As has been previously reported, the new and exciting anti-retroviral, dolutegravir, is soon to become widely available in South Africa. Whilst its very real advantages have been extensively reported, Dr Tom Boyles, a senior research clinician at the Wits Reproductive Health and HIV Institute writes in Spotlight that the potential disadvantages have received relatively little attention.
Boyles writes: “In the past when new HIV drugs have become available, the advantages have clearly outweighed the disadvantages for the vast majority of people. For example, when tenofovir became available to replace D4T (stavudine), the choice to switch was straightforward for most patients; similarly when the current first line drugs became available in a fixed dose combination (FDC).
“In both cases there were clear advantages and very few disadvantages for most patients so they quite rightly demanded the new drugs.
“Now that the dolutegravir roll-out is on the horizon, we see an impatience to access the drug. However, it’s important to realise that it might not be right for everyone and that new does not necessarily mean better. For patients to make informed choices, they need to know how the advantages of dolutegravir may or may not apply to them and weigh these against the potential disadvantages.
“One issue with dolutegravir that has received considerable attention is the possible risk of serious birth defects if women conceive while taking the drug. This issue will not be discussed further here, other than to say that hopefully all women will be offered correct and up to date information as well as access to contraception so that they can make empowered decisions.
Six reasons to be cautious of dolutegravir
Potential risk of serious birth defects. See above.
Potential for insomnia. The commonest side effect of dolutegravir is insomnia, whilst this may be mitigated by taking treatment in the morning and may wane over time, it has led to some patients stopping the drug. Efavirenz has similar side effects when people first take it but many patients are now stable on efavirenz and free of this distressing side effect.
Potential for weight gain. It has not been widely reported, but early studies have suggested that dolutegravir might lead to weight gain in some patients. For example, a 2017 study found that virally suppressed patients who switched from an efavirenz-based regimen to dolutegravir (or a similar drug) gained around 3kg after taking it for 18 months. The effect was greatest for dolutegravir compared to other similar drugs. Another 2017 study found that among 462 patients who were virally suppressed and changed to dolutegravir, the average weight gain was also around 3 kg after only 9 months of treatment and was greater for women than men. While these are relatively small studies it is clear that one potential effect of switching from efavirenz to dolutegravir might be weight gain, which is associated with serious non-AIDS events, impacts body image, and can be a barrier to ARV adherence.
Skin and liver reactions. Almost all drugs used to treat HIV have been known to cause skin rashes or problems with the liver, and dolutegravir is no different. There is no suggestion that dolutegravir causes these problems more commonly than drugs such as efavirenz or lopinavir/ritonavir (tradename Aluvia). However, patients who are side-effect free on their current drugs do run a small risk of developing skin or liver problems if they change to dolutegravir.
Drug interactions. Dolutegravir rarely causes interactions with other drugs but it can be the ‘victim’ of drug interactions. Notably, it is necessary to double the dose when it is taken with rifampicin, the most important drug for treating TB.
Potential for the unknown. Possibly the most serious reason to be cautious about dolutegravir is the potential for as yet unknown side effects. History is littered with examples of drugs that were introduced with fanfare after successful trials, only to later be withdrawn from the market due to side effects that only became apparent when the drug was used by large numbers of patients and for a longer duration. This review lists 462 such examples from 1950 to 2013.
Boyles writes that in conclusion, there are several clear advantages to dolutegravir, notably its tolerability and high barrier to resistance and few would argue against its use in patients in whom this is most relevant.
He writes: “For example, patients who are newly diagnosed with HIV, returning to care after a period of treatment interruption and therefore at risk of drug resistance, those suffering side effects on their current regimen eg lopinavir/ritonavir, or those taking complex multi-tablet regimens. I would certainly advise patients to choose dolutegravir under any of those circumstances.
“However, the vast majority of patients in South Africa who will be offered dolutegravir, possibly over 2m, are currently virally suppressed and side effect-free on an efavirenz based FDC. For those patients the balance of advantages and disadvantages is less clear cut.
“The fact that dolutegravir is well tolerated and is a potent suppressor of viral load are of limited relevance to patients who are already side effect free and virally suppressed. However, those taking dolutegravir for the first time run the risk of developing new side effects, be they rashes, liver problems, insomnia, weight gain, or some new unknown side effect. They will also need to take dolutegravir twice a day if they need rifampicin for TB treatment.
“For these reasons, patients who are already virally suppressed and side effect free on the current first line FDC may have more to lose than to gain by switching to dolutegravir. A more sensible option may be to stick with their current regimen for now and see what side effects are seen in others before considering a switch. Hopefully, such patients will be counselled that in this case new does not necessarily mean better and they are empowered to make their own decisions on this important issue.”
[link url="https://www.spotlightnsp.co.za/2018/12/14/dolutegravir-why-new-does-not-automatically-mean-better/"]Spotlight report[/link]