Key points

 

• Two integrase strand transfer inhibitors (InSTIs) are available in southern Africa, namely dolutegravir (DTG) and raltegravir (RAL).
• DTG is preferred to RAL because it has a higher barrier to resistance, is available in FDC formulation, and can be taken once daily.
• DTG has been shown to have greater efficacy than efavirenz (EFV), driven largely by superior tolerability.
• DTG causes a small increase in serum creatinine (SCr) (usually 10–20 μmol/L) due to interference with tubular creatinine secretion; however, this does not represent a decline in renal function.
• Although definitive data are still lacking, DTG may be teratogenic in a small proportion of cases, thus treatment decisions in women of reproductive age should be discussed and evaluated carefully (see Module 19).
• Weight gain is a newly recognised side-effect of InSTIs, more so with DTG than with RAL, and more so in black women and in patients with lower baseline CD4⁺ counts and higher VLs.

Integrase strand transfer inhibitors (InSTIs) – often simply termed ‘integrase inhibitors’ – work by preventing the transfer of proviral DNA strands into the host chromosomal DNA. Currently, two InSTIs are available in southern Africa: dolutegravir (DTG) and raltegravir (RAL). DTG is preferred to RAL due to its higher barrier to resistance, its availability in FDC formulation, and the ability to take the drug once daily. The SPRING-2 trial compared DTG- and RAL-containing first-line regimens and found no significant differences in virological suppression, and adverse effects were similar between treatment groups;¹¹ however, although no patients in the DTG arm were found to have developed resistance, one patient in the RAL arm developed InSTI resistance and four developed NRTI resistance. The high barrier to resistance of DTG-containing ART regimens has been replicated in other first-line studies and in a study of ART-experienced patients in which DTG was compared to RAL.^12-14 In a meta-analysis that included clinical trials and observational studies, the emergence of InSTI resistance was more common with RAL than with DTG (3.9% vs. 0.1%).¹⁵ However, the emergence of InSTI resistance in patients receiving RAL can compromise second-generation InSTIs such as DTG.

DTG use has been shown to be superior to EFV-based ART in the SINGLE trial.¹² This difference was largely driven by the superior tolerability of the DTG arm: 2% vs. 10% in the EFV arm had an adverse event leading to discontinuation of the study drug. DTG showed superior rates of viral suppression (71% vs. 63% respectively at 144 weeks).

DTG-based regimens have also been shown to be superior to PI-based regimens. As first-line therapy, DTG was superior to DRV/r with respect to both viral suppression rates and side-effect profile.¹³ The ARIA trial of ART-naïve women demonstrated DTG’s non-inferiority to ATV/r, although with a statistically significantly higher rate of viral suppression and fewer side-effects overall.¹⁶ In the DAWNING trial considering second-line regimens, DTG was superior to LPV/r.¹⁷ Importantly, at least one fully active NRTI was genotypically confirmed at baseline in this trial.

Data from the Tsepamo surveillance study in Botswana demonstrated a statistically higher rate of neural-tube defects (NTDs) among women who were taking DTG at the time of conception (0.3% vs. 0.1% in women receiving other ART in the periconception period).¹⁸ Unlike in South Africa, folate fortification of staple foods does not occur in Botswana. In contrast to the Botswana data, no NTDs were reported in a Brazilian cohort of 1468 women, 382 of whom were DTG-exposed.¹⁹ Although additional data will undoubtedly be forthcoming, it should be noted that the absolute risk is < 0.5%, and this risk may be outweighed by the additional benefits of DTG over alternative therapies. We recommend that women of childbearing potential (WOCP), particularly those who wish to become pregnant or who have no reliable access to effective contraception should be counselled adequately about the potential risks and benefits of DTG- vs. EFV-based ART, and should be offered a choice of first-line regimens.

DTG and RAL are generally well tolerated, with most side-effects being mild and very rarely leading to discontinuation. DTG may cause a mild increase in sCr due to interference with tubular secretion. This does not represent renal damage and is not an indication for switching to another drug. The rise in sCr occurs within the first few weeks, and persists for as long as the patient remains on DTG.

Common pitfall: Assuming that the rise in sCr seen in patients on DTG necessarily represents renal failure. In reality, the effect of DTG on creatinine secretion is of no consequence and does not represent a decline in renal function.

RAL and DTG can cause headaches when started, but this usually resolves. These drugs may also cause insomnia and neuropsychiatric side-effects. RAL and DTG can occasionally cause hypersensitivity rashes, including life-threatening rashes. Weight gain is more pronounced in patients taking an InSTI as part of their ART regimen (with the exception of cabotegravir, which is not currently available in South Africa). Black women, patients with low baseline CD4⁺ counts, and patients with high baseline VLs appear to be at greatest risk.²⁰ The risk also appears to be moderated by the companion drugs in the patient’s ART regimen. In the ADVANCE trial, women on a tenofovir alafenamide (TAF) + FTC + DTG regimen gained a median of 10 kg over 96 weeks, with little evidence of a plateau in the increase.²¹ In women, median weight gain in the same period in the TDF + FTC + DTG arm was 5 kg, and 3 kg in the TDF + FTC + EFV arm. In men, weight gain was approximately half as much in each arm. The long-term health implications of these findings are currently unclear, but clinicians should be aware of the possibility of weight gain, and encourage appropriate exercise and dietary measures to limit this.

Dosage and common adverse drug reactions of InSTIs are described in Table 3.
 

Key drug-drug interactions involving DTG are summarised in Table 4.