New ARV drugs

Introduction. Over the past 10 years, there has been an increase in HIV-1 resistance to antiretroviral drugs worldwide. HIV infection patients with low adherence to antiretroviral therapy (ART) are most often at risk of developing acquired HIV-1 resistance. The identification of key factors affecting the degree of adherence will allow timely detection of patients with a high risk of poor adherence to ART and treatment defaulting, and develop individual management tactics for such patients to reduce the risk of resistance development. Aim. To study the factors influencing adherence to ART in patients with virological failure and the effect of adherence on the risk of developing acquired HIV-1 resistance to first-line antiretroviral drugs. Materials and methods. Two hundred and seventy one patients with an confirmed diagnosis of HIV infection, with different stages of the disease, aged 21 to 59 years, who were followed-up from March 2018 to August 2022 at the Center for the Prevention and Control of AIDS (City Infectious Clinical Hospital No. 1, Novosibirsk) and received ART, were enrolled in a study. The criterion to include patients in the study was a virological breakthrough during previously effective ART with first-line drugs (when an undetectable level of HIV RNA load was recorded for 3–6 months). A retrospective analysis of the degree of adherence to ART of the studied patients with HIV infection and virological breakthrough was performed, considering various factors. The HIV-1 drug resistance testing was carried out based on the State Research Center of Virology and Biotechnology VECTOR. Results. Men predominated among the patients – 56.4% (n = 153). The average age was 35.4 ± 2.85 years. Heterosexual transmission of HIV was dominant – 64.8%. Parenteral transmission of HIV (intravenous drug abuse) accounted for 31.5% of cases. According to the results of the retrospective analysis of the degree of adherence to ART, it was found that 48.3% (131 out of 271) of patients had missed medications, including low adherence in 31.7% (86 out of 271) patients; average – in 16.6% of patients (45 out of 271). Most often, poor adherence was reported in people with parenteral HIV transmission– 75.3% compared with sexual transmission – 36% (p < 0.001), and in rural residents – 62.5% compared with urban residents – 34.1% (p < 0.001). Among men, missed medication was detected more often than in women – 57.5 and 36.4%, respectively (p < 0.001). Also, a significant factor was the lack of permanent employment – poor adherence was in 69.5% of patients in this group compared with patients having permanent employment – 26.3% (p < 0.05). On the contrary, high adherence was more often observed in female patients – 63.6% compared with male ones – 42.5%; in the presence of permanent employment – 73.7% compared with 30.5% in it’s absence; in the case of sexual transmission – 64.0% compared with parenteral transmission – 24.7%; in urban residents – 65.9% versus 37.5% in rural residents (p < 0.05). According to the totality of all mutations revealed, HIV drug-resistant variants were found in 54.6% of the patients with virological ART failure (148 out of 271). Of the 148 HIV-1 drug-resistant variants, a combination of drug resistance mutations from the group of nucleoside reverse transcriptase inhibitors (NRTIs) was most often detected and non-nucleoside reverse transcriptase inhibitors (NNRTIs) – in 60.1% (89 cases). Isolated mutations to NRTIs were found in 15.5% (23) cases, for NNRTIs – in 12.2% (18). A combination of mutations of resistance to NRTIs + integrase inhibitors (IIs) was found in 4.1% (6) patients. The proportion of patients with resistance to NRTIs and PIs (protease inhibitors) was 2% (3); to NRTIs + IIs – 1.4% (2). A combination of mutations to three classes of drugs at once was detected in 6 patients: NRTIs + NNRTIs + IIs – 2.7% (4) and NRTIs + NNRTIs + PIs – 1.4% (2). An isolated mutation to IIs was in one patient (0.6%). Conclusion. The analysis showed that non-adherence was reported in a significant part of patients – 48.3% (low – 31.7%, moderate – 16.6%). Factors contributing to poor adherence to ART were: parenteral transmission of HIV (in 75.3% of people with poor adherence); living in rural areas (in 62.5%); lack of permanent employment (in 69.5%); male sex (in 57.5%). Among patients with detected HIV drug resistance (n = 148), individuals with poor adherence prevailed (70.9%) compared with patients who did not have HIV drug resistance (23.6%) (p < 0.001). Taking into account the data obtained, when choosing the initial ART regimen, it is necessary to analyze the degree of risk of non-adherence depending on social and other factors. The high frequency of registration of HIV drug-resistant mutations found in the Novosibirsk Region necessitates timely testing for drug-resistant HIV patients with virological ART failure and the introduction of screening for primary drug resistance in patients at risk of poor adherence.

There are 27 approved antiretroviral drugs and combinations of these drugs clearly change the natural history of HIV infection, dramatically decreasing HIV‐related morbidity and mortality and promoting healthy survival. Despite the proven benefits, we continue to consider basic strategic questions about antiretroviral therapy: When should we start ART? What regimen to start? When should we change ART? What ART regimen should we change to?Also, despite the benefits of treatment, some antiretroviral regimens may be inconvenient, toxic, and/or have suboptimal antiretroviral activity, particularly against drug‐resistant viruses. Thus, newer compounds are needed that continue to improve convenience and tolerability, reduce toxicity, and improve antiretroviral activity, particularly against drug‐resistant viruses. Additionally, new drugs may better penetrate tissue reservoirs (e.g. genital tract, central nervous system) or exploit new targets with new mechanisms of action.There are a number of HIV drugs in development currently. These include a new pharmacokinetic “boosting” agent and newer antiretroviral agents in a number of existing classes, including new nucleoside reverse transcriptase inhibitors, non‐nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, and integrase inhibitors. In addition there are drugs with new mechanisms of action in development, including the CD4 attachment inhibitors. The clinical use of the newer agents will depend on the results of clinical trials, and the timeline for development and availability.

BackgroundHIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15–24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15–24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control.MethodsA cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes.ResultsA total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine.ConclusionsThere is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.

Purpose: A meta-analysis of randomized controlled trials (RCTs) was performed to evaluate effectiveness and tolerability of triple antiretroviral therapy regimens in HIV-infected patients. Method: RCTs including the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine (NVP) or efavirenz (EFV) compared to two nucleoside reverse transcriptase inhibitor (NRTI) regimens and to three-drug regimens based on two NRTIs and one protease inhibitor (PI; highly active antiretroviral therapy [HAART]) were analyzed by Peto’s method. Results: A significant virological response was observed in patients treated with NNRTIs (odds ratio [OR] 3.6; 95% CI, 2.2-6.0), particularly in naïve patients (OR 7.4; 95% CI, 4.1-13.5). A fair reduction of HIV disease progression was also observed in patients treated with NNRTIs (OR 0.8; 95% CI, 0.6-1.0). Moreover, a significantly lower rate of HIV progression was observed in patients with a CD4 + lymphocyte count below 100/mm3. Five RCTs comparing two NRTIs and one NNRTI to HAART were subsequently evaluated. A slightly higher rate of virological response was observed with NNRTIs (OR 1.6; 95% CI, 1.1-2.1), whereas no difference was observed concerning progression of HIV disease. Conclusion: Antiretroviral therapy including NVP or EFV was more effective in reducing viral load than therapy with only two NRTIs and was slightly more effective than HAART. Effectiveness in delaying HIV disease progression was less evident, even though lower rate of progression was observed in patients with advanced HIV infection compared to two NRTIs alone.

IntroductionThis retrospective study aimed to investigate that if switch of combination antiretroviral therapy (cART) would result in viral suppression (<40 copies/mL) at 48 weeks for patients with persistent low-level viremia after having received cART for six months or more at two hospitals designated for HIV care in Taiwan.Materials and MethodsBetween January 2001 and January 2013, patients were enrolled if plasma HIV RNA load (PVL) were >20 to <1000 copies/mL detected for six months or more [1, 2]. Using a standardized data collection form, we recorded data of PVL and CD4 count before cART and at the detection of low-level viremia, serologies for hepatitis B and C virus, risk factors, duration of cART exposure, years of HIV diagnosed and ever experiencing treatment failure. The strategy of switch is based on the clinical guidelines of BHIVA, which suggest change of cART from non-nucleoside reverse-transcriptase inhibitors (nNRTIs) or unboosted protease inhibitor (PI) to boosted PI, newer boosted PI or ARV of different mechanism [3].ResultsIn this study, 165 patients were enrolled, 119 patients (72.1%) did not switch (Group 1), and 46 patients (27.9%) switched previous regimens to ARV of different mechanism (Group 2). The two groups differed significantly in the proportion of injecting drug users (IDU) (Group 1 vs Group 2, 10.9 vs 26.1%) and median PVL (67 vs 159 copies/mL), and the proportion of PVL<200 copies/mL (84.0% vs 58.7%) when low-level viremia was first detected. In Group 1, 39 (32.8%) continued two nucleoside reverse-transcriptase inhibitors (NRTIs) plus nNRTI; 29 (24.4%) 2 NRTIs plus PI, 47 (39.5%) 2 NRTIs plus boosted PI, and 4 (3.3%) 2 NRTIs plus integrase inhibitor (II). In Group 2, two (4.3%) switched to 2 NRTIs plus PI, 38 (82.6%) 2 NRTIs plus boosted PI, three (6.5%) 2 NRTIs plus II and three (6.5%) boosted PI plus II. In multivariate analysis, IDUs (adjusted odds ratio [AOR], 6.757; 95% CI 2.427–18.868) and PVL of 200–999 copies/mL at enrollment (AOR, 4.902; 95% CI 1.992–12.048) were more likely to be switched. At 48 weeks, patients in Group 2 were more likely to achieve PVL<40 copies/mL than Group 1 (82.6% vs 63.0%, p=0.016), while no difference was observed in achieving PVL <200 copies/mL between the two groups (95.7% vs 92.4%, p=0.729). ConclusionsAccording to the clinical guidelines of BHIVA, patients with low-level viremia who switched to cART consisting of 2 NRTIs plus boosted PI or newer mechanisms were more likely to re-establish viral suppression to <40 copies/mL at week 48.

The pyrophosphate (PPi) analogue phosphonoformic acid (PFA or foscarnet) inhibits the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1); however, the mechanisms of drug action and resistance remain elusive. Here we studied the effects of the translocational status of HIV-1 RT on drug binding and inhibition of DNA synthesis. We identified "hot spots" for inhibition during active elongation. Site-specific footprinting analyses revealed that the corresponding complexes exist predominantly in the pre-translocational state. The sensitivity to PFA is significantly reduced with sequences that show a bias toward the post-translocational state. Binding studies showed that PFA stabilizes selectively the complex in the pre-translocated configuration. These findings are consistent with a Brownian ratchet model of polymerase translocation. The enzyme can rapidly shuttle between pre- and post-translocated states. The bound inhibitor acts like a pawl of a ratchet and prevents the forward motion of HIV-1 RT, whereas the bound nucleotide binds to the post-translocated complex and prevents the reverse motion. The proposed mechanisms of RT translocation and drug action are consistent with the PFA-resistant phenotypes. We show that certain sequences and the PFA-resistant E89K mutant diminishes the stability of the pre-translocated complex. In these cases, the enzyme is seen at multiple positions around the 3' end of the primer, which provides a novel mechanism for resistance. These findings validate the pre-translocated complex as a target for the development of novel, perhaps less toxic and more potent inhibitors that block HIV-1 RT translocation.

HIV-infected patients receiving antiretroviral therapy (ART) are at risk for contraindicated drug-drug interactions (XDDIs). This study compared the frequency of XDDIs between different types of ART regimens. A retrospective cohort study was performed among adult HIV-infected patients receiving care at either the Upstate New York Veterans' Healthcare Administration or the University of New Mexico Truman Health Services between 2000 and 2013. The cohort consisted of patients receiving traditional ART regimens composed of 2 nucleoside reverse transcriptase inhibitors plus either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase strand transfer inhibitor (INSTI). The primary outcome was the presence of XDDIs. Lexi-Interact was used to define XDDIs. Of the 1329 patients who met inclusion criteria, 45.7%, 34.2%, and 20.1% were receiving an NNRTI-, PI-, or INSTI- based ART regimen, respectively. Among the 128 (9.6%) patients with an XDDI, more than half (53.9%) had an interaction involving ART. The presence of XDDIs was highest for PI-based regimens (16.3%) compared with INSTI- (7.9%) and NNRTI-based (5.4%) regimens; P < 0.001. The variables independently associated with XDDIs were ART regimen type (prevalence ratio [PR] = 1.91; 95% CI = 1.51-2.40, P < 0.001), use of ≥6 non-HIV medications (PR = 5.84; 95% CI = 3.92-8.71, P < 0.001), and age ≥40 years (PR = 1.62; 95% CI = 0.92-2.86, P = 0.10). The probability of XDDIs varies as a function of ART regimen type, advanced age, and use of multiple non-HIV medications.

In HIV treatment, surveillance of mutations inducing resistance to NRTIs (Nucleoside Reverse Transcriptase Inhibitors) and NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors) is important. This study analyzed 2,071 HIV-1 genomic sequences directed to detection of major NRTIs and NNRTIs resistance mutations and viral tropism. CRF08_BC and X4 strain more likely had major NRTIs (adjusted odds ratio (aOR) 3.0, 95% CI 1.182-7.820, p=0.021 and aOR 1.7, 95% CI 1.233-2.368, p=0.001; respectively) and NNRTIs (aOR 3.3, 95% CI 1.281-8.365, p=0.013 and aOR 1.4, 95% CI 1.037-1.977, p=0.029, respectively) resistance mutations. Subtype A1 (aOR 0.2, 95% CI 0.069-0.702, p=0.011) and C (aOR 0.4, 95% CI 0.241-0.648, p&lt;0.001) were associated with major NRTIs resistance mutations. The occurrence of major NRTIs and NNRTIs resistance mutations in HIV subtype A1, C, CRF08_BC, and X4 viruses should be a particular concern.

HIV-infected patients have a higher risk of developing cutaneous reactions than the general population, which has a significant impact on patients' current and future care options. The severity of cutaneous adverse reactions varies greatly, and some may be difficult to manage. HIV-infected patients just at the beginning of antiretroviral treatment can frequently show a wide variety of adverse drug effects such as drug rashes, hyperpigmentation, hair loss, hypersensitivity reactions, injection site reaction, urticarial reaction, erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome. The early detection and treatment of cutaneous adverse drug reactions, plus identification of the causative agent, are essential to prevent the progression of the reaction, preventing additional exposures and ensuring the appropriate use of medications for the current condition and keeping in mind others, such as patient age. This article emphasizes the most common features of an antiretroviral drug-induced cutaneous reaction from protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, fusion inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors and inhibitors of the CCR5 chemokine receptor, paying special attention to the newest drugs approved for the treatment of HIV infection, such as tipranavir, darunavir, etravirine, enfuvirtide, raltegravir and maraviroc.

BACKGROUND: The efficacy of treatment containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) could be compromised in NNRTI-naÏve patients already harboring a virus resistant to NNRTIs. On the contrary, hypersusceptibility to NNRTIs in patients having failed nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens has been described and has been associated with improved outcome. METHOD: We assessed the prevalence of NNRTI resistance-associated mutations or polymorphisms in 146 antiretroviral-naÏve patients and in 181 HIV-infected patients who were given an NNRTI-based regimen. We phenotypically evaluated the NNRTI susceptibility of 41 strains presenting with amino acid substitutions at positions involved in NNRTI resistance. RESULTS: In the 268 genotypically analyzable samples, the overall prevalence of NNRTI resistance-associated mutations was 2% (6/268 patients). The prevalence of strains with amino acid substitutions at reverse transcriptase (RT) gene positions (A98, K101, K103, V106, V108, V179) involved in NNRTI resistance was 15%. Hypersusceptibility to NNRTI was rare (2%, 1/41) in those samples. RT substitutions at positions involved in NNRTI resistance were not associated with a significantly worse virologic outcome in NNRTI-treated patients. Our understanding of small shifts in IC50 values (higher or lower) toward NNRTI is very limited. The significance of many RT mutations on NNRTI susceptibility is not clear. CONCLUSION: In contrast to resistance mutations, RT substitutions at positions involved in NNRTI resistance are frequent. They are not associated with a worse virologic outcome or with decreased phenotypic susceptibility to NNRTIs. It may be prudent not to rule out the use of NNRTIs in patients with small shifts in IC50 values or poorly understood mutations.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).

The use of highly active antiretroviral therapy (HAART) has profoundly altered the life expectancy of individuals infected with HIV. Metabolic abnormalities associated with antiretrovirals and cumulative exposure to combination antiretroviral therapy, including dyslipidaemia and insulin resistance, have been linked to an increased risk of myocardial infarction. Longitudinal data from a large prospectively collected clinical database were analysed. All patients who commenced first antiretroviral therapy (ART) [two nucleoside reverse transcriptase inhibitors (NRTIs)+one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one active protease inhibitor (PI)] since 1996 were identified. Patients with elevated cholesterol levels [>5.5 mmol/L (215 mg/dL)] prior to therapy initiation were excluded. Quantitative data were categorized into quartiles and presented stratified by individuals developing abnormal levels of cholesterol during first-line HAART. Event time was defined as time from commencing first-line ART to either development of cholesterol level >6.5 mmol/L (254 mg/dL) or switch of first-line therapy. The Kaplan-Meier product limit survival method was used to estimate time to abnormal cholesterol level, and the chi2 test was used for comparisons between drug classes. Cox's proportional hazards regression analysis was used to identify factors predicting a likelihood of raised cholesterol level. A total of 1664 patients were included in the study: 57.1% on two NRTIs+one NNRTI, 38.4% on two NRTIs+one PI, and 4.4% on two NRTIs+a boosted PI regimen. Regimens containing stavudine or PIs were associated with a significantly higher event risk and earlier time to event. No differences between efavirenz and nevirapine or between didanosine and lamivudine were observed. In 28 patients exposed to the combination of tenofovir+lamivudine+efavirenz, there were no episodes of elevated cholesterol level. Dyslipidaemia has emerged as an important issue in HIV-infected individuals receiving antiretroviral therapy. This study demonstrates that age at start of therapy, baseline cholesterol level, stavudine use and PI use are all associated with increased risk of hypercholesterolemia on initial therapy. Both NRTI and NNRTI/PI choice influence risk of hypercholesterolaemia.

BackgroundAlthough the introduction of combined therapy with reverse transcriptase and protease inhibitors has resulted in considerable decrease in HIV related mortality; it has also induced the development of multiple drug-resistant HIV-1 variants.The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients.ResultsA cross sectional study was conducted to evaluate the impact of treatment regimens and resistance mutation patterns on the clinical, virological, and immunological presentation of HIV disease in 41 children (25 male and 16 female) at the Robert Wood Johnson Pediatric AIDS Program in New Brunswick, New Jersey. The study participants were symptomatic and had preceding treatment history with combined ARV regimens including protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Fifteen (36.6%) children were treated with NRTI+NNRTI+ PI, 6 (14.6%) with NRTI+NNRTIs, 13 (31.7%) with NRTI+PIs, and the remaining 7 (17.1%) received NRTIs only.Combined ARV regimens did not significantly influence the incidence of NRTI and NNRTI associated mutations. The duration of ARV therapy and the child's age had no significant impact on the ARV related mutations. The clinico-immunological presentation of the HIV disease was not associated with ARV treatment regimens or number of resistance mutations. However, primary mutations in the protease (PR) gene increased the likelihood of plasma viral load (PVL) ≥ 10,000 copies/mL irrespective of the child's age, duration of ARV therapy, presence of NRTI and NNRTI mutation. Viremia ≥ 10,000 copies/mL was recorded in almost all the children with primary mutations in the PR region (n = 12/13, 92.3%) as compared with only 50.0% (n = 14/28) of HIV infected children without (PR-), P < 0.008. However, CD-4 T cells were not affected by the mutations in the PR gene of the HIV-1 isolates.ConclusionPrimary PR resistance mutations significantly increase the likelihood for high viral replication in pediatric patients with moderate/severe HIV-1 infection, which may affect the long-term clinical prognosis of the HIV infected children.

Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

This study sought to examine the human immunodeficiency virus type 1 (HIV-1) genetic diversity on drug resistance among men who have sex with men (MSM) with virologic failure in antiretroviral therapy (ART), and investigate linking-associated factors for genetic transmission networks.Seven hundred and thirty-four HIV-positive MSM with virologic failure in ART were recruited into our study from 2011 to 2017. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The drug resistance mutations were determined using the Stanford University HIV Drug Resistance Database. The genetic transmission networks were analyzed for CRF01_AE and CRF07_BC sequences by the genetic distance-based method.Of 734 subjects, 372 (50.68%) showed drug resistance, in which CRF01_AE and CRF07_BC were the predominating subtypes. Drug resistance more frequently occurred in non-nucleoside reverse transcriptase inhibitors (NNRTIs) treatment (48.64%), and followed by nucleoside reverse transcriptase inhibitors (NRTIs) (36.51%) and PIs (4.03%). The most common drug resistance-associated mutations in protease inhibitors (PIs), NRTIs and NNRTIs were K20I/R, M184V/I and K103N/KN, respectively. For 283CRF01_AE sequences, 64 (22.61%) fell into clusters at a genetic distance of 0.011, resulting in 17 clusters ranging in size from 2 to 16 individuals. For 230 CRF07_BC sequences, 66 (28.69%) were connected to at least one other sequence with 0.005 genetic distances, resulting in 8 clusters ranging in size from 2 to 52 individuals. Individuals who showed drug resistance to ART were less likely to fall into clusters than those who did not. The genetic linkage was robust by the exclusion of sites associated with drug resistance.CRF01_AE and CRF07_BC were the main strains among MSM with virologic failure in ART, and the drug resistance more frequently occurred in NNRTIs, followed by NRTIs and PIs. Genetic transmission networks revealed a complexity of transmission pattern, suggesting early-diagnosis and in-time intervention among MSM.