Primary Resistance of Viruses in Reported New Cases of HIV, 2017–2020

Findings of a Nationwide Molecular HIV Surveillance Program

A project dedicated to the molecular surveillance of newly diagnosed HIV cases serves the Robert Koch Institute as an instrument for nationwide surveillance of primary HIV-1 drug resistance in Germany. In contrast to acquired drug resistance, resulting from selection during treatment, transmitted (or primary) drug resistance refers to a situation in which the transmitted virus already has mutations that lead to a reduction in the antiretroviral effect of potential therapeutic agents (1). Consequently, primary resistance is clinically highly relevant and can limit the portfolio of effective antiretroviral therapeutic and preventative regimens. Following national and international guidelines, genotypic resistance testing should be performed prior to initiation of therapy (2). In 2020, its structure was redesigned and now includes fee scale items which cover primary resistance testing for nucleoside reverse transcriptase (RT) inhibitors (NRTIs), non-nucleoside RT inhibitors (NNRTIs), protease (PR) inhibitors (PIs), and integrase (IN) inhibitors (INIs).

Methods

Due to the anonymous statutory reporting pursuant to sections 7 and 10 of the German Protection against Infection Act (IfSG, Infektionsschutzgesetz), the RKI is informed about newly diagnosed cases of HIV. In addition, the IfSG (section 13) allows for supporting epidemiological surveys for molecular surveillance of infecting organisms. Within this legal framework, a nationwide network comprising about 70 laboratories in Germany (www.rki.de/DE/Content/InfAZ/H/HIVAIDS/Studien/InzSurv_HIV/beteiligte_Labore.html) also sends plasma or serum samples of new cases of HIV to the RKI, linked via a number to the respective reporting form. From this sample material, RNA was isolated and used to sequence viral genome regions of PR (amino acid 9–99), RT (amino acid 1–252) and IN (amino acid 1–279) (3). Mutations were recorded using a cut-off value of 20%. The algorithm of the Stanford HIV Drug Resistance Database version 8.9 (Stanford HIVdb; www.hivdb.stanford.edu/) were used to identify and assess drug resistances. Sequences with mutation penalty scores greater than 10 were classified as resistant to a therapeutic agent (at least low-level resistance). The molecular surveillance data were combined with information from the reporting forms. Statistical analyses were performed using Excel (chi-square test, confidence intervals) and Stata, version 17.0 (Cochran-Armitage Test for Trend).

Results

In the four-year period 2017–2020, a total of 11 527 new cases of HIV were reported to the RKI. Sequences of PR and RT were obtained from 4559 (39.6%) cases. In addition, the IN genomic regions (PR, RT, IN) of 3097 (26.9%) of the reported cases were amplified and examined (Table). Among the 3097 newly diagnosed cases with genotypic data of all three genomic regions, mutations, causing a clinically relevant weakening of the susceptibility to one or more antiviral agents, were found in 470 cases (15.2%; 95% confidence interval [13.9; 16.4]; 470/3097). If only the agents currently recommended for initial treatment were included, the proportion was 8.9% [7.9; 9.9], 276/3 097). In each of the four classes of antiretroviral drugs, several antiretroviral substances are approved in Germany and recommended for HIV treatment (2). The figure shows the proportion of newly diagnosed cases with HIV with drug resistance to 24 of these substances for each year of the analysis. The highest prevalence rates were found among NNRTIs where rates reached up to 7.2% (rilpivirine in 2017). Cases with primary resistance to the integrase inhibitors (INIs) bictegravir (BIC) und dolutegravir were very rare (0.2% in 2020 and no cases in 2017–2019). Currently, there is a special focus on the surveillance of primary resistance to tenofovir formulations (TDF/TAF) and emtricitabine (FTC), because TDF/FTC combinations have been approved for pre-exposure prophylaxis (PrEP). During the analyzed period, 80 (1.8% [1.4; 2.1], 80/4559) of the newly diagnosed cases with HIV drug resistance to one or both PrEP agents were detected. The proportions in the various years among MSM and other transmission groups (non-MSM) did not follow any trend (MSM: p_Trend = 0.148, non-MSM p_Trend = 0.482, overall: p_Trend = 0.107).

Figure

Prevalence of reported new cases of HIV with resistance to approved drugs

Table

Number of newly diagnosed cases of HIV and proportions of analyzed sequences, 2017–2020

Discussion

The proportion of new cases of HIV with primary resistance to approved drugs was with 15.2% at a level >10% in the period 2017–2020. In accordance with the decision of the Federal Joint Committee (G-BA, Gemeinsamer Bundesausschuss; www.g-ba.de/downloads/39–261–228/2005–09–20-HIV-Resistenztestung.pdf) from the year 2005, genotypic resistance testing is therefore still required prior to initiation of treatment. However, many of these drug resistances are related to older active ingredients that are rarely used anymore. The prescription of these drugs should be further restricted and an HIV treatment regimen with newer agents should be chosen. With about 1% to 2%, the frequency of clinically relevant primary drug resistance is markedly lower for agents preferentially used today in initial regimens (4), with the exception of rilpivirine (RPV). This also applies to the PrEP drugs TDF/FTC. While the percentage of resistances was higher in the second half of the four-year period than in the first two years, this cannot be considered a trend due to the small number of cases and the range of variation associated with it. Since the increase is noted in both MSM and non-MSM cases, it should not be linked to PrEP. Nevertheless, in view of documented cases of resistance development during PrEP, this aspect requires increased attention (5). Our study is not without limitations: Cases already diagnosed and treated abroad and having developed drug resistance could have been misinterpreted as cases with primary resistance.

Uwe Fiebig*, Britta Altmann*, Andrea Hauser, Uwe Koppe, Kirsten Hanke, Barbara Gunsenheimer-Bartmeyer, Viviane Bremer, Axel Baumgarten, Norbert Bannert

*These two authors are co-first authors.

Department 1, Infectious Diseases, Robert Koch Institute, Berlin, Germany
(Fiebig, Altmann, Hauser, Hanke, Bannert) [e-mail]

Department 3, Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany
(Koppe, Gunsenheimer-Bartmeyer, Bremer);

zfi – Center for Infectiology Berlin–Prenzlauer Berg, Berlin, Germany (Baumgarten)

Funding

This study was funded by internal special research funds of the RKI dedicated to molecular surveillance.

Conflict of interest statement

VB received travel cost support from the organizer of the German-Austrian AIDS Congress. She is member of the DAIG and of the Coordinating Body of the German Government for the Implementation of the Strategy to Contain HIV, Hepatitis B and C, and Other Sexually Transmitted Infections.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 18 November 2022; revised version accepted on 6 February 2023.

Cite this as:
Fiebig U, Altmann B, Hauser A, Koppe U, Hanke K, Gunsenheimer-Bartmeyer B, Bremer V, Baumgarten A, Bannert N: Primary resistance of viruses in reported new cases of HIV, 2017–2020—findings of a nationwide molecular HIV surveillance program. Dtsch Arztebl Int 2023; 120: 479–80. DOI: 10.3238/arztebl.m2023.0038

References

1. Wittkop L, Gunthard HF, de Wolf F, et al.: Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis 2011; 11: 363–71

2. AWMF: Deutsch-Österreichische Leitlinien zur antiretroviralen Therapie der HIV-1-Infektion, AWMF 055–001, Version 8. Stand 31.12.2021. https://register.awmf.org/de/leitlinien/detail/055-001 (last accessed on 15 November 2022

3. Hauser A, Hofmann A, Meixenberger K, et al.: Increasing proportions of HIV-1 non-B subtypes and of NNRTI resistance between 2013 and 2016 in Germany: results from the national molecular surveillance of new HIV-diagnoses. PLoS One 2018; 13: e0206234

4. Lottes M, Bremer V, Prugger C, Kollan C, Schmidt D: Cost-savings and potential cost-savings through the distribution of generic antiretroviral drugs within the statutory health insurance market of Germany between January 2017 and June 2019. BMC Health Serv Res 2022; 22: 63

5. Naicker CL, Mansoor LE, Dawood H, et al.: Importance of early identification of PrEP breakthrough infections in a generalized HIV epidemic: a case report from a PrEP demonstration project in South Africa. BMC Infect Dis 2020; 20: 532