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OBJECTIVES To assess the risk of adverse diagnoses and laboratory abnormalities associated with a 300 or 150 mg daily dose of lamivudine (3TC) initiated by people with HIV (PWH) with an estimated glomerular filtration rate (eGFR) between at least 30 and 49 ml/min per 1.73 m2 or less. DESIGN Longitudinal study based on electronic health records of 539 PWH with eGFR between at least 30 and 49 ml/min per 1.73 m2 or less from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. METHODS Common unintended effects of 3TC were evaluated as composite outcomes. We estimated the incidence (univariate Poisson regression) and association between dose and incident composite outcomes (multivariate Poisson regression) among PWH without the relevant diagnoses or laboratory abnormalities at 3TC initiation. RESULTS PWH initiating 150 mg 3TC had higher HIV RNA, lower eGFR, and more comorbidities than those initiating 300 mg 3TC. The prevalence of relevant diagnoses and laboratory abnormalities was similar in both groups. The most common lab abnormality was low hemoglobin. There was no statistically significant difference in incident adverse diagnoses/severe lab abnormalities with 300 mg versus 150 mg [incidence rate ratio (IRR): 1.51; 95% confidence interval (CI) 0.59--3.92). However, a statistically significant association was observed when gastrointestinal symptoms/moderate lab abnormalities were included in the outcome (IRR: 3.07, 95% CI 1.12--8.40). CONCLUSION As 3TC is a well tolerated drug with a wide therapeutic window, dose adjustment may be unnecessary among PWH with eGFR between at least 30 and 49 ml/min per 1.73 m2 or less. Clinical judgement is key when weighing the risks and benefits of 3TC dose adjustment for PWH experiencing gastrointestinal symptoms or moderate lab abnormalities.

Objectives To describe the prevalence and incidence of prediabetes and type 2 diabetes mellitus (T2DM) among people living with HIV (PLHIV) and evaluate the association between antiretroviral therapy (ART) initiation with dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), or boosted darunavir (bDRV) and incident T2DM. Design Longitudinal study based on electronic health records of 29,674 PLHIV from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort. Methods Calculate prevalence of prediabetes and T2DM at regimen initiation. Among PLHIV without prevalent disease, estimate prediabetes and T2DM incidence (Poisson regression) and association between regimen and incident T2DM (multivariate Cox proportional hazards regression). Analyses stratified by ART-experience. Results Among ART-naive and ART-experienced/suppressed PLHIV, the estimated prevalence of prediabetes was 8% and 11%; that of T2DM was 4% and 10%, respectively. The T2DM incidence rate was 9 per 1,000 person-years (95% confidence interval [CI]: 8, 11) among ART-naive and 13 per 1,000 person-years (95% CI: 12, 15) among ART-experienced/suppressed PLHIV, with no statistically significant differences between regimens. Compared to DTG, no statistically significant association between T2DM risk and regimen was observed among ART-naive on EVG/c (adjusted hazard ratios: 0.70 [95% CI: 0.47, 1.05]) or bDRV (0.53 [0.26, 1.04]) and ART-experienced/suppressed on EVG/c (0.96 [0.70, 1.33]), RAL (1.17 [0.70, 1.96]) or bDRV (0.90 [0.57, 1.42]). Conclusions No increased risk of T2DM was observed with EVG/c, RAL or bDRV compared to DTG in ART-naive and experienced PLHIV. However, despite a large cohort, there was a small number of events and differential risk cannot be excluded.

Introduction Although weight gain has been reported with the use of integrase strand transfer inhibitors (InSTI), concurrent use of tenofovir alafenamide (TAF) has been implicated in recent studies. This study examined weight changes in people living with HIV (PLWH) who switched from tenofovir disoproxil fumarate (TDF) to TAF, to clarify the relative contribution to weight gain of core agents versus TDF to TAF switch. Methods Antiretroviral‐experienced, virologically suppressed PLWH in the U.S. OPERA cohort were included if they switched from TDF to TAF (5NOV2015‐28FEB2019) and either maintained all other antiretrovirals or switched from a non‐InSTI to an InSTI. Linear mixed models were used to assess weight changes before/after the switch to TAF (restricted cubic splines on time) and rates of change over time (linear splines on time, based on the shape of the weight change curves). Changes in weight on TDF or TAF were assessed among those who maintained other antiretrovirals (overall, by core class), and those who maintained an InSTI or switched to an InSTI (by core agent). All models were adjusted for age, sex, race, (age‐sex, race‐sex interactions), BMI, CD4 cell count, endocrine disorders and concurrent medications that could affect weight. Results A total of 6908 PLWH were included, with 5479 maintaining all other antiretrovirals (boosted protease inhibitor: 746, non‐nucleoside reverse transcriptase inhibitor: 1452, InSTI: 3281) and 1429 switching from a non‐InSTI to an InSTI (elvitegravir/cobicistat: 1120, dolutegravir: 174, bictegravir: 129). In adjusted models, modest weight gain was observed over time on TDF for most (0.24 to 0.71 kg/year); raltegravir was the exception with weight loss. Switching to TAF was associated with early, pronounced weight gain for all (1.80 to 4.47 kg/year). This effect with TAF switch was observed both in PLWH maintaining other antiretrovirals and those switching to an InSTI, regardless of which InSTI agent was used. Weight gain tended to slow down or plateau approximately nine months after switch to TAF. Conclusions In this large, diverse U.S. cohort of PLWH, switching from TDF to TAF was associated with pronounced weight gain immediately after switch, regardless of the core class or core agent, suggesting an independent effect of TAF on weight gain.

Introduction Human leukocyte antigen (HLA)‐B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta‐analyses of trials pre–HLA‐B*5701 screening reported HSR rates of 4–8%. We analyzed the effectiveness of HLA‐B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco‐Epidemiology Research & Analysis (OPERA) cohort, and spontaneous reporting data. Methods A meta‐analysis examined 12 trials in 3063 HLA‐B*5701–negative patients receiving an ABC‐containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator‐diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC‐containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest‐following censoring event: ABC discontinuation, loss to follow‐up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre‐ and post‐2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC‐containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. Results Suspected ABC HSR rates were 1.3% or less in the meta‐analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post‐2008 versus 1.3% pre‐2008 (p

Supplemental Digital Content is Available in the Text., Introduction: Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs. Methods: Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed. Results: In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%–8% versus comparator: 3%–7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%–0.6%) and highest for RAL (0%–2.5%). Spontaneously reported events were similar in nature to clinical trial data. Conclusions: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.

Background and Objectives The standard of care for HIV treatment is a three-drug regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor (PI) or an integrase strand transfer inhibitor. Darunavir boosted with ritonavir (DRV/r) is the only preferred PI in the US Department of Health and Human Services (DHHS) HIV treatment guidelines for antiretroviral-naïve patients, recommended in combination with tenofovir/emtricitabine for antiretroviral-naïve patients. For treatment-experienced and certain antiretroviral-naïve patients, abacavir and lamivudine (ABC/3TC) in combination with DRV/r is considered an effective and tolerable alternative, despite limited research on the effectiveness of this particular combination. This study evaluated virologic outcomes in treatment-experienced patients taking ABC/3TC + DRV/r compared to treatment-experienced patients taking ABC/3TC with any other PI. Methods Treatment-experienced HIV-infected patients initiating their first regimen containing ABC/3TC in combination with any PI in the year 2005 or later were selected from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort, a prospective observational cohort reflecting routine medical care. Viral load measurements taken during follow-up were compared between patients taking ABC/3TC + DRV/r and ABC/3TC with a PI other than DRV/r. Logistic regression models were fit to assess the association between regimen exposure and viral load suppression. Results A total of 151 patients initiating ABC/3TC + DRV/r and 525 patients initiating ABC/3TC + a non-darunavir PI were included. Patients in both treatment groups had comparable clinical indicators (viral load, CD4) at baseline. A regimen of ABC/3TC + DRV/r was more likely to be prescribed in the later years of the study period, leading to a shorter median follow-up in the DRV/r treatment group (as-treated analysis: 14 vs. 17 months, p = 0.04; intent-to-treat analysis: 33 vs. 68 months, p

Background Treatment of HIV-infected men during early hepatitis C virus (HCV) infection with interferon results in a higher cure rate with a shorter duration of treatment than during chronic HCV infection. We recently demonstrated that this phenomenon applied to interferon-free treatment as well, curing most participants with short-course sofosbuvir and ribavirin. Due to the significantly higher potency of the ledipasvir/sofosbuvir (LDV/SOF) combination, we hypothesized that we would be more successful in curing early HCV infections using a shorter course of LDV/SOF than that used for treating chronic HCV infections. Methods We performed a prospective, open-label, consecutive case series study of 8 weeks of LDV/SOF in HIV-infected men with early genotype 1 HCV infection. The primary end point was aviremia at least 12 weeks after completion of treatment. Results We treated 25 HIV-infected men with early sexually acquired HCV infection with 8 weeks of LDV/SOF, and all 25 (100%) were cured. Twelve (48%) reported sexualized drug use with methamphetamine. Conclusions Eight weeks of LDV/SOF cured all 25 HIV-infected men with early HCV infection, including those who were actively using drugs. Based on these results, we recommend treatment of newly HCV-infected men during early infection, regardless of drug use, to both take advantage of this 8-week treatment and to decrease further HCV transmission among this group of men.

Background A potential association between integrase inhibitor (INSTI) use and weight gain has been reported in people living with HIV (PLWH). We examined body mass index (BMI) increases after a switch to dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), rilpivirine (RPV), or boosted darunavir (bDRV) among virologically suppressed ART-experienced PLWH. Methods ART-experienced, suppressed (ART-ES; baseline viral load < 200 copies/mL) PLWH ≥ 18 years of age initiating DTG, EVG/c, RAL, RPV, or bDRV for the first time were identified in the OPERA® cohort. The association between core agents and mean increases in BMI at 6, 12, and 24 months was estimated with multivariable linear regression. Inverse probability-of-censoring weights (IPCW) were used to account for censoring (regimen discontinuation, loss to follow-up, death, pregnancy, or no BMI measured). Analyses were stratified by baseline BMI categories (underweight: Results At baseline, endocrine disorders were reported in >40% of PLWH receiving DTG and RAL; >60% were overweight/obese in all groups (Figure 1). Mean BMI (unadjusted) increased for all ARVs over time, with changes at 24 months ranging from 0.30 (DRV) to 0.83 (RPV, Figure 2). At 6 months, the adjusted mean BMI increase was statistically smaller with EVG/c, RAL, and bDRV (range –0.15 to –0.30) than with DTG (Figure 3); these differences only remained significantly different for bDRV at 12 (–0.29) and 24 months (–0.29, Figure 3). Among those with a normal baseline BMI, the adjusted mean change in BMI at 12 months was smaller with EVG/c, bDRV, and RAL than DTG (range –0.26 to –0.27). Among overweight PLWH, the adjusted mean BMI increase was statistically smaller with bDRV than DTG (–0.32, Figure 4). Results were consistent in IPCW estimates. Conclusion The majority of PLWH on stable ART in this US-based cohort were overweight/obese at the time of switch to the regimens of interest. Small mean increases in BMI for all regimens were noted over time, for which the clinical significance is not yet known. Apparent differences in BMI changes favoring EVG/c, RAL, and bDRV vs. DTG over the short term were largely attenuated with longer follow-up, with significant differences mainly observed in those with a normal BMI at baseline. Disclosures All Authors: No reported Disclosures.

Background Limited data exist on the risk of type 2 diabetes mellitus (T2DM) with the use of integrase inhibitors. We assessed the risk of incident T2DM with antiretroviral therapy (ART). Methods ART-naïve (ART-N) and -experienced, suppressed (ART-ES; baseline viral load 13 years of age initiating dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL) or boosted darunavir (bDRV) in the OPERA® cohort. After excluding prevalent prediabetes/T2DM and missing baseline covariates, incidence rates of T2DM (i.e., diagnosis, antidiabetic drug, and/orHbA1C >6.5%) were estimated with Poisson regression. The association between core agents and incident T2DM was estimated with multivariate Cox proportional hazards regression adjusted for age, sex, race, HCV co-infection and BMI at baseline. Median (IQR) absolute BMI change from baseline was evaluated at 6, 12, 18, and 24 months in those who developed incident T2DM and those who did not. All analyses were stratified by ART experience. Results Individuals prescribed these ART regimens varied significantly (Figure 1). Overall, incidence rate per 1,000 person-years was low for T2DM (ART-N IR: 9.1; 95% CI: 7.5, 10.9; ART-ES IR: 13.3; 95% CI: 11.6, 15.2; Figure 2). Among ART-N initiators, no statistical difference was observed in the risk of progression to T2DM between DTG and EVG/c (aHR: 0.70; 95% CI: 0.47, 1.05) or bDRV (aHR: 0.53; 95% CI: 0.26, 1.04); RAL could not be evaluated due to the small number of T2DM events. Among ART-ES initiators; no difference was observed between DTG and EVG/c (aHR: 0.96; 95% CI: 0.70, 1.33), RAL (aHR: 1.17; 95% CI: 0.70, 1.96) or bDRV (aHR: 0.90; 95% CI: 0.57, 1.42) (Figure 3). A greater absolute change in BMI was observed for ART-N initiators developing T2DM at all timepoints; reaching statistical significance at 12 and 18 months (Figure 4). No differences were observed for ART-ES initiators. Conclusion Incident T2DM was uncommon among ART-N and ART-ES persons initiating DTG, EVG/c, RAL or bDRV in this large clinical population. None of the comparisons between DTG and other core agents showed a statistically significant increased risk of T2DM. However, due to the small number of events in the ART-N population differential risk cannot be excluded and monitoring HbA1c remains prudent. Disclosures All authors: No reported disclosures.

Background Raltegravir has been used to treat HIV infection for over a decade. In 2017, a 1200 mg, once-daily, formulation of raltegravir (RALQD) was approved. We sought to characterize the utilization and effectiveness of RALQD in ART-experienced, virologically suppressed, HIV+ adults in a real-world cohort of patients treated in the United States. Methods HIV+ adults, suppressed to = 200 copies/mL or 1 VL ≥ 200 copies + RALQD discontinuation. Kaplan–Meier methods were used to describe VF. Results The study eligible population (n = 121) was older (median 54 years, IQR: 44, 61) than the overall ART experienced OPERA population (median 47 years, IQR: 35, 55), equally as likely to be male (84% vs. 83%), or African American (38%), but more likely to be Hispanic (23% vs. 20%) and receiving care in the southern United States (61% vs. 56%). RALQD initiators were also more likely to be heavily treatment experienced (≥3 lines ART) than the overall ART experienced OPERA population (57% vs 43%). They were also more likely to have at least one comorbid condition complicating their care (88% vs. 72%), most frequently hyperlipidemia (50%), hypertension (47%), anemia (26%), anxiety disorders (25%) and diabetes (22%). Half of all RALQD initiators had ≥3 comorbidities at the time of RALQD initiation. Two-thirds of RALQD initiators had baseline CD4 cell counts >500 cells/µL. Median (IQR) time on RALQD was 57 weeks (43–65); 89% of RALQD initiators had ≥1 VL test result during follow-up. Among these patients, VF occurred in 3 patients at a rate of 2.7 (0.9, 8.4) per 100 person years of observation. Figure 1 depicts Kaplan–Meier curves. Conclusion RALQD was found to be an effective treatment option in ART experienced patients who are virologically suppressed at initiation, and who often face challenges associated with managing comorbid conditions. Disclosures All authors: No reported disclosures.

(See the Editorial Commentary by Zeremski et al on pages 880–2.) Hepatitis C virus (HCV) chronically infects an estimated 5.2 million people in the United States and 170 million people worldwide [1]. However, as most initial (“acute”) infections are completely asymptomatic, newly infected people are rarely identified. The importance of finding these newly HCV-infected people during the acute phase was made clear in the seminal paper by Jaeckel et al [2] that showed a nearly 100% sustained virologic response (SVR) rate using just 24 weeks of interferon alone, an SVR rate many times higher than that of chronically infected patients at that time, and with just half the duration of interferon [3]. We are now faced with an entirely new group of patients who are becoming HCV infected in the international epidemic of sexually transmitted HCV infection among human immunodeficiency virus (HIV)–infected men who have sex with men (MSM). Published cure rates after treatment of acute HCV in these men, using pegylated interferon (peg-IFN) plus ribavirin (RBV) for 24–48 weeks’ duration, are not as good as those of Jaeckel et al [2], ranging from 53% to 83% [4–15], but are clearly better than the 27%–40% success rates in treatment of chronic HCV in HIV-infected men [16, 17]. Still, even with 48 weeks of treatment in many of these studies of acute HCV, fewer than two-thirds of patients achieved SVR, leaving a large proportion of these men uncured, with the possibility of experiencing rapidly advancing liver disease [18–21] and of infecting others and further propagating the epidemic. With the commercial availability of telaprevir (TVR) in the United States, we hypothesized that its potent activity against genotype 1 HCV would allow us to further shorten the treatment period while also improving the SVR rate. We therefore undertook a study of a 12-week treatment course with a combination of TVR, peg-IFN, and RBV in HIV-infected MSM with newly acquired genotype 1 HCV.

In vitro, the reverse transcriptase mutation K65R can simultaneously reduce drug susceptibility, replicative capacity and restrict HIV-1 replication. Here, we assessed the effect of tenofovir discontinuation for a patient receiving antiretroviral therapy whose HIV-1 had a dominant K65R/M184V genotype. Although limited by the single-case nature, the data support a hypothesis that there is no HIV viral RNA or CD4+ T-cell count benefit of taking tenofovir for experienced patients with genotypic evidence of K65R/M184V.

COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNAor = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNAor = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNAor = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.

To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA 30,000 copies/mL at 48 weeks.All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy.Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm3. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (-9 mg/dL), HDL (+1 mg/dL), LDL (-9 mg/dL), and triglycerides (-4 mg/dL).A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.