Surveillance Drug Resistance Mutation List Research Articles

Transmitted HIV Drug Resistance in Bulgaria Occurs in Clusters of Individuals from Different Transmission Groups and Various Subtypes (2012-2020).

Transmitted HIV drug resistance in Bulgaria was first reported in 2015 using data from 1988-2011. We determined the prevalence of surveillance drug resistance mutations (SDRMs) and HIV-1 genetic diversity in Bulgaria during 2012-2020 using polymerase sequences from 1053 of 2010 (52.4%) antiretroviral therapy (ART)-naive individuals. Sequences were analyzed for DRM using the WHO HIV SDRM list implemented in the calculated population resistance tool at Stanford University. Genetic diversity was inferred using automated subtyping tools and phylogenetics. Cluster detection and characterization was performed using MicrobeTrace. The overall rate of SDRMs was 5.7% (60/1053), with 2.2% having resistance to nucleoside reverse transcriptase inhibitors (NRTIs), 1.8% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), 2.1% to protease inhibitors (PIs), and 0.4% with dual-class SDRMs. We found high HIV-1 diversity, with the majority being subtype B (60.4%), followed by F1 (6.9%), CRF02_AG (5.2%), A1 (3.7%), CRF12_BF (0.8%), and other subtypes and recombinant forms (23%). Most (34/60, 56.7%) of the SDRMs were present in transmission clusters of different subtypes composed mostly of male-to-male sexual contact (MMSC), including a 14-member cluster of subtype B sequences from 12 MMSC and two males reporting heterosexual contact; 13 had the L90M PI mutation and one had the T215S NRTI SDRM. We found a low SDRM prevalence amid high HIV-1 diversity among ART-naive patients in Bulgaria during 2012-2020. The majority of SDRMs were found in transmission clusters containing MMSC, indicative of onward spread of SDRM in drug-naive individuals. Our study provides valuable information on the transmission dynamics of HIV drug resistance in the context of high genetic diversity in Bulgaria, for the development of enhanced prevention strategies to end the epidemic.

Temporal Trends in HIV-1 Mutations Used for the Surveillance of Transmitted Drug Resistance

In 2009, a list of nonpolymorphic HIV-1 drug resistance mutations (DRMs), called surveillance DRMs (SDRMs), was created to monitor transmitted drug resistance (TDR). Since 2009, TDR increased and antiretroviral therapy (ART) practices changed. We examined the changing prevalence of SDRMs and identified candidate SDRMs defined as nonpolymorphic DRMs present on ≥ 1 expert DRM list and in ≥0.1% of ART-experienced persons. Candidate DRMs were further characterized according to their association with antiretrovirals and changing prevalence. Among NRTI-SDRMs, tenofovir-associated mutations increased in prevalence while thymidine analog mutations decreased in prevalence. Among candidate NRTI-SDRMs, there were six tenofovir-associated mutations including three which increased in prevalence (K65N, T69deletion, K70G/N/Q/T). Among candidate NNRTI-SDRMs, six that increased in prevalence were associated with rilpivirine (E138K/Q, V179L, H221Y) or doravirine (F227C/L) resistance. With the notable exceptions of I47A and I50L, most PI-SDRMs decreased in prevalence. Three candidate PI-SDRMs were accessory darunavir-resistance mutations (L10F, T74P, L89V). Adding the candidate SDRMs listed above was estimated to increase NRTI, NNRTI, and PI TDR prevalence by 0.1%, 0.3%, and 0.3%, respectively. We describe trends in the prevalence of nonpolymorphic HIV-1 DRMs in ART-experienced persons. These data should be considered in decisions regarding SDRM list updates and TDR monitoring.

Epidemiological Surveillance of HIV-1 Transmitted Drug Resistance in Spain in 2004-2012: Relevance of Transmission Clusters in the Propagation of Resistance Mutations.

Our objectives were to carry out an epidemiological surveillance study on transmitted drug resistance (TDR) among individuals newly diagnosed of HIV-1 infection during a nine year period in Spain and to assess the role of transmission clusters (TC) in the propagation of resistant strains. An overall of 1614 newly diagnosed individuals were included in the study from January 2004 through December 2012. Individuals come from two different Spanish regions: Galicia and the Basque Country. Resistance mutations to reverse transcriptase inhibitors (RTI) and protease inhibitors (PI) were analyzed according to mutations included in the surveillance drug-resistance mutations list updated in 2009. TC were defined as those comprising viruses from five or more individuals whose sequences clustered in maximum likelihood phylogenetic trees with a bootstrap value ≥90%. The overall prevalence of TDR to any drug was 9.9%: 4.9% to nucleoside RTIs (NRTIs), 3.6% to non-nucleoside RTIs (NNRTIs), and 2.7% to PIs. A significant decrease of TDR to NRTIs over time was observed [from 10% in 2004 to 2% in 2012 (p=0.01)]. Sixty eight (42.2%) of 161 sequences with TDR were included in 25 TC composed of 5 or more individuals. Of them, 9 clusters harbored TDR associated with high level resistance to antiretroviral drugs. T215D revertant mutation was transmitted in a large cluster comprising 25 individuals. The impact of epidemiological networks on TDR frequency may explain its persistence in newly diagnosed individuals. The knowledge of the populations involved in TC would facilitate the design of prevention programs and public health interventions.

Transmitted HIV drug resistance at the Thai Red Cross anonymous clinic in Bangkok: results from three consecutive years of annual surveillance.

The aim of this study was to prospectively survey transmitted drug resistance (TDR) among recently infected individuals (mostly MSM). TDR was determined in prospective annual cohorts of recently HIV-1-infected individuals consecutively recruited from 2008 to 2010. Resistance interpretation was carried out using Stanford Database tools and the WHO surveillance drug resistance mutation list. Kruskal-Wallis and Fisher's exact tests were used to compare demographic and laboratory outcomes. A total of 299 subjects were enrolled, with 89% MSM. Median viral load was significantly higher in 2010 than in 2008 (P=0.004). Of the 284 analysable reverse transcriptase/protease sequences, TDR to any drug was found in 14/284 (4.9%); 4.0% in 2008, 5.9% in 2009 and 5.3% in 2010, with an increasing trend of TDR to NRTIs and NNRTIs from 2008 to 2010 (P=0.07). Good correlation was found between our data and the WHO threshold surveillance method. Only rilpivirine had significantly higher (P<0.05) predicted resistance in 2010 than in 2008 and 2009. A trend towards an increase in TDR in Thailand where the major epidemic is among MSM was observed, but did not reach the WHO-defined high-level threshold (>15%). Attention to prevent the development and spread of drug resistance is needed.

Short communication: Prevalence of HIV-1 transmitted drug resistance in Liberia.

No data on HIV-transmitted drug resistance (TDR) are available in Liberia in which the HIV prevalence in the general population is estimated at 1.5%. The aim of the study was to assess the prevalence of TDR in HIV-1 from recently diagnosed and untreated patients living in Monrovia, Liberia. The study was performed in the John F. Kennedy Medical Center and in the Redemption Hospital, both located in Monrovia. All newly HIV-1 diagnosed patients attending voluntary counseling testing centers and antiretroviral therapy naive were consecutively included. Protease and reverse transcriptase (RT) regions sequencing was performed using the ANRS procedures (www.hivfrenchresistance.org). Drug resistance mutations (DRM) were identified according to the 2009 updated WHO surveillance DRM list. Among the 116 HIV-1-infected patients enrolled in the study, 85 (73%) were women. Protease and RT sequencing was successful in 109 (94%) and 102 (88%) samples, respectively. Seventy-five (66%) patients were infected with CRF02_AG. One DRM was observed in six samples, leading to a TDR prevalence of 5.9% (CI 95%=1.7-10.1). DRM were observed in two patients (2.0%; CI 95%=0.0-4.7), four patients (3.9%; CI 95%=0.1-7.7), and one patient (0.9%; CI 95%=0.0-2.7) for nucleoside RT inhibitors (NRTI), non-NRTI (NNRTI), and protease inhibitors, respectively. Overall, one patient exhibited dual class-resistant viruses, harboring NRTI and NNRTI resistance mutations (1.0%; CI 95%=0.0-2.9). This first survey study in Liberia reported a TDR prevalence of 5.9%, classified as moderate according to the WHO criteria, indicating that further surveillance is warranted to follow the level and evolution of TDR prevalence in recently HIV-1 diagnosed patients.

Incidence of Transmitted Antiretroviral Drug Resistance in Treatment-Naive HIV-1-Infected Persons in a Large South Central United States Clinic

Transmitted drug resistance (TDR) can limit effective treatment options to antiretroviral-naive HIV-infected persons and increase the risk of treatment failure. Limited estimates of TDR have been reported from the South Central United States. To describe the incidence of TDR in Oklahoma and to examine whether TDR rates have increased with time. This was a retrospective observational study of antiretroviral-naive patients at the Infectious Diseases Institute, a large infectious diseases clinic in Oklahoma City, Oklahoma, who had received baseline antiretroviral resistance testing. Mutations were screened using the 2011 International Antiviral Society-USA Drug Resistance Mutation (DRM) update, and categorized using the 2009 World Health Organization (WHO) Surveillance Drug Resistance Mutation (SDRM) list. Genotypic sequences from 428 patients revealed a 6.0% to 13.6% incidence of SDRMs between 2007 and 2011, though no progression in the frequency was apparent during the study period. Primary DRMs were detected in 12.6% of the sampled patients, most commonly involving nonnucleoside reverse transcriptase inhibitors (NNRTIs; 8.2%), followed by protease inhibitors (PIs; 3.5%) and nucleoside reverse transcriptase inhibitors (NRTIs; 3.3%). The K103N/S and E138A reverse transcriptase mutations were the most common DRMs identified, both present in 3.5% of patients. The L90M mutation was the most frequently observed PI SDRM (1.6%), while the T215C/D/I mutation was the most common NRTI SDRM identified (1.9%). This study was limited by the fact that the WHO SDRM list was last updated in 2009. The frequency of DRMs in central and western Oklahoma is similar to recently reported rates in the United States which lack data from this region. However, the frequency of second-generation NNRTI DRMs (4.4%) suggests the need to closely monitor epidemiologic trends for increasing resistance rates to individual classes of ARVs in order to predict the impact of TDR on therapeutic options.

Antiretroviral drug resistance in HIV-1 therapy-naive patients in Cuba

In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007–2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%–4.8%) in 2003 versus 12.5% (CI 7.2%–14.5%) in 2007–2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%–17.0%) in 2007–2011 versus 3.8% (CI 0.9%–4.7%) in 2003 (OR 3.9, CI 1.5–17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the commonly prescribed first-line therapies was 2.5. This analysis emphasizes the need to perform additional surveillance studies to accurately assess the level of transmitted drug resistance in Cuba, as the extent of drug resistance might jeopardize effectiveness of first-line regimens prescribed in Cuba and might necessitate the implementation of baseline drug resistance testing.

Genetic diversity and primary resistance among HIV-1-positive patients from Maringá, Paraná, Brazil

The objective of this study is to identify subtypes of Human Immunodeficiency Virus type 1 (HIV-1) and to analyze the presence of mutations associated to antiretroviral resistance in the protease (PR) and reverse transcriptase (RT) regions from 48 HIV-1 positive treatment naïve patients from an outpatient clinic in Maringá, Paraná, Brazil. Sequencing was conducted using PR, partial RT and group-specific antigen gene (gag) nested PCR products from retrotranscribed RNA. Transmitted resistance was determined according to the Surveillance Drug Resistance Mutation List (SDRM) algorithm. Phylogenetic and SimPlot analysis of concatenated genetic segments classified sequences as subtype B 19/48 (39.6%), subtype C 12/48 (25%), subtype F 4/48 (8.3%), with 13/48 (27.1%) recombinant forms. Most recombinant forms were B mosaics (B/F 12.5%, B/C 10.4%), with one C/F (2.1%) and one complex B/C/F mosaic (2.1%). Low levels of transmitted resistance were found in this study, 2/48 (2.1% to NRTIs and 2.1% for PI). This preliminary data may subsidize the monitoring of the HIV evolution in the region.

Molecular and epidemiological characterization of HIV-1 infection networks involving transmitted drug resistance mutations in Northern Greece

To determine the contribution of transmission clusters to transmitted drug resistance (TDR) in newly diagnosed antiretroviral-naive HIV-1-infected patients in Northern Greece during 2000-07. The prevalence of TDR was estimated in 369 individuals who were diagnosed with HIV-1 infection in the period 2000-07 at the National AIDS Reference Laboratory of Northern Greece. Phylogenetic analysis was performed using a maximum likelihood method on partial pol sequences. TDR was defined in accordance with the surveillance drug resistance mutation list (2009 update). The overall prevalence of TDR in our population was 12.5% [46/369, 95% confidence interval (CI) 9.1%-15.8%], comprising 7.6% (28/369) resistant to nucleoside reverse transcriptase inhibitors, 5.4% (20/369) resistant to non-nucleoside reverse transcriptase inhibitors and 3.3% (12/369) resistant to protease inhibitors. Dual class resistance was identified in 3.8% (14/369). Infection with subtype A was the sole predictor associated with TDR in multivariate analysis (odds ratio 2.15, 95% CI 1.10-4.19, P = 0.025). Phylogenetic analyses revealed three statistically robust transmission clusters involving drug-resistant strains, including one cluster of 12 patients, 10 of whom were infected with a strain carrying both T215 revertants and Y181C mutations. Our findings underline the substantial impact of transmission networks on TDR in our population.

Co‐circulation HIV‐1 subtypes B, C, and CRF31_BC in a drug‐naïve population from Southernmost Brazil: Analysis of primary resistance mutations

In Southernmost Brazil HIV-1 subtypes B, C, and CRF31_BC co-circulates and, since 1996 with the implementation of free access to highly active antiretroviral treatment (HAART), this epidemic is under a quite characteristic selective pressure. The profile of mutations and polymorphisms in the protease (PR) and reverse transcriptase (RT) genes of HIV-1 from untreated patients living in Porto Alegre, Southernmost Brazil were evaluated in order to identify the subtypes and circulating drug resistant genotypes. Blood samples from 99 HIV-1 positive drugs-naïve patients were collected from 2006 to 2007 in Porto Alegre, Brazil. HIV PR and RT genes were amplified, sequenced, and subtyped. The HIV-1 genotyping was performed by partial sequence analysis of the pol in the HIV Drug Resistance Database of Stanford University. Phylogenetic analyses allowed to classify the HIV samples according to their subtypes: B (26.2%), C (39.4%), F (1.1%), CRF31_CB (19.2%), and URF (14.1%). Eight (8.1%) samples showed primary resistance mutations according to the Calibrated Population Resistance tool based in the 2009 Surveillance Drug Resistance Mutation list. Two samples presented resistance mutations to PI, three NRTI and three NNRTI. There was no significant association between presence of resistant genotypes and subtypes, but resistance mutations seem to be less frequent in the subtype C. In addition, this study describes for the first time the mutational profile of CRF31_BC to PI, NRTI, and NNRTI. Genetic analyses of HIV-1 from naïve patients are a promising and important method for surveillance of HIV infection.

Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort.

BackgroundThe aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort.MethodsGenotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008). A genotypic resistance result was obtained for 1,276/1,312 (97.3%). The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml.ResultsPrevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CIwilson 10.7–14.3; p for trend = 0.25). NRTI resistance was predominant (7.5%) but decreased significantly over time (CIWilson: 6.2–9.1, p for trend = 0.02). NNRTI resistance tended to increase over time (NNRTI: 3.5%; CIWilson: 2.6–4.6; p for trend = 0.07), whereas PI resistance remained stable (PI: 3.0%; CIWilson: 2.1–4.0; p for trend = 0.24). Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%). The majority of NRTI-resistant strains (79.8%) carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61). The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%).ConclusionOverall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected with HIV might be related to the introduction of novel antiretroviral drugs and a wider use of genotypic resistance analysis prior to treatment initiation.