The viral integrase enzyme has recently emerged as a primary alternative

The viral integrase enzyme has recently emerged as a primary alternative target to block HIV-1 replication and integrase inhibitors are considered a pivotal new class of antiretroviral drugs. 1A1 with a minor component of the cytochrome P450 3A4 isoform thereby limiting drug-drug interactions. Furthermore its metabolic profile enables coadministration with most of (S)-Reticuline the other available antiretroviral agents without dose adjustment. Recent findings also demonstrate that dolutegravir has significant activity against HIV-1 isolates with resistance mutations associated with raltegravir and/or elvitegravir. The attributes of once-daily administration and the potential to treat integrase inhibitor-resistant viruses make dolutegravir an interesting and promising investigational drug. In this review the main concerns about the efficacy and safety of dolutegravir as well as its resistance profile are explored by analysis of currently available data from preclinical and clinical studies. < 0.001) with a mean decrease of 1.51-2.46 log10 copies/mL. More than 90% of patients who received dolutegravir irrespective of dose had a decrease in viral load to <400 copies/mL while 70% of those in the 50 mg arm achieved undetectable viremia. In addition a well characterized dose-response relationship was observed for the decrease in (S)-Reticuline viral load. Pharmacokinetic variability was low. There was no relationship between dolutegravir dose and adverse events.43 The dose chosen for Phase III studies in antiretroviral-na?ve subjects infected with HIV-1 was 50 mg once daily. The most important dolutegravir clinical trials which are still ongoing or have reached their primary endpoints are summarized in Table 2. In the randomized partially blinded dose-finding Phase IIb SPRING-1study 205 antiretroviral-na?ve patients infected with HIV-1 were enrolled. Baseline characteristics were a CD4+ T cell count > 200/μL and HIV-1 RNA > 1000 copies/mL. The subjects were randomized 1:1:1:1 to receive once-daily dolutegravir (n = 155) at 10 mg 25 mg or 50 mg doses or efavirenz 600 mg (n = 50) combined with fixed doses of tenofovir-emtricitabine or abacavir-lamivudine as background therapy. This study was conducted at 34 sites in Western Europe Russia and the United States. The primary endpoint was the proportion of patients obtaining a viral load < 50 copies/mL at 16 weeks. In the (S)-Reticuline dolutegravir arms about 90% of participants had undetectable plasma viremia after 24 weeks irrespective of the background nucleoside reverse transcriptase inhibitor (NRTI) combination used thus establishing (S)-Reticuline the noninferiority of dolutegravir versus efavirenz. The rate of viral decay was much faster in the dolutegravir arms than in the efavirenz arm and was similar to that reported for raltegravir. After 48 weeks about 90% of patients receiving dolutegravir and 82% of those receiving efavirenz achieved a viral load < 50 copies/mL. CD4+ T cells increased from baseline to week 48 in all groups and were higher in dolutegravir recipients than in efavirenz controls (+231 cells/μL versus +174 cells/μL). No relationship between dolutegravir exposure and response was observed during the study and no treatment-emergent integrase mutations were detected in the dolutegravir groups.44 45 Results at week 96 were recently (S)-Reticuline presented confirming a similar trend in the rate of virologic suppression in the dolutegravir 50 mg arm versus the efavirenz arm (Figure 2).46 Figure 2 Percentage of subjects reaching human immunodeficiency virus type-1 RNA Rabbit Polyclonal to TAF4. levels < 50 copies/mL at week 96 in the SPRING-1 trial. Table 2 Main clinical studies with dolutegravir: an overview The 48-week results of the randomized double-blind double-dummy noninferiority (S)-Reticuline Phase III SPRING-2 study were reported at the Nineteenth International AIDS Conference in Washington DC 2012 This study compared the safety and efficacy of dolutegravir 50 mg once daily versus raltegravir 400 mg twice daily in combination with an investigator-selected NRTI backbone in 822 treatment-na?ve patients infected with HIV-1 (411 patients per treatment arm). The main inclusion criteria were no previous antiretroviral therapy HIV-1 RNA ≥ 1000 copies/mL and no resistance mutations. The primary endpoint was HIV-1 RNA < 50 copies/mL at week 48 by FDA snapshot intent-to-treat-exposed analysis. Viral suppression was achieved in 88% of patients on.