Weight gain stopping/switch rules for antiretroviral clinical trials

Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.

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Update on Adverse Effects of HIV Integrase Inhibitors

Current Treatment Options in Infectious Diseases ◽

10.1007/s40506-019-00203-7 ◽

2019 ◽

Vol 11 (4) ◽

pp. 372-387

Author(s):

Agnieszka Kolakowska ◽

Anaenza Freire Maresca ◽

Intira Jeannie Collins ◽

Johann Cailhol

Keyword(s):

Clinical Trials ◽

Weight Gain ◽

Adverse Effects ◽

Adverse Events ◽

Real Life ◽

Future Research ◽

People Living With Hiv ◽

Childbearing Age ◽

Vascular Events ◽

Increased Risk

Abstract Purpose of review The goal of this paper is to provide an up-to-date review of adverse events related to the class of integrase strand transfer inhibitors (INSTIs), which became the class of choice in few years. We sought answers specifically to issues pertaining to neuropsychiatric adverse events, as well as weight gain, which were the two most important categories of adverse events raised in recent studies based on real-life experience. The primary focus of this paper is on adults with a brief summary on pregnant women and children/adolescents. Recent findings Dolutegravir (DTG) bears the heaviest burden of neuropsychiatric side effects. Weight gain was reported with all INSTIs, although there are methodological caveats in the analyses and the findings need to be interpreted with caution. Moreover, due to recent findings on neural tube defects in infants exposed to dolutegravir during their peri-conception period, its use is not recommended for women of childbearing age without proper birth control method, while raltegravir remains the only drug which may be prescribed without caution. Given the importance of cognitive and metabolic co-morbidities in people living with HIV in regard to their quality of life, future research needs to focus on long-term effects of INSTIs in relation to these adverse events. Pharmacogenetics seems to be a promising tool. Safety during pregnancy is also another important issue to further clarify. Summary INSTIs are a generally well-tolerated class of antiretrovirals (ARV), and has a higher antiviral potency compared to other classes of ARV. Clinicians and patients need however to be aware of some red flags when starting with and monitoring patients on INSTIs. All INSTIs can lead to mild increases in creatinine levels, usually without clinical significance, but caution is needed in patients with low eGFR (<30ml/min), when using other nephrotoxic drugs, such as as tenofovir disoproxil. Neuro-psychiatric (NP) effects are to be monitored with INSTIs, especially with DTG (though reports are at times contradictory); clinicians might want to avoid DTG for patients with history of severe NP symptoms, until clarity is provided. Weight gain was reported with all INSTIs, especially with DTG, with possible differential effects according to sex and ethnicity (female and non-white patients being at increased risk). This is worrying since patients from African descent are at higher risk of cardio-vascular events and increased body mass index (BMI) can cause further increase metabolic risk. There is possibly an additional effect of tenofovir alafenamide (TAF) on weight increase. Discrepancies between clinical trials – with low rates of adverse events – and reports from real-life settings might be due partly to under-representation of some groups of patients in clinical trials, and/or the short duration of follow-up, since some adverse effects may only occur after prolonged exposure. Preliminary data on safety of bictegravir (BIC), from clinical trials and non-trial settings, are very reassuring and seem to show lower rates of adverse events compared to DTG. Elvitegravir/cobicistat (EVG/cobi) need to be used with caution in patients with other co-morbidities given potential for polypharmacy, as it is the case for aging patients, because of the high potential of drug-drug interactions due to effects of the cobicistat booster. We are awaiting the release of cabotegravir (CAB), which could represent a good option for patients struggling with adherence, despite injection site reactions. Pharmacogenetics is a promising way to explore adverse effects occurrence in the INSTI class.

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882. Use of Tenofovir Disoproxil Fumarate Shows Weight Loss vs Placebo: A Meta-Analysis of 7 Clinical Trials in 19,359 HIV-negative Individuals

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1077 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S533-S533

Author(s):

Shahini Shah ◽

Victoria Pilkington ◽

Andrew Hill

Keyword(s):

Weight Loss ◽

Clinical Trials ◽

Weight Gain ◽

Adverse Events ◽

Tenofovir Disoproxil Fumarate ◽

Meta Analysis ◽

Total Sample ◽

Separate Analysis ◽

Loss Of Appetite ◽

Hiv Negative

Abstract Background Recent clinical trials have shown weight gain associated with newer antiretrovirals. It is unclear how the nucleoside reverse transcriptase inhibitor backbone affects weight. Recent evidence suggests greater weight gain with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF). However, it is not fully understood whether TDF contributes to weight suppression or weight loss. Methods A systematic search of PubMed, Embase and clinicaltrials.gov was conducted to identify all randomised control trials comparing TDF/FTC or TDF to control in HIV-negative individuals. The primary endpoint included the number of events of ‘5% weight loss’ or ‘abnormal loss of weight’. The Mantel-Haenszel test with random-effects modelling was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Further analyses of gastrointestinal (GI) adverse events (AEs) were undertaken, including the number of reported adverse events of nausea, vomiting, loss of appetite and diarrhoea. Results Seven PrEP trials: PARTNERS, VOICE, TDF-2, Bangkok PrEP, iPrEX, FEM-PrEP and HPTN 084 were included in the analysis of weight loss, with a total sample size of 19,359. One study (HPTN 084) compared TDF/FTC to cabotegravir (CAB). The remaining compared either TDF or TDF/FTC or placebo. HIV-negative individuals taking TDF were more likely to experience weight loss compared to control (OR 1.44 95% CI 1.12 – 1.85 p = 0.005 (table 1)). In a separate analysis of GI AEs, exposure to TDF was also linked to greater odds of vomiting (OR 1.81 95% CI (1.20, 2.73) p < 0.005). There were no increased odds of nausea, diarrhoea, or loss of appetite. Weight loss events in PrEP trials. Conclusion There is evidence in HIV-negative individuals that TDF may be associated weight loss when compared to placebo. Further research should be carried out in HIV positive individuals, and clinical trials of TDF/FTC should publish weight data to widen the evidence base Disclosures All Authors: No reported disclosures

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Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials

Clinical Infectious Diseases ◽

10.1093/cid/ciz999 ◽

2019 ◽

Vol 71 (6) ◽

pp. 1379-1389 ◽

Cited By ~ 49

Author(s):

Paul E Sax ◽

Kristine M Erlandson ◽

Jordan E Lake ◽

Grace A Mccomsey ◽

Chloe Orkin ◽

...

Keyword(s):

Clinical Trials ◽

Weight Gain ◽

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Health Effect ◽

Demographic Factors ◽

Pooled Analysis ◽

Reverse Transcriptase Inhibitors ◽

Factors Associated ◽

Art Initiation

Abstract Background Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. Methods We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. Results Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. Conclusions Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

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Non-insulin therapies in addition to insulin in Type 1 DM treatment

British Medical Bulletin ◽

10.1093/bmb/ldaa011 ◽

2020 ◽

Vol 134 (1) ◽

pp. 54-62

Author(s):

Andrea Llano ◽

Gerard A McKay

Keyword(s):

Clinical Trials ◽

Weight Gain ◽

Glycaemic Control ◽

Diabetic Ketoacidosis ◽

Sglt2 Inhibitor ◽

Safety Data ◽

Sglt2 Inhibitors ◽

Current Time ◽

Insulin Dependent

Abstract Introduction Complications of Type 1 diabetes (T1DM) remain prevalent due to suboptimal glycaemic control despite advances in analogue insulin, its delivery and technological advances in glucose monitoring. Intensive insulin therapy is associated with hypoglycaemia and weight gain. Non–insulin-dependent glucose lowering strategies may provide a strategy in improving glycaemic control without hypoglycaemia and weight gain. Sources of data Research papers and reviews about adjunctive treatment with insulin in T1DM in the published literature. Areas of agreement Non–insulin-dependent strategies may be beneficial inT1DM particularly when there is insulin resistance, but the evidence for benefit at the current time is limited. Although there have been trials with various drugs as adjunctive therapy to insulin in T1DM currently in the UK, there is only one sodium glucose transport protein 2 (SGLT2) inhibitor with a marketing authorization for use in this indication. Areas of controversy Potential for harm with SGLT2 inhibitors in T1DM is a potential issue, particularly euglycaemic diabetic ketoacidosis. Clinical trials confirm that there is a risk albeit small, but emerging safety data have led to questions as to whether the risk of euglycaemic diabetic ketoacidosis is higher with the use of SGLT2 inhibitors in clinical practice. Growing points Patient education is paramount—the work being done in T1DM to ensure safe use of SGLT2 inhibitors may help improve safety in the prescribing of SGLT2 inhibitors in Type 2 diabetes. Areas timely for developing research There is a need for larger clinical trials with SGLT2 inhibitors in T1DM and real world studies to clarify safety.

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Pharmacological management of treatment-resistant schizophrenia: fundamentals of clozapine

10.1093/med/9780198828761.003.0006 ◽

2018 ◽

Author(s):

Yvonne Yang ◽

Stephen Marder

Keyword(s):

Clinical Trials ◽

Weight Gain ◽

Side Effects ◽

Plasma Concentrations ◽

Psychotic Symptoms ◽

Controlled Clinical Trials ◽

Treatment Resistant ◽

Minimum Duration ◽

Pharmacological Management ◽

Clozapine Treatment

Evidence from controlled clinical trials supports the prescribing of clozapine for patients with treatment-resistant schizophrenia (TRS). Early studies focused on severely ill TRS patients. More recent studies indicate that clozapine can be effective for patients who are relatively stable but are burdened by persistent psychotic symptoms. Clozapine treatment is associated with a substantial side effect burden, including sedation, orthostasis, weight gain, constipation, and seizures. In addition, because of a risk of potentially fatal agranulocytosis, clozapine patients require regular monitoring of their neutrophil count. Measuring clozapine plasma concentrations can be helpful in managing patients with severe side effects and those with an inadequate clinical response. A trial of clozapine should consist of a minimum duration of 12 weeks.

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PDB5 BODY WEIGHT GAIN EXPERIENCED BY DIABETIC PATIENTS DUE TO THIAZOLIDINEDIONES (TZDS): META-ANALYSIS OF PUBLISHED RANDOMIZED SHORT-TERM CLINICAL TRIALS

Value in Health ◽

10.1016/s1098-3015(10)68722-0 ◽

2007 ◽

Vol 10 (3) ◽

pp. A60

Author(s):

HM Phatak ◽

D Yin

Keyword(s):

Clinical Trials ◽

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Meta Analysis ◽

Diabetic Patients ◽

Short Term

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Applications of Massage in Children from the Perspective of Persian Medicine

Traditional and Integrative Medicine ◽

10.18502/tim.v5i4.5167 ◽

2021 ◽

Author(s):

Fatemeh Behdad ◽

Fataneh Hashem-Dabaghian

Keyword(s):

Clinical Trials ◽

Weight Gain ◽

Clinical Studies ◽

Joint Pain ◽

Selection Criteria ◽

Scientific Evidence ◽

Modern Medicine ◽

Persian Language ◽

Persian Medicine ◽

Growth Development

In Persian medicine (PM), massage is one of the principles for maintaining health. This study presents the viewpoint of PM about massage in pediatrics and the scientific evidence for its efficacy. The PM textbooks including Canon of Medicine, Mufarrah al-qulub, Kholase-alHekmah, Kholase-al-Tajareb, Tadbir al-hobali val atfal va-sebyan, Exir-e-Azam, Ehya-al-Atfal, Risalat-al-Dallakieh were reviewed for applications of massage in children. The keywords were Dalk, Ghamz, rubbing, and massage. The effectiveness of PM recommendations for massage in modern medicine was searched in Google Scholar, PubMed, Scopus and science direct, SID, and Magiran with the keywords massage, pediatrics, and children. The selection criteria were clinical trials or reviews on pediatric massage in English or Persian language without time limitation. Applications of pediatric massage in PM which scientific articles approve their efficacy include facilitating the growth, development, and weight gain, reducing muscle and joint pain, relieving colic and bloating, helping to treat skin dryness, and convulsion. Other applications including sore throats, colds, vomiting, and eye aberrations are needed to be evaluated in clinical studies.

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