Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? A case report

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization. This followed widespread reports of primary resistance to non-nucleoside reverse transcriptase inhibitors. Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, dolutegravir as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes. Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated. We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on dolutegravir. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.


Background
Integrase strand transfer inhibitors (INSTIs) have been demonstrated to have reduced risk of incident type 2 diabetes mellitus (T2DM) compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in different sub-populations in two meta-analyses [1], [2].The risk was heightened in African populations which were generally under-represented [2] and multiple case reports of patients presenting with accelerated hyperglycemia within weeks to a few months of starting INSTIs have been published [3]- [7].Following these case reports, the Uganda Ministry of Health guidelines recommended dolutegravir substitution in all patients with incident diabetes mellitus (T2DM) [8].In this case report, we describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG in a patient who was diagnosed with T2DM at 36 weeks on DTG.
At 36 weeks, on routine evaluation (no symptoms of hyperglycemia) he was diagnosed with T2DM basing on a 2hBG of 259 mg/dl.His BMI had increased to 20.9.Other tests included: HBA1C-4.2%,HOMA IR-2, HOMA% β-101.4%.DTG was substituted with efavirenz according to the Uganda HIV treatment guidelines [8].He was managed on diet adjustment without T2DM pharmacologic intervention.
Not mentioned.

Discussion and conclusions
Review of current suggests that at population level, integrase inhibitors are associated with a reduced risk of incident diabetes mellitus compared to NNRTIs and PIs [1], [2].There is also evidence to demonstrate insigni cant differences in effects on insulin resistance compared to other HIV drug classes [2].Additionally, there are published case reports documenting that a certain section of heavily ART experienced PWH, probably with a currently unclear predisposition develop accelerated hyperglycemia when exposed to integrase inhibitors[3]- [7].These patients typically present with diabetic ketoacidosis preceded by weight loss, a phenotype typical of insulin de ciency states, but with normal Cpeptide levels as summarized in Table 1.In these patients, the temporality between introduction of INSTIs and development of hyperglycemia is easily demonstrable.Similarly, withholding INSTIs has been demonstrated to lead to markedly reduced T2DM pharmacological treatment requirements and complete resolution of hyperglycemia in some cases (Table 1).
The patient we present had an asymptomatic onset of glucose intolerance over 36 weeks (diagnosed on routine screening) and gained weight before diabetes diagnosis in contrast to the above group of patients.Various factors such as immune reconstitution, improved appetite as well as dolutegravir itself could have contributed to the weight gain [12], [13].Over the same period, he experienced worsening insulin resistance and concurrent increase in pancreatic beta cell function which could have been compensatory.Much as the worsening insulin resistance could be attributed to the weight gain, on evaluation of glucose changes in the whole study cohort, there was signi cant improvement in blood glucose despite a signi cant increase in BMI over the 48 weeks of follow up [9].This may suggest that this patient had an inherent risk of developing T2DM, independent of weight gain and exposure to DTG.Blood glucose after T2DM diagnosis may have improved because of the dietary modi cation as well as compensatory hyperinsulinemia.It can as well be argued that blood glucose may have improved because DTG was discontinued but this may be unlikely because of the continued worsening insulin resistance and probable compensatory hyperinsulinemia.
In conclusion, this case report suggests that dolutegravir should not be universally withheld in ART naïve PWH who develop diabetes mellitus but the decision made on a case-by-case basis.More research is however needed to ascertain these ndings.This is programmatically pertinent in sub-Saharan Africa given dolutegravir is rst line treatment in majority HIV programs with millions of PWH on DTG due to wide spread primary resistance to NNRTIs [14].

Table 1
Summary of published case reports of accelerated severe hyperglycemia in people with HIV on integrase inhibitors