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Dolutegravir-based treatment regimens for adults with HIV

PRACTICAL THERAPEUTICS

 

Combination antiretroviral therapy is recommended as first-line treatment for HIV and developments in dolutegravir-based regimens are discussed in this article

 

Nadia Naous MPharm

Lead Pharmacist – HIV and Sexual Health

Imperial College Healthcare NHS Trust, UK

Email: nadia.naous@imperial.nhs.uk

 

Over the 30 years since the first described case of acquired immunodeficiency syndrome (AIDS),1 antiretroviral therapy (ART) has enabled people living with HIV a near-normal life expectancy.2 Despite the success of ART, HIV infection rates remain high and implementation of measures to prevent onward transmission remain a challenge. Combination antiretroviral therapy (cART) using three antiretrovirals (ARVs) is recommended for first-line treatment of HIV and the aims of treatment are to prevent disease progression, prolong and improve quality of life and reduce onward transmission of the virus. 

 

Combination antiretroviral treatment should suppress viral replication below the limits of detection, thereby terminating the destruction of CD4+ lymphocytes (CD4+ cells), allowing the CD4+ cell count to recover and enabling restoration of immune system functionality. There are now five available classes of ARV drug, with the class reflecting where in the HIV replication cycle the drug acts. 

 

First-line treatment for ARV-naïve patients consists of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in combination with one additional medicine from the following three ARV classes:3

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs
  • Ritonavir-boosted protease inhibitors (PIs)
  • Integrase inhibitors (INSTIs).

 

Choice of ART regimen

Choice of ART regimen should be tailored to the needs of the individual and important considerations include baseline viral load (amount of HIV virus in the blood), baseline CD4+ cell count, renal function, hepatic function, cardiovascular risk, potential for drug–drug interactions (DDIs), co-infection with hepatitis B and C viruses and genetic markers such as human leukocyte antigen (HLAB*5701) status. 

 

NRTIs

Recommended NRTI backbones include tenofovir with emtricitabine or abacavir with lamivudine; both of these combinations are available as fixed-dose combination tablets for once-daily dosing.  Tenofovir is nephrotoxic and should be used with caution in patients with pre-existing renal disease or risk factors for kidney disease (such as concomitant nephrotoxic drugs). Patients starting tenofovir-containing regimens may also experience a greater initial decrease in bone mineral density than those who start abacavir containing therapy, although bone density levels subsequently stabilise.  Abacavir is contraindicated if a patient has a positive test for the HLA B*5701 allele, as this is associated with risk of abacavir hypersensitivity.4,5 Even if patients are HLA B*5701 negative, counselling on hypersensitivity risk is still mandatory.3 Abacavir should be used with caution in persons with a high cardiovascular risk and/or persons with a baseline viral load of greater than 100,000 copies/ml.

 

NNRTI

Currently recommended NNRTI options are efavirenz and rilpivirine.3 Initiation of efavirenz is not recommended in pregnant women or women with no reliable and consistent contraception although continuation is possible if the mother has already commenced therapy prior to conception. Efavirenz is not active against HIV-2. Rilpivirine is a relatively novel member of the NNRTI class and should be initiated only if the baseline CD4 count cell count is greater than 200 cells/μl and the HIV viral load is less than 100,000 copies/ml. It cannot be used with concomitant proton pump inhibitor therapy and H2 antagonists should be taken 12 hours before or four hours after rilpivirine.

 

PIs

The boosted PIs, atazanavir and darunavir, are currently recommended as options for PI-containing regimens. PI-based ART is advantageous in some patients as the PIs have a higher genetic barrier to resistance. Ritonavir is not used at a therapeutic dose in such regimens but is used as a pharmacokinetic ‘booster’ by inhibiting the cytochrome P450 enzymes which metabolise the active PIs. This allows less frequent dosing and a more favourable pharmacokinetic profile. A disadvantage of ritonavir boosting is an increased propensity for DDIs, due to its effects on the cytochrome P450 enzymes.

 

INSTIs

The integrase inhibitors are a relatively novel class of ARVs and raltegravir was the first available drug in this class. Raltegravir has demonstrated similar virological efficacy to efavirenz in in treatment-naïve patients and a favourable lipid profile.6,7 More recently, a large randomised open-label trial, compared boosted atazanavir, boosted darunavir and raltegravir with a tenofovir/emtricitabine NRTI backbone. At week 96, all three regimens had similar virological efficacy. However, a composite endpoint, which was adjusted for tolerability failure, demonstrated that raltegravir was superior to both boosted PI-based regimens.8 

 

Raltegravir requires twice-daily dosing has a relatively modest genetic barrier to the development of resistance. Absorption of all integrase inhibitors can be reduced by co-administration of polyvalent cations, so patients taking these should be advised to separate doses of raltegravir from preparations containing cations such as calcium, zinc, magnesium, iron and aluminium.

 

Elvitegravir is a newer integrase inhibitor which when administered with ritonavir or the pharmacokinetic booster cobicistat, can be taken once-daily. Cobicistat has no ARV activity and a potent CYP3A4 inhibitor that can lead to clinically significant drug–drug interactions, and has a similar interaction profile to that of ritonavir. Elvitegravir also has a modest genetic barrier to resistance, an overlapping resistance profile to that of raltegravir and interacts with polyvalent cations as described above. Elvitegravir is available in a single tablet regimen containing tenofovir, emtricitabine, elvitegravir and cobicistat as well as a single component and a co-formulation with cobicistat. 

 

The elvitegravir containing single tablet regimen has demonstrated non-inferiority to both tenofovir, emtricitabine and efavirenz as a single tablet regimen and tenofovir, emtricitabine and boosted atazanavir in randomised controlled trials.9,10 Cobicistat inhibits the active tubular secretion of creatinine, which results in an increase in serum creatinine and therefore a decrease in estimated creatinine clearance, however, glomerular function is not reduced. Renal function should be closely monitored in the first four to eight weeks of therapy3 and any patients whose creatinine clearance continues to rise beyond this time should be closely monitored and evaluated for evidence of proximal renal tubulopathy.

 

Dolutegravir 

Dolutegravir is the most recently available drug in the integrase inhibitor family.

In randomised controlled trials in ARV-naïve subjects, dolutegravir has demonstrated either non-inferiority or superiority to alternative ‘third drugs’. 

 

SPRING-2

The SPRING-2 study compared 50mg once-daily to raltegravir 400mg twice-daily, each in combination with an NRTI backbone of either abacavir/lamivudine or tenofovir/emtricitabine. In this 96 week, Phase III, randomised double-blind, study, a total of 822 subjects were stratified by screening HIV-1 RNA plasma levels of greater than or less than or equal to 100,000 copies/ml) At week 96, 81% of subjects in the dolutegravir arm and 76% of subjects in the raltegravir achieved virological suppression (HIV-1 RNA <50 copies/ml), therefore confirming non-inferiority for dolutegravir. Within treatment groups, virological non-response was similar for either backbone, in contrast to the ACTG 5202 study where there was an inferior virological response in patients with baseline HIV RNA less than or equal to 100,000 copies/ml when abacavir/lamivudine was given with efavirenz or boosted atazanavir in comparison with tenofovir/emtricitabine. The tolerability and safety of both drugs were comparable for the duration of the study. 

 

SINGLE

The SINGLE study compared dolutegravir 50mg once-daily with an abacavir/lamivudine NRTI backbone to tenofovir/emtricitabine and efavirenz in 833 subjects. At week 48, virological suppression the dolutegravir was superior to that in the efavirenz arm; this was largely driven by the treatment discontinuation rate being higher in the efavirenz (10%) arm than in the dolutegravir arm (2%).13

 

FLAMINGO

Dolutegravir 50mg once-daily was compared to once-daily boosted darunavir with an abacavir/lamivudine or tenofovir/emtrcitabine backbone in the FLAMINGO study, a randomised open-label clinical trial. At week 48, dolutegravir was found to be superior to efavirenz (90% versus 83% had an HIV-1 RNA <50 copies/ml, p=0.025), with no statistically significant differences in virological response according to the NRTI backbone in the dolutegravir arm.14

 

These data support the use of once daily dolutegravir in ARV-naïve patients with either an abacavir/lamivudine or tenofovir/emtricitabine at any baseline viral load. Dolutegravir is generally well tolerated with a favourable lipid profile and can be taken with or without food, in treatment-naïve patients. Dolutegravir also inhibits tubular secretion of creatinine without affecting glomerular function, so as with cobicistat, renal function should be closely monitored in the first four to eight weeks of therapy3 and any patients whose creatinine clearance continues to rise beyond this time should be closely monitored and evaluated for evidence of proximal renal tubulopathy. Dolutegravir should be administered two hours before or six hours after taking medications containing polyvalent due to the interaction with integrase inhibitors detailed above. 

 

Dolutegravir is now available in a co-formulated single tablet regimen, with abacavir and lamivudine at doses of 50mg, 600mg and 300mg respectively, for the treatment of HIV-infected individuals. Because this preparation contains abacavir, screening for the HLA-B*5701 allele should be performed before initiating therapy, and a positive result is a contraindication to the initiation of abacavir-containing therapy. It should also be noted that if dosage adjustment of the lamivudine component is required, for example in renal impairment, separate components are more suitable. Patients co-infected with hepatitis B virus should also be treated with a tenofovir/emtricitabine containing regimen if appropriate as tenofovir, emtricitabine and lamivudine are active against hepatitis B virus, but abacavir is not.3 Treatment of ARV-experienced patients with integrase resistance can require twice-daily dosing of dolutegravir and this should also be considered when choosing an appropriate regimen and formulation.

 

In the case of resistance to ARVs, regimens should include at least two and preferably three active drugs, including active drugs from previously used classes. Such regimens should use at least one fully active PI with the addition of one drug from a class not used previously.3 A number of studies have been conducted using dolutegravir in treatment experienced patients.  

 

SAILING

The SAILING study was a 48-week, Phase III, randomised, controlled, double-blinded clinical trial. Participants were treatment experienced but not previously exposed to integrase inhibitors.15 They were not fully virologically supressed and had resistance to two or more classes of ARV. Their study regimens consisted of one to two fully active drugs for optimised background therapy with the addition of either once-daily dolutegravir or twice-daily raltegravir. At week 48, 71% (715 subjects) on the dolutegravir arm were virologically supressed compared to 64% on the comparator arm, demonstrating superiority of dolutegravir (p=0.03). The incidence of virological failure with integrase resistance was also significantly lower on dolutegravir arm (p=0.003). 

 

VIKING

VIKING-3 is an ongoing Phase III, randomised, placebo-controlled open-label, single arm study. ART-experienced participants with failure on integrase inhibitor-containing regimens (raltegravir and/or elvitegravir) were included in the trial. Dolutegravir was included in the failing regimen for seven days at a 50mg twice-daily dose and after that the ART background regimen was optimised. The proportion of study participants who were subsequently virologically suppressed (HIV-1 RNA <50 copies/ml) with optimised background regimen was 63% at week 24. Overall, 3% (6/183) of study participants discontinued treatment due to adverse events. The primary endpoints include the change at day eight from baseline in HIV-1 RNA with dolutegravir added to the currently failing regimen and the proportion of study participants with <50 copies/ml with the optimised background regimen at week 24 and beyond.16

 

Dolutegravir is metabolised mainly by glucuronidation via uridine diphosphate glucuronosyl-transferase 1A1, which accounts for about 95% of its metabolism and under 10% by cytochrome P450 enzymes. It does not have any significant induction or inhibition effects on the cytochrome P45 family of isoenzymes and is extensively protein bound. It is is a substrate for the transporters P-glycoprotein and breast cancer resistance protein, but does not demonstrate inhibition or induction of the transporters of these. 

In vitro data suggest that dolutegravir potently inhibits the renal organic OCT2 which is involved in the renal elimination of metformin. Therefore, it could potentially increase metformin concentrations so patients taking dolutegravir with metformin should be monitored for signs of metformin toxicity, such as lactic acidosis and changes in renal function, as dose adjustment may be necessary.

 

Key points

  • Dolutegravir is a novel HIV integrase inhibitor which is suitable for use in antiretroviral therapy-ART naïve and experienced patients.
  • Dolutegravir should not be taken at the same time as preparations containing polyvalent cations.
  • Dolutegravir is generally well tolerated with a low incidence of serious adverse reactions.
  • Dolutegravir is available in a fixed dose combination with abacavir/lamivudine.
  • Dolutegravir may be a suitable treatment option for patients with resistance to raltegravir and elvitegravir.

 

References

  1. Gottlieb MS et al. Pneumocystis pneumonia--Los Angeles. MMWR Morb Mortal Wkly Rep 1981;30(21):250–2.
  2. Nakagawa F et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012;26(3):335–43.
  3. European Aids Clinical Society. Guidelines for the clinical management and treatment of HIV-infected adults in Europe, November 2014 Version 7.1. www.eacsociety.org. (accessed 24 December 2014).
  4. Mallal S et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359(9308):727–32.
  5. Hetherington S et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359(9312):1121–2.
  6. Lennox JL et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796–806.
  7. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013;63(1):77–85.
  8. Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir or darunavir with FTC/tenofovir: ACTG 5257. Abstract 85. Paper presented at the 21st Conference on Retroviruses and Opportunistic Infections; March 3–6, 2014; Boston, MA.
  9. Zolopa A et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013;63(1):96–100. 
  10. Clumeck N et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Synr 014;65(3):e121–124. 
  11. Raffi F et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naïve adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13(11):927–35.
  12. Sax PE et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: Final results. J Infect Dis 2011;204(8):1191–201.
  13. Walmsley SL et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369(19):1807–18.
  14. Clotet B et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naïve adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014;383(9936):2222–31.
  15. Cahn P et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor naïve adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013;382(9893):700–8.
  16. Eron JJ et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 2013;207(5):740–8.

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