Letter to the Editor: Dolutegravir Monotherapy and Body Weight Gain in Antiretroviral Naïve Patients

Dear Editor,

In the past months many scientific studies have been published about excess weight gain with integrase inhibitors. ¹ They reported what is known about potential mechanisms of antiretroviral therapy-associated weight gain, using data from highly active antiretroviral therapy (HAART) initiation trials, switch studies, pre-exposure prophylaxis trials, case report, and case series. Many questions are still open from mechanisms responsible for dolutegravir (DGT)-associated weight gain to an increased risk of cardiometabolic complications related to this excessive weight gain.

We would like add our clinical experience, to these data, about a small group of naive HIV-infected patients treated with DGT monotherapy.

We, previously, reported our experience in 20 HIV-infected patients, naive to HAART and with a zenith HIV RNA <100,000 copies/mL, followed at the infectious diseases outpatient department of G.B. Rossi Hospital in Verona, Italy, who started DGT monotherapy after refusing nucleoside reverse transcriptase inhibitors. ² We now report the results of an extended follow-up looking at virological outcome and body weight changes.

Baseline characteristics of the patients were reported previously. ³ In 2019, we published the results about body weight gain in this little cohort of antiretroviral naive patients on DGT monotherapy. ⁴

In that article we reported after 12 months of DGT monotherapy in a cohort of 23 naive patients a mean increase of body mass index (BMI) of 1.28 kg/m² with a mean rise of body weight of 3.82 kg. In that period of observation, no patients developed hypertension or diabetes and nobody started lipid-lowering therapy. Total cholesterol and high-density lipoprotein cholesterol increased significantly after 12 months of DGT monotherapy, whereas low-density lipoprotein (LDL) cholesterol and triglycerides did not. ⁴

After a mean duration of follow-up of 66.6 months (range 56–74), 13 patients (4 women and 9 men) are still on DGT monotherapy. Their mean CD4 cell count was, when last determined, 735/mm³ (range 262–1281), with an undetectable HIV RNA (10 with undetectable HIV RNA and 3 with <20 copies/mL). As previously reported, ² one patient developed an enanthema that led to DGT discontinuation after few days. Six patients developed virological failure after a mean time of 32.5 months (range 7–47); HIV RNA levels were, at virological failure, >1000 copies/mL.

Of them, nobody developed integrase resistance mutations and, after intensification with nucleoside/nucleotide reverse transcriptase inhibitor backbone (three patients with abacavir/lamivudine and four patients with tenofovir alafenamide), all patients were virologically suppressed again. We also compared body weight and BMI at baseline, at 12 months, and after >55 months using a paired sample t test (p value of <.005 was considered statistically significant) in these 13 patients still on DGT monotherapy.

The mean body weight at baseline was 71.9 kg (range 57.5–96.5) with a mean BMI of 23.78 kg/m² (22.39–26.38). After 1 year of treatment, the mean body weight was 76.06 kg (62–99) and the mean BMI was 25.16 kg/m² (22.39–28.34), with a mean weight gain of 4.077 kg (p < .005) and a rise in BMI of 1.37 kg/m² (p < .005). After >55 months, the mean body weight rose to 79.030 kg (60–91) with a mean BMI of 26.21 kg/m² (22.53–32.27). The mean increase in body weight was 7.03 kg in respect of baseline (p < .005) and the mean rise of BMI was 2.49 kg/m² (p < .005).

The median body weight at baseline was 71.4 kg (range 57.5–96.5) with a median BMI of 23.32 kg/m² (22.39–26.38). After 1 year of treatment, the mean body weight was 75 kg (62–99) and the median BMI was 25.46 kg/m² (22.39–28.34), with a median weight gain of 3.6 kg and a rise in BMI of 1.24 kg/m². After >55 months, the median body weight rose to 76 kg (60–91) with a median BMI of 25.69 kg/m² (22.53–32.27). The median increase in body weight was 6.3 kg in respect of baseline and the median rise of BMI was 2.03 kg/m². At baseline, four patients were overweight; after 12 months, seven were overweight, and after >55 months, five patients were still overweight and two had become obese.

Lipids and glucose values showed the development of LDL-hypercholesterolemia (>130 mg/dL) in three patients (no patients are on statins because they refused the treatment) and of hyperglycemia (blood glucose values between 100 and 125 mg/dL) in two patients (Table 1).

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Table 1.

Serum Levels of Total Cholesterol, Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol, Triglycerides and Glucose Before Starting Dolutegravir and at Last Control, and Months on Dolutegravir

Patient no.	Total cholesterol pretreatment level (n.v.: <200 mg/dL)	Total cholesterol level at last visit	LDL/HDL pretreatment level (n.v.: LDL <130 mg/dL, HDL >40 mg/dL)	LDL/HDL levels at last visit	Triglycerides pretreatment level (n.v.: <150 mg/dL)	Triglycerides level at last visit	Hyperglycemia/diabetes (hyperglycemia 100–125 mg/dL; diabetes >125 mg/dL) (n.v.: 63–99 mg/dL)	Months on dolutegravir
1	194	238	111/52	136/78	153	112	no	74
2	107	131	72/42	61/57	43	67	no	74
3	173	210	107/51	106/61	75	213	Hyperglycemia 113 mg/dL	69
4	160	191	104/42	118/44	68	141	no	72
5	221	206	144/59	119/55	152	152	no	73
6	160	149	99/48	95/46	59	55	no	70
7	225	188	129/76	91/84	92	62	no	67
8	123	121	Not tested/40	Not tested/54	59	50	no	64
9	150	170	81/43	97/61	126	58	no	62
10	187	192	107/64	116/56	73	95	Hyperglycemia (106 mg/dL)	62
11	180	234	122/35	167/50	108	86	no	58
12	145	214	Not tested/44	132/64	68	107	no	56
13	137	226	Not tested/50	123/68	87	172	no	65

LDL, low-density lipoprotein; HDL, high-density lipoprotein; n.v., normal values.

Hyperglycemia developed in the two patients became obese. Of them, nobody developed or was hospitalized for cardiometabolic events in this period of follow-up.

Our extended follow-up confirms the association between integrase inhibitors and body weight gain in antiretroviral naïve patients. ⁵ As other studies, weight gain related to DGT use in naive HIV-infected patients is significant and lasted for 5 years after treatment initiation ⁶ as showed in our little cohort. However, in our small patient cohort after >55 months of follow-up, this weight gain is linked to an apparent small increased risk of metabolic complications. These data would confirm the minor impact on lipids and glycemia of DGT ^7,8 after a long follow-up.