Obesity and HIV Treatmentregist2.virology-education.com/presentations/2019/HealthyLiving/13... · • Obesity overview • The ART & weight gain story • Possible mechanisms •

Obesity and HIV Treatment Knowns and unknowns

Laura Waters

Consultant Physician GU/HIV MedicineMortimer Market Centre, CNWL, London

Content

• Obesity overview

• The ART & weight gain story

• Possible mechanisms

• What should we do?

• The unknowns

• What can we learn from other fields?

What’s happening at home

Adult obesity in England

• The Health Survey for England 2017 – 28.7% of adults are obese BMI of (30+)

– 35.6% are overweight but not obese (25-30)

• Risk factors for being overweight/obesity:– 67.2% of men, 61.5% of women

– 65-74 yr olds most likely to be overweight/obese

• In the most deprived areas prevalence of excess weight is 11% > least deprived areas

https://researchbriefings.parliament.uk/ResearchBriefing/Summary/SN03336

Complications of obesity

• Major public health problem due to association with:– T2DM, HTN & hyperlipidaemia (all major CVD risk factors for CVD)

– Cancer

– Liver disease

– Disability

– Poor mental & psychological health

– Reduced QoL

– Premature death: in England 6.8% of deaths are attributable to obesity

https://www.england.nhs.uk/wp-content/uploads/2016/05/appndx-7-obesity-surgery-guid.pdf

THE ART & WEIGHT STORY

The weight & ART story in a nutshell

• Patient reports

• Case series & cohort analyses

• Analyses of RCTs

• Ongoing uncertainty– Mechanisms

– Implications

– Reversibility

A pre-2019 summary

Hill A et al, J Virus Erad 2019

Paper summary: observational studies

• In 2017–2018, results from four observational cohort studiessuggested integrase inhibitors are associated with greater increases in body weight, particularly among women

• Several (not all) studies (switch & 1st line) report greater weight on INSTI vs other classes– DTG > earlier INSTI

– ABC & TAF > TDF

– Risk factors: Female, non-white, >50 years

Hill A et al, J Virus Erad 2019

Weight: randomised studies

Waters L et al. P102 Glasgow 2018; Hill A et al, J Virus Erad 2019; Landowitz et al., CROI 2019 abstract 34LB; Hare et al., abstract 104

NEAT-001Trunk fat 7.3%more on RAL/DRV/rvs TDF/FTC + DRV/r

ACTG 5256sMore severe Weight gain on RAL vs ATV/r

Spring-1Greater weightrise on all DTG doses vs EFV

GS-1490 W96+3.9 kg on DTG+3.5 kg on BIC

All first line studiesReturn to health???

NEAT-022

PrEP studiesDISCOVER 48W: +1.1kg TAF/FTCNo change TDF/FTC

HPTN077No difference CAB vsplacebo

NRTI backbone contribution?

• AMBER trial:– Greater increase in body weight with 1st-line TAF/FTC/DRV/c (+1.8 kg)

vs with TDF/FTC + DRV/c (0.8 kg)

• German cohort study:– Mean body weight increase of 2.3 kg after switching from TDF to TAF

• STEAL Study (randomised switch to ABC or TDF) – Increases in body weight to week 96 were 1 kg higher in the ABC arm

Hill A et al, J Virus Erad 2019

UPDATES SINCE….

Variable levels of weight gain observed in different studies Variable reporting of mean and median weight gain

Differences in gender, race, age, weight, and other baseline demographics between clinical trial populations.

First-line studiesWeight Change at 96 Weeks

Weight: updates at IAS 2019

• NAMSAL 48 weeks (baseline BMI: 23)– Significantly more weight/BMI gain & emergent obesity on TDF/3TC +

DTG vs TDF/3TC/EFV400

• ADVANCE 96 weeks (baseline BMI: 22 in men, 27 in women)– TAF/F/DTG vs TDF/F/DTG vs TDF/FTC/EFV

– Men +5kg, +4kg, +1kg (DEXA: similar fat/lean mass gain)

– Women +10kg, +5kg, +3kg (DEXA: fat>lean mass gain)

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ADVANCE: BMI category over time: women (obese at baseline excluded)

What about TANGO?

• Suppressed switch: continued TAF-based 3DR vs DTG/3TC– 48 week weight change: +0.8kg on each arm

• What does this tell us?– Not much!

– Most participants were not on DTG (or BIC) at baseline so the addition of DTG may be counterbalancing the removal of TAF

– Or the weight gain in both arms could be ‘normal’

WHAT ARE THE MECHANISMS?

Is this just weight ‘normalisation’?Original Article

Incidence and Risk Factors for Overweightand Obesity after Init iat ion of Ant iret roviralTherapy in Dar es Salaam, Tanzania

Alexander Kintu, MD, MS1, Enju Liu, MD, PhD2,Ellen Her tzmark, MA2,3,4, Donna Spiegelman, SD2,3,4,Rachel Margaret Zack, SM3, A isa Muya, MD, MPH5, David Sando, MD, SM1,5,T ill Barnighausen, MD, SD1, and W afaie Fawzi, MBBS, SD1,2,3

Abst ract

Object ive: To describe the incidence of and risk factors for overweight and obesity following antiretroviral therapy (ART)

initiation. Methods: We used Cox proportional hazardsmodels to investigate risk factors for incident overweight and obesity in

79 074 individuals aged 15 years or older who initiated ART in Dar es Salaam, Tanzania. Results: Twenty-five percent of the

patients became overweight and 10%became obese. The incidence rate of obesity was3.2 per 100 person-years (95%confidence

interval [CI]: 3.1-3.3) in patients who were of normal weight before starting ART and 22.6 per 100 person-years (95%CI: 21.9-

23.3) in those who were overweight. Lower CD4 count was associated with ahigher risk of overweight and obesity (Pvalue for

trend < .0001). Conclusion: There isahigh burden of overweight and obesity after startingART, leading to proportions of these

2 conditions that are similar to those in the general population.

Keywords

antiretroviral therapy, overweight, obesity, incidence, risk factors

Int roduct ion

The scale-up of HIV treatment and careservices in sub-Saharan

Africa (SSA) has resulted in a large increase in the number of

patientson antiretroviral therapy (ART).1 In Tanzania, over 470

000 (31%) of the 1.5 million HIV-positive adults had been

started on ART by 2014.2 Wider access to ART in similar set-

tingshasled to fewer deathsdueto HIV/AIDSand hasalso been

shown to result in increased life expectancy at birth.3 Addition-

ally, many patients now start ART before progressing to

advanced stagesof HIV dueto changesin treatment guidelines.4

Increased survival predisposes HIV-positive individuals to

conditionsassociated with aging. Several studieshavedescribed

increasingproportionsof overweight andobesity inpeopleliving

withHIV/AIDSinSSA.5-7Inalargecross-sectional study inDar

es Salaam, Tanzania, we found that 18% of HIV-positive indi-

vidualswereoverweight (25 body massindex [BMI] < 30) and

7% were obese (BMI 30).5 Population-based studiescompar-

ing overweight and obesity prevalence in HIV-positive individ-

uals to HIV-negative individuals are l imi ted in SSA.

Demographic surveillance data from rural South Africa showed

a similar prevalence of overweight in HIV-positive and HIV-

negative individuals.7 With more HIV-positive patients becom-

ing overweight and obese, there is a need for improvements in

monitoring and managing excessive weight gain in patients on

ART. Thisrequiresabetter understandingof risk factorsfor over-

weight andobesity inthispopulation.Thereisalsolimiteddataon

progression tooverweight and obesity in patientsstartedonART

in SSA. Morestudieshaveinstead evaluatedshort-term trendsin

1 Department of Global Health and Population, Harvard T.H. Chan School of

Public Health, Boston, MA, USA2 Department of Nutrition, Harvard T.H. Chan School of Public Health,

Boston, MA, USA3 Department of Epidemiology, Harvard T.H. Chan School of Public Health,

Boston, MA, USA4 Department of Biostatistics, Harvard T.H. Chan School of Public Health,

Boston, MA, USA5 Management and Development for Health, Dar es Salaam, Tanzania

Corresponding Author :

Alexander Kintu, Department of Global Health and Population, Harvard T.H.

Chan School of Public Health, 665 Huntington Avenue Building 1, 11th Floor,

Boston, MA 02115, USA.

Email: [email protected]

Journal of the International

Association of Providers of AIDSCare

Volume 17: 1–10

ª The Author(s) 2018

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/2325958218759759

journals.sagepub.com/home/jia

Creative Commons Non Commercial CC BY-NC: This article isdistributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License

(http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission

provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

• 79,074 ≥15 year olds who initiated ART, median CD4 149

• 25% became overweight, 10% obese, assoc with lower CD4

• End result = overweight/obesity similar to general population

Or not, for some….?

• (NA-ACCORD) & US National Health and Nutrition Examination Survey (NHANES) comparison

• White WLWH had higher BMI after 3 years of ART vs age-matched controls ( p = 0.02); no difference for men & non-white women

Could this be?

• A new lipohypertrophy?

• ‘Obesogenic’ environment?

• Fewer GI side effects?

• Secondary to impact on mood? Or sleep?

• Is TDF protective due to it’s lipid-lowering impact?

• Return to health?

Francois Venter: IAS 2019

“This cannot be return to health as the weight trajectory

did not change after viral suppression was achieved”

• CD4:8 ratio continued to increase up to 15 yrs after starting ART; normalisation (>1) strongly related to baseline CD4 (only observed if baseline >200)

Could this be?

• A new lipohypertrophy?

• ‘Obesogenic’ environment?

• Fewer GI side effects?

• Secondary to impact on mood? Or sleep?

• Is TDF protective due to it’s lipid-lowering impact?

• Return to health?

• Something else?

Melanocortin

• In vitro, dolutegravir inhibits binding of radiolabelled α-melanocyte-stimulating hormone (MSH) to the human recombinant melanocortin 4 (MC4R) receptor by 64% at a concentration equal to the clinical Cmax

• MC4R involved in food intake & energy homeostasis regulation; MC4R deficiency associated with monogenic obesity

• Is this clinically relevant? What about other INSTI?

Why?

• Return to health?

• A new lipohypertrophy?

• ‘Obesogenic’ environment?

• Fewer GI side effects?

• Are people happier (or sadder) on integrases?

• Is it driven by backbone? Is TDF protective?

• Something else? DTG & melanocortin….

• Is it clinically important????

Morbidity

• Does drug-induced weight gain have the same consequences as other types of weight gain?

• Is the fat:mean mass ratio predictive of harm?

Pharmacokinetics

• Obese (n=291) vs BMI 20-25 (n=196) – On ABC, FTC, 3TC, TDF, EFV, ETR, nevirapine, ATV/r, DRV/r or LPV/r

– TFV, EFV & LPV C12 significantly lower & more likely to be below efficacy thresholds for obese individuals

Every cloud….

Neurology. 2019 Jun 14.

WHAT SHOULD WE DO?

What can we do?

• Counsel people

• Promote healthy lifestyle

• Record weight & waist circumference

• Collate data

Counsel people

• Starting ART may increase your weight– This may be more pronounced on INSTI and/or TAF

• No drug creates energy from thin air

• It is likely that any effect will be due to changes in appetite and/or metabolism

• Be prepared to do more and eat less

• Psychiatry evidence: a counselled person is less likely to gain weight

Provide health lifestyle information

• Give specific advice

• Follow up with additional resources– Written info

– Weblinks/apps

• Repeat that advice

• Include advice provided in GP letters

• Use it an opportunity to address other lifestyle factors

For people complaining of weight gain

• Review other causes

• Review family history

• Lifestyle promotion

• Consider switch…..

• At the moment there is no evidence to support ART switch to reduce weight

Measure weight & analyse/collate data

• We are not very good at this (in my clinic at least)

• We are definitely not very good at standardising it

• Would home measurement be more reliable?

• Regardless, the more data we collect, and share, the more we may understand this!

THE UNKNOWNS

Questions

• Do we have adequate control data?

• Does a rapid, drug-induced weight gain have the same metabolic complications as ‘endogenous’ weight gain?

• Will switch reverse weight gain?

• Is this a pharmocogenomics issue?– There are genetic predispositions to antipsychotic weight gain*

• Are there therapeutic interventions?

*J Clin Psychopharmacol. 2010 Dec;30(6):661-6.

WHAT CAN WE LEARN FROM OTHER FIELDS

Which other drugs are associated with weight gain?

• DMPA contraception

• Anti-depressants & anti-psychotics

Hormonal contraceptives

Antipsychotic-related weight gainNon-pharmacological trials (CBT &/or nutritional counselling)

Mean diff-2.6kg

RCT: 8 flexible intervention modules

(behavioral, nutrition, and exercise) vs warning + advice to “eat less do

more”

Metformin for antipsychotic weight gain

Mean diff-3.27kg

Benefits of metformin for people with HIV

Effects of Lifestyle Modification and Metformin on

Atherosclerotic Indices among HIV-Infected Patients with the

Metabolic Syndrome

Kathleen Fitch, MSN, Suhny Abbara, MD, Hang Lee, PhD, Eleni Stavrou, BA, Rachel Sacks,

BA, Theresa Michel, DPT, Linda Hemphill, MD, Martin Torriani, MD, and Steven Grinspoon,

MD

Massachusetts General Hospital (MGH) Program in Nutritional Metabolism (K.F., E.S., R.S.,

S.G.), MGH Cardiovascular Imaging Section (S.A.), MGH Department of Physical Therapy (T.M.),

MGH Cardiovascular Division (L.H.), MGH Division of Musculoskeletal Radiology (M.T.), MGH

Biostatistics Center (H.L.)

Abstract

Objective—Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and

abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery

calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population.

We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in

HIV patients with metabolic syndrome.

Design—A randomized, placebo controlled trial to investigate LSM and metformin, alone and in

combination, over one year, among 50 HIV-infected patients with metabolic syndrome.

Methods—We assessed CAC, cardiovascular and metabolic indices.

Results—Among the participants, duration of HIV-infection was 14± 1 yr and duration of

antiretroviral therapy was 6±1 yr. Metformin-treated subjects demonstrated significantly less

progression of CAC (−1±2 vs. 33±17, P=0.004, metformin vs. placebo) whereas the effect of LSM

on CAC progression was not significant (8± 6 vs. 21±14, P=0.82, LSM vs. no LSM). Metformin

had a significantly greater effect on CAC than LSM (P=0.01). Metformin-treated subjects also

demonstrated less progression in calcified plaque volume ( −0.4±1.9 vs. 27.6±13.8 mm3, P=0.008)

and improved HOMA-IR (P=0.05) compared to placebo. Subjects randomized to LSM vs. no

LSM showed significant improvement in HDL (P=0.03), hsCRP (P=0.05), and cardiorespiratory

fitness. Changes in CAC among the 4 groups: 1) no LSM, placebo (43± 30); 2) LSM, placebo

(19±7); 3) no LSM, metformin (1±1); and 4) LSM, metformin (−4±6) were different (P=0.03 for

ANOVA and linear trend across groups), the majority of this effect was mediated by metformin.

Results are mean ± SEM.

Conclusion—Metformin prevents plaque progression in HIV-infected patients with the

metabolic syndrome.

Keywords

Lifestyle modification; metformin; HIV; atherosclerosis

Correspondence and Reprint Requests: Steven Grinspoon, M.D., Director, MGH Program in Nutritional Metabolism, LON5-207;55 Fruit St.; Boston, MA 02114, Phone: 617-724-9109; Fax: 617-724-8998; [email protected].

Disclosures: The authors have no disclosures to make relative to this work.

NIH Public AccessAuthor ManuscriptAIDS. Author manuscript; available in PMC 2013 June 07.

Published in final edited form as:

AIDS. 2012 March 13; 26(5): 587–597. doi:10.1097/QAD.0b013e32834f33cc.

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• Randomised, placebo controlled trial: LSM vs metformin vsboth, over one year, in 50 PLWH with metabolic syndrome

• Metformin, not LSM, prevented coronary plaque progression

Metformin modulates T-cell activation & inflammation

Conclusions

• The are emerging differences between drugs regarding weight gain

• We don’t know why but we can still counsel patients

• Measure weight routinely

• Much work needed, particularly to understand impact on obesity-related diseases

• Listen to your patients!!

Thank you!

[email protected]@drlaurajwaters