Caveat emptor: Seven things every HIV patient should know about switching from efavirenz to dolutegravir

The launch of government’s long-awaited new antiretroviral therapy (ART) guidelines, including the widespread roll-out of the medicine dolutegravir, is imminent. While hailed by some as a wonder drug, like any other new drug dolutegravir comes with risks and benefits and patients deserve the right to be fully informed before deciding whether they would like to take this new medication.

Dolutegravir will be offered to new, returning, and stable patients with suppressed viral load, with the latter making up by far the largest group. Most of these patients currently take efavirenz and will be offered a single drug substitution to dolutegravir. The new guidelines will suggest that all patients should be counselled about the risks and benefits of making this switch. The following is a list of issues that should be discussed with any patient considering a switch from efavirenz to dolutegravir.

1. Safety in pregnancy

Efavirenz is known to be very safe in pregnancy. There is a roughly eight-fold increased risk of neural tube defects (NTDs) such as spina bifida in women who conceive while taking dolutegravir compared to efavirenz. It’s worth remembering that the absolute risks of NTDs on dolutegravir remains low at about three per 1,000 births, but the birth defects are serious.

Can anything be done? As well as avoiding unintended pregnancy with contraception, it may be possible to mitigate the risk of NTDs by taking folate (folic acid) around the time of conception. This is good advice for any woman wishing to fall pregnant, but is so far an unproven strategy for reducing the risks of dolutegravir in pregnancy.

2. Weight gain

Unfortunately, there have been no large-scale randomised studies on the effects of switching from efavirenz to dolutegravir, which makes it difficult to know exactly what will happen. However, studies of new and returning patients, who all tend to put on weight as they return to health, show that patients on dolutegravir tend to put on more weight than those on efavirenz — about 2kg extra in the first two years. The difference is most pronounced in black women; weight may continue to rise beyond two years, and may be aggravated by certain contraceptive methods.

While this cannot necessarily be extrapolated to patients who are currently stable on efavirenz, most experts believe that patients, and particularly black women, will tend to gain weight if they make the switch. It’s not known how much weight they will gain or whether the weight gain levels off over time.

Can anything be done? Patients who have undesirable weight gain on dolutegravir could request to switch back to efavirenz in the hope that their weight will return to where it was before.

3. Drug interactions

Both dolutegravir and efavirenz interact with other drugs (don’t mix well in the body). Drug interactions can lead to either toxic or sub-therapeutic levels of either ART or the interacting drug.

Dolutegravir generally has less drug interactions than efavirenz, but an important one is with rifampicin, the most important drug in standard TB treatment. Dolutegravir must not be taken with anti-acid medications and can increase blood levels of metformin, a common drug for treating diabetes.

Efavirenz has no significant interaction with rifampicin but cannot be taken with some epilepsy medications and can make some hormonal contraceptives less effective. There is a list of other medications that you might require for a shorter period that cannot be taken with efavirenz.

Can anything be done? Dolutegravir can be taken twice a day when also taking rifampicin, anti-acids can be safely taken at different times of day, and the dose of metformin can be reduced. Patients on efavirenz may need to use alternative methods of contraception and anti-epileptics and sometimes temporarily switch to another ARV if the interacting drug is only required for a short time.

4. Barrier to resistance

Dolutegravir has a much higher “barrier to resistance” than efavirenz which means that it’s harder for the HIV virus to become resistant to dolutegravir. In practical terms, this means that if patients have difficulty taking their ARVs every day, or stop taking them completely, there is more chance of dolutegravir working in the future than efavirenz.

This is of limited relevance to virally suppressed patients who rarely or never miss their medication, but might be important for patients who struggle with daily pills.

Can anything be done? Patients who do develop resistance to efavirenz would be able to switch to dolutegravir at that point.

5. Short-term side-effects

Patients who are currently taking efavirenz may remember some unpleasant side-effects in the first few weeks that they took it, particularly dizziness and vivid dreams. While this will now have passed, there is a risk of new short-term side-effects with dolutegravir. The commonest complaint with dolutegravir is insomnia.

Can anything be done? Short-term side-effects usually wear off over the first few weeks. Patients suffering insomnia with dolutegravir can take their medication when they wake up.

6. Long-term side-effects

The long-term side-effects of efavirenz are quite well known as it has now been used extensively in South Africa since 2005. Liver injury can occur in up to 8% of patients and usually begins in the first eight weeks of starting therapy, so patients who have been taking efavirenz for several years without liver injury are less likely to be affected. There is some evidence that long-term exposure to efavirenz has a negative effect on brain function in some patients, and this can be worsened when taking isoniazid as TB preventive therapy.

The long-term side-effects of dolutegravir are largely unknown so far as it has not been taken by large numbers of patients for long enough. There therefore remains the possibility of as yet unknown, but serious side-effects. So far, there has been a preliminary study showing that patients taking dolutegravir have smaller brains than those who take other ARVs, but this is yet to be confirmed.

Can anything be done? The current fixed dose combination with efavirenz contains 600mg of the drug. It is known that 400mg of efavirenz is just as effective so it may be possible to decrease the dose and therefore the side effects with no ill effects.

7. Service delivery

The new guidelines will state that patients can only be switched to dolutegravir if they have a suppressed viral load result within the past six months. This creates a problem for the about 1.9 million clinically stable patients who are currently enrolled in differentiated service delivery (DSD) models such as spaced fast lane, facility-based or community-based adherence clubs or external pick-up points. These patients only have a viral load taken once a year. So, in order to switch within the current guidelines, they would need to make at least one extra visit to see a clinician at their clinic. This may be a significant barrier to many patients who find it difficult to take time off work or childcare to attend clinics, as well as an unwanted burden on the healthcare system.

Can anything be done? There is little that patients can do about this, but a change in the guidelines to allow patients in DSD models with long-term suppression to switch to dolutegravir with a viral load result that is one year old would solve the problem.

Conclusion

In conclusion, there are multiple competing risks and benefits of virally suppressed patients switching from efavirenz to dolutegravir, making counselling a complex issue. Patients are likely to perceive the risks differently based on factors such as childbearing potential or desire, attitude to weight gain, fear of long-term side-effects, and the need for other medications.

All patients deserve to be fully informed of all these issues and have an opportunity to discuss their individual case. Given the large number of clinically stable patients in South Africa, it will be a mammoth task for a pressurised public health system. However, failure to properly discuss these issues will be a failure to provide a level of service that our patients deserve. MC

Dr Tom Boyles is an infectious diseases consultant at Helen Joseph Hospital, Johannesburg.