alone
	ETR/DRV/RTV	No significant effect was observed	DTG and ETR can be used only if DRV/r is also included in the regimen
PIs	ATV/r	Increase in DTG plasma concentration	No change in dose
Acid-reducing agents
Bivalent cations including calcium, iron, or zinc supplements, or with vitamin-D supplements		Significant reduction in DTG plasma concentration, but no interaction with PPI	Administer antacids or bivalent containing supplements 2 h after or 6 h before DTG dosing
Antituberculous agents
	RIF	Significant reduction in DTG plasma concentration	Increase the DTG dosing frequency to 50 mg twice daily
	RBT	No significant effect was observed	No change in dose
Oral contraceptives
Ortho-cyclen		No significant effect was observed	No change in dose
Antihepatitis C virus agents
PIs	BCV	No significant effect was observed	No change in dose
	TRV	No significant effect was observed	No change in dose
Opioid agonist
	Methadone	No significant effect was observed	No change in dose

Note: Data from the following studies.^{11,16,18,21,22,25,39,40}

Abbreviations: ATV/r, atazanvir/ritonavir; BCV, boceprevir; DTG, dolutegravir; DRV/RTV, darunavir/ritonavir; EFV, efavirenz; ETR, etravirine; h, hour; NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; RBT, rifabutin; RIF, rifampin; TDF, tenofovir disoproxil fumarate; TRV, telaprevir.

Table 2 Key efficacy studies of dolutegravir

Naïve studies	Participants (N)	Design	Duration	Comparing arm	VL <50 (%)	Conclusion
SINGLE^Citation42	844	Randomized 1:1	144 wk	DTG 50 mg + ABC/3TC EFV/FTC/TDF	80% 72%	DTG superior to EFV No treatment-emergent resistance in DTG arm
SPRING-2^Citation43	822	Randomized 1:1	96 wk	DTG 50 mg + two NRTIs RAL 400 mg BD + two NRTIs	81% 76%	DTG was noninferior to RAL No additional resistance to INSTIs or NRTIs since week 48 in DTG arm
FLAMINGO^Citation45	484	Randomized 1:1	96 wk	DTG 50 mg + two NRTIs DRV/RTV + two NRTIs	82% 52%	DTG superior to DRV/RTV at 96 wk. Difference most pronounced at baseline VL >100,000 copies/mL
Experienced studies
SAILING^Citation46	715	Randomized 1:1	48 wk	DTG 50 mg + two NRTIs RAL 400 mg BD + NRTIs	71% 64%	Treatment-emergent INSTIs resistance (four in DTG arm) vs (17 in RAL arm). DTG superior to RAL (P=0.03).
VIKING-3^Citation48	183	Single-arm study	24 wk	DTG 50 mg BD + (continuing a failing regimen [without RAL or EVG] 7 days) optimized ≥1 fully active drug and DTG continued	69%	Reduced response with Q148 + ≥2 resistance mutations DTG 50 mg BD-based therapy was effective in highly treatment experience with INSTI-resistance
VIKING-4^Citation49	30	Randomized 1:1	24 wk	DTG 50 mg BD, 7 days on failing regimen without RAL or EVG vs placebo DTG	40% no drop	DTG 50 mg BD-based therapy was effective in INSTI failing regimen

Abbreviations: ABC/3TC, abacavir/lamivudine; DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTIs, integrase strand transfer inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; RAL, raltegravir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; wk, weeks; VL, viral load; BD, twice a day.

Table 3 Dolutegravir adverse effects grades 2–4 in treatment-naïve trials

Side effects	Range (%)	Comments
Gastrointestinal	2–17	Diarrhea and nausea were the most common GI side effects, mainly mild-to-moderate in severity
Headache	1–15	Mainly mild in nature
Insomnia	1–4	Were typically mild in intensity
Rash	1	Were significantly low in most of the studies (generalized macular rash, maculopapular rash, pruritic rash)
Liver abnormality	2–3	Alternative causes for raised ALT identified in few patients. Very few patients had DTG-associated DILI with hypersensitivity reaction
Nasopharyngitis	<1	Mild in nature

Note: Data from the following studies.^41–45

Abbreviations: DTG, dolutegravir; DILI, drug-induced liver injury; GI, gastrointestinal; ALT, alanine transaminase.

Figure 1 Mean TC changes from baseline at 48 weeks.

Abbreviations: DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; TC, total cholesterol.

Figure 2 Mean LDL-C changes from baseline at 48 weeks.

Abbreviations: DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; LDL-C, low-density lipoprotein cholesterol; RAL, raltegravir.

Figure 3 Mean TG changes from baseline at 48 weeks.

Abbreviations: DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; TG, triglyceride.

Figure 4 Mean HDL-C changes from baseline at 48 weeks.

Abbreviations: DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; HDL-C, high-density lipoprotein cholesterol; RAL, raltegravir.

Figure 5 TC:HDL ratio changes from baseline at 48 weeks.

Abbreviations: DRV/RTV, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; TC:HDL, total cholesterol:high-density lipoprotein.

Table 4 Use of dolutegravir in special population

Conditions	Findings	Comment
Pregnancy	Categorized as pregnancy category B. No adequate and well-controlled studies in pregnant women because animal reproduction studies are not always predictive of human response.^Citation8,Citation72	To be used with caution.
Nursing mother	In animal studies DTG was present in rat milk, human data are not available.^Citation72	No clear evidence.
Pediatric	Safety and efficacy of use of DTG has not been established in pediatric patients younger than 12 years and weighing <40 kg.	No clear evidence.
Elderly	The data of safety in patients aged over 65 years is very limited.	To be used with caution.
Renal	The plasma concentration of DTG was found to be decreased in subjects with severe renal impairment compared to those in the healthy controls; however, no dose adjustment was necessary where renal impairment was mild-to-moderate.^Citation73,Citation74 No data on renal dialysis patients.	Caution in severe renal impairment.
Hepatic	There have not been any differences between subjects with moderate hepatic impairment and hepatic subjects.^Citation63,Citation75,Citation76	No dose adjustment in mild or moderate hepatic impairment.
Hepatitis B and C coinfection	DTG can be safely used with boceprevir and telaprevir.^Citation30,Citation63	No dose adjustment.

Abbreviation: DTG, dolutegravir.

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