The science on Stribild

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24 Sep 2014

Stribild (sometimes known as the 'Quad' pill) was listed on the PBS on 1 May 2014 and is the third single tablet regimen (STR) available for people living with HIV in Australia.

Like the other two STRs, Atripla and Eviplera, Stribild is a highly effective HIV antiretroviral (ARV) drug that offers the convenience of once daily dosing in one pill, making it easier for people to remain adherent to their treatment and reducing costs.

Stribild is a combination of a newly licensed integrase inhibitor, elvitegravir (EVG), and two reverse transcriptase inhibitors: tenofovir DF (TDF) and emtricitabine (FTC). These are the three active antiviral drugs. The fourth drug in this quad combination is a new 'booster' drug, cobicistat (COBI), which has a similar structure to ritonavir (RTV) but which has no anti-HIV activity. Because Stribild contains two new drugs (EVG and COBI) it is worth considering how these work together to control HIV replication.

Elvitegravir (along with raltegravir and dolutegravir, the other integrase inhibitors) prevents the effective integration of HIV into the DNA in CD4+ T-cells. HIV propagation is thus prevented, which results in a rapid and sustained driving down of the amount of HIV in circulating blood (viral load). When EVG is administered with a booster drug which inhibits the rapid metabolism of EVG in the liver, more active drug becomes available and remains longer in the bloodstream.

Elvitegravir has been compared head-to-head over 96 weeks with raltegravir (RAL) in Study 0145 involving PLHIV who had failed previous treatments. In this highly treated group of patients (nearly two-thirds had resistance to two or more HIV drug classes) EVG was demonstrated to be equally effective as RAL and was well tolerated. It had fewer liver effects than RAL, but the frequency of diarrhoea in the first few weeks on treatment was slightly higher.

A small number of people developed resistance to either of these two integrase inhibitors. Elvitegravir resistance patterns overlap with those of RAL. This cross-resistance indicates that if someone develops resistance to one, they will probably have significant resistance to the other.

An extension to this study out to 144 weeks found that over 85% of the people choosing to maintain or switch to EVG had undetectable viral load .Once daily dosing of EVG (boosted with RTV) was thus shown be highly effective and non-inferior to RAL.

Elvitegravir must be taken with a meal (like rilpivirine in Eviplera) and at least two hours before or after antacids containing aluminium, magnesium hydroxide or calcium carbonate. If you don't take Stribild with food you'll probably not be getting enough EVG and your HIV may become resistant to its antiviral effect.

Cobicistat was developed as a boosting drug specifically to overcome some of the pill burden, drug-drug interactions, and side-effect issues of RTV. One of the concerns around COBI is the fact that, like tenofovir, it is excreted through the kidneys and may result in damage to what are known as the proximal tubules. However, COBI and tenofovir use different pathways through these tubules, and while tenofovir is known to increase in concentration in the tubules (and cause damage), COBI has no such effect. If you're on Stribild your doctor will monitor your kidney function carefully (in fact all the STRs have tenofovir, so all require careful monitoring and are not recommended for people with significant kidney problems).

 In PLHIV who have not previously taken HIV ARVs (treatment naïve), Stribild has been compared in clinical trials to atazanavir (ATV/r) and efavirenz (EFV), both in combination with TDF and FTC. Because it is a new single tablet regimen, its efficacy and safety in comparison to Atripla is of special interest.

Study 102 compared EFV with EVG/COBI both with TDF+FTC (equivalent respectively to Stribild and Atripla) in 700 participants who had not taken HIV meds previously. At week 48, the EVG arm was non-inferior to the EFV arm (88% vs 84% achieving undetectable viral load ). This virologic success was maintained through week 96 (84% vs 82% with UVL) and to 144 weeks (80.2% vs 75.3%).

Drug discontinuations were slightly more frequent in the EFV arm ,with 6% in the EVG arm vs 7.4% in the EFV arm discontinuing due to an adverse event. No patients after week 48 discontinued due to kidney issues.

Neuropsychiatric side effects were reported in 50.9% vs 67.9% for EVG and EFV arms respectively. Depression led to drug discontinuation in 1.4% of participants receiving EFV; similarly 1.4% receiving EFV discontinued due to rash. These results indicate that Stribild will maintain durable efficacy with fewer treatment-limiting side effects in comparison with Atripla.

Study 103 compared ATV/r with EVG/COBI both with TDF+FTC in 700 participants who had not taken HIV meds previously. At week 48, the EVG arm was non-inferior to the ATV/r arm (90% vs 87% achieving undetectable viral load ). This virologic success was maintained through week 96 (83% vs 82% with undetectable viral load ) and to 144 weeks (77.6% vs 74.6%).

Drug discontinuations were slightly more frequent in the ATV/r arm with 5.9% in the EVG arm vs 8.5% in the ATV/r arm discontinuing due to an adverse event .These included more frequent renal events, nausea, jaundice, dizziness and yellowing of the eyes in the ATV/r arms. However, such discontinuation affected less than 2% of participants.

Both arms saw small decreases in bone mineral density (BMD) in spine and hip; the loss of BMD in spine was significantly more in the ATV/r arm (-1.43% vs -3.68%). The side effects experienced by people between the two arms were similar, and were infrequent after 48 weeks. There were no significant differences in changes in blood lipids or triglycerides between the arms.

Overall, Stribild is a welcome addition to the range of single tablet regimens available in Australia. It has the advantage of including a highly effective integrase inhibitor with few side effects and drug-drug interactions. It is effective over all patient groups by age, ethnicity, gender and hepatitis status.

BY NEIL MCKELLER-STEWART