Darunavir/ritonavir Research Articles

Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA)

To the authors' knowledge, there is currently no literature or guidance recommendation regarding whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and compared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretroviral therapy within <24 h of enrolment: DTG 50 mg BID, DRV/r 800/100 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs thereafter (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approximately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads ≤40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States

BackgroundData on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.MethodsWe conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir–ritonavir, darunavir–ritonavir, oral rilpivirine, raltegravir, or elvitegravir–cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non–dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.ResultsOf the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir–ritonavir, 185 in those who received darunavir–ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir–cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir–ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir–cobicistat (adjusted risk differences vs. dolutegravir, −13.0 percentage points [95% confidence interval {CI}, −17.0 to −6.1], −17.0 percentage points [95% CI, −27.0 to −2.4], and −7.0 percentage points [95% CI, −13.3 to −0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non–dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.ConclusionsAtazanavir–ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non–dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

SummaryBackgroundThe World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens.MethodsWe conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987.FindingsOf 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08–1.43; I2=66.7%) and VSGA (RR 1.40, 1.09–1.81; I2=0.0%), but not PTB (RR 1.09, 0.95–1.24; I2=68.3%), VPTB (RR 1.30, 0.78–2.18; I2=43.0%), sPTB (RR 1.91, 0.61–5.99; I2=95.7%), LBW (RR 1.04, 0.85–1.27; I2=63.9%), VLBW (RR 0.72, 0.37–1.43; I2=37.9%), term LBW (RR 0.94, 0.30–3.02; I2=0.0%), stillbirth (RR 1.04, 0.60–1.79; I2=0.0%), and neonatal death (RR 1.82, 0.97–3.40; I2=0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs.InterpretationPI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV.FundingNone.

873. A Retrospective Cohort Study on Treatment Outcomes of Patients on Third-Line Therapy at the HIV Advanced Treatment Centre, University Teaching Hospital, Zambia

BackgroundIn Zambia, third-line regimens consist of a switch to darunavir/ritonavir (DRV/r) and/or raltegravir (RAL) and/or etravirine (ETV), and as of 2017, dolutegravir (DTG), from a failing second-line therapy.5 We assessed virologic suppression (HIV viral load (VL) ≤1000 copies/ml per Zambian national guidelines), immunological response, and patterns of HIV drug resistance mutation among patients on third-line ART at the University Teaching Hospital (UTH) in Lusaka, Zambia.MethodsA retrospective evaluation of adults ≥18 years old on third-line ART regimens at UTH between January 2012 to June 30, 2020 was conducted. Patients were referred for second-line virologic failure defined as HIV RNA VL > 1000 copies/mL on two consecutive measurements after 6 months on second-line ART.5 We assessed virologic suppression VL ≤1000 copies/ml, CD4, mutations, and third-line regimens of this cohort. Patients were excluded if they were on third-line ART < 6 months or received RAL and/or ETV and/or DTG before starting third-line ART. ResultsA total of 539 patients were included; 231 males (42.9%) and 308 (57.1%) females. The mean age of third-line initiation was 29.8 years; mean time from ART initiation to third-line initiation was 9.9 years. Out of 25 combination 349 (64.7%) received DTG, 272 (50.5%) DRV/r, 85(15.8%) ETR, and 49 (9.1%) RAL. There were 215 (39.9%) genotypes; common mutations were to zidovudine (80%), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (78%), and protease inhibitors (PIs) (41%). Patients with at least one viral load and CD4 upon third-line initiation was 296 (54.9%) and 350 (64.9%), respectively. Among patients with sufficient data (21%, n=115), VL suppression increased from 44 (38%) patients at baseline to 53 (46%) at next available follow-up; with mean baseline VL and follow-up VL of log10 3.60 and 3.33, respectively. The immunologic response revealed 49 (56.3%) had CD4 increase with mean increase of 61.1 cells/mm3. (See Table 1.) ConclusionWe found moderate improvements in VL suppression and immunologic response. Nearly all third-line patients had genotypic resistance to first-line NNRTI and nearly half to second-line PI regimens. Quality improvement measures are needed to improve viral load timing following ART changes to better assess regimen efficacy.Disclosures All Authors: No reported disclosures

Cohort profile: the Netherlands Cohort Study on Acute HIV infection (NOVA), a prospective cohort study of people with acute or early HIV infection who immediately initiate HIV treatment

PurposeInitiation of combination antiretroviral therapy (cART) during acute or early HIV-infection (AEHI) limits the size of the viral reservoir and preserves immune function. This renders individuals who started cART during...

Comparison of Tolerability and Impact on Metabolic Profiles of Antiretroviral Regimens Containing Darunavir/Ritonavir or Darunavir/Cobicistat in Romanian HIV Infected Patients.

The management of the side effects caused by the antiretroviral therapy is one of the main problems facing clinicians. The patient’s tolerability and safety influence the success of the therapy. This retrospective study assesses the tolerability and impact on metabolic profiles of antiretroviral regimens containing darunavir/ritonavir (DRV/r) versus those containing darunavir/cobicistat (DRV/c), in routine clinical practice. The database of Prof. Dr Matei Bals of the National Institute of Infectious Diseases (INBI MB) was studied for the period 2017–2020, allowing the inclusion in the study of 462 HIV-infected patients who received the current regimen at least three months before evaluation. The following parameters were collected and analyzed: significant medical history, associated diseases, serum levels for profile evaluation: carbohydrate, lipidic, serum level of liver and pancreatic enzymes, serum markers of cardiac function, coagulation, and renal function. DRV/c (800 mg/150 mg, once daily) administrated in combination with other antiretroviral (ARV) in HIV-1 infected subjects proved to be better tolerated and with a lower impact on metabolic profile than DRV/r (600 mg/100 mg, twice daily). Patients in DRV/r group are significantly more at risk of developing, over time, side effects and metabolic impairments than those in DRV/c group, in all body functions studied, with statistically significant differences (p < 0.05) between the two groups. Laboratory data were correlated with patient’s demographic and clinical characteristics and statistically significant outcomes have been found, proving that a personalized regimen is needed to minimize the ART side effects and to maximize the success of therapy. The results of the study showed that DRV/c, associated with other antiretroviral drugs in the regimens of Romanian HIV infected subjects, have a more favorable metabolic profile than those containing DRV/r.

Efficiency of antiviral treatment in COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is responsible for generating a global effort to discover urgent therapeutic solutions to limit the human damage caused by COVID-19. In the period of April to June 2020, 105 patients diagnosed with COVID-19 met the conditions for inclusion in the present study. They were treated with antiviral therapy according to local guidelines: D group (53 cases), treated with darunavir/ritonavir (DRV/r); and K group (52 cases), treated with lopinavir/ritonavir (LPV/r). Patients from the K group required 7.5 days of hospitalization less compared to those from the D group (P<0.001). The blood oxygen saturation values recorded in the groups were statistically different [K group (94.02±3.12%) vs. D group (92.13±4.24%), P=0.010]. The percentage of patients with unsatisfactory clinical evolution were non-significantly higher in the D group compared with the K group [20 (37.74%) vs. 12 (23.08%), P=0.157]. We did not note statistically significant differences between the two groups tracked considering the values for the Brescia-COVID Respiratory Severity Scale (BCRSS) of the patients with unsatisfactory clinical evolution, nor of the chest CT' evolution after 10 days of therapy. We did not register significant adverse effects after antiviral therapy in the two groups. Antiviral therapy with LPV/r had some favorable results compared to DRV/r in patients with COVID-19. Both therapies were well tolerated.

Advances and challenges in antiretroviral therapy for acquired immunodeficiency syndrome.

Advances and challenges in antiretroviral therapy for acquired immunodeficiency syndrome.

Long-term virological effectiveness with darunavir/ritonavir-based salvage therapy in people living with HIV/AIDS from São Paulo, Brazil.

Even though darunavir/ritonavir (DRV/r) has high potency and a greater genetic barrier, there are few studies on the long-term effectiveness of DRV/r-based salvage therapy in people living with HIV (PLWH) in low and middle-income countries. This retrospective cohort study, from São Paulo, Brazil, included ART-experienced PLWH aged ≥18 years with virological failure (VF) who had started DRV/r plus an optimized background regimen (OBR) between 2008 and 2012. The proportion of patients with viral load (VL) <50 copies/mL, the improved mean CD4+ T cell count and the factors associated with VF during the 144-week follow-up were assessed. The study included 173 patients with the following characteristics [median (interquartile range)]: age 48 (42 -53) years; CD4+ T cell count, 229 (89 -376) cells/mm3; VL, 4.26 (3.70 -4.74) log10; 6 (4 -7) previous regimens; and 100 (38 -156) months of VF. After 144 weeks, 129 (75%) patients had VL< 50 copies/mL and a mean increase in the CD4+ T cell count of 190 cells/mm3. VL>100,000 copies/mL and poor adherence were associated with VF. DRV/r plus an OBR showed high long-term virological suppression and immunological recovery. VL>100,000 copies/mL and poor adherence were associated with VF at 144 weeks.

96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus − 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.

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

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). 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. As a whole, 680 patients (470 males, mean age 42.1years) 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 12months, mean increase in body weight was 1.93kg in the RAL group, 2.38kg in the DTG group, 2.14kg in the EVG group, and 1.85 in the DRV/r group. Mean increase in BMI was 0.71, 0.84, 0.77 and 0.63kg/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. In our study, patients starting an initial cART including one INSTI or DRV/r after 12months showed a small and comparable, but not significant, increase in body weight, whose long-term clinical consequences are unknown.

Changes in the Fungal Marker β-D-Glucan After Antiretroviral Therapy and Association With Adiposity.

BackgroundBacterial translocation in HIV is associated with inflammation and metabolic complications; few data exist on the role of fungal translocation.MethodsA5260s was a substudy of A5257, a prospective open label randomized trial in which treatment-naïve people with HIV (PWH) were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Baseline was assessed, and changes in β-D-glucan (BDG) were assessed at weeks 4, 24, and 96. Wilcoxon rank-sum tests were used to compare distribution shifts in the changes from baseline between treatment arms and linear regression models to assess associations between BDG and measures of inflammation, body composition, and insulin resistance.ResultsTwo hundred thirty-one participants were randomized; 90% were male, the median age was 36 years, HIV-1 RNA was 4.56 log10c/mL, and CD4 cell count was 338 cells/mm3. There was an overall increase in BDG over 96 weeks (1.57 mean fold-change; 95% confidence interval, 1.39 to 1.77) with no differences between arms. Twofold higher BDG levels at week 96 were associated with increases in trunk fat (8%) and total fat (7%) over 96 weeks (P ≤ .035). At week 4, BDG correlated with I-FABP, a marker of enterocyte damage, and zonulin, a marker of intestinal permeability (r = .19–.20; P < .01).ConclusionsIn treatment-naïve participants initiating antiretroviral therapy (ART) with TDF/FTC and either RAL or ATV/r, DRV/r, BDG, a marker of fungal translocation, increased similarly in all arms over 96 weeks. This may represent continued intestinal damage during ART and resulting fungal translocation. Higher BDG was associated with larger fat gains on ART.

Reduction of Immune Activation and Partial Recovery of Staphylococcal Enterotoxin B-Induced Cytokine Production After Switching to an Integrase Strand Transfer Inhibitor-Containing Regimen: Results from an Observational Cohort Study.

Background and ObjectiveDespite integrase strand transfer inhibitor (INSTI)-containing regimens now being considered a preferred option for both initial therapy and switching strategies in virologically suppressed patients, their effects on lymphocyte phenotypes and functions in the course of effective combination antiretroviral therapy (cART) are still unclear. Thus, we investigated the effect of a 24-week elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) regimen on the T cell compartment and HIV reservoirs in HIV-infected patients switching from a suppressive protease inhibitor-based regimen.MethodsThirty HIV-positive patients receiving suppressive tenofovir disoproxil fumarate/emtricitabine (TDF + FTC) (for a median of 5 years) in association with either darunavir/ritonavir (DVR/r) (47%) or atazanavir/ritonavir (ATV/r) (53%) were followed up for 24 weeks after switching to EVG/c/FTC/TDF. At baseline (week 0 [W0]) and after 12 (W12) and 24 (W24) weeks we analyzed HLA-DR (human leukocyte antigen–DR isotype)/CD38/Ki67/CCR7 (C-C chemokine receptor type 7)/CD45RA/CD127/PD-1 (programmed cell death-1) on CD4/CD8, interferon (IFN)-γ/interleukin (IL)-2 after HIV/Staphylococcal enterotoxin B (SEB) exposure (flow cytometry); total, integrated, and unintegrated HIV-DNA; and residual low-level HIV viremia (quantitative polymerase chain reaction [qPCR]).ResultsWhile EVG/c/FTC/TDF introduction resulted in a stable CD4+ and CD8+ count, residual low-level HIV-RNA viremia, and HIV reservoirs, we observed a significant reduction in both activated CD4+ (p = 0.016) and CD8+ (p = 0.048) T cells, coupled with an increase in IL-2 and IFN-γ release by CD4+ and CD8+ effector memory T cells, and a decrease in cytokine production by terminally differentiated CD8+ T cells following SEB exposure. Furthermore, the magnitude of the reduction of activated HLA-DR + CD38 + CD8+ T cells (r = − 0.63, p = 0.014) inversely correlates with the amount of total HIV-DNA at W24.ConclusionsOur data show a favorable effect of EVG/c/FTC/TDF switch to preserve immune activation-driven damage to T cell homeostasis, restore the multifunctional properties of effector T cells, and possibly contain cell-associated HIV viral burden in already virologically suppressed patients.

Dual therapy with ritonavir-boosted protease inhibitor (PI) plus lamivudine versus triple therapy with ritonavir-boosted PI plus two nucleos(t)ide reverse-transcriptase inhibitor in HIV-infected patients with viral suppression.

Dual antiretroviral regimens are attractive options to optimize the combination antiretroviral therapy in light of potential toxicities with long-term cumulative exposure to nucleos(t)ide reverse-transcriptase inhibitors (NRTIs). In this retrospective observational study, we included HIV-infected patients on suppressive antiretroviral therapy with plasma viral load (PVL)<200 copies/mL for at least 6 months who were switched to dual regimens containing lamivudine (3TC) (150mg twice daily or 300mg once daily) plus lopinavir/ritonavir (LPV/r) 250/50mg twice daily or darunavir/ritonavir (DRV/r) 800/100mg once daily. Patients maintaining on suppressive triple therapy with DRV/r or LPV/r plus two NRTIs were included for comparisons. The primary endpoint was the proportion of patients with PVL <50 copies/mL after 48 weeks of follow-up. In total, 364 patients were included with 93 (25.5%) switched to dual therapy After 48 weeks of observation, PVL <50 copies/mL was observed in 96.8% and 94.1% of dual-therapy and triple-therapy group, respectively, in per-protocol analysis (difference 2.7%; 95% CI -2.5%-7.9%). Nineteen patients (3 [3.2%] in dual-therapy and 16 [7.6%] in triple-therapy group) developed virologic failure, with none having emergent M184V resistance-associated mutation. A statistically significant increase of cholesterol level (13mg/dL versus 2mg/dL, p=0.003) and high-density lipoprotein (3mg/dL versus -2mg/dL, p=0.019) were observed in dual-therapy than in triple-therapy group. Changes of triglyceride, low-density lipoprotein and glycated hemoglobin levels were similar between the two groups. Dual therapy with DRV/r or LPV/r plus lamivudine demonstrated similar effectiveness in maintaining viral suppression to triple therapy.

Mathematical modeling of HIV-1 transmission risk from condomless anal intercourse in HIV-infected MSM by the type of initial ART.

BackgroundInitiation of antiretroviral therapy (ART) for HIV infection using regimens that include integrase strand transfer inhibitors (INSTIs) is associated with a faster decline in HIV-1 RNA than what is observed with regimens that are anchored by other ART drug classes. We compared the impact of ART regimens that include dolutegravir (DTG), raltegravir (RAL), efavirenz (EFV), or darunavir/ritonavir (DRV/r), in treatment naïve men who have sex with men (MSM) on the probability of HIV-1 sexual transmission events (HIV-TE).SettingMathematical model.MethodsWe used discrete event simulation modeling to estimate HIV-TE during the first 8 weeks after initiation of ART. HIV-1 RNA decay in men was modeled from the databases of three clinical trials: Single (DTG vs. EFV), Spring-2 (DTG vs. RAL) and Flamingo (DTG vs. DRV/r).ResultsAll regimens substantially reduced the number of HIV-TE compared to no treatment. DTG led to fewer HIV-TE than its comparator in each of the three trials: 22.72% fewer transmissions than EFV; 0.52% fewer transmissions than RAL; and 38.67% fewer transmissions than DRV/r. The number of patients needed to treat with DTG to prevent one transmission event instead of comparator was 48 vs EFV, 2,194 vs RAL, and 31 vs DRV/r.ConclusionUnsurprisingly, this mathematical model showed that all regimens reduced HIV-TE compared to no treatment. The results also suggest that that initial use of INSTIs, by virtue of their superior viral decay kinetics, have the potential to reduce HIV-1 horizontal transmission following initiation of ART in naïve MSM.Trial registrationClinicalTrials.gov NCT03183154.

Simplification of Antiretroviral Treatment from Darunavir/Ritonavir Monotherapy to Darunavir/Cobicistat Monotherapy: Effectiveness and Safety in Routine Clinical Practice.

Our aim was to evaluate the effectiveness and safety of darunavir/cobicistat (DRV/c) monotherapy as an antiretroviral treatment simplification strategy in HIV-infected patients already on suppressive darunavir/ritonavir (DRV/r) monotherapy in routine clinical practice. We conducted a retrospective multicenter study including all adult patients switched from DRV/r monotherapy to DRV/c monotherapy while HIV-1 RNA was <50 copies/mL and who had at least one follow-up visit. The primary endpoint was the percentage of patients remaining free of treatment failure (TF), defined as discontinuation of monotherapy for any reason, including loss of follow-up. Virological failure (VF) was defined as a confirmed HIV-1 RNA ≥50 copies/mL or any change in the regimen after a single determination with HIV-1 RNA ≥50 copies/mL. Changes in renal function parameters and lipid profile were also evaluated. Factors associated with VF were analyzed using Cox regression. In this study, 173 subjects were included. The median (interquartile range) time of follow-up was 58 (50-67) weeks. Overall, 90% of patients remained free of TF during follow-up. Ten (6%) patients discontinued DRV/c monotherapy for nonvirological reasons and eight (5%) developed VF. No DRV-related mutations were identified in patients with VF. A decrease in triglyceride levels (p = .006) and estimated glomerular filtration rate (p = .005) were observed during follow-up. The presence of blips and CD4+ nadir <100 cells/mm3 were predictors of VF. In conclusion, switching to DRV/c monotherapy seems to be safe and effective in routine clinical practice in HIV-infected patients undergoing suppressive DRV/r monotherapy.

PP12 Cost-Utility Analysis Of Dolutegravir For HIV-1 Infection In Thailand

IntroductionHIV drug resistance (HIVDR) has significantly increased in Thailand. However, a new generation integrase inhibitor, dolutegravir, has not yet been included in the country's National List of Essential Medicines (NLEM). Since these drugs are high in costs, an economic evaluation is needed to support the decision. This study aims to assess the cost-utility analysis of dolutegravir for HIV-1 infection in Thailand.MethodsA Markov model was developed to evaluate the cost-utility as follows: (i) the current practice of darunavir/ritonavir (DRV/r) + tenofovir (TDF) + lamivudine (3TC); (ii) DRV/r + etravirine (ETR) + TDF + 3TC; (iii) DRV/r + raltegravir (RAL) + TDF + 3TC; (iv) DRV/r + RAL + ETR; and (v) DRV/r + RAL + maraviroc (MVC); (vi) DRV/r + dolutegravir (DTG) + MVC; (vii) DRV/r + DTG + ETR; (viii) DRV/r + DTG + TDF + 3TC. The model incorporated cost data adjusted for 2017 using the consumer price index, and effectiveness data from a review of published studies. Outcomes were measured in life years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), and future costs and outcomes were discounted at 3 percent per annum. Finally, a probabilistic sensitivity analysis was conducted to deal with uncertainties around the parameters.ResultsAll alternative treatment regimens for HIV patients resistant to first- and second-line antiretroviral therapies (ARTs) in Thailand were found to be not cost-effective at the willingness-to-pay (WTP) of THB 160,000/QALY (USD 5,197/QALY). However, the eighth regimen of DRV/r + DTG + TDF + 3TC had the lowest lifetime cost at THB 5.3 million (USD 172,145) while increasing QALY by approximately 14 QALYs.ConclusionsAt a societal WTP of THB 160,000 per QALY gained (USD 5,197 per QALY gained), dolutegravir for HIV patients resistant to first- and second-line ARTs in Thailand was found to be not cost-effective.

Changes in Waist Circumference in HIV-Infected Individuals Initiating a Raltegravir or Protease Inhibitor Regimen: Effects of Sex and Race

BackgroundThis study investigates the association of clinical and demographic predictors with abdominal fat gain, measured using waist circumference (WC) and self-reported abdominal size.MethodsWe analyzed data from ACTG A5257, a clinical trial that randomized treatment-naïve HIV-infected participants to 1 of 3 antiretroviral regimens: raltegravir (RAL) or the protease inhibitors (PIs) atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. Associations of treatment and baseline/demographic characteristics with 96-week WC change were assessed using repeated-measures models. Ordinal logistic regression was used to examine the associations of predictors with week 96 self-reported abdominal changes.ResultsThe study population (n = 1809) was 76.0% male and predominantly black non-Hispanic (41.9%) and white non-Hispanic (34.1%). Mean baseline WC was 90.6 cm, with an average 96-week increase of 3.4 cm. WC increases were higher in the RAL arm compared with DRV/r (P = .0130). Females experienced greater increases in WC on RAL vs ATV/r than males (P = .0065). Similarly, a larger difference in WC change was found for RAL vs DRV/r for black vs nonblack individuals (P = .0043). A separate multivariable model found that in addition to the treatment regimen, higher baseline viral load and lower CD4+ were also associated with WC increases.ConclusionsWith antiretroviral therapy initiation, higher WC increases in the RAL arm compared with PIs were more pronounced in female and black participants, and a more advanced baseline HIV disease state was a strong predictor of larger abdominal increases. Understanding factors predisposing individuals to abdominal fat gain could inform health management after therapy initiation.

Darunavir/cobicistat maintains the effectiveness of darunavir/ritonavir in HIV-infected patients under mono or dual therapy

Objectives: Darunavir/ritonavir (DRV/r) in mono or dual therapy has proven efficacy in selected patients. The aim of this study was to evaluate the efficacy of switching from DRV/r to DRV/cobicistat (DRV/c) in patients under mono or dual therapy.Methods: This was a prospective multicenter cohort study of patients using DRV/r under mono or dual therapy plus lamivudine who changed to DRV/c maintaining the previous regimen. All patients had a controlled HIV viral load (<50 copies/ml) when switched and were examined every 12 weeks. The primary end-point was the percentage of participants without virological failure (VF) at week 48 in the intent-to-treat analysis. The CD4 cell count and concentrations of cholesterol, triglyceride, and creatinine were measured from baseline to week 48.Results: A total of 162 patients were included: 68.5% were men, and their mean age was 46 ± 12 years. Seventy (43.2%) patients were treated with DRV/r monotherapy, and 92 (56.8%) were treated with DRV/r plus lamivudine. The efficacy at week 48 was 95.1% (95% CI: 90.6%–97.5%) in the intent-to-treat analysis and 98.7% (95.5–99.6%) in the on-treatment analysis. Two VFs were documented but without development of resistance mutations. No significant changes were found in the lipid profile. Creatinine concentration increased significantly by 0.07 mg/dl (0.04–0.10, P < 0.001).Conclusions: Switching from DRV/r to DRV/c in patients under mono or dual therapy is safe and effective.

Clinical Outcomes Associated With Once-Daily Ritonavir-Boosted Darunavir Plus Tenofovir/Emtricitabine in HIV-Infected Patients Harboring at Minimum a M184V/I Resistance Mutation.

Limited data exist on the use of a boosted protease inhibitor plus <2 active nucleoside/nucleotide reverse transcriptase inhibitors without use of additional classes of antiretroviral (ARV) therapy in treatment-experienced patients with background resistance. To evaluate clinical outcomes in HIV-infected patients harboring single- or multiclass resistant virus and receiving once-daily tenofovir/emtricitabine (TDF/FTC) plus darunavir/ritonavir (DRV/r) administered for >24 weeks. This was a single-center chart review of HIV-infected patients receiving daily TDF/FTC plus DRV/r and identified with resistant virus (including, but not limited to, an M184V/I). The primary outcome was HIV viral load (VL) <200 copies/mL (cp/mL) at last measurement. Additional end points included virological rebound (VR), resuppression, or failure (VF); VL <40 cp/mL at last measurement; and development of additional mutations. Of 171 eligible patients, 32 were included in the study and received DRV 800 mg/r 100 mg daily with fixed-combination TDF/FTC. All patients had a baseline M184V/I mutation, with 10 (31%) having resistance to TDF; 27 (84%) achieved a VL <200 cp/mL, and 25(78%) had a VL <200 cp/mL at the last reading; 22 (69%) achieved a VL <40 cp/mL. VF occurred in 6/32 (19%) patients and VR in 1/32 (3%) patients. Conclusion and Relevance: Although providing a regimen containing ≤2 active drugs, the use of once-daily DRV/r plus TDF/FTC in treatment-experienced patients with single-/multiclass resistant virus resulted in virological suppression in more than three-fourths of patients. These retrospective data suggest that despite the presence of an M184V/I, this combination may be an option in patients seeking a once-daily ARV therapy to improve adherence.