HIV: TAF inc weight /metabolic changes

 A recent Swiss cohort study confirmed prior studies finding increased weight gain and lipid changes with tenofovir alafenamide (TAF); this study assessed changes after having been switched from tenofovir disoproxil fumarate, TDF, to TAF (see hiv TAF inc wt metab change AIM2021 in dropbox, or doi:10.7326/M20-4853)

 

Details: 

-- 4375 adults living with HIV who had been on TDF-containing regimens for 6 months or longer, comparing pre-vs post-switch to TAF vs those remaining on TDF, after 18 months. From January 2016 to August 2019

-- 5 University hospitals, affiliated hospitals, and private physicians in Switzerland participated

-- median age 50, 26% female, 51% normal BMI, median CD4 count 650, median duration of ART 11 years, mean duration of TDF before the index visit 8 years,

-- medical comorbidities: diabetes 5%, history of vascular disease 6%, smoker 37%, lipid-lowering therapy 15%, median weight 74 kg, median BMI 24, median HDL 50 mg/dL, median LDL 107 mg/dL, median triglycerides 118 mg/dL, median cholesterol/HDL ratio 3.7

-- 80% (3484 patients) switched to TAF, 20% (891 patients) continued TDF

-- those who switched to TAF were more likely to be male (75% vs 69%), MSM (50% vs 42%), had a lower eGFR (88 vs 96), and were more likely to be on an INSTI-based regimen (38% vs 21%)

-- median follow-up 17 months

 

Results: 

-- 18 months after switching to TAF: adjusted mean weight increase of 1.7 kg (1.5-2.0) vs 0.7 kg (0.4-1.0)

    -- these results were adjusted for the confounders of age, sex, BMI, CD4 count at index visit, and time since antiretroviral therapy initiated

-- review of their graphs showed that those who switched to TAF started to increase their weight significantly by about 6 months, and this continued for the next 6 months when it began to plateau

-- change in weight after 18 months, per 3^rd drug used:

        -- INSTI: the highest increase, 1.7 kg (1.0-2.4).

        -- either NNRTIs or PIs: 1.1kg

-- among those with baseline normal BMI: 14% on TAF became overweight/obese vs 8% continuing TDF. more significant weight gain if wt <80 kg

-- cholesterol levels 18 months after switching to TAF: HDL increased 1.9 mg/dL, LDL increased 4.7 mg/dL, triglycerides 16.1 mg/dL (a marginal increase in the LDL/HDL ratio: 2.14 increasing to 2.15)

-- new onset diabetes was not significantly different, incidence rate ratio 1.3 (0.7-2.8)

-- subgroup analysis also found that switching from abacavir to TAF was also associated with weight increases (i.e. the weight increases were not just from stopping the TDF)

 

Commentary: 

-- this was an impressive study in that it involved about 80% of all people living with HIV in Switzerland

-- they were able to compare patients who continued TDF vs those who switched to TAF, restricted to those with at least 6 and 12 months of follow-up

-- no difference in outcomes by restricting the study to individuals who had and HIV viral load of <50 copies per mL during the prior year and throughout follow-up

-- they also decreased confounding by restricting the analysis to those who otherwise had the rest of their HIV drug regimen unchanged

-- in their final analysis, those switching to TAF were more likely to become overweight and to experience worsening of the serum lipid levels. this was independent of whether the TAF was coadministered with PIs, NNRTIs, or INSTIs

-- this study complements other studies, (see http://gmodestmedblogs.blogspot.com/2020/10/hiv-treatmentprevention-guidelines-2020.html , which includes a meta-analysis of 8 RCTs in treatment naïve HIV patients, finding 4 kg increases with INSTIs, 2 to 3 kg increases with NNRTIs, and varying high amounts of weight gain with TAF (4.25 kg), abacavir (3.08 kg), TDF (2.07 kg), and ZDV ( 0.39 kg). Interestingly, TAF in this study had the highest weight gain of all, though only marginally higher than the INSTIs.

    -- one advantage of the Swiss study above is that it was a single large study with a consistently high-level database to access, and included the vast majority of people living with HIV in a single country (therefore it was not subject to the vagaries of different study methodologies incorporated into a meta-analysis)

-- the lack of finding of new onset diabetes is not so surprising in this healthy cohort, with mostly normal BMI is to start and followed only a short time

--  the study does raise the issue that we might more seriously consider switching people who are well-controlled on an INSTI plus (TAF or TDF)/(3TC or FTC) to an approved 2-drug (non-tenofovir) regime, such as dolutegravir/3TC (available as the single combo pill of Dovato), or perhaps dolutegravir/rilpivirine, or perhaps the newer injectable cabotegravir/rilpivirine

 

Limitations:

-- retrospective analysis of the large database, so there may be unmeasured confounders that bias results. For example, we do not know the reasons why some patients were changed from TDF to TAF, or why some remained on TDF.

-- This study had a short follow-up, and the weight gain curves were flattening out after 2 years. Would be useful to know longer-term outcomes, given that the increase in weight likely has more grave health consequences in the long term

-- i have not seen studies finding that stopping the TAF leads to weight loss...

so, this study adds more detail to prior studies finding that several HIV drugs are associated with increased weight, and this seems to be independent of the initial increase in weight that might have been attributed to the initial control of the virus and its bodily effects (including, of course, weight loss). a few points:

--weight increases are so potentially devastating (associated increased bodily inflammation, and the array of associated diseases such as diabetes, hypertension, heart disease, many cancers.....)

--even in this thin, healthy Swiss population, there were adverse metabolic consequences, including significant increases in overweight/obesity

--perhaps the most difficult primary care/public health task we face in the long-term is weight control (at least we have vaccines for covid-19...)

--it might make sense to consider more highly the 2-drug HIV regimens that do not include tenofovir, both as an initial therapy or as a switch in virally-controlled patients on tenofovir-containing regimens .....

for more info or the 2-drug regimen, see http://gmodestmedblogs.blogspot.com/2020/10/hiv-treatmentprevention-guidelines-2020.html for recommendations, and http://gmodestmedblogs.blogspot.com/2018/12/2-drug-therapy-for-hiv.html for the 2-drug GEMINI trials

geoff

 

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