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. 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.

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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

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