Comparison of weight gain after antiretroviral switch to integrase strand transfer inhibitor or tenofovir alafenamide-based therapy.

PURPOSE: Several studies have reported weight gain after switching to integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART). Debate persists if weight gain also occurs when switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF)-based ART. METHODS: We performed a retrospective chart review of virally suppressed HIV-infected patients who were switched from non INSTI- to INSTI-based ART (INSTI switch group) as well as patients switched from TDF- to TAF-based ART (TAF switch group), and compared the mean weight change in these groups to the mean change in weight in patients maintained on NNRTI-based regimens (control group). RESULTS: 329 patients were identified. 256 patients in the INSTI switch group gained a mean 2.4 kg over 17 months compared to 0.5 kg in 54 patients in the control group over the same period (p = 0.008). 161 patients in the TAF switch group gained a mean 2.8 kg over 17 months compared to 0.5 kg in the control group (p = 0.003). There was no statistical difference in weight gain between the INSTI and TAF switch groups. Although the highest mean weight gain of 3.2 kg was seen in those 90 patients switched from both TDF- to TAF-based and non INSTI- to INSTI-based ART (TAF/INSTI switch group), this weight gain was not statistically different compared with the INSTI switch or TAF switch groups. CONCLUSION: Our study suggests that weight gain is associated with both switching HIV regimens from non INSTI- to INSTI-based ART and TDF- to TAF-based ART.

Increased risk of IRIS-associated tuberculosis in HIV-infected patients receiving Integrase Inhibitors.

BACKGROUND: Tuberculosis is associated with a risk of immune reconstitution inflammatory syndrome (IRIS) after ART initiation. METHODS: Data from all patients with newly diagnosed tuberculosis disease and uncontrolled HIV infection from 1997 to 2017 in a French center were retrospectively collected. We evaluated the incidence of tuberculosis-IRIS in patients initiating ART with or without integrase inhibitors (INSTI) RESULTS: Fifty-five patients were included: 21 receiving an INSTI regimen and 34 a non-INSTI regimen. Except with regard to ART regimen, the two groups were comparable (median CD4 of 85/mm3). The overall percentage of IRIS was 34% (19/55), with 52% IRIS in INSTI regimen and 23% in non-INSTI regimen respectively (P=0.04). In a multivariate logistic model, we observed an increased risk of IRIS in the INSTI regimen compared to the non-INSTI, with an OR at 3.33 [95% CI, 1.01-11.1] (P=0.05) CONCLUSIONS: ART containing integrase inhibitors could be associated with increased incidence of TB-associated IRIS.

Prevalence and Risk Factors of Moderate-to-Severe Hepatic Steatosis in Human Immunodeficiency Virus Infection: The Copenhagen Co-morbidity Liver Study.

BACKGROUND: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH. METHODS: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression. RESULTS: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS. CONCLUSIONS: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH.

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Pregnancy and neonatal outcomes in women with HIV-1 exposed to integrase inhibitors, protease inhibitors and non-nucleoside reverse transcriptase inhibitors: an observational study.

PURPOSE: Recommended regimens for pregnant women with HIV-1 are composed of two nucleoside reverse transcriptase inhibitors (NRTI) plus either a ritonavir-boosted protease inhibitor (PI) or an integrase strand transfer inhibitor (ISTI), with non-nucleoside reverse transcriptase inhibitors (NNRTI) representing an alternative drug class. The study's purpose was to compare these three options in terms of pregnancy outcomes. METHODS: Data from a national observational study of pregnant women with HIV-1 were used. The analysis included all pregnancies reported between 2008 and 2018, ending in live births and exposed within 32 weeks of gestation to three-drug regimens composed of a NRTI backbone plus a PI, a NNRTI or a ISTI, without class switching during pregnancy. Clinical and laboratory outcomes were evaluated in univariate and multivariable analyses. RESULTS: Overall, 794 exposed pregnancies were analyzed (PI 78.4%, NNRTI 15.4%, ISTI 6.2%). Almost all outcomes had similar rates in the three groups. Women who received PI in pregnancy were less likely to be virologically suppressed at third trimester. PI use was associated with higher bilirubin and triglyceride levels, and ISTI use with a lower rate of low birthweight. The differences in viral suppression at third trimester and in low birthweight were not maintained in multivariable analyses that were adjusted for confounders. DISCUSSION: We found no major differences in a wide range of outcomes relevant for pregnant women with HIV. Such results are reassuring, and this information may be helpful in a context of preconception counseling when therapeutic choices for pregnancy are discussed between women and care providers.

Weight gain in antiretroviral therapy-naive HIV-1-infected patients starting a regimen including an integrase strand transfer inhibitor or darunavir/ritonavir.

BACKGROUND: Weight gain after initiation of combination antiretroviral therapy (cART) is a possible side effect of all antiretroviral regimens, but it seems to be more evident in association with integrase strand transfer inhibitors (INSTIs). So, we aimed to evaluate weight change associated with an initial cART including one INSTI or darunavir-ritonavir (DRV/r). METHODS: A retrospective, observational, cohort study of antiretroviral therapy-naive adult HIV-positive patients starting an initial cART including raltegravir (RAL), dolutegravir (DTG), elvitegravir-cobicistat (EVG), or DRV/r. We compared changes in weight and body mass index (BMI) across the four groups during a 12-month follow-up. RESULTS: As a whole, 680 patients (470 males, mean age 42.1 years) were enrolled: 196 starting RAL, 174 DTG, 158 EVG/c, and 152 DRV/r. Baseline mean CD4 lymphocyte count was 455 cells/mm3 and 7.3% had an AIDS diagnosis. After 12 months, mean increase in body weight was 1.93 kg in the RAL group, 2.38 kg in the DTG group, 2.14 kg in the EVG group, and 1.85 in the DRV/r group. Mean increase in BMI was 0.71, 0.84, 0.77 and 0.63 kg/m2, respectively (p > 0.05 for each comparison). Therefore, no significant increases in weight and BMI were reported in each group, and no significant differences in weight and BMI changes were described across the four treatment groups. CONCLUSIONS: In our study, patients starting an initial cART including one INSTI or DRV/r after 12 months showed a small and comparable, but not significant, increase in body weight, whose long-term clinical consequences are unknown.

Durability of first-line antiretroviral regimens in the era of integrase inhibitors: a cohort of HIV-positive individuals in Spain, 2014-2015.

BACKGROUND: We compared time to treatment change (TC), viral suppression (VS) and change in CD4+ T-cell counts of first-line antiretroviral regimens (ART). METHODS: We analysed HIV treatment-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) initiating the most commonly used ART regimens from September 2014 to November 2015. We used proportional hazards models on the sub-distribution hazard to estimate sub-distribution hazard ratios (sHR) for time to TC, logistic regression to estimate odds ratios (ORs) for VS (viral load <50 copies/ml), and linear regression to assess mean differences in CD4+ T-cell changes from ART initiation. RESULTS: Among 960 individuals, tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) was the most frequently prescribed regimen (24.2%), followed by elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC (22.8%), abacavir (ABC)/lamivudine (3TC)/dolutegavir (DTG; 17.4%), TDF/FTC+darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c; 12.1%), TDF/FTC/efavirenz (EFV; 8.8%), TDF/FTC+raltegravir (RAL; 7.7%) and TDF/FTC+DTG (7.0%). Initiating ART with TDF/FTC+DRV/r or DRV/c (adjusted sHR: 2.96; 95% CI: 1.44, 6.08), TDF/FTC/EFV (2.18; 0.98, 4.82), TDF/FTC+RAL (2.37; 1.08, 5.22) and TDF/FTC+DTG (6.34; 3.18, 12.64) was associated with a higher risk of TC compared to ABC/3TC/DTG. At 24 weeks, VS was lower in TDF/FTC+DRV/r or DRV/c (adjusted OR: 0.37, 95% CI: 0.18, 0.74) compared with ABC/3TC/DTG, and CD4+ T-cell increase was lower in patients initiating with TDF/FTC/RPV (adjusted mean difference: -75.9, 95% CI: -130.6, -21.2) compared with those who did with ABC/3TC/DTG. CONCLUSIONS: Time to TC, VS and change in CD4+ T-cell counts varies by initial regimen. These differences may be useful for making decision when initiating ART.

HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study.

BACKGROUND: As a simplification strategy for treatment-experienced HIV-infected patients who have achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir. METHODS: A single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ≥ 6 months, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, and no genotypic resistance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ≥ 2 weeks after the regimen change. RESULTS: Ten HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained virologic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50-59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05). CONCLUSIONS: Despite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regimen of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients. Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014.

Latest advances in the efficacy, tolerability, and monotherapy of integrase inhibitors.

More than 30 drugs for antiretroviral therapy (ART), including integrase inhibitors (INIs), have been approved by the U.S. Food and Drug Administration (FDA) as of 2017. Integrase is the third essential enzyme in the cycle of human immunodeficiency virus (HIV) replication. INIs can effectively inhibit the replication of HIV and HIV is less prone to develop resistance to INIs clinically. Previous studies based on 7 phase III clinic trials indicate that INIs have satisfactory efficacy and tolerability in patients infected with HIV. The latest advances in INIs indicate that: i) dolutegravir (DTG)-based regimens are more efficacious, tolerable, and safer forms of first-, second-, and third-Line ART; ii) current studies have indicated that DTG monotherapy fails both virologically and clinically; and iii) whether the most cost-effective treatment for DTG is to replace efavirenz (EFV) as a first-line ART, to replace protease inhibitors (PIs) in second-line ART, or to replace both as a monotherapy is unclear. Given these circumstances, further study of INIs in terms of drug interactions, dose reduction, drug convenience, and drug costs is warranted.

Human Immunodeficiency Virus Infection, Antiretroviral Therapy, and Liver Pathology.

The improvement in antiretroviral therapy has significantly impacted the lives of people living with human immunodeficiency virus (HIV). In high-income countries, HIV deaths are predominated by liver disease consequent to viral hepatitis coinfection, alcohol, and nonalcoholic fatty liver disease. Published liver pathology findings have shifted from being predominated by opportunistic infections to the metabolic effects of HIV and antiretroviral therapy as well as drug-induced liver injuries. Differences remain between high-income and low-income countries, where opportunistic infections and immune reconstitution syndromes, dominate findings.

Relapse of Kaposi's Sarcoma and HHV-8 viremia in an HIV-infected patient switching from protease inhibitor to integrase inhibitor-based antiretroviral therapy.

Combination antiretroviral therapy (cART) reduced the incidence of Kaposi's Sarcoma (KS), mainly mediated by the suppression of HIV replication and the recovery of the immune system. The effect of specific classes of antiretrovirals on KS remains unclear. However, both in vitro and clinical studies provided evidences that protease inhibitors (PI) can inhibit Human Herpesvirus 8 (HHV-8) replication and reduce KS risk and progression. Moreover, relapses of KS in HIV-infected patients switching from a PI to a non-nucleoside reverse transcriptase inhibitor-based cART have been reported. We describe here the case of a patient who experienced a relapse of KS and a rebound of HHV-8 viremia two months after switching from a PI to an integrase inhibitor-based cART.

Novel targets for antiretroviral therapy: clinical progress to date.

The advent of HIV-1 resistance to antiretroviral medications, the need for lifelong antiretroviral therapy (ART) for HIV-infected individuals, and the goal of minimizing ART-related adverse effects and toxicity all drive the need for new antiretroviral drugs. Two new classes of antiretroviral medications for HIV treatment, the CCR5 and integrase inhibitors, have recently been approved for use in patients in whom previous HIV treatment regimens have failed. These new agent classes are a welcome addition to other antiretroviral classes, which include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Maraviroc is a CCR5 co-receptor antagonist that blocks HIV binding to the CCR5 receptor, which is a CD4 co-receptor necessary for cell entry. It is approved for use in ART-experienced patients with CCR5-tropic HIV, and was found to significantly reduce HIV viral load and increase CD4+ cell count when combined with an optimized background ART regimen (OBR). Treatment failure with maraviroc has been described and is primarily associated with the presence of CXCR4-tropic virus. Vicriviroc is another CCR5 co-receptor antagonist that is in late clinical trials. Raltegravir is the first US FDA-approved HIV-1 integrase inhibitor. It is approved for use in ART-experienced patients and was found to significantly reduce HIV viral load and increase CD4+ cell counts compared with placebo in combination with an OBR. Raltegravir has also been studied in treatment-naive patients and was found to be non-inferior to an efavirenz-based regimen. Elvitegravir is another HIV-1 integrase inhibitor in clinical development. Other new antiretroviral agents in clinical development include PRO140, a monoclonal antibody against CCR5, and bevirimat, a maturation inhibitor that prevents late-stage gag polyprotein processing. A number of other drug targets, such as CCR5 co-receptor agonists, CXCR4 co-receptor antagonists, novel fusion inhibitors, and alternative antiretroviral strategies, such as immune stimulation and gene therapy, are under investigation.

Raltegravir: new Drug. Alternative to enfuvirtide/darunavir in multidrug-resistant HIV.

(1) HIV-infected patients who have exhausted most existing antiretroviral treatment options benefit when enfuvirtide or darunavir is added to an optimised multidrug regimen based on the resistance profile; (2) Raltegravir is the first HIV integrase inhibitor to arrive on the market. It was authorised in 2007 in the European Union for patients with multiple antidrug failure; (3) A dose-finding study and two double-blind placebo-controlled trials showed that when raltegravir is added to an optimised antiretroviral regimen about two-thirds of patients achieve undetectable viral load, compared to about one-third of patients treated with an optimised regimen plus placebo. Data are currently limited to 48 weeks. In contrast, adding raltegravir barely increases the efficacy of treatments already containing enfuvirtide and darunavir. Half of patients in whom treatment failed developed viral resistance to raltegravir during these trials; (4) In previously untreated patients, a double-blind controlled trial showed no statistically significant difference in viral load at 48 weeks between raltegravir/tenofovir/lamivudine and efavirenz/tenofovir/lamivudine, but there were only about 40 patients in each group; (5) The adverse effects of raltegravir are poorly documented. In vitro findings, along with the limited clinical data available, point to a potential risk of autoimmune and lymphoproliferative disorders in the long term. (6) Raltegravir is not metabolised by the cytochrome P450 enzyme system, meaning that it should have fewer pharmacokinetic interactions than darunavir. But raltegravir is sensitive to enzyme inducers, which activate its metabolism; (7) Raltegravir is taken orally, twice a day, either during or between meals; (8) In practice, raltegravir is an option for HIV-infected patients with multiple antiretroviral drug failure and few remaining treatment options. It represents an alternative to the darunavir/enfuvirtide combination, and has the advantage of being more convenient to use. Assessment must continue, however, especially in order to identify long-term adverse effects.