Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 16;14(1):e0209605.
doi: 10.1371/journal.pone.0209605. eCollection 2019.

Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort

Patrycja Machnowska  1 , Karolin Meixenberger  1 , Daniel Schmidt  2 , Heiko Jessen  3 , Heribert Hillenbrand  4 , Barbara Gunsenheimer-Bartmeyer  2 , Osamah Hamouda  2 , Claudia Kücherer  1 , Norbert Bannert  1   5 ; German HIV-1 Seroconverter Study Group
Affiliations

Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort

Patrycja Machnowska et al. PLoS One. .

Abstract

The prevalence of transmitted drug resistance (TDR) in antiretroviral therapy (ART)-naïve individuals remains stable in most developed countries despite a decrease in the prevalence of acquired drug resistance. This suggests that persistence and further transmission of HIV-1 that encodes transmitted drug resistance mutations (TDRMs) is occurring in ART-naïve individuals. In this study, we analysed the prevalence and persistence of TDRMs in the protease and reverse transcriptase-sequences of ART-naïve patients within the German HIV-1 Seroconverter Study Cohort who were infected between 1996 and 2017. The prevalence of TDRMs and baseline susceptibility to antiretroviral drugs were assessed using the Stanford HIVdb list and algorithm. Mean survival times of TDRMs were calculated by Kaplan-Meier analysis. The overall prevalence of TDR was 17.2% (95% CI 15.7-18.6, N = 466/2715). Transmitted NNRTI resistance was observed most frequently with 7.8% (95% CI 6.8-8.8), followed by NRTI resistance (5.0%, 95% CI 4.2-5.9) and PI resistance (2.8%, 95% CI 2.2-3.4). Total TDR (OR = 0.89, p = 0.034) and transmitted NRTI resistance (OR = 0.65, p = 0.000) decreased between 1996 and 2017 but has remained stable during the last decade. Viral susceptibility to NNRTIs (6.5%-6.9% for individual drugs) was mainly reduced, while <3% of the recommended NRTIs and PIs were affected. The longest mean survival times were calculated for the NNRTI mutations K103N (5.3 years, 95% CI 4.2-5.6) and E138A/G/K (8.0 years, 95% CI 5.8-10.2 / 7.9 years, 95% CI 5.4-10.3 / 6.7 years, 95% CI 6.7-6.7) and for the NRTI mutation M41L (6.4 years, 95% CI 6.0-6.7).The long persistence of single TDRMs indicates that onward transmission from ART-naïve individuals is the main cause for TDR in Germany. Transmitted NNRTI resistance was the most frequent TDR, showing simultaneously the highest impact on baseline ART susceptibility and on TDRMs with prolonged persistence. These results give cause for concern regarding the use of NNRTI in first-line regimens.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Overall prevalence of drug resistance classes in the German HIV-1 Seroconverter Study Cohort (1996–2017).
Prevalence with 95% CI are given.
Fig 2
Fig 2. Prevalence trends of TDR in the German HIV-1 Seroconverter Study Cohort (1996–2017).
N(1996–2002) = 296, N(2003–2007) = 985, N(2008–2012) = 885, N(2013–2017) = 549. A) Prevalence trend for total TDR. B) Prevalence trend for transmitted NRTI resistance. C) Prevalence trend for transmitted NNRTI resistance. D) Prevalence trend for transmitted PI resistance.
Fig 3
Fig 3. Predicted resistance to antiretroviral drugs in the German HIV-1 Seroconverter Study Cohort (1996–2017).
*: first line-regimen; **: no longer recommended in European ART guidelines; /r: ritonavir-boosted; 3TC: lamivudine; ABC: abacavir; AZT: zidovudine; D4T: stavudine; DDI: didanosine; FTC: emtricitabine; TDF: tenofovir disoproxil fumarate; EFV: efavirenz; ETR: etravirine; NVP: nevirapine; RPV: rilpivirine; ATV: atazanavir; DRV: darunavir; FPV: fosamprenavir; IDV: indinavir; LPV: lopinavir; NFV: nelfinavir; SQV: saquinavir; TPV: tipranavir.
Fig 4
Fig 4. Drugs prescribed in first-line regimens in the German HIV-1 Seroconverter Study Cohort (1996–2017).
A total of 2529 study patients started first-line ART between 1996 and 2017. The proportion of single drugs among all drugs prescribed in first line-regimens per year are given. N(1996) = 63, N(1997) = 157, N(1998) = 119, N(1999) = 130, N(2000) = 87, N(2001) = 85, N(2002) = 160, N(2003) = 177, N(2004) = 233, N(2005) = 236, N(2006) = 255, N(2007) = 392, N(2008) = 475, N(2009) = 497, N(2010) = 596, N(2011) = 592, N(2012) = 639, N(2013) = 684, N(2014) = 543, N(2015) = 565, N(2016) = 505, N(2017) = 303. A) NRTIs in first-line regimens. 3TC: lamivudine; ABC: abacavir; AZT: zidovudine; D4T: stavudine; DDC: zalcitabine; DDI: didanosine; FTC: emtricitabine; TAF: tenofovir alafenamide fumarate; TDF: tenofovir disoproxil fumarate. B) NNRTIs in first-line regimens. EFV: efavirenz; ETR: etravirine; NVP: nevirapine; RPV: rilpivirine. C) PIs in first-line regimens. ATV: atazanavir; DRV: darunavir; FPV: fosamprenavir; IDV: indinavir; LPV: lopinavir; NFV: nelfinavir; RTV: ritonavir; SQV: saquinavir. D) Integrase inhibitors (INIs) in first-line regimens. RAL: raltegravir; EVG: elvitegravir; DTG: dolutegravir.
Fig 5
Fig 5. Mean survival times of TDRMs during ART-naïve course of infection.
Mean Kaplan-Meier estimates with 95% CI are given. Different mutations occurring at the same position are shown in blue. A) TDRMs affecting NRTIs. B) TDRMs affecting NNRTIs. C) TDRMs affecting PIs.
See this image and copyright information in PMC

Similar articles

  • Diversity of HIV-1 Subtypes and Transmitted Drug-resistance Mutations Among Minority HIV-1 Variants in a Turkish Cohort.
    Sarinoglu RC, Sili U, Hasdemir U, Aksu B, Soyletir G, Korten V. Sarinoglu RC, et al. Curr HIV Res. 2022;20(1):54-62. doi: 10.2174/1570162X19666211119111740. Curr HIV Res. 2022. PMID: 34802406
  • Recent trends and patterns in HIV-1 transmitted drug resistance in the United Kingdom.
    Tostevin A, White E, Dunn D, Croxford S, Delpech V, Williams I, Asboe D, Pozniak A, Churchill D, Geretti AM, Pillay D, Sabin C, Leigh-Brown A, Smit E; UK HIV Drug Resistance Database. Tostevin A, et al. HIV Med. 2017 Mar;18(3):204-213. doi: 10.1111/hiv.12414. Epub 2016 Aug 1. HIV Med. 2017. PMID: 27476929 Free PMC article.
  • Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.
    Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ; SPREAD Program; Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Van Laethem K, Beshkov D, Alexiev I, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Linka M, Maly M, Machala L, Nielsen C, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Liitsola K, Ristola M, Suni J, Sutinen J, Descamps D, Assoumou L… See abstract for full author list ➔ Hofstra LM, et al. Clin Infect Dis. 2016 Mar 1;62(5):655-663. doi: 10.1093/cid/civ963. Epub 2015 Nov 29. Clin Infect Dis. 2016. PMID: 26620652 Free PMC article.
  • Study of the impact of HIV genotypic drug resistance testing on therapy efficacy.
    Van Vaerenbergh K. Van Vaerenbergh K. Verh K Acad Geneeskd Belg. 2001;63(5):447-73. Verh K Acad Geneeskd Belg. 2001. PMID: 11813503 Review.
  • HIV-1 transmitted drug resistance surveillance: shifting trends in study design and prevalence estimates.
    Rhee SY, Kassaye SG, Barrow G, Sundaramurthi JC, Jordan MR, Shafer RW. Rhee SY, et al. J Int AIDS Soc. 2020 Sep;23(9):e25611. doi: 10.1002/jia2.25611. J Int AIDS Soc. 2020. PMID: 32936523 Free PMC article. Review.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. WHO. HIV/AIDS—Fact sheet 2017.
    1. 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(2):227–35. . - PubMed
    1. Zaccarelli M, Tozzi V, Lorenzini P, Trotta MP, Forbici F, Visco-Comandini U, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. Aids. 2005;19(10):1081–9. 10.1097/01.aids.0000174455.01369.ad PubMed PMID: WOS:000230468000014. - DOI - PubMed
    1. Sachdeva N, Sehgal S, Arora SK. Frequency of drug-resistant variants of HIV-1 coexistent with wild-type in treatment-naive patients of India. MedGenMed. 2005;7(3):68 - PMC - PubMed
    1. Cong ME, Heneine W, Garcia-Lerma JG. The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions. J Virol. 2007;81(6):3037–41. 10.1128/JVI.02712-06 - DOI - PMC - PubMed

Publication types

MeSH terms