A small number of patients had accessory integrase mutations
A small number of patients (11%) had accessory integrase mutations (E157Q, G163R, L74IM, and/or V151I) that confer potential or low-level resistance and generally only when they occur in combination with other high/intermediate level resistance mutations. This is a somewhat higher incidence than that reported elsewhere. A UK-wide study (albeit based on small numbers, n=101) found 6% of patient sequences contained minor or accessory mutations . Ceccherini-Silberstein found they occurred in 1.5–2.2% of patients (n=134), and Charpentier and colleagues found they occurred in 3/103 patients (<3%) enrolled in the ANRS 139 TRIO trial , . They were detected at the 20% level using ultra deep sequencing, which is equivalent to the level detected by TKI258 synthesis based sequencing . All three contained E157Q or L74I, which are considered accessory mutations and confer little or low-level resistance to elvitegravir and raltegravir. As they are polymorphic mutations that arise in the absence of selective drug pressure they are usually not suggestive of transmitted drug resistance. Charpentier did report higher numbers of patients with baseline integrase resistance (9%) when they reduced the threshold to 1% level . However, the significance of mutations detected at this level (referred to as minority resistant variants) has yet to be elucidated and they found no difference in the prevalence of these mutations (at <1% level) in patients who failed treatment compared to those who responded to treatment.
Conclusion Following initial reports of transmitted integrase resistance in 2011, it was speculated that we would see increasing numbers of patients with transmitted integrase resistance similar to that observed following the first reports of NRTI and NNRTI resistance; however, this has not materialised . Transmitted integrase resistance remains rare; we identified only 1 case in 96 patient samples. This appears to be the first case of transmitted integrase resistance in the UK. The use of HAART has meant the majority of patients on treatment tend to have very low or undetectable viral loads, which greatly reduces the chances of transmission. The arrival of dolutegravir, which has a high genetic barrier to resistance and has now been adopted as the integrase inhibitor of choice for first-line treatment in both treatment naïve and treatment experienced patients (with no pre-existing integrase resistance); the likelihood/risk has decreased even further. The results of the present study do not support performing integrase resistance testing at baseline.
Introduction Anti-HIV drug development is one of the leading tasks in the drug discovery area due to the improving rate of sufferers with HIV and related infections. AIDS, a result of HIV infection is a serious risk to public health and can be regarded as one of the biggest reasons responsible for numbers of death annually in near future. The infection of this virus particle even invites a variety of other microbial infections, cancers and other diseases . Since the beginning of the epidemic, almost 70 thousand individuals have been contaminated with the HIV virus and about 35 thousand individuals have passed away of AIDS. Globally, 34.0 thousand [31.4–35.9 million] individuals were residing with HIV at the end of 2011. An approximate 0.8% of grownups older 15–49 years are residing with HIV, although the pressure of the outbreak is constantly on the different considerably between nations and areas . Though current anti-HIV drugs can suppress HIV infection at some extent, the multi-drug resistance prevalence of some HIV mutant strains is one of the major threats for the HIV arsenal . To avoid the problem, current searches for new anti-HIV agents are focused on discovering compounds with novel components and different mechanisms of action . Research on HIV chemistry have offered strong knowledge of the molecular activities engaged in the HIV replicative pattern, which involve several steps as entry-fusion of HIV virus particle with CD4 cell, reverse transcription, integration, gene expression, gene assembly, budding and maturation . In particular, scaffolds focusing on reverse transcriptase (RT), protease (P) and integrase (IN) enzymes in the HIV replicative cycle, remain important targets in drug development. To date, several drugs are established for the treatment of this disease like zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine as NRTIs, tenofovir as NtRTIs, nevirapine, delavirdine, efavirenz and etravirine as NNRTIs, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir as PIs, enfuvirtide as FIs, maraviroc as CRA and raltegravir as well as elvitegravir as INIs . From this point, less numbers of anti-HIV integrase inhibitors are developed till date, hence the figures strongly recommend the development of further class of integrase inhibitors expressing a clear mode of anti-HIV action. Several scientists over the world working to discover new anti-HIV drug-like elements upon holding architectural difference of a particular type of substances to improve their efficiency and possibly discover new clinical trial candidates. Herein, we review a type of appealing anti-HIV substances, pyrimidones with anti-HIV potency towards IN enzyme of HIV virus. The articles are the extensive selection of pyrimidine based merged or annulated elements presenting effective anti-HIV effectiveness along with information of the key architectural features which will aid therapeutic apothecaries in their continuous drug discovery process.