Dolutegravir (Tivicay)

Detailed information

Dolutegravir (Tivicay) belongs to the class of antiretroviral drugs known as integrase inhibitors. The drug works against HIV's integrase protein, blocking its ability to integrate its genetic code into human cells.

It was given marketing approval by the Food and Drug Administration (FDA) in the US in 2013 and in Europe in January 2014 for use by adults and adolescents over 12 years of age.

Dolutegravir is also available as part of a fixed-dose combination pill called Triumeq. See Triumeq for further details.

Clinical trials leading to the approval of dolutegravir show that three-drug regimens containing the drug are highly effective and well tolerated. Several studies have shown that dolutegravir-based treatment is superior to treatment containing either darunavir/ritonavir or efavirenz in previously untreated people. The FLAMINGO study showed that dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) was superior to darunavir/ritonavir (90% vs 83% virally suppressed after 48 weeks), especially in people with high viral loads. (Feinberg) The SINGLE study compared dolutegravir/abacavir/lamivudine to Atripla. Here again, dolutegravir-based treatment was superior (88% vs 81% virally suppressed at 48 weeks) due to fewer side effects leading to treatment discontinuation. (Walmsley) The SPRING-2 study found that dolutegravir was equivalent to raltegravir in a 96-week study in previously untreated people. (Raffi)

Due to its high potency and good tolerability dolutegravir is recommended as a preferred element of first-line treatment in British HIV Association, US and European AIDS Clinical Society treatment guidelines.

Due to its lack of cross-resistance to raltegravir, dolutegravir is highly effective in suppressing viral load in people with raltegravir treatment failure, especially when dosed twice daily and combined with at least one other active drug. (Eron)

Dolutegravir has also been tested in clinical trials as part of a two-drug therapy in combination with  lamivudine or rilpivirine or darunavir. The combination of dolutegravir and lamivudine has been approved as a two-drug pill, marketed under the name Dovato. See Dovato for details of studies that led to its approval and further information about the combination.

The combination of dolutegravir and rilpivirine has been approved as a two-drug pill, marketed under the name Juluca. See Juluca for details of studies that led to its approval and further information about the combination.

The DUALIS study tested switching to dolutegravir and darunavir (boosted by ritonavir) in people with suppressed viral load on a three-drug regimen containing boosted darunavir. (Spinner). After 48 weeks, people who were assigned to switch to the two-drug regimen had a similar rate of viral suppression to those who remained on the three-drug regimen. Dolutegravir and darunavir each have a high barrier to resistance and this regimen may be an appropriate switch option for people with limited treatment options due to drug resistance and/or poor tolerance for nucleoside reverse transcriptase inhibitors.

Taking it

Dolutegravir is formulated as a yellow 50mg tablet. The dose of dolutegravir is 50mg (one tablet) once a day, or twice a day if taken with efavirenz, nevirapine, tipranavir, or for HIV known to be resistant to integrase inhibitors. It can be taken with our without food.

Glossary

resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

regimen

A combination of medications and the way it is taken.

effectiveness

How well something works (in real life conditions). See also 'efficacy'.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

antiretroviral (ARV)

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

You should not take antacids (used to treat indigestion and heartburn), calcium supplements, iron supplements or multivitamins for six hours before you take dolutegravir, or for at least two hours after taking dolutegravir.

Side effects

Important warning: An allergic (hypersensitivity) reaction has been reported in some people taking dolutegravir. This is not common, but you should see a doctor immediately if you think you are experiencing an allergic reaction. The symptoms are skin rash; fever; fatigue; swelling, sometimes of the face or mouth, causing breathing problems; muscle or joint aches.

Common side effects experienced by people taking dolutegravir include: nausea, diarrhoea, headache, rash, itching, vomiting, stomach pain or discomfort, abnormal dreams, fatigue, flatulence, increase in liver enzymes, increase in creatine phosphokinase (enzymes produced in the muscles). People taking dolutegravir may also be at higher risk of some central nervous system side effects, most commonly insomnia, dizziness and headache. These side effects may be more common in women, in people who take the drug combined with abacavir and in people over 60 years of age.

Rare side effects include allergic reaction, and liver inflammation.

Weight gain has been observed in people with HIV after starting antiretroviral treatment.

An analysis of eight clinical trials of new drugs introduced after 2003 found that weight gain was significantly greater in people taking an integrase inhibitor and that dolutegravir or bictegravir were associated with a higher risk of substantial weight gain (>10% of body mass) than other drugs of this type. (Sax 2019) A randomised study in South Africa which compared two dolutegravir-containing regimens to an efavirenz-containing regimen found that the combination of dolutegravir and tenofovir alafenamide was associated with greater weight gain (+6kg in men and +9kg in women over 96 weeks) and the risk of substantial weight gain was greater in women than men. (Venter). However, other randomised studies have not reported weight gain of similar magnitude and the extent of weight gain may be influenced by pre-treatment CD4 cell count, viral load, sex and race. (Sax 2019)

Drug interactions

It is very important to tell your prescribing doctor about any drugs you are taking, whether they are prescribed by another doctor, bought from a pharmacy, or herbal, recreational, or other drugs. There are some key drug interactions for dolutegravir, but your doctor or pharmacist should check for other interactions too. Do not take dolutegravir with dofetilide, a drug used to treat certain heart conditions. Dolutegravir also interacts with other drugs, which may mean you need to adjust the dose you take or need closer monitoring from your doctor. This includes metformin, rifampicin, some epilepsy drugs, and St John’s wort.

Resistance

Dolutegravir has a high barrier to the development of resistance. The emergence of resistance to dolutegravir in previously untreated or treatment-experienced people treated with three-drug or two-drug regimens containing dolutegravir is extremely rare unless resistance to another integrase inhibitor is already present. (Rhee)

The development of resistance to dolutegravir is more likely to occur when the drug is used as the sole treatment (monotherapy).

Dolutegravir is active against HIV that is resistant to the integrase inhibitor raltegravir at a dose of 50mg twice daily. As elvitegravir shares a similar resistance pattern to raltegravir, it is likely that dolutegravir is also active against HIV resistant to elvitegravir. (Eron)

Pregnancy

Women who take dolutegravir around the time of conception had a slightly higher risk of giving birth to an infant with a neural tube defect such as spina bifida compared to women taking other antiretroviral regimens, a surveillance study in Botswana has reported. The study investigators calculated that two excess cases of neural tube defect occurred per thousand infants exposed to the drug. (Zash) Other surveillance studies have not found a higher risk of neural tube defects, including studies in the United States and France. (Albano; Sibiude)

The World Health Organization has recommended that all adults and adolescents with HIV should start treatment with a dolutegravir-containing regimen.

The British HIV Association recommends that women wishing to conceive should be counselled about the potential risk of neural tube defects. If women choose to take dolutegravir during the first three months of pregnancy, folic acid supplementation is recommended.

Children

Dolutegravir is safe and effective in children and adolescents with HIV as part of a three-drug combination. The IMPAACT 1093 study showed that dolutegravir-containing antiretroviral therapy was highly effective in treatment-experienced children aged 6-12 years and moderately effective in adolescents aged 12-18. (Wiznia) (Viani)

Adult dosing (50mg once a day) is suitable for children weighing 20kg and over. (Bollen)

Dispersible 5mg tablets to be dissolved in water are available for children weighing between 3kg and 20kg, dosed by weight.

References

Feinberg J et al. Once-daily dolutegravir (DTG) is superior to darunavir/ ritonavir (DRV/r) in antiretroviral naive adults: 48 week results from FLAMINGO (ING114915). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, abstract H-1464a, 2013.

Walmsley S et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results - SINGLE (ING114467). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-556b, 2012.

Raffi F et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. The Lancet Infectious Diseases, 13: 927-935, November 2013.

Eron J et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24 week results in the VIKING study. Journal of Infectious Diseases, 207: 740-748 , 2013.

Spinner C et al. Efficacy and safety of switching to dolutegravir with boosted darunavir in virologically suppressed adults with HIV-1: a randomized, open-label non-inferiority trial: the DUALIS study. Open Forum Infectious Diseases, 7: ofaa356, 2020.

Sax P et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clinical Infectious Diseases, 71: 1379-89, 2019.

Venter W et al. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. The Lancet HIV, 7: e666-e676, October 2020.

Rhee S et al. A systematic review of the genetic mechanisms of dolutegravir resistance. Journal of Antimicrobial Chemotherapy, 74: 3135-3149, 2019.

Zash R et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. New England Journal of Medicine, 381:827-840, 2019.

Albano J et al. Integrase inhibitor exposure and CNS and neural tube defects: data from the Antiretroviral Pregnancy Registry. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 747, 2019.

Sibiude J et al. No increase in birth defects in infants exposed to integrase inhibitors at conception. Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 744, 2019.

Wiznia et al. IMPAACT 1093: Dolutegravir in 6- to 12-year old HIV-infected children: 48-week results. Conference on Retroviruses and Opportunistic Infections, Boston, abstract 816, 2016.

Viani R et al. Long-term safety and efficacy of dolutegravir in treatment-experienced adolescents with human immunodeficiency virus infection: results of the IMPAACT P1093 study. Journal of the Pediatric Infectious Diseases Society, 9: 159-165, 2020.

Bollen PDJ et al. Simplified dolutegravir dosing for children with HIV weighing 20kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. The Lancet HIV, 7: e533-44, 2020.

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