Overview of weight gain, integrase inhibitors and ART

Kirk Taylor, HIV i-Base

BHIVA 2023 included a detailed overview of the association between weight gain and antiretrovirals by Professor Andrew Carr from St Vincent’s Hospital Sydney. [1]

Both tenofovir disoproxil (TD) and efavirenz (EFV) have been linked to weight loss, whilst tenofovir alafenamide (TAF), dolutegravir (DTG) and bictegravir (BIC) are linked to weight gain.

In addition to the effect on quality of life, the clinical impact from each 5 kg/m² increase in BMI is a 30% increase in mortality. This effect is independent of age, sex or geographic region. For an average Australian man this would require a 15 kg increase in weight. ART-associated weight gain is between 2 kg to 10 kg.

WHO statistics show a tripling of the global prevalence of obesity (BMI >30 kg/m2) between 1975 to 2016, then standing at 13%. Seven countries have a prevalence >30%, including the UK, led by America where 40% of adults are now estimated to be obese. Based on limited data, obesity is estimated between 15 to 39% in people living with HIV, showing a need for better research. Being overweight increases risk of comorbidities (e.g. cardiovascular disease (CVD), hypertension, type-2 diabetes, multiple cancers, sleep apnea and fatty liver disease).

Professor Carr emphasised the historical lag time (taking from 4 to 18 years) for establishing links between ART and comorbidities and that initial attribution has not always been correct. For example, the signal between myocardial infarction and abacavir (ABC) use took 10 years. Meanwhile, TDF-associated weight loss took 18 years and DTG-related weight gain has taken 6 years to establish. Although lipoatrophy was initially linked to PIs, it took five years to show that this was caused by the thymidine analogues AZT and d4T.

ART and weight gain: evidence from research studies

The talk reviewed several studies that reported weight changes.

START reported weight loss for those with viral load <3000 copies/mL who started TDF-efavirenz (EFV) immediately. There were no differences in weight gain with higher baseline viral load when there would have been a return-to-health increase in weight.
NA-ACCORD reported weight gain over six years for people receiving INSTIs (+5.9 kg, n=4093), protease inhibitors (+5.5 kg, n=7063) and NNRTIs (+3.7 kg, n=1071). The majority of the weight gain occurred within two years and then continued in line with the USA average (+0.5 to 1.0 kg/year).
Gilead reviewed weight gain in their studies and reported odds ratios (OR) for weight gain with use of BIC or DTG vs EFV (OR: 1.82), rilpivirine (RPV) vs EFV (OR: 1.57), TAF vs ABC (OR: 1.90) or TAF vs TDF (OR: 1.47). Baseline CD4 count <200 cells/mm3 (OR: 4.36), RNA >100,000 copies/mL (OR: 4.98), baseline BMI >25 kg/m² (OR 1.54), being a women (OR: 1.54) and Black ethnicity (OR: 1.32) all increased chance of weight gain (OR: ≥1.66).
ADVANCE reported greater weight gain for women compared to men. This was higher in people using TAF vs TDF. It was also greater in people who received DTG vs EFV, although this effect was only seen in slow metabolisers of EFV. It is still unclear whether weight gain will continue or whether it reaches a plateau after about three years. Given the importance of ADVANCE in identifying weight increases, Carr showed two large South African datasets showing that after three years, the average weight in ADVANCE only returned to the average weight. These population studies also report BMI as approximately 5 kg/m² higher for women compared to men.
IMPAACT/VESTED was largely run in Uganda, South Africa and Zimbabwe, and reported weight gain during pregnancy for DTG/TAF (+0.38 kg/week) that was close to the expected level (+0.42 kg/week) but this was significantly lower with EFV/TDF (+0.29 kg/week). Lower weight gain is linked to more adverse pregnancy outcomes and smaller babies.
OPERA reported an approximate 2 kg increase over the first nine months after switching from TDF to TAF, before returning to a steady weight gain over five years similar to pre-switch. Weight gain at nine months for those also switching to an INSTI, NNRTI or PI was 2.64 kg, 2.25 kg or 1.98 kg, respectively. Subsequent weight gain was steady, suggesting it is not a sustained phenomenon.
STEAL reported an approximate +1 kg difference in people switching NRTIs to include abacavir compared to TDF.
TANGO reported no change in weight gain for people switching from TAF to DTG after three years, showing potentially a similar impact.
NEAT022 reported greater weight gain at one year (+0.56 kg) for people who switched immediately from a PI to DTG. However, there is great variation in these data showing some people gain significantly more weight than others. During the second year, a similar increase was seen in the deferred switch group.

When considering the effect of ART on weight gain, we learn more from individual trials where single components are switched. At this level, data suggests that switching from elvitegravir (EVG) to BIC, from EFV to rilpivirine (RPV) or from ABC/TDF to TAF leads to a small increase in weight. No differences in weight occur when switching from DTG to BIC.

Data from PrEP in people who were HIV negative

PrEP studies provide opportunities to study direct effect of ART on weight gain without HIV-associated factors. Weight increases across one year for cabotegravir (CAB) were greater than for TDF-FTC at +1.3 kg and +0.3 kg, respectively (p<0.001). There were no differences when cabotegravir was compared to placebo, suggesting that weight loss caused by TDF was more likely than increases from cabotegravir.

Participants that received TDF in the iPrEX study experienced initial weight loss of 0.8 kg, which recovered to normal levels by year two. Conversely, participants on TAF or TDF in the DISCOVER study gained 1.7 kg or 0.5 kg across two years, respectively.

Comorbidities and INSTIs

RESPOND data show a prevalence rate for hypertension of 12.6% per 100 person years. Hypertension was more common on INSTIs than NNRTIs, but risk was similar for PIs and INSTIs.

Incidence of NAFLD (non-alcoholic fatty liver disease) is greater for people living with HIV who have diabetes (OR: 4.7), increased BMI (OR: 2.1) and women (OR: 7.3) but is not due to INSTI use (OR: 0.8). The risk of progression to fibrosis is greater for women (OR: 7.3). Excessive weight gain increases the incidence of diabetes and is more common in people who receive DTG or EVG.

Although the risk of CVD rises in the first three years of INSTI in unadjusted data, in adjusted analyses the signal peaks in the first six months and it is likely that people starting INSTI-based therapy have greater baseline CVD risk. The Swiss cohort study reported that the risk of myocardial infarction was 34.3% for people receiving an INSTI, compared to 65.7% for those on other ART regimens. Since 2013, this large cohort (n=5362) includes a third of people starting with INSTI-based regimen due to updated EACS guidelines.

The ATHENA cohort reported that CVD risk in the era of PIs was driven largely by traditional factors (e.g. smoking and hypertension). Carr believes that as INSTIs don’t have similar metabolic effects to PIs, traditional factors will primarily drive CVD risk for people receiving INSTIs.

Approaches to reducing weight

In primary care settings, the single most effective weight loss strategy is to combine calorie restriction with increased physical activity.

People living with HIV who are already overweight or obese people can also consider: (i) switching away from an INSTI or TAF, (ii) weight loss medication (e.g. GLP-1 agonists), or (iii) bariatric surgery (currently only supported for HIV in limited case reports). Reviewing medications for comorbid conditions may also help (e.g. antipsychotics and steroids). Although GLP-1 agonists report significant weight reductions (12% after a year) this commonly returns to baseline if therapy stopped.

A randomised placebo-controlled trial of switching from B/F/TAF to doravirine/islatravir (DOR/ISL) reported no significant increase in weight at year one (+0.3 kg, p=0.39). SOLAR reported no significant weight gain at one year after switching from B/F/TAF to long-acting injections of CAB+RPV. Notably, SOLAR participants were neither overweight at baseline nor did they experience weight gain on B/F/TAF.

In a placebo-controlled study, weekly dosing of a GLP-1 agonist (e.g. semaglutide) induced a 12% decrease in weight across a year, whilst reducing incidence of diabetes and CVD. Semaglutide is currently being investigated for use in people living with HIV who are obese.

What does this mean?

This data was then interpreted using the example of an average Australian man weighing 86 kg with a BMI of 27.8 kg/m² to model ART-related weight gain.

For each 15 kg of weight gain, their BMI increases by 5 kg/m² and their mortality risk rises by 30%. Expected weight gain on INSTIs or TAF is between 2 kg to 10 kg and may increase morbidity, which is linked to smaller BMI increments. However, Australian men are not an adequate marker for people living with HIV globally, especially as the ADVANCE study reported that weight gain disproportionately affected African women.

Whilst weight gain might not generally be severe, there are outliers and sub-groups where increased weight is likely to drive comorbidities and deaths, even without obesity. Weight gain associated with initiating INSTI-based therapy is greater than switching ART or taking PrEP, which may reflect the return to health phenomenon.

TDF and EFV have been linked to weight loss but TAF, DTG and BIC can increase weight. Other INSTIs (i.e. CAB) have not been linked to weight gain but dolutegravir was often used in the control groups.

It remains unclear why high levels of plasma tenofovir (TDF) induce fat loss but low levels (TAF) lead to weight gain. Traditional interventions to prevent and treat CVD and weight gain remain more beneficial than switching from an INSTI or TAF, but doing both might have additive results.

Less optimistically, the talk included the possibility that weight changes induced by ART might not be reversible, similar to weight gain experiences reported with steroids, antipsychotics and after pregnancy.

The Q&A to the talk included a discussion of whether TAF-associated weight gain is more related to the drugs that people have switched from (e.g. TDF or EFV). Although data to inform this question could come from a study that added either an INSTI or TAF to non-TDF containing ART, very few people use such combinations. There would be ethical issues in this approach and also for placebo-controlled studies in this area.

There is currently no mechanism to explain weight gain, although as 5% of people in PrEP studies withdraw due to nausea, there may be an effect on mitochondria and metabolism changes with INSTIs. However, there are limited mechanistic studies and we still don’t know the root cause(s).

comment

This excellent review highlighted the complexity of interpreting results from different study designs in different populations. Nevertheless, a common consideration was that the clinical implications are more significant for those with greatest increases in weight, including outliers and that these participants are often overlooked when average changes are reported.

For example, in ADVANCE some drugs are associated with weight gain and others with weight loss and these changes will cancel each effect when comparing average outcomes to expected weight in the South African general population datasets. The changes seen in ADVANCE linked to different components of ART are supported by the randomised study design.

Diet and exercise (ideally combining both) are currently first-line management for reducing weight, but this needs to be based on achievable goals and supported by professional advice. [2]

However, behaviour change can be difficult to sustain in the long-term, and these are not always easy to achieve in all settings. A WHO analysis from 121 studies looking at dietary interventions in over 20,000 participants only reported an average weight loss of –3 kg over 12 months. Adding exercise can have much more significant results.

Clarity about the impact of antiretrovirals is therefore critical to be able to individualise options for people who are most affected.

References

Carr A. Longer-term safety of integrase inhibitors. BHIVA Spring Conference 2023 (BHIVA 2023), 24-26 April 2023, Gateshead.
https://www.bhiva.org/file/645ba42c50868/Andrew-Carr.pdf (PDF slides)
https://vimeo.com/823052252 (webcast)
Collins S. Weight changes on ART and how to lose weight successfully. HTB (1 June 2021).
https://i-base.info/htb/40717