Dolutegravir impairs stem cell-based 3D morphogenesis models in a manner dependent on dose and timing of exposure: an implication for its developmental toxicity

Dolutegravir is an anti-retroviral drug of the integrase strand transfer inhibitor class used to treat HIV infection. It is the recommended first-line regimen for most people, including women of childbearing age. However, some human and animal studies have suggested that dolutegravir causes birth defects, although its developmental toxicity remains controversial. Here, we investigated the adverse effects of dolutegravir using pluripotent stem cell-based in vitro morphogenesis models that have previously been validated as effective tools to assess the developmental toxicity of various chemicals. Dolutegravir diminished the growth and axial elongation of the morphogenesis model of mouse pluripotent stem cells at exposures of 2 μM and above in a concentration-dependent manner. Concomitantly, dolutegravir altered the expression profiles of developmental regulator genes involved in embryonic patterning. The adverse effects were observed when the morphogenesis model was exposed to dolutegravir at early stages of development, but not at later stages. The potency and molecular impact of dolutegravir on the morphogenesis model were distinct from other integrase strand transfer inhibitors. Lastly, dolutegravir altered the growth and gene expression profiles of the morphogenesis model of human embryonic stem cells at 1 μM and above. These studies demonstrate that dolutegravir impairs morphological and molecular aspects of the in vitro morphogenesis models in a manner dependent on dose and timing of exposure through mechanisms that are unrelated to its action as an integrase strand transfer inhibitor. This finding will be useful for interpreting the conflicting outcomes regarding the developmental toxicity of dolutegravir in human and animal studies.

National Landscape of HIV+ Deceased Organ Donors in the United States

Background Organ transplantation from donors with HIV to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV+ donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) testing within the HOPE in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262; NCT03500315; NCT03734393). We compared clinical characteristics in HIV+ versus FP donors. We measured CD4+ T cells, HIV viral load (VL), drug resistance mutations (DRMs), co-receptor tropism, and serum antiretroviral therapy (ART) detection using mass spectrometry in HIV+ donors. Results Between 03/2016-03/2020, 92 donors (58 HIV+, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidney, 46 liver). Each year the number of donors increased. Prevalence of hepatitis B (16% vs. 0%), syphilis (16% vs. 0%), and cytomegalovirus (91% vs. 58%) was higher in HIV+ versus FP donors; hepatitis C viremia was similar (2% vs. 6%). Most HIV+ donors (71%) had known HIV diagnosis, of whom 90% were prescribed ART and 68% had VL<400 copies/mL. Median CD4 count was 194 cells/uL (IQR=77-331); median CD4% was 27.0 (IQR=16.8-36.1). Major HIV DRMs were detected in 42%, including non-nucleoside reverse transcriptase inhibitors (33%), integrase strand transfer inhibitor (INSTI, 4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. Conclusion Utilization of HIV+ donor organs is increasing. HIV DRMs are common, yet resistance that would compromise INSTI-based regimens is rare, which is reassuring regarding safety.

Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.

Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25–200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis. Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25–200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

Cost-Efficacy of Antiretroviral Regimens Recommended in Treatment-Naive HIV-Infected Adults. A Single Center Experience

We aimed to assess the prescription trends of combined antiretroviral therapy (cART) in one infectious diseases department and the cost-efficacy (C/E) of different regimens used in treatment-naïve patients. The C/E was assessed with a software application developed by a group of researchers in Spain. The efficacy was already calculated in the application. The costs included the local cost of antiretrovirals and other direct costs specific to our institution. In the software application, the C/E reference regimen was ABC/3TC/DTG. In total, 181 HIV-infected patients were diagnosed and initiated cART during 2015–2019. The proportion of patients treated with integrase-strand transfer inhibitor (INSTI)-based regimens increased from 2015–2018 (54%) to the end of 2019 (81%). The relative C/E ranged from 0.90 to 1.28 for the evaluated INSTI-based regimens. Among INSTI-based regimens, ABC/3TC/DTG and TAF/FTC/EVG/c are the regimens with similar efficacy and relative C/E.

RETRACTED: A low-cost in-house HIV integrase strand transfer inhibitor drug resistance test for resource-limited settings [version 1; peer review: awaiting peer review]

At the request of the authors, the article titled 'A low-cost in-house HIV integrase strand transfer inhibitor drug resistance test for resource-limited settings' ([version 1; peer review: awaiting peer review]. F1000Research 2021, 10:260, https://doi.org/10.12688/f1000research.28404.1) has been retracted from F1000Research. Since publication, it has come to the attention of the authors that the primers described in Table 1 were incorrect. As this article contains information which should not be publicly available the content of the article has been removed. The authors apologise for this honest error, and intend to republish the article with the correct primer information. Unfortunately, Dr Graeme B. Jacobs has passed away since publication of version 1 of this article.

Bictegravir-based antiretroviral therapy associated accelerated hyperglycemia and diabetes mellitus

Integrase strand transfer inhibitor (INSTI) based antiretroviral therapy (ART) is first line for treatment of people with HIV (PWH). Emerging data suggests the possibility of adverse metabolic effects of these medications. We describe three cases in which PWH developed hyperglycemia and ketoacidosis within months of being switched to bictegravir-based ART.