To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as a single-tablet regimen (STR) using the PCR signal of the plasma viral load (pVL) assay and determination of plasma drug concentration ( C 24 ).This was an observational single-centre study enrolling antiretroviral-treated patients with pVL <50 copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal.One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5 years (IQR 3-9) and 24 months (IQR 9-44), respectively. By week (W) 48, 26 (17%) of the patients had discontinued STR due to adverse events. The proportion of patients maintaining pVL <50 copies/mL on treatment was 98%, 96%, 93% and 97% at W12, W24, W36 and W48, respectively. Five patients (3.3%) experienced a virological failure and emergence of resistance was observed in two of them with the selection of M184V and N155H mutations. At baseline, W12, W24, W36 and W48, 70%, 57%, 72%, 61% and 74% of the patients with pVL <20 copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648 ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values >45 ng/mL, the protein-adjusted IC 95 .In this clinical cohort of virologically suppressed patients switching to STR, most subjects had adequate elvitegravir C 24 values with a high proportion maintaining virological suppression with no residual viraemia until W48.
In the context of stagnating development assistance for health, the sixth Replenishment Conference of the Global Fund to Fight AIDS, Tuberculosis, and Malaria, held on Oct 9–10, 2019, in Lyon, France, was a success. Pledges from donors for the next 3 years reached the minimum US$14 billion target that was needed to contribute to saving 16 million additional lives. Yet, although there have been positive synergies between vertical programmes for each of the three pandemics, as well as between those programmes and other components of health-care systems, the effective contribution of the Global Fund towards strengthening health-care systems has remained low. Only in a few exceptional cases (namely Rwanda1Chemouni B The political path to universal health coverage: power, ideas and community-based health insurance in Rwanda?.World Dev. 2018; 106: 87-98Crossref Scopus (74) Google Scholar and Ethiopia2Assefa Y Tesfaye D Damme WV Hill PS Effectiveness and sustainability of a diagonal investment approach to strengthen the primary health-care system in Ethiopia.Lancet. 2018; 392: 1473-1481Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar) has the Global Fund directly contributed to improvements in financing the pathway towards universal health coverage. The 2030 Agenda3UNTransforming our world: the 2030 Agenda for Sustainable Development.https://sustainabledevelopment.un.org/post2015/transformingourworld/publicationDate: 2015Date accessed: October 13, 2019Google Scholar offers new opportunities by emphasising the need to better link interventions related to individual targets for each of the Sustainable Development Goals (SDGs). Such links are needed within SDG3 between the targets for various diseases and for strengthening universal health coverage, and, more importantly, between different SDGs. For example, interventions relating to SDG3 on health should be aligned with those dealing with environmental issues—namely SDG6 on water, SDG12 on responsible consumption and production, SDG1 on the climate, SDG14 on oceans, and SDG15 on land and biodiversity. Agenda 2030 is directly related to the emergence of a new field of interdisciplinary research aimed at finding solutions for transforming our current, damaging models of growth and development.4Messerli P Kim EM Lutz W et al.Expansion of sustainability science needed for the SDGs.Nat Sustain. 2019; 2: 892-894Crossref Scopus (62) Google Scholar Global health research should be more explicitly part of this field of sustainability science, and the Global Fund can help by assuming a leading role in renewing funding for global health operational research. Science is key to generating innovative solutions and helping to scale up their adoption and implementation. For instance, if access to antiretroviral therapy could be guaranteed for everyone who had already contracted HIV, and if pre-exposure prophylaxis could be provided for all those at high-risk of contracting HIV, we could rapidly end the AIDS epidemic.5Fauci AS Redfield RR Sigounas G Weahkee MD Giroir BP Ending the HIV epidemic: a plan for the United States.JAMA. 2019; 321: 844-845Crossref PubMed Scopus (669) Google Scholar There is an urgent need to bridge the gap between theory and reality. Propelling the Global Fund into the era of SDGs is crucial. This movement could be achieved through three main actions. First, the implementation of Global Fund treatment and prevention programmes should also be used as an opportunity for supporting improvements of the research capacities in those countries. Second, rigorous scientific impact evaluations should be done more frequently alongside Global Fund interventions, as is done by the World Bank Strategic Impact Evaluation Fund. Third, the Global Fund should serve as a template for increasing synergies between the fight against the three diseases and all other 17 SDGs, to maximise the complementarity of people-centred research, action, and interventions among the SDGs.6Independent Group of Scientists appointed by the UN Secretary-GeneralGlobal sustainable development report 2019: the future is now: science for achieving sustainable development. United Nations, New York2019Google Scholar The Global Fund will soon start elaborating a new strategy for the period after 2022, it should be a major opportunity for embedding its actions within Agenda 2030 and the SDGs. We declare no competing interests.
The SARS-CoV-2 pandemic has entered an uncertain race between the emergence of variants that are more transmissible and vaccine roll-out. Here, we developed a mathematical model to evaluate how the interplay of variants, vaccines and non-pharmaceutical interventions might shape the pandemic dynamics, using the rise of the B.1.1.7 variant in metropolitan France as a case study. Our analysis highlights the challenges ahead for the management of the SARS-CoV-2 pandemic and shows how the quick roll-out of vaccines to at-risk individuals and non-pharmaceutical interventions are needed to mitigate the impact of the emerging variants.
We read with interest the thoughtful review by Cattaneo and Gervasoni [1] of our article [2] describing the pharmacokinetics of etravirine, raltegravir and darunavir/ritonavir in treatment-experienced patients. Our data demonstrate that addition of etravirine to a darunavir/ritonavir and raltegravir antiretroviral (ARV) drug regimen does not lead to a decrease in raltegravir concentrations, but unexpectedly lead to a statistically significant modest increase in raltegravir trough concentration (Ctrough) and a trend to an increase in truncated area under the curve (AUC) measured during a dosing interval up to 8 h after drug intake. These data show no deleterious drug–drug interaction and support the administration of such a drug combination in heavily pretreated HIV-infected patients. Cattaneo and Gervasoni [1] pointed out, first, that raltegravir trough concentrations are highly variable and failed to correlate with AUC0–12 and, second, that with raltegravir being administered twice daily, the right pharmacokinetic parameter to assess drug exposure should be measured during a dosing interval, AUC0–12. Indeed, we agree that Ctrough is not the only parameter to consider for drug–drug interaction studies and that AUC calculated during a 12-h dosing interval for a twice-daily administration is the gold standard. For patient convenience, our last sampling time was 8 h after drug intake for the two study periods. As a consequence of the at least 50-fold difference between Cmax and Cmin, whenever the decline in concentration as a function of time is log-linear between Cmax and C8 h, and AUC0–12 is extrapolated, we could demonstrate that the average AUC0–8 to AUC0–12 ratio was close to 0.90, ruling out methodological drawbacks; therefore, we could validate the AUC0–8 as surrogates of AUC0–12 in this study, as in previous one [3]. We agree that our data are in contrast with previous studies. Anderson et al.[4] demonstrate a minimal decrease in raltegravir concentrations (shown with both C12 h and AUC0–12) in healthy volunteers explained by the enzyme-inductive property of etravirine. As recently pointed out by Fletcher [5], drug interactions should be studied in patients, particularly given the complexity of interactions among new ARVs such as etravirine and raltegravir combined to protease inhibitors and uncertainty about whether the results in healthy volunteers can be extrapolated to patients. Menard et al.[6] reported four cases of a very low trough concentration of raltegravir after addition of etravirine to the ARV regimen and none of these heavily treatment-experienced patients achieved undetectable plasma HIV-RNA. In contrast, we demonstrated that raltegravir concentrations were increased after the addition of etravirine to a darunavir/ritonavir and raltegravir combination. Supporting the statement by Fletcher [5], these studies clearly show that data from two-way interaction studies conducted in healthy volunteers cannot be extrapolated to three-way interaction in heavily pretreated HIV-infected patients. Several reasons can explain such discrepancies. First, there is now clear evidence that concentrations and pharmacokinetic parameters of raltegravir are much more variable in HIV-infected patients [2,7] than in healthy volunteers [8], most likely as a consequence of a nonreliable rate of absorption and bioavailability. These findings, as well as a possible variable extent of raltegravir or raltegravir glucuronide enterohepatic cycle, could explain why no relationship could be established between Cmin and AUC of raltegravir. Furthermore, all patients received several lines of ARV therapy, which include drug-metabolizing enzyme or transporter inducers or inhibitors. Whether such treatments could affect the biotransformation of the newly administered ARVs is presently unknown. Finally, it is increasingly evident that patient adherence to treatment is different in the setting of routine therapeutic drug monitoring or in a clinical trial. Taking into account all these sources of variability for raltegravir pharmacokinetics, it is unlikely that the Ctrough reported by Menard et al.[6] in four patients and ours in 10 patients [2] in different settings can be compared. We agree that our study failed to demonstrate the mechanism of this complex three-way drug interaction. However, it clearly shows that etravirine does not decrease raltegravir concentrations in heavily pretreated patients and these results are in line with clinical and immuno-virological outcomes of the patients included in the ANRS139-TRIO trial showing the excellent efficacy of darunavir/ritonavir raltegravir and etravirine combination in the study population [9].
French, European and US guidelines recommend earlier initiation of combined anti-retroviral treatments (cART) [1–3]. Currently, cARTs are overall associated with fewer adverse events. Fixed dose combinations (FDCs) and single treatment regimen are more and more frequently used in HIV-infected patients because they are easier to take and thus considered to improve adherence. However, hindsight is still needed to fully assess the rare adverse events. We describe here the first case of skeletal muscle toxicity associated with rilpivirine (RPV). A 63-year-old man was consulted in June 2013 for subacute weight gain, fatigue and muscular pain. He had an A1 stage past medical history of HIV infection since 1985, with good immunologic profile and an undetectable plasma HIV-1 RNA for 12 years. His cART history began with zidovudine/lamivudine/abacavir FDC, continued with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)/efavirenz (EFV) FDC during 12 years recently changed from January 2013 for FTC/TDF/RPV FDC due to lipid abnormalities. Apart from HIV, he had a stable history of heart angina. He also presented HCV infection successfully treated in 2011 with sustained viral response. He was a semi-professional swimmer and still recently in excellent physical condition. Since the last switch to TDF/FTC/RPV FDC, he rapidly complained of change in his body shape, a gain of 8 kg of abdominal fat, myalgia at mild efforts and proximal muscular loss. Physical examination showed dual lipodystrophia with android obesity and amyotrophy of the proximal muscles. Creatine phosphokinase, aldolase and aspartate aminotransferase were normal. An abdominal computed tomographic scan showed inter-visceral fat accumulation. A muscular biopsy was performed and diagnosed a toxic myopathy with mitochondrial proliferations and cyclo-oxygenase (Cox)-negative fibres. There were no lipid inclusions, no vasculitis and no infiltrates. Tumour necrosis factor-alpha (TNF)-alpha and leptin circulating levels increased whereas adiponectin decreased during the acute cytopathy event (2.4, 5.6 and 4.2 pg/ml; 4.4, 5.7 and 4.5 ng/ml, respectively, before and during the cytopathy event). RPV, tenofovir and FTC concentrations 12 h after the last drug intake were at 377, 180, and 429 ng/ml, respectively. All were above the upper limit of acceptable concentrations. Consequently, RPV was discontinued in this patient and the EFV reinitiated with the same TDF/FTC backbone. Two months after the switch, the patient was doing well, no more complaining of fatigue and muscular pain; he has lost 6 kg in less than 2 weeks after switching. Circulating levels of TNF-alpha, leptin and adiponectin went back to normal values after the RPV switch (5.8, 3.6 and 5.3 μg/ml). Six months after the switch, he has now returned to his original weight (a total loss of 10 kg) and was able to practice swimming as well. Figure 1 presents disease slides with succinate dehydrogenase and Cox activities.Fig. 1: Histo-Enzymology on frozen section of deltoid muscle fragment.(a) Succinate dehydrogenase activity (arrow show fiber with mitochondrial proliferation). (b) Cyclo-oxygenase (Cox) activity (arrow show fiber with no Cox activity).RPV is a recently approved second-generation non-nucleoside reverse transcriptase inhibitor, marketed in coformulation with TDF and FTC in fixed-dose combination. It has demonstrated its noninferiority when compared with EFV as a first-line therapy and is an attractive option for switching therapy. Since the first clinical trials in 2008 and its approval in 2011, RPV has shown an excellent safety profile, compared in particular to EFV. The latest follow-up at 96 weeks has shown few neurologic or psychiatric symptoms, dermatologic abnormalities and mild changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride [4,5]. A case report of severe induced hepatitis on RPV has been published [6,7]. We describe here, to our knowledge, the first case of muscle toxicity associated with a FDC containing RPV. Although we have no clear causal relationship, the accountability of RPV is strong because it was the only changed drug during this period, and its discontinuation has led to an improvement of the symptoms. It was not ruled out whether this adverse event was the result of an excessive concentration or an intrinsic property of RPV. Both EFV and RPV plasma concentrations were above the respective toxicity cut-offs (4000 and 300 ng/ml, respectively). For EFV, such high concentrations might be explained by Cytochrome P450 2B6 genetic polymorphism. For RPV, the recent HCV liver disease (despite the successful treatment in 2011 and any significant fibrosis) might be an explanation of the higher plasma exposure observed. To conclude, even with new FDC regimens considered to be much better tolerated than previous ART regimens, data regarding follow-up of the new drugs are still scarce. This case report describes the first case of skeletal muscle toxicity. Our data suggest that it could be dose-dependent. Plasma concentrations must be of interest when adverse events are suspected to rule out toxicity. Acknowledgements Conflicts of interest S.H. has received travel grants from BMS and MSD. G.P. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare and Splicos. Y.Y. is a board member and reports receiving consultancy honoria from Abbott, BMS, Gilead, MSD, Roche, Tibotec and ViiV Healthcare; he also reports receiving honoraria for development of educational presentations from Abbott, BMS, Gilead, Tibotec and ViiV Healthcare. F.X.L. has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers-Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare.
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