By: Ada Seldin, Staff Editor

–

On August 12,2013, a new weapon against HIV-1 infection was added to the existing armada. Dolutegravir, the third integrase strand transfer inhibitor to attain FDA approval, targets a protein essential to HIV replication. HIV-1 is the predominant type of HIV virus, the other being HIV-2, which is endogenous to West Africa. Although both types of the virus cause clinically indistinguishable AIDs, HIV-1 is more easily transmitted and has a shorter incubation period.¹ Because HIV therapy is so patient-specific and often involves a combination of agents, dolutegravir has the potential to enhance drug regimens. It is approved for use in treatment-naïve as well as treatment-experienced adults and children over 12 years of age who weigh at least 40 kg. The only distinction between the populations is that children who have previously taken raltegravir, another integrase strand transfer inhibitor, are not eligible for dolutegravir while adults are.² HIV integrase processes and transports viral DNA into the nucleus, where integration into the host genome occurs. Integration allows the viral DNA to be transcribed into mRNA, which is subsequently translated into viral proteins. Dolutegravir works by binding to integrase and blocking the incorporation of viral DNA into the host genome.³

Dolutegravir’s safety and effectiveness were established by four clinical trials involving 2,539 subjects. The randomized, multicenter, double-blind, active-controlled studies, SPRING-2 and SINGLE, provided evidence of the efficacy of dolutegravir in treatment-naïve adults. In   SPRING-2, dolutegravir was compared with raltegravir, and the results showed no significant difference in efficacy between the two. In SINGLE, dolutegravir in combination with Epzicom® was shown to be superior to just Atripla®. Treatment-experienced patients who had never received another integrase strand transfer inhibitor were tested in the trial SAILING, during which they were randomized to take either dolutegravir or raltegravir along with a background regimen. This time, dolutegravir actually outperformed raltegravir by 9.7% (95% CI: 3.4 – 15.9%). The multicenter, open-label, single-arm VIKING-3 trial studied the effects of dolutegravir on patients who had inadequate responses to other antiretroviral therapy and had evidence of raltegravir and/or elvitegravir resistance. These patients were given dolutegravir twice daily with the current failing background regimen for 7 days and were then switched to an optimized background therapy. The primary endpoint, the mean reduction from baseline in HIV-1 RNA at Day 8, was 1.4 log₁₀ (95% CI: 1.3 log₁₀-1.5 log₁₀). Data on pediatric patients were obtained from a fifth trial called IMPAACT. At week 24, 70% of the 23 subjects ages 12 to 17 who had received a once daily dose of dolutegravir in combination with background therapy achieved a viral load <50 copies/ml.⁴

Based on information gathered during the aforementioned clinical trials, in addition to Phase I and II studies, the recommended dosage of dolutegravir is 50 mg once daily for integrase strand transfer inhibitor-naïve patients and 50 mg twice daily for INSTI-experienced patients with suspected resistance. Certain drugs, such as rifampin, efavirenz, fosamprenavir/ritonavir, and tipranavir/ritonavir, are potent inducers of UGT1A1/CYP3A, and thus co-administration with these agents necessitates a dosage adjustment to 50 mg twice daily. Coadministration with dofetilide is contraindicated due to potentially life-threatening events. Cation-containing products, such as antacids, laxatives, oral iron or calcium supplements, or buffered medications, should be taken two hours before or six hours after drug administration.

Dolutegravir’s safety profile appears favorable. The most common adverse reactions associated with the drug are insomnia and headache. Patients with underlying hepatitis B or C are at increased risk for worsening transaminase elevations.⁴

Dolutegravir is marketed by ViiV Healthcare and manufactured by GlaxoSmithKline under the trade name, Tivicay®.² Since its ravaging emergence in the 1980s, HIV has gone from a deadly killer to a manageable disease state. Our knowledge of the viral machinery used to invade and replicate within our cells has led to the discovery of numerous drug entities. Thanks to HAART (highly active antiretroviral therapy), a combination regimen of several antiretroviral drugs, people with AIDs can live longer, healthier lives. Dolutegravir represents the continued effort of scientists to expand treatment options for people afflicted with HIV and improve their prognoses.

SOURCES:

1. What is the difference between HIV-1 and HIV-2? FoundCare 2013. http://www.foundcare.org/difference-HIV1-HIV2. Accessed September 16, 2013.
2. FDA approves new drug to treat HIV infection. U.S Food and Drug Administration Website. FDA News Release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm. Updated August 13, 2013. Accessed September 3, 2013.
3. Olivier Delelis, Kevin Carayon, Ali Saïb, et al. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology.2008; 114(5): 1742-4690.
4. Prescribing Information. U.S Food and Drug Administration Website.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf. Updated August, 2013. Accessed September 3, 2013.

Published by Rho Chi Post