Epidemiology and Social
HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance
Shafer, Robert Wa; Rhee, Soo-Yona; Pillay, Deenanb; Miller, Veronicac; Sandstrom, Pauld; Schapiro, Jonathan Ma; Kuritzkes, Daniel Re; Bennett, Dianef
From the aDivision of Infectious Diseases, Stanford University, Stanford, California, USA
bCentre for Virology, Division of Infection and Immunity, University College London and Centre for Infections, Health Protection Agency, London, UK
cForum for Collaborative HIV Research, The George Washington University, Washington, DC, USA
dCentre for Infectious Disease Prevention and Control, Public Health Agency of Canada, Ottawa, Ontario, Canada
eBrigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
fWorld Health Organization, Geneva, Switzerland.
Received 11 February, 2006
Revised 6 July, 2006
Accepted 14 September, 2006
Correspondence to Robert W. Shafer, Division of Infectious Diseases, Room S-169, Stanford University, Stanford, CA, 94305, USA. e-mail: firstname.lastname@example.org
Objectives: Monitoring regional levels of transmitted HIV-1 resistance informs treatment guidelines and provides feedback on the success of HIV-1 prevention efforts. Surveillance programs for estimating the frequency of transmitted resistance are being developed in both industrialized and resource-poor countries. However, such programs will not produce comparable estimates unless a standardized list of drug-resistance mutations is used to define transmitted resistance.
Methods: In this paper, we outline considerations for developing a list of drug-resistance mutations for epidemiologic estimates of transmitted resistance. First, the mutations should cause or contribute to drug resistance and should develop in persons receiving antiretroviral therapy. Second, the mutations should not occur as polymorphisms in the absence of therapy. Third, the mutation list should be applicable to all group M subtypes. Fourth, the mutation list should be simple, unambiguous, and parsimonious.
Results: Applying these considerations, we developed a list of 31 protease inhibitor-resistance mutations at 14 protease positions, 31 nucleoside reverse transcriptase inhibitor-resistance mutations at 15 reverse transcriptase positions, and 18 non-nucleoside reverse transcriptase inhibitor-resistance mutations at 10 reverse transcriptase positions.
Conclusions: This list, which should be updated regularly using the same or similar criteria, can be used for genotypic surveillance of transmitted HIV-1 drug resistance.
HIV-1 drug resistance can be acquired (developing in a person receiving antiretroviral treatment) or transmitted (occurring because a virus with drug-resistance mutations was transmitted to a drug-naive person; Fig. 1). Although both acquired and transmitted HIV-1 drug resistance are public health concerns, transmitted resistance has the potential to more rapidly reverse the effectiveness of first-line antiretroviral therapy at the population level. Persons with transmitted drug resistance begin antiretroviral therapy with a lower genetic barrier to resistance, a higher risk of virologic failure, and a higher risk of developing resistance even to those drugs in their regimen that were originally fully active [5,10–12]. Surveillance of transmitted resistance can supply information to support public health bodies in designing education and prevention programs to minimize the development and transmission of drug-resistant viruses, and to support the rational use of antiretroviral drugs by treatment programs, clinicians and policy makers [WHO HIV Drug Resistance Surveillance Programme (V. 07-08-05), unpublished].
In Europe, North America, and Brazil, prevalence studies generally performed in specialist clinical centers have reported prevalences of drug resistance ranging from 5 to 15% in newly diagnosed persons and 10 to 25% in acutely infected persons (reviewed in [12,13]). However, it has been difficult to compare national, regional, and local estimates of transmitted resistance because of differences in study design and because estimates have been based on different lists of resistance mutations . As antiretroviral treatment and surveillance programs are now beginning in many resource-limited countries, it is particularly important to develop a standard list of mutations to characterize the epidemiology of transmitted resistance [WHO HIV Drug Resistance Surveillance Programme (V. 07-08-05), unpublished].
This paper summarizes the points to be considered when selecting mutations for epidemiologic studies. Mutations should be commonly recognized as causing or contributing to resistance, should be nonpolymorphic in untreated persons, and should be applicable to all HIV-1 subtypes. Furthermore, the list should be relatively short: inclusion of a large number of mutations, particularly rare mutations, would unnecessarily complicate surveillance efforts and would decrease the uniform acceptance and widespread adoption of a standard list. In this review of the considerations for choosing drug-resistance mutations for the epidemiology of transmitted HIV drug resistance, we use publicly available data on the associations between genotype and antiretroviral treatment from the Stanford HIV Drug Resistance Database. We apply our criteria to propose a set of candidate mutations and then apply this set of mutations to five published studies of primary HIV-1 infection for which sequences have been submitted to GenBank.
Criterion 1: association with drug resistance
Several types of data can be used to assess the role of a mutation in causing drug resistance: (1) correlations between a mutation and treatment: does drug therapy select for the mutation? (2). Correlations between a mutation and decreased in-vitro drug susceptibility; and (3) correlations between a mutation and a diminished in-vivo virologic response to a new antiretroviral regimen. These data often require expert interpretation. Therefore, for the purposes of this manuscript, we defined drug-resistance mutations primarily as those that are included in three or more of the following five expert panel lists of HIV-1 drug resistance mutations: (1) IAS-USA ; (2) Los Alamos HIV Sequence Database ; (3) HIVdb drug resistance interpretation algorithm (version 4.1.9) ; (4) ANRS drug resistance interpretation algorithm (version 2005.07) ; and (5) Rega Institute drug resistance interpretation algorithm (version 6.4.1) .
However, because none of the above mutation lists was designed for epidemiologic purposes, we have extended our criterion to include one category of mutations that is not present in three of the above lists. This category includes the T215 revertant mutations (T215C/D/E/I/S/V), which evolve from the nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations T215F/Y when viruses with T215F/Y are transmitted to a new patient in which case reversion to wild-type must evolve by back mutation rather than from a reservoir of drug-susceptible viruses [1–3,6]. Although most of the T215 revertants do not directly reduce drug susceptibility, they have been associated with an increased risk of virologic failure either because they are surrogates for the presence of T215F/Y or because they lower the genetic barrier to a major resistance mutation from two to one nucleotide [4,6]. Among the possible amino acids at this position (other than wild-type T and drug-resistant F/Y), the revertant mutations were selected for inclusion based on their frequency in published papers, their frequency in unambiguous form in published sequences (e.g. not part of a complex mixture of amino acids), their association with previous but discontinued drug therapy, and their nucleotide distance from the mutant forms F and Y.
Criterion 2: nonpolymorphic
Polymorphic drug-resistance mutations cannot be used for surveillance because they would lead to falsely high estimates of transmitted resistance. However, identifying mutations that are nonpolymorphic in the absence of antiretroviral drug therapy is confounded by three problems. First, nonpolymorphic treatment-associated mutations may appear polymorphic if the analysis includes a large proportion of untreated persons who were primarily infected with resistant viruses – a frequent occurrence in areas where antiretroviral drugs have been available for many years. Second, publicly available sequence data have been generated by many research groups using different methods of sequencing with varying levels of accuracy. Third, the high mutation rate of HIV-1 ensures that, in each patient, every mutation is created thousands of time each day. Genetic drift within a patient and the occasional disproportionate amplification of a rare variant prior to sequencing may lead to the detection in untreated persons of a mutation that usually occurs only in treated persons.
In the following paragraphs, we describe methods for identifying nonpolymorphic drug-resistance mutations using publicly available sequence data from treatment-naive persons infected with viruses belonging to different subtypes. For this analysis only a single isolate per person was used.
Influence of transmitted resistance on estimates of polymorphism rates
Two approaches were used to minimize the influence of transmitted resistance on estimating the polymorphism frequency in the absence of selective drug pressure. First, we excluded isolates from studies of untreated persons with primary HIV-1 infection in regions where transmitted resistance is common. Second, we excluded isolates from untreated persons with two or more drug-resistance mutations at residues that are already known either to be nonpolymorphic or to have low polymorphism rates. This second exclusion criterion is predicated on the strong likelihood that the presence of two or more drug-resistance mutations at nonpolymorphic positions in untreated persons is unlikely to reflect natural variation in protease and reverse transcriptase (RT) but is instead most consistent with previous selective drug pressure.
Effect of sequencing method and sequence quality on estimates of polymorphism rates
Two approaches were taken to minimize the effect that heterogeneous sequencing methods and outright sequencing errors could have on estimates of polymorphism rates: (1) published sequences performed using oligonucleotide arrays were excluded because these sequences have a higher error rate than HIV-1 sequences determined using dideoxynucleoside sequencing ; (2) A sequence quality score – defined as the total number of stop codons, highly ambiguous nucleotides (B, D, H, V, N) and highly unusual mutations (frequency < 0.05% in pooled viruses of all Group M subtypes from treated and untreated persons) – was assigned to all sequences in the database. Protease sequences with a sequence quality score of four or higher and RT sequences (positions 1–240) with a sequence quality score of six or higher were excluded from the dataset.
Distinguishing nonpolymorphic from rarely polymorphic drug-resistance mutations
In human genetics, a polymorphism is arbitrarily defined as a mutation that occurs in at least 1% of a population. However, because of the large number of HIV-1 positions associated with drug resistance, using a cut-off of 1% could lead to inflated estimates of transmitted resistance. As a more conservative criterion, we propose that the list of resistance mutations used for epidemiology should ideally exclude mutations occurring in untreated persons at a frequency of > 0.5%. However, we cannot yet apply this criterion uniformly to all subtypes, because the numbers of isolates currently available from non-B subtypes are relatively small and may not be representative. The appearance of a mutation once or twice among the sequences from a non-B subtype with fewer than 200 sequences available could lead to that mutation's unjustified exclusion from the list. Therefore, we excluded from the list any mutation in more than 1% of untreated isolates from any one non-B subtype in our dataset, and have provisionally included those occurring > 0.5 to 1% until a larger dataset for each of the non-B subtypes become available.
An epidemiologic list may lead to overestimates of prevalence of resistance if the list includes mutations that occur at a low level without exposure to drug pressure. For example, nearly one-half of the drug-resistance surveillance mutations derived here occurred at a level of 0.1% or higher in one or more subtypes (see Tables 1–3 below). The presence of these mutations in untreated persons probably reflects a combination of two phenomena: transmitted resistance and natural occurrence. There is no definitive approach for distinguishing between these two possibilities because, even in recently infected persons, the genotype and treatment history of the source of infection are rarely known.
Criterion 3: applicability to all HIV-1 subtypes
Most data on the genetic mechanisms of HIV-1 drug resistance come from studies of subtype B viruses, the predominant subtype in the North American and Europe. Nonetheless several preliminary observations have been made about drug-resistance in non-B viruses. With few exceptions, nearly all of the differences between subtypes in reported viruses from untreated persons occur at positions that are also polymorphic in subtype B. Indeed, the vast majority of in-vitro and in-vivo studies suggest that the currently available protease and RT inhibitors are as active against non-B viruses as they are against subtype B viruses [20–25].
The mutations that cause drug resistance in subtype B viruses appear to be the main mutations that cause drug resistance in non-B viruses . However, the spectrum of mutations at some drug-resistance positions differs among subtypes. For example, the RT mutation V106M, which rarely occurs in subtype B isolates after non nucleoside reverse transcriptase inhibitor (NNRTI) exposure, is one of the most common mutations responsible for NNRTI resistance in subtype C isolates [27,28]. The protease mutation V82M, which rarely occurs in subtype B isolates after protease inhibitor exposure, is a common cause of protease inhibitor resistance in subtype G isolates . Failure to consider these exceptions would lead to falsely low estimates of transmitted resistance for persons infected with viruses belonging to these subtypes. Conversely, including mutations that are polymorphic in any subtype in a mutation list could lead to falsely high estimates of drug resistance in epidemiologic studies where non-B subtypes are common or where their prevalence is increasing.
These preliminary observations support the concept that a single mutation list applicable to epidemiology involving all subtypes can be created. Many surveys involve more than one subtype, and maintaining different lists for different subtypes would be impractical. Further, as sequencing of viral isolates from around the world increases an increasing number of new infections appear to be inter-subtype recombinants. We therefore propose a single list excluding mutations found to be polymorphic among sequences from any subtype, and including the drug-resistance mutations associated with treatment in any subtype.
Criterion 4: parsimonious and unambiguous
HIV-1 drug resistance incidence and prevalence surveys will often be performed by epidemiologists who do not have expert knowledge of HIV-1 drug resistance. Therefore, the simplest and shortest possible list of drug-resistance mutations that reliably assesses the prevalence of resistance should be used for epidemiologic studies of transmitted drug resistance. The process of developing the list should be transparent and reproducible. Although the list does not require all clinically relevant mutations, the majority of the mutations should be meaningful to clinicians at the sites of epidemiologic studies.
To simplify the list, we excluded mutations occurring at positions that are known to be highly polymorphic. Specifically, the protease mutations L10F/R/Y and A71I are each in three or more expert lists and are non-polymorphic in untreated persons. However, because these mutations occur at positions for which the most common drug-resistance mutations (L10I/V and A71V/T) are polymorphic, the inclusion of these mutations would complicate the performance of resistance analyses in epidemiologic settings.
Protease inhibitor-resistance surveillance mutations
Table 1 lists 31 mutations at 14 protease positions likely to be appropriate for genotypic resistance epidemiology. Commonly recognized drug-resistance mutations excluded from the list because of occurrence above the cut-off in at least one subtype with no evidence of exposure to drug pressure included L10I/V, K20R/M/I, L33F, M36I/L/V, M46L, L63P, A71V/T, and V77I. Three of these exclusions are based on data from non-B isolates: K20I is the consensus amino acid for CRF01_AG and subtype G, M46L has been reported in 1.5% (4/264) of subtype G sequences and L33F has been reported in 1.0% (7/686) of subtype A and 1.2% (8/684) of CRF01_AE sequences.
Drug-resistance mutations that occur with a frequency of > 0.5 to 1.0% in datasets with relatively small numbers of non-B subtypes have been provisionally included: M46I (0.6%, 1/180 of subtype F sequences), I47V (0.7%, 2/270 of subtype G sequences), G73S (0.6%, 1/180 of subtype F sequences), N88S (0.7%, 2/270 of subtype G sequences), and L90M (0.7%, 2/270 of subtype G sequences). When a larger number of subtype F and G sequences become available for analysis, the frequency of these mutations can be estimated more precisely. In the interim, they are included, but the possibility that these mutations could be sufficiently polymorphic to bias estimates of transmitted resistance upward should be recognized.
Nucleoside reverse transcriptase inhibitor-resistance surveillance mutations
Table 2 lists 31 NRTI-resistance mutations at 15 RT positions likely to be appropriate for genotypic resistance epidemiology. Commonly recognized drug-resistance mutations provisionally excluded from the list because of occurrence at > 1% in one or more subtype sets in the database with no evidence of exposure to drug pressure included E44D, reported in 1.6, 1.5 and 0.7% of persons with subtype D, F, and G sequences, respectively; A62V, reported in 17% of persons with subtype A sequences; T69S, reported in 0.6, 1.0, and 1.1% of persons with subtype B, C, and D sequences, respectively; T69N, reported in 0.7% of persons with subtype B and F sequences; V75I, reported in 2.6% (5/189) persons with subtype D sequences; and V118I, reported in > 1% of persons with subtype B, C, D, F, and G sequences.
Drug-resistance mutations that occur with a frequency of > 0.5 to 1.0% among a relatively small set of one non-B subtype in the database have been provisionally included: M41L (1.0%, 2/192 in subtype D); K70R (0.7%, 1/145 in subtype G); L74V (0.7%, 1/145 in subtype G), V75M (0.6%, 4/635 in CRF01_AE), and K219Q (1.0%, 2/192 in subtype D). When a larger number of subtype D, F, and G sequences become available for analysis, their frequency can be estimated more precisely. The possibility that these mutations could be sufficiently polymorphic to bias estimates of transmitted resistance upward should be recognized.
Non-nucleoside reverse transcriptase-resistance surveillance mutations
Table 3 lists 18 NNRTI-resistance mutations at 10 RT positions likely to be appropriate for genotypic resistance epidemiology. Commonly recognized drug-resistance mutations provisionally excluded from the list because of occurrence at > 1% in one or more subtypes with no evidence of exposure to drug pressure include: V108I, reported in 0.6 to 1.1% of sequences from untreated persons with subtypes, A, CRF02, D, and G; V179D, reported in > 1.0% in of persons with subtypes B, F, and CRF01_AE sequences; V179E, reported in 4.3% of persons with subtype G sequences; and F227L, reported in 1.9% of persons with subtype F sequences.
Drug-resistance mutations that occur with a frequency of > 0.5 to 1.0% among a relatively small set of one non-B subtype in the database have been provisionally included: M230L (0.7%, 1/137 in subtype F).
Application to published studies of primary HIV-1 infection
There have been five studies of primary HIV-1 infection for which RT and/or protease sequence data have been submitted to GenBank [30–34] (Table 4). Twenty-three of the 32 NRTI-resistance mutations and nine of the 18 NNRTI-resistance mutations on our list were present in the 656 RT sequences in these studies; and nine of the 31 protease-resistance mutations on our list were present in the 407 protease sequences in these studies.
For four of the 15 estimates of drug class resistance in these studies, there was complete agreement between the results described in the published study and those obtained using the mutation list we have derived. For 10 of the estimates, the results obtained using our mutation list differed from the results reported by the authors by a median of 1.2% (range, 0.9–3.6%). For one study, protease sequences were not available and no comparison was possible.
Although none of the five studies enumerated a specific list of drug resistance surveillance mutations, the analysis of the sequences from these studies in conjunction with tables in the primary publication containing the mutations of drug-resistant isolates made it possible to identify the likely sources for differences between the published analyses and our results. In one study, the difference arose from the authors' inclusion of the NRTI mutation V118I and the NNRTI mutation V179D, mutations that are not on our list as they occur at a frequency of more than 1% in the absence of therapy.
In the remaining studies, differences arose from mutations that are in our mutation list but did not appear to be counted in the primary study, including the RT mutations F77L (present as a mixture in two persons), K103N (three persons), T215D/E/S (three persons), K219Q (three persons), P236L, and M41L+L74V+M184V+L210W+T215Y and the protease mutations L24I (present as a mixture in two persons), F53L, I54T, G73A, and I54V+V82F+L90M. Some of these differences appear to reflect differences in how mutations were classified and others to reflect differences in how the final results were tabulated.
In this paper, we propose criteria for selecting mutations for drug resistance surveillance and develop a provisional list of mutations based on these criteria. Widespread application of the list proposed here, or of a similar list based on standard criteria, will facilitate inter-study comparisons and will support ongoing representative surveillance to evaluate trends over time.
Although there is no gold standard for the identification of transmitted resistance, continued studies of virus sequences of different subtypes from untreated and treated chronically infected persons are required to avoid the exclusion of mutations that are selected by therapy in one or more subtypes and to avoid the inclusion of mutations that are nonpolymorphic in one or more subtypes. Continued studies of virus sequences of different subtypes from untreated acutely infected persons facilitates the identification of mutations important for surveillance such as the T215 revertants that evolve from known drug-resistant variants in the absence of selective drug pressure and competing wild-type variants.
A definitive, unambiguous list of genotypic mutations for surveillance systems and other epidemiologic studies is also likely to change over time with the introduction of new drugs, the identification of new drug-resistance mutations, and the availability of more non-B sequences for analysis. Active efforts are required to base the analyses on sufficient numbers of sequences from all countries in the world and all recognized subtypes.
1. Goudsmit J, de Ronde A, Ho DD, Perelson AS. Human immunodeficiency virus fitness in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase. J Virol 1996; 70:5662–5664.
2. Yerly S, Rakik A, De Loes SK, Hirschel B, Descamps D, Brun-Vezinet F, Perrin L. Switch to unusual amino acids at codon 215 of the human immunodeficiency virus type 1 reverse transcriptase gene in seroconvertors infected with zidovudine-resistant variants. J Virol 1998; 72:3520–3523.
3. de Ronde A, van Dooren M, van Der Hoek L, Bouwhuis D, de Rooij E, van Gemen B, et al
. Establishment of new transmissible and drug-sensitive human immunodeficiency virus type 1 wild types due to transmission of nucleoside analogue-resistant virus. J Virol 2001; 75:595–602.
4. Violin M, Cozzi-Lepri A, Velleca R, Vincenti A, D'Elia S, Chiodo F, et al
. Risk of failure in patients with 215 HIV-1 revertants starting their first thymidine analog-containing highly active antiretroviral therapy. AIDS 2004; 18:227–235.
5. Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC, et al
. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 2002; 347:385–394.
6. Garcia-Lerma JG, Nidtha S, Blumoff K, Weinstock H, Heneine W. Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons. Proc Natl Acad Sci U S A 2001; 98:13907–13912.
7. Cane P, Chrystie I, Dunn D, Evans B, Geretti AM, Green H, et al
. Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ 2005; 331:1368.
8. Wensing AM, van de Vijver DA, Angarano G, Asjo B, Balotta C, Boeri E, et al
. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: Implications for clinical management. J Infect Dis 2005; 192:958–966.
9. Oette M, Kaiser R, Daumer M, Petch R, Fatkenheuer G, Carls H, et al
. Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing. J Acquir Immune Defic Syndr 2006; 41:573–581.
10. Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, Petropoulos CJ, et al
. Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 2002; 288:181–188.
11. Markowitz M, Mohri H, Mehandru S, Shet A, Berry L, Kalyanaraman R, et al
. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report. Lancet 2005; 365:1031–1038.
12. Daar ES, Richman DD. Confronting the emergence of drug-resistant HIV type 1: impact of antiretroviral therapy on individual and population resistance. AIDS Res Hum Retroviruses 2005; 21:343–357.
13. Pillay D. Current patterns in the epidemiology of primary HIV drug resistance in North America and Europe. Antivir Ther 2004; 9:695–702.
14. Johnson VA, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, Pillay D, et al
. Update of the Drug Resistance Mutations in HIV-1: 2005. Top HIV Med 2005; 13:51–57.
15. Clark S, Calef C, Mellors JW. Mutations in retroviral genes associated with resistance.
In: Leitner T, Foley B, Hahn B, Marx P, McCutchan F, Mellors J, et al.
editors. HIV sequence compendium
. Los Alamos, NM: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory; 2005. pp. 83–128.
16. Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003; 31:298–303.
17. Meynard JL, Vray M, Morand-Joubert L, Race E, Descamps D, Peytavin G, et al
. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS 2002; 16:727–736.
18. Van Laethem K, De Luca A, Antinori A, Cingolani A, Perno CF, Vandamme A-M. A genotypic drug resistance interpretation algorithm that significantly predicts therapy response in HIV-1-infected patients. Antivir Ther 2002; 7:123–129.
19. Vahey M, Nau ME, Barrick S, Cooley JD, Sawyer R, Sleeker AA, et al
. Performance of the Affymetrix GeneChip HIV PRT 440 platform for antiretroviral drug resistance genotyping of human immunodeficiency virus type 1 clades and viral isolates with length polymorphisms. J Clin Microbiol 1999; 37:2533–2537.
20. Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al
. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002; 360:34–40.
21. Pillay D, Walker AS, Gibb DM, de Rossi A, Kaye S, Ait-Khaled M, et al
. Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. J Infect Dis 2002; 186:617–625.
22. Kebba A, Atwine D, Mwebaze R, Kityo C, Nakityo R, Peter M. Therapeutic responses to AZT + 3TC + EFV in advanced antiretroviral naive HIV type 1-infected Ugandan patients. AIDS Res Hum Retroviruses 2002; 18:1181–1187.
23. Landman R, Schiemann R, Thiam S, Vray M, Canestri A, Mboup S, et al
. Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal. AIDS 2003; 17:1017–1022.
24. Parkin NT, Schapiro JM. Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV. Antivir Ther 2004; 9:3–12.
25. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A, Calmy A, et al
. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004; 364:29–34.
26. Kantor R, Katzenstein DA, Efron B, Carvalho AP, Wynhoven B, Cane P, et al
. Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLoS Med 2005; 2:e112.
27. Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, Carobene M, et al
. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 2003; 17:F1–F5.
28. Grossman Z, Istomin V, Averbuch D, Lorber M, Risenberg K, Levi I, et al
. Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C. AIDS 2004; 18:909–915.
29. Camacho R, Godinho A, Gomes P, Abecasis A, Vandamme A-M, Palma C, et al
. Different substitutions under drug pressure at protease codon 82 in HIV-1 subtype G compared to subtype B infected individuals including a novel I82M resistance mutations. Antiviral Therapy 2005; 10:S151.
30. Balotta C, Berlusconi A, Pan A, Violin M, Riva C, Colombo MC, et al
. Prevalence of transmitted nucleoside analogue-resistant HIV-1 strains and pre-existing mutations in pol reverse transcriptase and protease region: outcome after treatment in recently infected individuals. Antiviral Therapy 2000; 5:7–14.
31. Simon V, Vanderhoeven J, Hurley A, Ramratnam B, Louie M, Dawson K, et al
. Evolving patterns of HIV-1 resistance to antiretroviral agents in newly infected individuals. AIDS 2002; 16:1511–1519.
32. Romano L, Venturi G, Ferruzzi R, Riccio ML, Corsi P, Leoncini F, et al
. Detection of genotypically drug-resistant HIV-1 variants and non-B subtypes in recently infected antiretroviral-naive adults in Italy. AIDS 2000; 14:2204–2206.
33. Toni T, Masquelier B, Bonard D, Faure M, Huet C, Caumont A, et al
. Primary HIV-1 drug resistance in Abidjan (Cote d'Ivoire): a genotypic and phenotypic study. AIDS 2002; 16:488–491.
34. Chaix ML, Descamps D, Harzic M, Schneider V, Deveau C, Tamalet C, et al
. Stable prevalence of genotypic drug resistance mutations but increase in non-B virus among patients with primary HIV-1 infection in France. AIDS 2003; 17:2635–2643.
35. Little SJ, Daar ES, D'Aquila RT, Keiser PH, Connick E, Whitcomb JM, et al
. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA 1999; 282:1142–1149.
36. Weinstock HS, Zaidi I, Heneine W, Bennett D, Garcia-Lerma JG, Douglas JM Jr, et al
. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis 2004; 189:2174–2180.
This article has been cited 104 time(s).
Epigenetics of HIV Infection: Promising Research Areas and Implications for Therapy
AIDS Reviews, 15(3):
Memorias DO Instituto Oswaldo CruzTransmitted human immunodeficiency virus-1 drug resistance in a cohort of men who have sex with men in Belo Horizonte, Brazil-1996-2012Memorias DO Instituto Oswaldo Cruz
VaccineImmunogenicity of sequences around HIV-1 protease cleavage sites: Potential targets and population coverage analysis for a HIV vaccine targeting protease cleavage sitesVaccine
AIDS Research and Human RetrovirusesLow Prevalence of Transmitted HIV Type 1 Drug Resistance Among Antiretroviral-Naive Adults in a Rural HIV Clinic in KenyaAIDS Research and Human Retroviruses
Journal of Medical VirologySubtype CRF01_AE dominate the sexually transmitted human immunodeficiency virus type 1 epidemic in Guangxi, ChinaJournal of Medical Virology
Journal of Medical VirologyUpdated prevalence of genotypic resistance among HIV-1 positive patients naive to antiretroviral therapy: A single center analysisJournal of Medical Virology
The World Health Organization's global strategy for prevention and assessment of HIV drug resistance
Antiviral Therapy, 13():
Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies
Antiviral Therapy, 13():
Plos MedicineMinority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacyPlos Medicine
Journal of Infectious DiseasesPhylogenetic Reconstruction of Transmission Events from Individuals with Acute HIV Infection: Toward More-Rigorous Epidemiological DefinitionsJournal of Infectious Diseases
Sexually Transmitted InfectionsImplications for HIV testing policy derived from combining data on voluntary confidential testing with viral sequences and serological analysesSexually Transmitted Infections
Journal of Pharmaceutical SciencesInteractions of Pluronic Block Copolymers on P-gp Efflux Activity: Experience With HIV-1 Protease InhibitorsJournal of Pharmaceutical Sciences
AIDS Research and Human RetrovirusesImpact of Low Abundance HIV Variants on Response to Ritonavir-Boosted Atazanavir or Fosamprenavir Given Once Daily with Tenofovir/Emtricitabine in Antiretroviral-Naive HIV-Infected PatientsAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesPrevalence of resistance mutations in HIV-1-Infected Hondurans at the beginning of the national Antiretroviral therapy programAIDS Research and Human Retroviruses
Proteins-Structure Function and Bioinformatics
HIV-1 protease function and structure studies with the simplicial neighborhood analysis of protein packing method
Proteins-Structure Function and Bioinformatics, 73(3):
Clinical Infectious DiseasesUse of peripheral blood DNA for genotype antiretroviral resistance testing in drug-naive HIV-infected subjectsClinical Infectious Diseases
Surveillance of transmitted HIV, drug resistance among women attending antenatal clinics in Dar es Salaam, Tanzania
Antiviral Therapy, 13():
Clinical Infectious DiseasesAntiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panelClinical Infectious Diseases
Annual Review of BiochemistryNew Antivirals and Drug ResistanceAnnual Review of Biochemistry
BiochemistryThe contribution of naturally occurring polymorphisms in altering the biochemical and structural characteristics of HIV-1 subtype C proteaseBiochemistry
BiopolymersA poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocketBiopolymers
Archives of VirologyGenotypic and phenotypic characterization of human immunodeficiency virus type 1 isolates circulating in pregnant women from MozambiqueArchives of Virology
Journal of InfectionPrevalence of C-terminal gag cleavage site mutations in HIV from therapy-naive patientsJournal of Infection
Antimicrobial Agents and ChemotherapyHuman Immunodeficiency Virus Type 1 Isolates with the Reverse Transcriptase (RT) Mutation Q145M Retain Nucleoside and Nonnucleoside RT Inhibitor SusceptibilityAntimicrobial Agents and Chemotherapy
BioinformaticsThe calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistanceBioinformatics
Evaluation of transmitted HIV drug resistance among recently-infected antenatal clinic attendees in four Central African Countries
Antiviral Therapy, 14(3):
Journal of Medical VirologyAnalysis of the Diversity of the HIV-1 pol Gene and Drug Resistance Associated Changes Among Drug-Naive Patients in Burkina FasoJournal of Medical Virology
Journal of Infectious DiseasesManaging antiretroviral therapy: Changing regimens, resistance testing, and the risks from structured treatment interruptionsJournal of Infectious Diseases
AIDS Patient Care and StdsProtease inhibitor resistance update: Where are we now?AIDS Patient Care and Stds
AIDS Research and Human RetrovirusesHuman immunodeficiency virus type 1 seroprevalence and antiretroviral drug resistance-associated mutations in miners in Gabon, central AfricaAIDS Research and Human Retroviruses
Journal of VirologyPhylogenetic surveillance of viral genetic diversity and the evolving molecular epidemiology of human immunodeficiency virus type 1Journal of Virology
Journal of Infectious DiseasesIncreased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapyJournal of Infectious Diseases
TransfusionHuman immunodeficiency virus-1 genotypic drug resistance among volunteer blood donors in Yunnan, ChinaTransfusion
Plos OneInitial Fitness Recovery of HIV-1 Is Associated with Quasispecies Heterogeneity and Can Occur without Modifications in the Consensus SequencePlos One
Clinical implications of resistance to antiretrovirals: new resistance technologies and interpretations
Antiviral Therapy, 13(2):
Surveillance of transmitted HIV drug resistance with the World Health Organization threshold survey method in Lilongwe, Malawi
Antiviral Therapy, 13():
AIDS Research and Human RetrovirusesModulation of K65R Selection by Zidovudine Inclusion: Analysis of HIV Resistance Selection in Subjects with Virologic Failure Receiving Once-Daily Abacavir/Lamivudine/Zidovudine and Tenofovir DF (Study COL40263)AIDS Research and Human Retroviruses
International Journal of Infectious DiseasesUnderstanding transmitted HIV resistance through the experience in the USAInternational Journal of Infectious Diseases
Bmc BioinformaticsPairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B proteaseBmc Bioinformatics
AIDS Research and Human RetrovirusesHIV Type 1 Transmitted Drug Resistance and Evidence of Transmission Clusters Among Recently Infected Antiretroviral-Naive Individuals from Ugandan Fishing Communities of Lake VictoriaAIDS Research and Human Retroviruses
Medecine Et Maladies InfectieusesEffects of prolonged exposure to antiretroviral treatment in Tunisian patients assessed by the HIV-1 resistance genotypic testMedecine Et Maladies Infectieuses
AIDS Research and Human RetrovirusesPrevalence of Primary Drug Resistance-Associated Mutations Among HIV Type 1 Vertically Infected Children in Belo Horizonte, BrazilAIDS Research and Human Retroviruses
Virus ResearchDrug resistance among chronic HIV-1-infected patients naive for use of anti-retroviral therapy in Sao Paulo cityVirus Research
Bmc Infectious DiseasesCharacterization of the patterns of drug-resistance mutations in newly diagnosed HIV-1 infected patients naive to the antiretroviral drugsBmc Infectious Diseases
Transmitted antiretroviral drug resistance among acute and recent HIV infections in North Carolina from 1998 to 2007
Antiviral Therapy, 14(5):
Journal of VirologyAmino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitorsJournal of Virology
AIDS Research and Human RetrovirusesPrevalence and epidemiology of HIV type 1 drug resistance among newly diagnosed therapy-naive patients in Belgium from 2003 to 2006AIDS Research and Human Retroviruses
Tohoku Journal of Experimental Medicine
Low Prevalence of Drug-Resistant HIV-1 in Patients Newly Diagnosed with Early Stage of HIV Infection in Korea
Tohoku Journal of Experimental Medicine, 216(3):
Journal of Chemical Information and ModelingMolecular Dynamics and Free Energy Studies on the Wild-Type and Mutated HIV-1 Protease Complexed with Four Approved Drugs: Mechanism of Binding and Drug ResistanceJournal of Chemical Information and Modeling
Antiretroviral drug resistance surveillance among drug-naive HIV-1-infected individuals in Gauteng Province, South Africa in 2002 and 2004
Antiviral Therapy, 13():
HIV drug resistance threshold survey using specimens from voluntary counselling and testing sites in Hanoi, Vietnam
Antiviral Therapy, 13():
Memorias DO Instituto Oswaldo Cruz
Molecular characterisation of newly identified HIV-1 infections in Curitiba, Brazil: preponderance of clade C among males with recent infections
Memorias DO Instituto Oswaldo Cruz, 103(8):
Plos OneDrug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 UpdatePlos One
Prevalence of resistance mutations in antiretroviral-naive chronically HIV-infected patients in 2006/2007: a French nationwide study
Antiviral Therapy, 13(4):
AIDS Research and Human RetrovirusesHigh HIV Type 1 Prevalence and Wide Genetic Diversity with Dominance of Recombinant Strains But Low Level of Antiretroviral Drug-Resistance Mutations in Untreated Patients in Northeast Gabon, Central AfricaAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesComparison of Genotypic Resistance Mutations in Treatment-Naive HIV Type 1-Infected Patients in Korea and ChinaAIDS Research and Human Retroviruses
Journal of VirologyNovel cyotoxic T-Lymphocyte escape mutation by a three-amino-acid insertion in the human immunodeficiency virus type 1 p6(Pol) and p6(Gag) late domain associated with drug resistanceJournal of Virology
Journal of Molecular BiologyEffect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavirJournal of Molecular Biology
Journal of Antimicrobial ChemotherapyEvolution of genetic diversity and drug resistance mutations in HIV-1 among untreated patients from Mali between 2005 and 2006Journal of Antimicrobial Chemotherapy
The reverse transcriptase of HIV-1: role of the domain connection and RNase H in anti-retroviral resistors
Journal of Antimicrobial ChemotherapyPrevalence and determinants of transmitted antiretroviral drug resistance in HIV-1 infectionJournal of Antimicrobial Chemotherapy
VirologyDrug-associated changes in amino acid residues in Gag p2, p7(NC), and p6(Gag)/p6(Pol) in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug responseVirology
Journal of VirologyAnalysis of natural sequence variation and covariation in human immunodeficiency virus type 1 integraseJournal of Virology
HIV Clinical TrialsGeographic and Temporal Trends of Transmitted HIV-1 Drug Resistance Among Antiretroviral-Naive Subjects Screening for Two Clinical Trials in North America and Western EuropeHIV Clinical Trials
Antimicrobial Agents and ChemotherapyAntiretroviral Drug Resistance Surveillance among Treatment-Naive Human Immunodeficiency Virus Type 1-Infected Individuals in Angola: Evidence for Low Level of Transmitted Drug ResistanceAntimicrobial Agents and Chemotherapy
HIV type-1 transmission dynamics in recent seroconverters: relationship with transmission of drug resistance and viral diversity
Antiviral Therapy, 14(4):
Proceedings of the National Academy of Sciences of the United States of AmericaDetecting and understanding combinatorial mutation patterns responsible for HIV drug resistanceProceedings of the National Academy of Sciences of the United States of America
Evolution of drug resistance after virological failure of a first-line highly active antiretroviral therapy regimen in Uganda
Antiviral Therapy, 14(2):
Antimicrobial Agents and ChemotherapyNonpolymorphic Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Treatment-Selected MutationsAntimicrobial Agents and Chemotherapy
Science Translational MedicineThe Origins of Sexually Transmitted HIV Among Men Who Have Sex with MenScience Translational Medicine
AIDS Research and Human RetrovirusesPhylogenetic diversity and low level antiretroviral resistance mutations in HIV type 1 treatment-naive patients from Cape Town, south AfricaAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesTransmitted HIV Type 1 Drug Resistance and Non-B Subtypes Prevalence among Seroconverters and Newly Diagnosed Patients from 1992 to 2005 in ItalyAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesHigh prevalence of human immunodeficiency virus type 1 drug resistance mutations in antiretroviral treatment-experienced patients from Pune, IndiaAIDS Research and Human Retroviruses
Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey
HIV-1 drug resistance mutations: an updated framework for the second decade of HAART
AIDS Reviews, 10(2):
Journal of Clinical VirologyNine-year trends in clinically relevant reduced susceptibility of HIV-1 to antiretroviralsJournal of Clinical Virology
Antiviral TherapyPrevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South AfricaAntiviral Therapy
Archives of VirologyFalse I50V resistance readings of HIV isolates: co-amplification of NASBA HIV-1 RNA QT internal calibrators and HIV-1 patient isolates may lead to a false I50V mutation resistance reading in genotypic testsArchives of Virology
HIV-1 Genotypic Drug Resistance Interpretation Rules-2009 Spanish Guidelines
AIDS Reviews, 11(1):
Current Opinion in HIV and AIDSTransmitted HIV drug resistance in AsiaCurrent Opinion in HIV and AIDS
Plos OneLow Primary and Secondary HIV Drug-Resistance after 12 Months of Antiretroviral Therapy in Human Immune-Deficiency Virus Type 1 (HIV-1)-Infected Individuals from Kigali, RwandaPlos One
Antimicrobial Agents and ChemotherapyP2' Benzene Carboxylic Acid Moiety Is Associated with Decrease in Cellular Uptake: Evaluation of Novel Nonpeptidic HIV-1 Protease Inhibitors Containing P2 bis-Tetrahydrofuran MoietyAntimicrobial Agents and Chemotherapy
Journal of Virological MethodsRapid deep sequencing of patient-derived HIV with ion semiconductor technologyJournal of Virological Methods
JAIDS Journal of Acquired Immune Deficiency SyndromesPrevalence of Drug-Resistant HIV-1 in Rural Areas of Hubei Province in the People's Republic of ChinaJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesThe Impact of Transmitted Drug-Resistance on Treatment Selection and Outcome of First-Line Highly Active Antiretroviral Therapy (HAART)JAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesIncreased Detection of HIV-1 Drug Resistance at Time of Diagnosis by Testing Viral DNA With a Sensitive AssayJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesThe Impact of Different Definitions on the Estimated Rate of Transmitted HIV Drug Resistance in the United KingdomJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesTransmission Cluster of Multiclass Highly Drug-Resistant HIV-1 Among 9 Men Who Have Sex With Men in Seattle/King County, WA, 2005-2007JAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesHIV-1 Transmission Cluster With T215D Revertant Mutation Among Newly Diagnosed Patients From the Basque Country, SpainJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesHIV-1 Genetic Diversity and Transmitted Drug Resistance in Health Care Settings in Maputo, MozambiqueJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesPhylogenetic Investigation of Transmission Pathways of Drug-Resistant HIV-1 Utilizing Pol Sequences Derived From Resistance GenotypingJAIDS Journal of Acquired Immune Deficiency Syndromes
HIV-1; Antiretroviral drug resistance; protease; reverse transcriptase; mutations; epidemiology; surveillance
© 2007 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read