Lactic acidosis and hyperlactatemia associated with lamivudine accumulation and sepsis in a kidney transplant recipient—a case report and review of the literature

Background We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation. Case presentation The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine. Conclusions NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

1005. Comparison of Weight Changes in Treatment-Naïve, HIV-Infected Patients Receiving Integrase Inhibitor-Based Therapy Versus Protease Inhibitor-Based Therapy

Background Recent data regarding integrase inhibitor (INSTI) therapy indicate possible association with weight gain. The incidence and degree of weight gain seems to vary by both patient-specific and regimen-related factors, such as nucleoside reverse transcriptase (NRTI) backbone. Methods This was a retrospective chart review of previously ART-naïve Indiana University Health LifeCare Clinic patients who started an INSTI- or PI-based regimens from 1/1/13 to 7/31/19. Adult patients without prior ART exposure receiving an INSTI- or PI-based regimen for at least 10 months were included. The primary objective was weight gain at 12 months after starting ART. Subgroup analyses were conducted by INSTI, PI, or NRTI backbone utilized. Statistical testing included Wilcoxon Rank-Sum Test and Chi Square analyses. Results The patient population (N=162) was predominately male and African American with relative immunocompetence, generally achieving viral suppression after 12 months of ART. Patients receiving PI-based therapy were more likely to be Asian American or Hispanic (p=0.04), and to receive a tenofovir disoproxil fumarate (TDF)-based regimen (p=0.0034). No statistically significant difference in weight change was observed between INSTI- and PI-based regimens (median weight gain 5.1 kg vs 3.9 kg, p=0.52). The proportion of obese or overweight patients in the INSTI arm increased significantly as compared to baseline (p=0.00001). Subgroup analyses demonstrated significant increases in weight gain and clinically significant weight gain with tenofovir-based (tenofovir alafenamide and TDF) regimens compared to those with abacavir/lamivudine (p< 0.05). Primary Objective BMI Category Changes by INSTI or PI Agent NRTI Subgroup Analyses Conclusion Lack of power makes meaningful interpretation of the results for the primary objective difficult. However, several of the prespecified secondary objectives and subgroup analyses demonstrated clinically significant results related to increased weight gain or BMI category changes with INSTI-, PI-, and tenofovir-based regimens. Checking the patient’s weight at every appointment is considered standard practice at IU Health clinics, but missing values despite qualifying encounters were observed. Further commitment to standardized weighing practices should be a priority at clinics caring for patients living with HIV. Disclosures All Authors: No reported disclosures

Efficacy and Safety of Switching to Dolutegravir With Boosted Darunavir in Virologically Suppressed Adults With HIV-1: A Randomized, Open-Label, Multicenter, Phase 3, Noninferiority Trial: The DUALIS Study

Background Dolutegravir (DTG) and boosted darunavir (bDRV) are potent antiretrovirals with a high resistance barrier and might be valuable switch options for people with HIV (PWH). Methods DUALIS, a randomized, open-label, phase 3b, noninferiority clinical trial, compared the switch to DTG + bDRV (2DR) with continuation of 2 nucleoside reverse transcriptase inhibitors (2NRTI) + bDRV (3DR). PWH with HIV RNA <50 copies/mL taking 2NRTI + bDRV (3DR) for ≥24 weeks (1 accepted blip <200 copies/mL) were randomized to either switch to DTG 50 mg + DRV 800 mg (boosted with 100 mg of ritonavir) or continue taking 3DR. The primary end point (PE) was the proportion of HIV RNA <50 copies/mL at week (W) 48. Change in NRTI backbone was not classified as failure. The estimated sample size for PE analysis was 292; the noninferiority margin was ≤–10.0%. Results In total, 263 subjects were randomized and treated (2DR n = 131, 3DR n = 132; 90.1% male; 89.7% Caucasian; median age [interquartile range], 48 [39–54] years). At W48, 86.3% (n = 113/131) of the 2DR subject and 87.9% (n = 116/132) of the 3DR subjects had HIV RNA <50 copies/mL; the difference between arms was –1.6% (95.48% CI, based on the adjusted alpha level accounting for the interim analysis at W24, –9.9% to +6.7%; discontinuations due to adverse events: 2DR, 4.6% [n = 6]; 3DR, 0.8% [n = 1]). Kaplan-Meier estimates of confirmed HIV RNA ≥50 copies/mL at W48 were 1.6% (n = 2) in the 2DR and 3.1% (n = 4) in the 3DR group. Development of treatment-emergent resistance was not observed. Conclusions Switching to DTG + bDRV was noninferior to continuing 3DR in subjects already treated with bDRV.