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USE OF GENOTYPIC HIV DNA TESTING: A
DELPHI-TYPE CONSENSUS Short running title:
Delphi Consensus on Genotypic HIV DNA Testing

Elisabeth Andre-Garnier, Laurence Bocket, Thomas Bourlet, Laurent Hocqueloux, Quentin Lepiller, Anne Maillard, Sandrine Reigadas, Guillaume Barriere, François Durand, Brigitte Montes, et al.

► To cite this version:

Elisabeth Andre-Garnier, Laurence Bocket, Thomas Bourlet, Laurent Hocqueloux, Quentin Lepiller, et al.. USE OF GENOTYPIC HIV DNA TESTING: A DELPHI-TYPE CONSENSUS Short running title: Delphi Consensus on Genotypic HIV DNA Testing. Journal of Antimicrobial Chemotherapy, 2024, 10.1093/jac/dkae007. hal-04423751

HAL Id: hal-04423751

https://hal.sorbonne-universite.fr/hal-04423751

Submitted on 29 Jan 2024

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1

USE OF GENOTYPIC HIV DNA TESTING:

2

A DELPHI-TYPE CONSENSUS

3

Short running title: Delphi Consensus on Genotypic HIV DNA Testing

4

Elisabeth ANDRE-GARNIER¹, Laurence BOCKET², Thomas BOURLET³, Laurent

5

HOCQUELOUX⁴, Quentin LEPILLER⁵, Anne MAILLARD⁶, Sandrine REIGADAS⁷,

6

Guillaume BARRIERE⁷, François DURAND⁷, Brigitte MONTES⁸, Karl STEFIC⁹, Anne-

7

Geneviève MARCELIN¹⁰*

8

1. University Hospital Nantes, CIC 1413 Nantes, France

9

2. University Hospital Lille, Lille, France

10

3. University Hospital of Saint Etienne, Infectious Agents and Hygiene Department, Saint-Etienne, France

11

12

4. University Hospital Orléans, Orléans, France

13

5. University Hospital Besançon, Besançon, France

14

6. University Hospital Rennes, Rennes, France

15

7. Gilead Sciences S.A.S., Boulogne-Billancourt, France

16

8. University Hospital Montpellier, Montpellier, France

17

9. University of Tours, INSERM U1259 MAVIVH, University Hospital Tours, Tours, France

18

19

10. Sorbonne University, INSERM, Pierre Louis Institute of epidemiology and public health, AP-HP, University Hospitals Pitié-Salpêtrière - Charles Foix, Virology laboratory, Paris, France

20

21

22

*Corresponding author:

23

Anne-Geneviève MARCELIN

24

Virology Department Pitié-Salpêtrière

25

APHP Hospital Group. Sorbonne University

26

83, Boulevard de l'hôpital, Paris, 75013, France

27

Tel (desk): +33 (0)1 42 17 74 01

28

Fax: +33 (0)1 42 17 74 11

29

Email: anne-genevieve.marcelin@aphp.fr
1

USE OF GENOTYPIC HIV DNA TESTING:

2

A DELPHI-TYPE CONSENSUS

3

Short running title: Delphi Consensus on Genotypic HIV DNA Testing

4

Elisabeth ANDRE-GARNIER¹, Laurence BOCKET², Thomas BOURLET³, Laurent

5

HOCQUELOUX⁴, Quentin LEPILLER⁵, Anne MAILLARD⁶, Sandrine REIGADAS⁷,

6

Guillaume BARRIERE⁷, François DURAND⁷, Brigitte MONTES⁸, Karl STEFIC⁹, Anne-

7

Geneviève MARCELIN¹⁰*

8

1. University Hospital Nantes, CIC 1413 Nantes, France

9

2. University Hospital Lille, Lille, France

10

3. University Hospital of Saint Etienne, Infectious Agents and Hygiene Department,
Saint-Etienne, France

11

12

4. University Hospital Orléans, Orléans, France

13

5. University Hospital Besançon, Besançon, France

14

6. University Hospital Rennes, Rennes, France

15

7. Gilead Sciences S.A.S., Boulogne-Billancourt, France

16

8. University Hospital Montpellier, Montpellier, France

17

9. University of Tours, INSERM U1259 MAVIVH, University Hospital Tours, Tours,
France

18

19

10. Sorbonne University, INSERM, Pierre Louis Institute of epidemiology and public
health, AP-HP, University Hospitals Pitié-Salpêtrière - Charles Foix, Virology
laboratory, Paris, France

20

21

22

*Corresponding author:

23

Anne-Geneviève MARCELIN

24

Virology Department Pitié-Salpêtrière

25

APHP Hospital Group. Sorbonne University

26

83, Boulevard de l'hôpital, Paris, 75013, France

27

Tel (desk): +33 (0)1 42 17 74 01

28

Fax: +33 (0)1 42 17 74 11

29

Email: anne-genevieve.marcelin@aphp.fr
30 **Abstract**

31 **Objectives:**

32 As many disparities in the clinical use of HIV DNA sequencing are observed, a DELPHI-type
33 consensus was initiated in France to homogenize use, techniques, and interpretation of results.

34 **Methods:**

35 Based on a literature review and clinical experience, a Steering Committee (SC) of eight
36 virologists and one infectious disease specialist formulated statements. Statements were
37 submitted to an independent and anonymous electronic vote of virologists and HIV clinicians
38 in France, between October and December 2022.

39 **Results:**

40 The SC developed 20 statements grouped into six categories: *clinical situations for the use of
41 HIV DNA genotyping; techniques for performing HIV DNA genotyping; consideration of
42 APOBEC mutations; genotyping results reporting; recycling of antiretrovirals; availability of
43 HIV DNA genotyping tests and delays*. Twenty-one virologists and 47 clinicians participated
44 in two voting rounds and 18/20 (90%) assertions reached a ‘strong’ consensus. For example,
45 that prior genotyping on HIV DNA is useful for clinical decision-making when considering
46 switching to some long-acting regimens or to reduce the number of antiretroviral agents in
47 virologically suppressed patients for whom RNA data are unavailable / not exploitable / not
48 sufficiently informative. Two statements achieved no consensus: reporting any detected viral
49 minority population for discussion in multidisciplinary meetings ( virologists), and possible
50 risk of virologic failure when using a second generation InSTI + XTC regimen in patients
51 with undetectable viral load ≥1 year and in the presence of a documented M184V mutation <5
52 years (clinicians).

53 **Conclusion:**
30 **Abstract**

31 **Objectives:**

32 As many disparities in the clinical use of HIV DNA sequencing are observed, a DELPHI-type
33 consensus was initiated in France to homogenize use, techniques, and interpretation of results.

34 **Methods:**

35 Based on a literature review and clinical experience, a Steering Committee (SC) of eight
36 virologists and one infectious disease specialist formulated statements. Statements were
37 submitted to an independent and anonymous electronic vote of virologists and HIV clinicians
38 in France, between October and December 2022.

39 **Results:**

40 The SC developed 20 statements grouped into six categories: *clinical situations for the use of
41 HIV DNA genotyping; techniques for performing HIV DNA genotyping; consideration of
42 APOBEC mutations; genotyping results reporting; recycling of antiretrovirals; availability of
43 HIV DNA genotyping tests and delays*. Twenty-one virologists and 47 clinicians participated
44 in two voting rounds and 18/20 (90%) assertions reached a ‘strong’ consensus. For example,
45 that prior genotyping on HIV DNA is useful for clinical decision-making when considering
46 switching to some long-acting regimens or to reduce the number of antiretroviral agents in
47 virologically suppressed patients for whom RNA data are unavailable / not exploitable / not
48 sufficiently informative. Two statements achieved no consensus: reporting any detected viral
49 minority population for discussion in multidisciplinary meetings ( virologists), and possible
50 risk of virologic failure when using a second generation InSTI + XTC regimen in patients
51 with undetectable viral load ≥1 year and in the presence of a documented M184V mutation <5
52 years (clinicians).

53 **Conclusion:**
This DELPHI-type consensus will facilitate the strengthening and harmonization of good practice when performing HIV DNA sequencing.

# 1. Introduction

Human Immunodeficiency Virus-1 infection has become a manageable chronic disease with the availability of antiretroviral therapies.¹, ² Lifelong treatment is currently required to obtain and maintain viral suppression. Either prior to initiation of ART or in the event of suboptimal response to ART, HIV drug resistance testing using plasma HIV RNA plays a key role in guiding treatment choices and optimization.¹, ² When switching to a new ART regimen due to toxicities, for simplification, drug reduction, or a long-acting regimen, it is also recommended to first check HIV genotyping data.² In these situations, HIV viral load (VL) usually under 50 copies/mL does not allow amplification for RNA drug resistance testing.³

In recent years, there has been growing interest in how HIV drug resistance testing using cellular HIV DNA could assist in clinical decision-making in the event of switching ART, especially when plasma HIV RNA genotype testing is not possible.⁴⁻⁶ The 2022 European AIDS Clinical Society (EACS) guidelines state that “Proviral DNA genotyping may be useful in persons with multiple virologic failures, unavailable resistance history or low-level viremia at the time of switch”.² European and French guidelines indicate that it is possible to perform genotypic resistance tests on HIV DNA from Peripheral Blood Mononuclear Cells (PBMCs) in the absence of historical data on plasma viral RNA.², ⁷ This test should be interpreted with caution since it has a good positive predictive value but a low negative predictive value.⁷

However, while these guidelines provide general guidance on the indications for cell-associated total HIV DNA resistance testing, practical recommendations to virologists and HIV clinicians are lacking, particularly regarding frequent specific ART switch situations, technique, and interpretation of results.

Since many disparities in clinical practice have been observed, both in the literature and in clinical practice, a modified DELPHI consensus research project was conducted in France
This DELPHI-type consensus will facilitate the strengthening and harmonization of good practice when performing HIV DNA sequencing.

# 1. Introduction

Human Immunodeficiency Virus-1 infection has become a manageable chronic disease with the availability of antiretroviral therapies.¹,² Lifelong treatment is currently required to obtain and maintain viral suppression. Either prior to initiation of ART or in the event of suboptimal response to ART, HIV drug resistance testing using plasma HIV RNA plays a key role in guiding treatment choices and optimization.¹,² When switching to a new ART regimen due to toxicities, for simplification, drug reduction, or a long-acting regimen, it is also recommended to first check HIV genotyping data.² In these situations, HIV viral load (VL) usually under 50 copies/mL does not allow amplification for RNA drug resistance testing.³

In recent years, there has been growing interest in how HIV drug resistance testing using cellular HIV DNA could assist in clinical decision-making in the event of switching ART, especially when plasma HIV RNA genotype testing is not possible.⁴⁻⁶ The 2022 European AIDS Clinical Society (EACS) guidelines state that “Proviral DNA genotyping may be useful in persons with multiple virologic failures, unavailable resistance history or low-level viremia at the time of switch”.² European and French guidelines indicate that it is possible to perform genotypic resistance tests on HIV DNA from Peripheral Blood Mononuclear Cells (PBMCs) in the absence of historical data on plasma viral RNA.²,⁷ This test should be interpreted with caution since it has a good positive predictive value but a low negative predictive value.⁷

However, while these guidelines provide general guidance on the indications for cell-associated total HIV DNA resistance testing, practical recommendations to virologists and HIV clinicians are lacking, particularly regarding frequent specific ART switch situations, technique, and interpretation of results.

Since many disparities in clinical practice have been observed, both in the literature and in clinical practice, a modified DELPHI consensus research project was conducted in France
with the aim of homogenizing situations in which HIV DNA sequencing could be used and
guiding interpretation of results.

## 2. Material and methods

The Delphi method is an iterative consensus approach based on information collected from a panel of voters with expertise in the subject under consideration.⁸⁻¹⁶ This approach has been widely used in many therapeutic areas and several times in HIV care.¹⁷⁻²⁸ Using this structured approach, voting experts give their opinion individually and anonymously, and express their degree of agreement on statements in order to achieve consensus on a specific and well-defined subject.

In accordance with both French and international methodologies,⁹⁻¹²,²⁹ our study was structured as a modified national Delphi consensus and conducted among French hospital clinicians and virologists between September and December 2022. The opinion of voting experts was collected during two assessment rounds using a questionnaire developed by a Steering Committee (SC) (Figure 1).

As recommended by the French National Authority for Health (HAS), voters specified their level of agreement with the statements using a 9-point Likert scale ranging from 1 “Strongly disagree” to 9 “Strongly agree”.²⁹⁻³¹ The percentage of scores and the median were calculated for each statement separately in each voting round. Consensus for a statement was considered ‘strong’ when >75% of the scores were ≥7 and the median score was ≥8, ‘good’ when only one of these two parameters was satisfied, and ‘lacking’ when none of the parameters was satisfied.⁹,¹⁰,³²

### Steering Committee (SC)

The SC included one infectious disease specialist and eight virologists directed by the last author of this article. Two initial SC meetings were held in June and August 2022.

### Voting Group
with the aim of homogenizing situations in which HIV DNA sequencing could be used and
guiding interpretation of results.

## 2. Material and methods

The Delphi method is an iterative consensus approach based on information collected from a panel of voters with expertise in the subject under consideration.⁸⁻¹⁶ This approach has been widely used in many therapeutic areas and several times in HIV care.¹⁷⁻²⁸ Using this structured approach, voting experts give their opinion individually and anonymously, and express their degree of agreement on statements in order to achieve consensus on a specific and well-defined subject.

In accordance with both French and international methodologies,⁹⁻¹²,²⁹ our study was structured as a modified national Delphi consensus and conducted among French hospital clinicians and virologists between September and December 2022. The opinion of voting experts was collected during two assessment rounds using a questionnaire developed by a Steering Committee (SC) (Figure 1).

As recommended by the French National Authority for Health (HAS), voters specified their level of agreement with the statements using a 9-point Likert scale ranging from 1 “Strongly disagree” to 9 “Strongly agree”.²⁹⁻³¹ The percentage of scores and the median were calculated for each statement separately in each voting round. Consensus for a statement was considered ‘strong’ when >75% of the scores were ≥7 and the median score was ≥8, ‘good’ when only one of these two parameters was satisfied, and ‘lacking’ when none of the parameters was satisfied.⁹,¹⁰,³²

### Steering Committee (SC)

The SC included one infectious disease specialist and eight virologists directed by the last author of this article. Two initial SC meetings were held in June and August 2022.

### Voting Group
Two voter profiles were identified: virologists and HIV clinicians. A list of voters was compiled based on the following criteria: experience, acquired knowledge and expertise in HIV care, presenting in national conferences or involvement in HIV care projects, with recruitment throughout France, including French overseas territories. The voters were invited via individual e-mails to participate in online voting, with personalized access via a dedicated website. Questions on techniques for performing HIV DNA genotyping were voted on by virologists only. The anonymity of both voting groups was guaranteed. Voters had no interaction with the SC, and SC members did not vote.²⁹

## Voting Round #1

During this first round of voting, a free text space for comments was made available enabling voters to develop or explain their opinion for each statement. At the end of the first round, scores and voter comments were summarized for each statement.

A third SC meeting took place in November 2022 to discuss the Round #1 results:

* Statements that achieved a 'strong' consensus (i.e., ≥75% of scores ≥7 AND median ≥8) were validated in full and included in the final summary.

* Statements that achieved a 'good' consensus (i.e., ≥75% of scores ≥7 OR median ≥8) were discussed and proposed for Voting Round #2 only when the SC was able to develop a revised version based on analysis of voter comments.

* Statements that did not achieve consensus were re-worded by the SC based on feedback from voters and submitted for Voting Round #2.

## Voting Round #2

Only voters from Voting Round #1 were invited to participate in Voting Round #2 to assess the statements amended by the SC from Voting Round #1 results. The free text comment option was deleted but replaced with an 'I don't know' option instead of the scoring response.
Two voter profiles were identified: virologists and HIV clinicians. A list of voters was compiled based on the following criteria: experience, acquired knowledge and expertise in HIV care, presenting in national conferences or involvement in HIV care projects, with recruitment throughout France, including French overseas territories. The voters were invited via individual e-mails to participate in online voting, with personalized access via a dedicated website. Questions on techniques for performing HIV DNA genotyping were voted on by virologists only. The anonymity of both voting groups was guaranteed. Voters had no interaction with the SC, and SC members did not vote.²⁹

## Voting Round #1

During this first round of voting, a free text space for comments was made available enabling voters to develop or explain their opinion for each statement. At the end of the first round, scores and voter comments were summarized for each statement.

A third SC meeting took place in November 2022 to discuss the Round #1 results:

* Statements that achieved a 'strong' consensus (i.e., ≥75% of scores ≥7 AND median ≥8) were validated in full and included in the final summary.

* Statements that achieved a 'good' consensus (i.e., ≥75% of scores ≥7 OR median ≥8) were discussed and proposed for Voting Round #2 only when the SC was able to develop a revised version based on analysis of voter comments.

* Statements that did not achieve consensus were re-worded by the SC based on feedback from voters and submitted for Voting Round #2.

## Voting Round #2

Only voters from Voting Round #1 were invited to participate in Voting Round #2 to assess the statements amended by the SC from Voting Round #1 results. The free text comment option was deleted but replaced with an 'I don't know' option instead of the scoring response.
129

Votes including this 'I don't know' option were excluded from the analysis. Following the results of Voting Round #2, the SC closed the process.

130

131

### *Ethical considerations*

132

This research was conducted in accordance with the Declaration of Helsinki. All personal data transmitted for the study was separated from the results and anonymized, pursuant to the French data protection law (GDPR – General Data Protection Regulation).

133

134

135

## **3. Results**

136

Based on a literature analysis, existing guidelines and clinical experience, the SC initially developed 21 statements (two were subsequently merged resulting in 20 statements) divided into 6 key areas: *clinical situations for the use of HIV DNA genotyping; techniques for performing HIV DNA genotyping; consideration of APOBEC mutations; genotyping results reporting; recycling of antiretrovirals; availability of HIV DNA genotyping tests and delays*.

137

138

139

140

141

### *Participation*

142

Voters in Round #1 included 21 virologists and 47 clinicians. All virologists (21/21, 100%) and 40 clinicians out of 47 (85.1%) from Round #1 actively voted in Round #2.

143

144

A summary of the characteristics of voters is shown in Table 1. The virologists were 76% (n=16) full-time hospital workers, 10% (n=2) part-time and 14% (n=3) engineers ('Others').

145

146

Their median experience in performing HIV DNA sequencing was 10 years (IQR [5-12]) and the median number of HIV DNA genotypes performed per year was 225 (IQR [42.5-425]).

147

148

Clinicians were 94% (n=44) full time hospital workers and 6% (n=3) part time. Their median experience with people living with HIV (PLWH) management was 25 years (IQR [15-31.5]) and the median number of patients they followed per year was 270 (IQR [200-400]).

149

150

151

All virologists and clinicians had extensive experience in HIV care-related activities over the previous five years, such as writing conference abstracts (76% and 83% respectively), writing scientific publications (76% and 74%), participating in research projects (100% and 91%),

152

153
129

Votes including this 'I don't know' option were excluded from the analysis. Following the results of Voting Round #2, the SC closed the process.

130

131

### *Ethical considerations*

132

This research was conducted in accordance with the Declaration of Helsinki. All personal data transmitted for the study was separated from the results and anonymized, pursuant to the French data protection law (GDPR – General Data Protection Regulation).

133

134

135

## **3. Results**

136

Based on a literature analysis, existing guidelines and clinical experience, the SC initially developed 21 statements (two were subsequently merged resulting in 20 statements) divided into 6 key areas: *clinical situations for the use of HIV DNA genotyping; techniques for performing HIV DNA genotyping; consideration of APOBEC mutations; genotyping results reporting; recycling of antiretrovirals; availability of HIV DNA genotyping tests and delays*.

137

138

139

140

141

### *Participation*

142

Voters in Round #1 included 21 virologists and 47 clinicians. All virologists (21/21, 100%) and 40 clinicians out of 47 (85.1%) from Round #1 actively voted in Round #2.

143

144

A summary of the characteristics of voters is shown in Table 1. The virologists were 76% (n=16) full-time hospital workers, 10% (n=2) part-time and 14% (n=3) engineers ('Others').

145

146

Their median experience in performing HIV DNA sequencing was 10 years (IQR [5-12]) and the median number of HIV DNA genotypes performed per year was 225 (IQR [42.5-425]).

147

148

Clinicians were 94% (n=44) full time hospital workers and 6% (n=3) part time. Their median experience with people living with HIV (PLWH) management was 25 years (IQR [15-31.5]) and the median number of patients they followed per year was 270 (IQR [200-400]).

149

150

151

All virologists and clinicians had extensive experience in HIV care-related activities over the previous five years, such as writing conference abstracts (76% and 83% respectively), writing scientific publications (76% and 74%), participating in research projects (100% and 91%),

152

153
154

involved in training (81% and 81%), belonging to a professional or associated group (76% and 81%) and speaking at scientific events (52% and 68%).

155

156

Statements (Table 2)

157

After Voting Round #1, 9/21 statements achieved a 'strong' consensus (≥75% votes ≥7 and median ≥8); 5/21 statements achieved a 'good' consensus (≥75% votes ≥7 or median ≥8) and 7 statements lacked a consensus: 12 statements were revised by the SC for Voting Round #2, including all those which achieved a 'good' consensus and all those which did not achieve a consensus, of which two were merged resulting in 20 statements. After Voting Round #2, 9/11 revised statements achieved a 'strong' consensus, and two statements did not achieve a consensus. In total, 18/20 statements (90%) achieved consensus. The distribution of cumulative votes, medians and results are provided in Table 2.

158

159

160

161

162

163

164

165

Consensus statement results (See Table S1 for Consensus results according to voter group, and Table S2 for Statements, detailed virologists and clinicians voting results, and cumulative results for both groups).

166

167

168

Clinical situations for the use of HIV DNA genotyping

169

In the context of a therapeutic decision requiring genotyping data, there was a 'strong' consensus from voters on the recommendation to perform HIV DNA genotyping when HIV RNA is non-amplifiable, when cumulative HIV RNA genotyping is not available and/or when the historical genotype is incomplete or unusable. Voters recognized with a 'strong' consensus that for the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value towards mutation detection (excluding APOBEC mutations) and an imperfect negative predictive value.

170

171

172

173

174

175

176

Voters also 'strongly' agreed that, in a virologically suppressed patient, in the absence of exploitable or sufficiently informative RNA data, and when considering a drug-reduction / simplification of the antiretroviral (ARV) regimen:

177

178
154
155

involved in training (81% and 81%), belonging to a professional or associated group (76% and 81%) and speaking at scientific events (52% and 68%).

156

Statements (Table 2)

157
158
159
160
161
162
163
164

After Voting Round #1, 9/21 statements achieved a 'strong' consensus (≥75% votes ≥7 and median ≥8); 5/21 statements achieved a 'good' consensus (≥75% votes ≥7 or median ≥8) and 7 statements lacked a consensus: 12 statements were revised by the SC for Voting Round #2, including all those which achieved a 'good' consensus and all those which did not achieve a consensus, of which two were merged resulting in 20 statements. After Voting Round #2, 9/11 revised statements achieved a 'strong' consensus, and two statements did not achieve a consensus. In total, 18/20 statements (90%) achieved consensus. The distribution of cumulative votes, medians and results are provided in Table 2.

165
166
167

Consensus statement results (See Table S1 for Consensus results according to voter group, and Table S2 for Statements, detailed virologists and clinicians voting results, and cumulative results for both groups).

168

Clinical situations for the use of HIV DNA genotyping

169
170
171
172
173
174
175

In the context of a therapeutic decision requiring genotyping data, there was a 'strong' consensus from voters on the recommendation to perform HIV DNA genotyping when HIV RNA is non-amplifiable, when cumulative HIV RNA genotyping is not available and/or when the historical genotype is incomplete or unusable. Voters recognized with a 'strong' consensus that for the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value towards mutation detection (excluding APOBEC mutations) and an imperfect negative predictive value.

176
177
178

Voters also 'strongly' agreed that, in a virologically suppressed patient, in the absence of exploitable or sufficiently informative RNA data, and when considering a drug-reduction / simplification of the antiretroviral (ARV) regimen:
179

- for a switch to some long-acting regimens, prior HIV DNA genotyping is useful for clinical decision-making,

180

181

- for sequential dosing (4 days out of 7 or 5 days out of 7) without changing any ARV in the current regimen, it is not mandatory to prior perform HIV DNA genotyping for clinical decision-making,

182

183

184

- for a reduced ARV number regimen, prior HIV DNA genotyping may be useful for clinical decision-making.

185

186

## Techniques for performing HIV-DNA genotyping

187

Virologists validated with a ‘strong’ consensus that, in current practice, HIV DNA genotyping has a decreased performance (sensitivity, representativeness of viral populations) when the DNA quantity is very low. It can be performed indifferently from whole blood, mononuclear cells isolated from peripheral blood or blood cell pellets, and although performance could be increased by performing duplicate, duplicate is not feasible in clinical practice.

188

189

190

191

192

193

Concerning HIV DNA genotyping techniques, virologists agreed with a ‘strong’ consensus that Sanger or ultra-deep sequencing (UDS) could be used. However, there was an absence of consensus on the relevance of discussing any viral minority population (i.e. variants below 15 to 20% of the viral population) detected after using UDS techniques in a multidisciplinary meeting in the absence of defined clinically relevant detection threshold, according to the current state of knowledge (‘no consensus’; with the exclusion of 1/21 (4.7%) virologists who answered ‘I don’t know’).

194

195

196

197

198

199

200

## Consideration of APOBEC mutations

201

The cytidine deaminases APOBEC3F and 3G enzymes might introduce G to A nucleotide mutations that can impair crucial enzymatic sites or generate stop codons that reduce the amount of replication competent proviruses.33-36 Voters validated with a ‘strong’ consensus

202

203
179

- for a switch to some long-acting regimens, prior HIV DNA genotyping is useful for clinical decision-making,

180

181

- for sequential dosing (4 days out of 7 or 5 days out of 7) without changing any ARV in the current regimen, it is not mandatory to prior perform HIV DNA genotyping for clinical decision-making,

182

183

184

- for a reduced ARV number regimen, prior HIV DNA genotyping may be useful for clinical decision-making.

185

186

## Techniques for performing HIV-DNA genotyping

187

Virologists validated with a ‘strong’ consensus that, in current practice, HIV DNA genotyping has a decreased performance (sensitivity, representativeness of viral populations) when the DNA quantity is very low. It can be performed indifferently from whole blood, mononuclear cells isolated from peripheral blood or blood cell pellets, and although performance could be increased by performing duplicate, duplicate is not feasible in clinical practice.

188

189

190

191

192

193

Concerning HIV DNA genotyping techniques, virologists agreed with a ‘strong’ consensus that Sanger or ultra-deep sequencing (UDS) could be used. However, there was an absence of consensus on the relevance of discussing any viral minority population (i.e. variants below 15 to 20% of the viral population) detected after using UDS techniques in a multidisciplinary meeting in the absence of defined clinically relevant detection threshold, according to the current state of knowledge (‘no consensus’; with the exclusion of 1/21 (4.7%) virologists who answered ‘I don’t know’).

194

195

196

197

198

199

200

## Consideration of APOBEC mutations

201

The cytidine deaminases APOBEC3F and 3G enzymes might introduce G to A nucleotide mutations that can impair crucial enzymatic sites or generate stop codons that reduce the amount of replication competent proviruses.³³⁻³⁶ Voters validated with a ‘strong’ consensus

202

203
204 that the detection of the *M184I* mutation in HIV DNA is suggestive of the presence of a
205 defective genome in the APOBEC enzyme when associated with other evocative mutations
206 (e.g., *M41I*, *M230I* on reverse transcriptase) and/or stop codons. They also recognized with a
207 ‘strong’ consensus that, when resistance mutations attributable to APOBEC are present, their
208 significance should be interpreted with caution according to the clinical context and
209 therapeutic history of the patient and should be indicated in the HIV DNA genotyping
210 analysis report.

211 **Reporting of genotyping results**

212 With a ‘strong’ consensus, virologists and clinicians felt that the clinical interpretation of
213 resistance mutations on HIV DNA genotyping should be discussed in multidisciplinary
214 meetings. They also agreed that the detection via HIV DNA sequencing of new resistance
215 mutations (excluding APOBEC and stop codons), which were previously undetected, must be
216 considered for the switch decision and subsequent patient follow-up.

217 <u>ARV recycling</u>

218 Virologists and clinicians agreed with a ‘strong’ consensus that, in a patient with an
219 undetectable viral load for at least one year and with documented *M184V* substitution on the
220 current DNA genotype and/or on an RNA genotype performed within the last five years, the
221 use of a 2^nd^ generation InSTI (Integrase Strand Transfer Inhibitor) + XTC (Lamivudine or
222 Emtricitabine) + 1 NRTI combination is at low risk of virological failure over time.
223 Virologists validated with a ‘strong’ consensus that, under the same conditions, the use of a
224 2^nd^ generation InSTI + XTC combination may present a risk of virological failure over time.
225 However, clinicians remained divided on this possible virological risk and their vote did not
226 reach a consensus (‘no consensus’, no clinicians answered ‘I don’t know’).

227 With a ‘strong’ consensus, virologists and clinicians validated that the use/recycling of
228 NNRTIs, if resistance to this class was detected in HIV-DNA and/or in previous historical
229 genotypes, is associated with a greater risk of virological failure, independently of the
that the detection of the *M184I* mutation in HIV DNA is suggestive of the presence of a
defective genome in the APOBEC enzyme when associated with other evocative mutations
(e.g., *M41I*, *M230I* on reverse transcriptase) and/or stop codons. They also recognized with a
'strong' consensus that, when resistance mutations attributable to APOBEC are present, their
significance should be interpreted with caution according to the clinical context and
therapeutic history of the patient and should be indicated in the HIV DNA genotyping
analysis report.

## Reporting of genotyping results

With a 'strong' consensus, virologists and clinicians felt that the clinical interpretation of
resistance mutations on HIV DNA genotyping should be discussed in multidisciplinary
meetings. They also agreed that the detection via HIV DNA sequencing of new resistance
mutations (excluding APOBEC and stop codons), which were previously undetected, must be
considered for the switch decision and subsequent patient follow-up.

## ARV recycling

Virologists and clinicians agreed with a 'strong' consensus that, in a patient with an
undetectable viral load for at least one year and with documented *M184V* substitution on the
current DNA genotype and/or on an RNA genotype performed within the last five years, the
use of a 2^nd^ generation InSTI (Integrase Strand Transfer Inhibitor) + XTC (Lamivudine or
Emtricitabine) + 1 NRTI combination is at low risk of virological failure over time.
Virologists validated with a 'strong' consensus that, under the same conditions, the use of a
2^nd^ generation InSTI + XTC combination may present a risk of virological failure over time.
However, clinicians remained divided on this possible virological risk and their vote did not
reach a consensus ('no consensus', no clinicians answered 'I don't know').

With a 'strong' consensus, virologists and clinicians validated that the use/recycling of
NNRTIs, if resistance to this class was detected in HIV-DNA and/or in previous historical
genotypes, is associated with a greater risk of virological failure, independently of the
duration of undetectable viral load, particularly in drug-reduction strategies using this ARV class.

## Availability of HIV DNA genotyping tests and time to report results

With a ‘strong’ consensus, virologists and clinicians felt that genotypic HIV DNA testing should be accessible in clinical practice to all clinicians managing PLWH, and that results from these tests should be available within 30 days.

## 4. Discussion

This consensus research, using the DELPHI method, aims at harmonizing HIV DNA sequencing practices.

All five assertions on clinical situations for use of HIV DNA genotyping developed by the SC were validated with a ‘strong’ consensus by the voters. Although HIV DNA sequencing is not routinely recommended² and does not systematically reveal the same results as those previously detected by cumulative plasma RNA genotyping in virologically controlled patients,⁴,⁵ it is useful to perform in several clinical circumstances. This is the case when historical HIV RNA resistance data are insufficient and/or incomplete, or when the viral load is too low to proceed with HIV RNA sequencing. A recent study - based on a very large genotypic database in France - describing the prevalence of genotypic baseline risk factors for some long-acting regimen failures among ARV-naive patients showed that 10.1% of patients displayed one baseline virological risk factor for virologic failure.³⁷ These findings emphasize the need to check the genotypic resistance profile prior to initiating a long-acting regimen to limit the potential risk of virologic failure and the emergence of resistance.

However, in the case of a virologically suppressed patient, in the event of a decision to reduce or simplify sequential treatment (4 days or 5 days out of 7) without changing the regimen, there was a ‘strong’ consensus that prior genotyping of HIV DNA is not essential to clinical decision-making, even in the absence of usable or sufficiently informative RNA data. This
duration of undetectable viral load, particularly in drug-reduction strategies using this ARV class.

## Availability of HIV DNA genotyping tests and time to report results

With a ‘strong’ consensus, virologists and clinicians felt that genotypic HIV DNA testing should be accessible in clinical practice to all clinicians managing PLWH, and that results from these tests should be available within 30 days.

## 4. Discussion

This consensus research, using the DELPHI method, aims at harmonizing HIV DNA sequencing practices.

All five assertions on clinical situations for use of HIV DNA genotyping developed by the SC were validated with a ‘strong’ consensus by the voters. Although HIV DNA sequencing is not routinely recommended² and does not systematically reveal the same results as those previously detected by cumulative plasma RNA genotyping in virologically controlled patients,⁴,⁵ it is useful to perform in several clinical circumstances. This is the case when historical HIV RNA resistance data are insufficient and/or incomplete, or when the viral load is too low to proceed with HIV RNA sequencing. A recent study - based on a very large genotypic database in France - describing the prevalence of genotypic baseline risk factors for some long-acting regimen failures among ARV-naive patients showed that 10.1% of patients displayed one baseline virological risk factor for virologic failure.³⁷ These findings emphasize the need to check the genotypic resistance profile prior to initiating a long-acting regimen to limit the potential risk of virologic failure and the emergence of resistance.

However, in the case of a virologically suppressed patient, in the event of a decision to reduce or simplify sequential treatment (4 days or 5 days out of 7) without changing the regimen, there was a ‘strong’ consensus that prior genotyping of HIV DNA is not essential to clinical decision-making, even in the absence of usable or sufficiently informative RNA data. This
matches literature findings showing that triple combination therapy of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI administered every 4 or 5 days maintains control of HIV replication in virologically suppressed PLWH while reducing cumulative exposure to ARV.<sup>38,39</sup>

There was a ‘strong’ consensus from virologist voters that HIV DNA sequencing should be performed when the viral quantity is sufficiently high (since the quantity of HIV DNA influences the quality of the results obtained), that it can be used from different blood sample matrix, indifferently by Sanger or UDS, and that duplicates increase test performance (although this cannot be used in current clinical practice). Nevertheless, knowing HIV-DNA genotyping underestimate resistance detection due to a phenomenon of dilution of resistant species in the reservoir regardless of the sequencing method used, UDS methods might improve resistance detection in HIV-DNA due to their greater sensitivity.<sup>40-42</sup> Virologists were unable to reach a consensus on the fact that, given the current state of knowledge, it may be worthwhile reporting any minority viral population detected for discussion in a multidisciplinary discussion. They also didn’t support the idea that it might be useful to report any minority viral population detected for multidisciplinary discussion in the current context of an undefined detection threshold for UDS techniques.

Although the 1% threshold for UDS techniques was found to be close to the sensitivity obtained in historical HIV RNA resistance tests,<sup>41</sup> it was difficult for the SC to generate a statement for voting with such a detection threshold. This is due to the variability of this threshold depending on the UDS technique used, and the lack of solid evidence on the impact of a minority variant as low as 1% on virological failure for newer ARVs with a high barrier to resistance. Considering that UDS on HIV-DNA is now affordable in clinical practice and may become the future the potential new gold standard in the future, the definition of a technical cut-off to warrant enough sequencing accuracy and a clinical cut-off to establish the clinical relevance of minority variants on treatment switch in virologically suppressed patients are still unmet needs. So further research into these thresholds for both RNA- and DNA-based techniques is warranted.
matches literature findings showing that triple combination therapy of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI administered every 4 or 5 days maintains control of HIV replication in virologically suppressed PLWH while reducing cumulative exposure to ARV.<sup>38,39</sup>

There was a ‘strong’ consensus from virologist voters that HIV DNA sequencing should be performed when the viral quantity is sufficiently high (since the quantity of HIV DNA influences the quality of the results obtained), that it can be used from different blood sample matrix, indifferently by Sanger or UDS, and that duplicates increase test performance (although this cannot be used in current clinical practice). Nevertheless, knowing HIV-DNA genotyping underestimate resistance detection due to a phenomenon of dilution of resistant species in the reservoir regardless of the sequencing method used, UDS methods might improve resistance detection in HIV-DNA due to their greater sensitivity.<sup>40-42</sup> Virologists were unable to reach a consensus on the fact that, given the current state of knowledge, it may be worthwhile reporting any minority viral population detected for discussion in a multidisciplinary discussion. They also didn’t support the idea that it might be useful to report any minority viral population detected for multidisciplinary discussion in the current context of an undefined detection threshold for UDS techniques.

Although the 1% threshold for UDS techniques was found to be close to the sensitivity obtained in historical HIV RNA resistance tests,<sup>41</sup> it was difficult for the SC to generate a statement for voting with such a detection threshold. This is due to the variability of this threshold depending on the UDS technique used, and the lack of solid evidence on the impact of a minority variant as low as 1% on virological failure for newer ARVs with a high barrier to resistance. Considering that UDS on HIV-DNA is now affordable in clinical practice and may become the future the potential new gold standard in the future, the definition of a technical cut-off to warrant enough sequencing accuracy and a clinical cut-off to establish the clinical relevance of minority variants on treatment switch in virologically suppressed patients are still unmet needs. So further research into these thresholds for both RNA- and DNA-based techniques is warranted.
As shown in the literature,⁴³,⁴⁴ the detection of the *M184I* mutation in HIV DNA suggests the presence of a defective genome due to the APOBEC enzyme when associated with other suggestive mutations (See Table S3 for the list of mutations)³⁶ and/or stop codons, and a ‘strong’ consensus was reached on this statement. The presence of *M184I* mutation can impair the activity of XTC and possibly some nucleoside reverse transcriptase translocation inhibitors (NRTTIs). These mutations should be considered possible artifacts if they occur at the same threshold at which multiple signature APOBEC mutations are also present.⁴⁵ When resistance mutations attributable to APOBEC are detected, it is recommended that their significance should be interpreted with caution³⁷ and should be indicated in the HIV DNA genotyping analysis.

The French National Authority for Health already recommends that the interpretation of results from a DNA-based genotypic resistance test requires consultation between clinician and virologist.⁴⁶ In this context, a ‘strong’ consensus was reached on the need to discuss clinical interpretation of resistance mutations obtained by HIV DNA genotyping at multidisciplinary discussions. This was also the case regarding clinical decisions about switching ART and patient follow-up in newly detected resistance mutations.

The question of how resistance mutations are 'archived' over time remains important for the potential re-use of specific ARVs. A recent study investigated the kinetics of the *M184V* mutation in proviral HIV DNA in long-term virologically suppressed patients.⁴⁷ The authors showed significant progressive clearance of the *M184V* mutation in proviral HIV DNA over the five years of the study. In the presence of a detected M184V substitution over the past 5 years, the SC looked for consensus statements on ARV recycling practices. In this context, the SC proposed statements on ARV recycling practices in the event of the presence of an M184V substitution detected within the last five years.

Regardless of the finding of an *M184V* mutation in the DNA genotype and clearance kinetics of the mutation, it has been observed that, in patients virologically suppressed for at least one year, the use of a 2^nd^ generation InSTI + XTC + 1 NRTI regimen presents a low risk of
As shown in the literature,⁴³,⁴⁴ the detection of the *M184I* mutation in HIV DNA suggests the presence of a defective genome due to the APOBEC enzyme when associated with other suggestive mutations (See Table S3 for the list of mutations)³⁶ and/or stop codons, and a ‘strong’ consensus was reached on this statement. The presence of *M184I* mutation can impair the activity of XTC and possibly some nucleoside reverse transcriptase translocation inhibitors (NRTTIs). These mutations should be considered possible artifacts if they occur at the same threshold at which multiple signature APOBEC mutations are also present.⁴⁵ When resistance mutations attributable to APOBEC are detected, it is recommended that their significance should be interpreted with caution³⁷ and should be indicated in the HIV DNA genotyping analysis.

The French National Authority for Health already recommends that the interpretation of results from a DNA-based genotypic resistance test requires consultation between clinician and virologist.⁴⁶ In this context, a ‘strong’ consensus was reached on the need to discuss clinical interpretation of resistance mutations obtained by HIV DNA genotyping at multidisciplinary discussions. This was also the case regarding clinical decisions about switching ART and patient follow-up in newly detected resistance mutations.

The question of how resistance mutations are 'archived' over time remains important for the potential re-use of specific ARVs. A recent study investigated the kinetics of the *M184V* mutation in proviral HIV DNA in long-term virologically suppressed patients.⁴⁷ The authors showed significant progressive clearance of the *M184V* mutation in proviral HIV DNA over the five years of the study. In the presence of a detected M184V substitution over the past 5 years, the SC looked for consensus statements on ARV recycling practices. In this context, the SC proposed statements on ARV recycling practices in the event of the presence of an M184V substitution detected within the last five years.

Regardless of the finding of an *M184V* mutation in the DNA genotype and clearance kinetics of the mutation, it has been observed that, in patients virologically suppressed for at least one year, the use of a 2^nd^ generation InSTI + XTC + 1 NRTI regimen presents a low risk of
virological failure over time.⁴⁸ The voters 'strongly' endorsed this statement. However, when a M184V mutation has been documented over the past five years in a virologically suppressed patient, the virologist voters 'strongly' agreed that the use of a 2nd generation InSTI + XTC regimen could present a risk of virological failure over time, as described in some literature.⁴⁹

For documented NNRTI mutations, there was a 'strong' consensus that the recycling of this ARV class is associated with an increased risk of virological failure, irrespective of the duration of viral suppression, particularly in drug reduction strategies and long-acting regimens using this ARV class.⁵⁰

Since HIV DNA sequencing adds an important contribution to many clinical situations and patient follow-up,² there was a 'strong' consensus that it should be accessible to all practitioners. Also, that its results should be received within one month. The literature rarely provides such an indication of time in which to report results but, with current HIV DNA sequencing methods being faster than before, this timeframe seems reasonable.⁵¹

The Delphi method is known as a structured procedure which enables many experts to be consulted individually and anonymously on a specific subject while guaranteeing free expression of each voter. However, this approach has some limitations associated with voters' profiles, statements elaboration and criteria considered to achieve a consensus.⁵² Our research sought to limit these potential biases as far as possible to ensure maximum objectivity.

Although voters were recruited only in France, they were selected on objective criteria based on their experience and expertise in HIV care and HIV virology. These criteria yielded a voter sample with reassuring characteristics: a median of 10 years' experience performing HIV DNA sequencing in the virologists' group and a median of 25 years' experience in PLWH management in the clinicians' group. As far as the SC statements are concerned, a literature review made it possible to identify key questions raised in clinical practice and propose precisely worded statements. In terms of the threshold used to reach consensus, our study was based on a rigorous two-criteria approach. This strict and demanding definition lends a high degree of credibility to our results. To ensure the virologist panel represented the whole of
virological failure over time.⁴⁸ The voters ‘strongly’ endorsed this statement. However, when a M184V mutation has been documented over the past five years in a virologically suppressed patient, the virologist voters ‘strongly’ agreed that the use of a 2nd generation InSTI + XTC regimen could present a risk of virological failure over time, as described in some literature.⁴⁹

For documented NNRTI mutations, there was a ‘strong’ consensus that the recycling of this ARV class is associated with an increased risk of virological failure, irrespective of the duration of viral suppression, particularly in drug reduction strategies and long-acting regimens using this ARV class.⁵⁰

Since HIV DNA sequencing adds an important contribution to many clinical situations and patient follow-up,² there was a ‘strong’ consensus that it should be accessible to all practitioners. Also, that its results should be received within one month. The literature rarely provides such an indication of time in which to report results but, with current HIV DNA sequencing methods being faster than before, this timeframe seems reasonable.⁵¹

The Delphi method is known as a structured procedure which enables many experts to be consulted individually and anonymously on a specific subject while guaranteeing free expression of each voter. However, this approach has some limitations associated with voters’ profiles, statements elaboration and criteria considered to achieve a consensus.⁵² Our research sought to limit these potential biases as far as possible to ensure maximum objectivity.

Although voters were recruited only in France, they were selected on objective criteria based on their experience and expertise in HIV care and HIV virology. These criteria yielded a voter sample with reassuring characteristics: a median of 10 years' experience performing HIV DNA sequencing in the virologists' group and a median of 25 years' experience in PLWH management in the clinicians’ group. As far as the SC statements are concerned, a literature review made it possible to identify key questions raised in clinical practice and propose precisely worded statements. In terms of the threshold used to reach consensus, our study was based on a rigorous two-criteria approach. This strict and demanding definition lends a high degree of credibility to our results. To ensure the virologist panel represented the whole of
France territory, the SC supported identification of some virologists. Finally, our research was conducted with a continuous and complete separation between voters who voted anonymously and SC members who neither participated in the vote nor interacted directly with voters. The constraint inherent in this separation was the absence of direct exchanges between voters and SC members: such exchanges could have been useful when revising statements for voting Round #2. Furthermore, like all Delphi-type consensus, the findings represent good practices for virologists and clinicians who remain masters of their own practice and must adapt findings to individual patient circumstances.

In conclusion, in this consensus research using the Delphi method, 18/20 (90%) statements achieved a consensus. Only two assertions did not reach consensus. Virologist voters remained divided on the value of discussing any minority population detected at a multidisciplinary meeting, and the clinician voters remained divided on the possible virological risk of using a combination of a 2^nd^ generation InSTI + XTC in HIV suppressed patients of more than one year in the presence of a documented M184V mutation of less than five years.

Our consensus findings constitute a solid basis for implementation and homogenization of practice regarding the use of DNA HIV sequencing, its performance, and its reporting, particularly when needing to reduce the number of ARV agents and when using some long-acting regimens.

### Acknowledgements

The SC would like to thank all virologists and clinicians who agreed to participate and vote on the statements in both rounds, and who made it possible to achieve this consensus.

### Funding

This consensus research was funded by Gilead Sciences.

### Transparency declarations
France territory, the SC supported identification of some virologists. Finally, our research was conducted with a continuous and complete separation between voters who voted anonymously and SC members who neither participated in the vote nor interacted directly with voters. The constraint inherent in this separation was the absence of direct exchanges between voters and SC members: such exchanges could have been useful when revising statements for voting Round #2. Furthermore, like all Delphi-type consensus, the findings represent good practices for virologists and clinicians who remain masters of their own practice and must adapt findings to individual patient circumstances.

In conclusion, in this consensus research using the Delphi method, 18/20 (90%) statements achieved a consensus. Only two assertions did not reach consensus. Virologist voters remained divided on the value of discussing any minority population detected at a multidisciplinary meeting, and the clinician voters remained divided on the possible virological risk of using a combination of a 2^nd^ generation InSTI + XTC in HIV suppressed patients of more than one year in the presence of a documented M184V mutation of less than five years.

Our consensus findings constitute a solid basis for implementation and homogenization of practice regarding the use of DNA HIV sequencing, its performance, and its reporting, particularly when needing to reduce the number of ARV agents and when using some long-acting regimens.

## Acknowledgements

The SC would like to thank all virologists and clinicians who agreed to participate and vote on the statements in both rounds, and who made it possible to achieve this consensus.

## Funding

This consensus research was funded by Gilead Sciences.

## Transparency declarations
361 Carried out with the institutional support of Gilead Sciences S.A.S. Operational and
362 publishing aspects of the interviews were managed by Medica Education Corpus agency.

363 Elisabeth ANDRE-GARNIER reports grants from Gilead Sciences, MSD and ViiV
364 Healthcare

365 Laurence BOCKET reports grants from Gilead Sciences, MSD and ViiV Healthcare

366 Thomas BOURLET reports grants from MSD and GILEAD Sciences, not in the scope of the
367 present work.

368 Laurent HOCQUELOUX reports non-financial support from Gilead Sciences, MSD and ViiV
369 Healthcare, payments for advisory board participation from Gilead Sciences and ViiV
370 Healthcare, and personal fees from Gilead Sciences, MSD and ViiV Healthcare, all outside
371 the submitted work.

372 Quentin LEPILLER reports grants from Gilead Sciences, MSD and ViiV Healthcare.

373 Anne MAILLARD reports grants from Gilead Sciences, MSD and ViiV Healthcare.

374 Sandrine REIGADAS, Guillaume BARRIERE and François DURAND are employees of
375 Gilead Sciences S.A.S.

376 Brigitte MONTES reports grants from Gilead Sciences, MSD and ViiV Healthcare.

377 Karl STEFIC reports payments for advisory board participation from Gilead Sciences and
378 ViiV Healthcare.

379 Anne-Geneviève MARCELIN reports grants from Gilead Sciences, MSD and ViiV
380 Healthcare, payments for advisory board participation from Gilead Sciences, MSD and ViiV
381 Healthcare.

382 **References**

383 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health
384 and Human Services. Guidelines for the use of antiretroviral agents in adults and
361 Carried out with the institutional support of Gilead Sciences S.A.S. Operational and
362 publishing aspects of the interviews were managed by Medica Education Corpus agency.

363 Elisabeth ANDRE-GARNIER reports grants from Gilead Sciences, MSD and ViiV
364 Healthcare

365 Laurence BOCKET reports grants from Gilead Sciences, MSD and ViiV Healthcare

366 Thomas BOURLET reports grants from MSD and GILEAD Sciences, not in the scope of the
367 present work.

368 Laurent HOCQUELOUX reports non-financial support from Gilead Sciences, MSD and ViiV
369 Healthcare, payments for advisory board participation from Gilead Sciences and ViiV
370 Healthcare, and personal fees from Gilead Sciences, MSD and ViiV Healthcare, all outside
371 the submitted work.

372 Quentin LEPILLER reports grants from Gilead Sciences, MSD and ViiV Healthcare.

373 Anne MAILLARD reports grants from Gilead Sciences, MSD and ViiV Healthcare.

374 Sandrine REIGADAS, Guillaume BARRIERE and François DURAND are employees of
375 Gilead Sciences S.A.S.

376 Brigitte MONTES reports grants from Gilead Sciences, MSD and ViiV Healthcare.

377 Karl STEFIC reports payments for advisory board participation from Gilead Sciences and
378 ViiV Healthcare.

379 Anne-Geneviève MARCELIN reports grants from Gilead Sciences, MSD and ViiV
380 Healthcare, payments for advisory board participation from Gilead Sciences, MSD and ViiV
381 Healthcare.

382 References

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413

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416

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417

418

419

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420

421

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422

423

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427

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431

432

17. Tsui S, Denison JA, Kennedy CE *et al*. Identifying models of HIV care and treatment service delivery in Tanzania, Uganda, and Zambia using cluster analysis and Delphi survey. *BMC Health Serv Res* 2017; **17**: 811.

433

434
435

18. Johnson MO, Neilands TB, Koester KA, et al. Detecting Disengagement From HIV Care Before It Is Too Late: Development and Preliminary Validation of a Novel Index of Engagement in HIV Care. *J Acquir Immune Defic Syndr* 2019; **81**: 145-152.

436

437

438

19. O'Connell KA, Kisteneff AV, Gill SS et al. HIV post-exposure prophylaxis in the emergency department: An updated assessment and opportunities for HIV prevention identified. *Am J Emerg Med* 2021; **46**: 323-328.

439

440

441

20. Fredericksen RJ, Edwards TC, Merlin JS et al. Patient and provider priorities for self-reported domains of HIV clinical care. *AIDS Care* 2015; **27**: 1255-64

442

443

21. Cummins D, Waters D, Aggar C et al. Assessing Risk of HIV-Associated Neurocognitive Disorder. *Nurs Res* 2019; **68**: 22-28.

444

445

22. Greacen T, Kersaudy-Rahib D, Le Gall JM et al. Comparing the Information and Support Needs of Different Population Groups in Preparation for 2015 Government Approval for HIV Self-testing in France. *PLoS One* 2016; **11**: e0152567.

446

447

448

23. Feyissa GT, Lockwood C, Woldie M et al. Evaluation of a guideline developed to reduce HIV-related stigma and discrimination in healthcare settings and establishing consensus. *PLoS One* 2018; **13**: e0198781.

449

450

451

24. Johnson MO Koester KA, Wood T et al. Development of an Index of Engagement in HIV Care: An Adapted Internet-Based Delphi Process. *JMIR Res Protoc* 2017; **6**: e224.

452

453

454

25. Uyei J, Li L, Braithwaite RS. HIV and Alcohol Research Priorities of City, State, and Federal Policymakers: Results of a Delphi Study. *Am J Public Health* 2015; **105**: e23-6.

455

456

457

26. Maserati R, Antinori A, Bonora S et al. Optimizing HIV therapy. A consensus project on differences between cytidine analogues and regime compactness. *New Microbiol* 2014; **37**: 285-306

458

459

460

27. Adegbehingbe SM, Paul-Ebhohimhem V, Marais D. Development of an AFASS assessment and screening tool towards the prevention of mother-to-child HIV

461
435

18. Johnson MO, Neilands TB, Koester KA, et al. Detecting Disengagement From HIV Care Before It Is Too Late: Development and Preliminary Validation of a Novel Index of Engagement in HIV Care. *J Acquir Immune Defic Syndr* 2019; **81**: 145-152.

436

437

438

19. O'Connell KA, Kisteneff AV, Gill SS et al. HIV post-exposure prophylaxis in the emergency department: An updated assessment and opportunities for HIV prevention identified. *Am J Emerg Med* 2021; **46**: 323-328.

439

440

441

20. Fredericksen RJ, Edwards TC, Merlin JS et al. Patient and provider priorities for self-reported domains of HIV clinical care. *AIDS Care* 2015; **27**: 1255-64

442

443

21. Cummins D, Waters D, Aggar C et al. Assessing Risk of HIV-Associated Neurocognitive Disorder. *Nurs Res* 2019; **68**: 22-28.

444

445

22. Greacen T, Kersaudy-Rahib D, Le Gall JM et al. Comparing the Information and Support Needs of Different Population Groups in Preparation for 2015 Government Approval for HIV Self-testing in France. *PLoS One* 2016; **11**: e0152567.

446

447

448

23. Feyissa GT, Lockwood C, Woldie M et al. Evaluation of a guideline developed to reduce HIV-related stigma and discrimination in healthcare settings and establishing consensus. *PLoS One* 2018; **13**: e0198781.

449

450

451

24. Johnson MO Koester KA, Wood T et al. Development of an Index of Engagement in HIV Care: An Adapted Internet-Based Delphi Process. *JMIR Res Protoc* 2017; **6**: e224.

452

453

454

25. Uyei J, Li L, Braithwaite RS. HIV and Alcohol Research Priorities of City, State, and Federal Policymakers: Results of a Delphi Study. *Am J Public Health* 2015; **105**: e23-6.

455

456

457

26. Maserati R, Antinori A, Bonora S et al. Optimizing HIV therapy. A consensus project on differences between cytidine analogues and regime compactness. *New Microbiol* 2014; **37**: 285-306

458

459

460

27. Adegbehingbe SM, Paul-Ebhohimhem V, Marais D. Development of an AFASS assessment and screening tool towards the prevention of mother-to-child HIV

461
462 transmission (PMTCT) in sub-Saharan Africa-a Delphi survey. *BMC Public Health*
463 2012; **12**: 402.

464 28. Engler K, Ahmed S, Lessard D *et al*. Assessing the Content Validity of a New Patient-
465 Reported Measure of Barriers to Antiretroviral Therapy Adherence for Electronic
466 Administration in Routine HIV Care: Proposal for a Web-Based Delphi Study. *JMIR
467 Res Protoc* 2019; **8**: e12836.

468 29. HAS (Haute Autorité de Santé) Guide méthodologique. 2010. *Élaboration de
469 recommandations de bonne pratique. Méthode « Recommandations pour la pratique
470 clinique »*. https://www.has-sante.fr/upload/docs/application/pdf/2011-
471 01/guide_methodologique_consensus_formalise.pdf

472 30. Letrilliart L, Milliat-Guittard L, Romestaing P *et al*. Building a shared patient record
473 for breast cancer management: a French Delphi study. *Eur J Cancer Care (Engl)*
474 2009; **18**: 131-9.

475 31. McMillan SS, King M, Tully MP. How to use the nominal group and Delphi
476 techniques. *Int J Clin Pharm* 2016; **38**: 655-62.

477 32. Koene S, van Bon L, Bertini E *et al*. Outcome measures for children with
478 mitochondrial disease: consensus recommendations for future studies from a Delphi-
479 based international workshop. *J Inherit Metab Dis* 2018; **41**: 1267-1273

480 33. Mangeat B, Turelli P, Caron G *et al*. Broad antiretroviral defence by human
481 APOBEC3G through lethal editing of nascent reverse transcripts. *Nature* 2003; **424**:
482 99-103

483 34. Armitage AE, Deforche K, Chang CH *et al*. APOBEC3G-induced hypermutation of
484 human immunodeficiency virus type-1 is typically a discrete “all or nothing”
485 phenomenon. *PLoS Genet* 2012; **8**: e1002550.

486 35. Russell RA, Moore MD, Hu WS *et al*. APOBEC3G induces a hypermutation gradient:
487 purifying selection at multiple steps during HIV-1 replication results in levels of G-to-
462 transmission (PMTCT) in sub-Saharan Africa-a Delphi survey. *BMC Public Health*
463 2012; **12**: 402.

464 28. Engler K, Ahmed S, Lessard D *et al*. Assessing the Content Validity of a New Patient-
465 Reported Measure of Barriers to Antiretroviral Therapy Adherence for Electronic
466 Administration in Routine HIV Care: Proposal for a Web-Based Delphi Study. *JMIR
467 Res Protoc* 2019; **8**: e12836.

468 29. HAS (Haute Autorité de Santé) Guide méthodologique. 2010. *Élaboration de
469 recommandations de bonne pratique. Méthode « Recommandations pour la pratique
470 clinique »*. https://www.has-sante.fr/upload/docs/application/pdf/2011-
471 01/guide_methodologique_consensus_formalise.pdf

472 30. Letrilliart L, Milliat-Guittard L, Romestaing P *et al*. Building a shared patient record
473 for breast cancer management: a French Delphi study. *Eur J Cancer Care (Engl)*
474 2009; **18**: 131-9.

475 31. McMillan SS, King M, Tully MP. How to use the nominal group and Delphi
476 techniques. *Int J Clin Pharm* 2016; **38**: 655-62.

477 32. Koene S, van Bon L, Bertini E *et al*. Outcome measures for children with
478 mitochondrial disease: consensus recommendations for future studies from a Delphi-
479 based international workshop. *J Inherit Metab Dis* 2018; **41**: 1267-1273

480 33. Mangeat B, Turelli P, Caron G *et al*. Broad antiretroviral defence by human
481 APOBEC3G through lethal editing of nascent reverse transcripts. *Nature* 2003; **424**:
482 99-103

483 34. Armitage AE, Deforche K, Chang CH *et al*. APOBEC3G-induced hypermutation of
484 human immunodeficiency virus type-1 is typically a discrete “all or nothing”
485 phenomenon. *PLoS Genet* 2012; **8**: e1002550.

486 35. Russell RA, Moore MD, Hu WS *et al*. APOBEC3G induces a hypermutation gradient:
487 purifying selection at multiple steps during HIV-1 replication results in levels of G-to-
488

A mutations that are high in DNA, intermediate in cellular viral RNA, and low in
virion RNA. *Retrovirology* 2009; **6**: 16.

489

490

36. Armenia D, Gagliardini R, Alteri *et al*. Temporal trend of drug-resistance and APOBEC editing in PBMC genotypic resistance tests from HIV-1 infected virologically suppressed individuals. *J Clin Virol* 2023; **168**: 105551.

491

492

493

37. Charpentier C, Storto A, Soulié C *et al*. Prevalence of genotypic baseline risk factors for cabotegravir + rilpivirine failure among ARV-naive patients. *J Antimicrob Chemother* 2021; **76**: 2983-2987.

494

495

496

38. Sellem B, Abdi B, Lê M *et al*. Intermittent Bictegravir/Emtricitabine/Tenofovir Alafenamide Treatment Maintains High Level of Viral Suppression in Virally Suppressed People Living with HIV. *J Pers Med* 2023; **13**: 583.

497

498

499

39. Landman R, de Truchis P, Assoumou L, *et al*. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. *Lancet HIV* 2022; **9**: e79-e90.

500

501

502

503

40. St John EP, Simen BB, Turenchalk GS *et al*. A Follow-Up of the Multicenter Collaborative Study on HIV-1 Drug Resistance and Tropism Testing Using 454 Ultra Deep Pyrosequencing. *PLoS ONE* 2016; **11**: e0146687.

504

505

506

41. Rodriguez C, Nere ML, Demontant V *et al*. Ultra-deep sequencing improves the detection of drug resistance in cellular DNA from HIV-infected patients on ART with suppressed viraemia. *J Antimicrob Chemother* 2018; **73**: 3122-3128.

507

508

509

42. Balakrishna S, Loosli T, Zaheri M *et al*. Frequency matters: comparison of drug resistance mutation detection by Sanger and next-generation sequencing in HIV-1. *J Antimicrob Chemother* 2023; **78**: 656-664.

510

511

512

43. Charpentier C., Montes B., Perrier M *et al*. HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir + lamivudine in the maintenance DOLULAM pilot study. *J Antimicrob Chemother* 2017; **72**: 2831-2836.

513

514
488

A mutations that are high in DNA, intermediate in cellular viral RNA, and low in
virion RNA. *Retrovirology* 2009; **6**: 16.

489

490

36. Armenia D, Gagliardini R, Alteri *et al*. Temporal trend of drug-resistance and APOBEC editing in PBMC genotypic resistance tests from HIV-1 infected virologically suppressed individuals. *J Clin Virol* 2023; **168**: 105551.

491

492

493

37. Charpentier C, Storto A, Soulié C *et al*. Prevalence of genotypic baseline risk factors for cabotegravir + rilpivirine failure among ARV-naive patients. *J Antimicrob Chemother* 2021; **76**: 2983-2987.

494

495

496

38. Sellem B, Abdi B, Lê M *et al*. Intermittent Bictegravir/Emtricitabine/Tenofovir Alafenamide Treatment Maintains High Level of Viral Suppression in Virally Suppressed People Living with HIV. *J Pers Med* 2023; **13**: 583.

497

498

499

39. Landman R, de Truchis P, Assoumou L, *et al*. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. *Lancet HIV* 2022; **9**: e79-e90.

500

501

502

503

40. St John EP, Simen BB, Turenchalk GS *et al*. A Follow-Up of the Multicenter Collaborative Study on HIV-1 Drug Resistance and Tropism Testing Using 454 Ultra Deep Pyrosequencing. *PLoS ONE* 2016; **11**: e0146687.

504

505

506

41. Rodriguez C, Nere ML, Demontant V *et al*. Ultra-deep sequencing improves the detection of drug resistance in cellular DNA from HIV-infected patients on ART with suppressed viraemia. *J Antimicrob Chemother* 2018; **73**: 3122-3128.

507

508

509

42. Balakrishna S, Loosli T, Zaheri M *et al*. Frequency matters: comparison of drug resistance mutation detection by Sanger and next-generation sequencing in HIV-1. *J Antimicrob Chemother* 2023; **78**: 656-664.

510

511

512

43. Charpentier C., Montes B., Perrier M *et al*. HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir + lamivudine in the maintenance DOLULAM pilot study. *J Antimicrob Chemother* 2017; **72**: 2831-2836.

513

514
515

516

517

44. Allavena C, Rodallec A, Leplat A, et al. Interest of proviral HIV-1 DNA genotypic resistance testing in virologically suppressed patients candidate for maintenance therapy. *J Virol Methods* 2018; **251**: 106-110.

518

519

520

45. Tzou PL, Kosakovsky Pond SL, Avila-Rios S et al. Analysis of unusual and signature APOBEC-mutations in HIV-1 pol next-generation sequences. *PLoS One* 2020; **15**: e0225352.

521

522

523

46. Morlat, C. Groupe d'experts pour la prise en charge du VIH. Résistance du VIH-1 aux antirétroviraux. 2016. *Prise en charge médicale des personnes vivant avec le VIH*. https://cns.sante.fr/wp-content/uploads/2017/02/experts-vih_resistance.pdf

524

525

526

47. Palich R, Teyssou E, Sayon S et al. Kinetics of Archived M184V Mutation in Treatment-Experienced Virally Suppressed HIV-Infected Patients. *J Infect Dis* 2022; **225**: 502-509.

527

528

529

530

48. Andreatta K, Willkom M, Martin R et al. Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I. *J Antimicrob Chemother* 2019; **74**: 3555-3564.

531

532

533

49. Santoro MM, Armenia D, Teyssou E et al. Virological efficacy of switch to DTG plus 3TC in a retrospective observational cohort of suppressed HIV-1 patients with or without past M184V: the LAMRES study. *J Glob Antimicrob Resist* 2022; **31**: 52-62.

534

535

536

537

50. Marcelin AG, Soulie C, Wirden M et al. The Virostar study: analysis of emergent resistance-associated mutations at first- or second-line HIV-1 virological failure with second-generation InSTIs in two- and three-drug regimens. *HIV Glasgow congress* 2022. Abstract P225.

538

539

540

51. Alidjinou EK, Deldalle J, Hallaert C et al. RNA and DNA Sanger sequencing versus next-generation sequencing for HIV-1 drug resistance testing in treatment-naïve patients. *Antimicrob Chemother* 2017; **72**: 2823-2830.
515

516

517

44. Allavena C, Rodallec A, Leplat A, et al. Interest of proviral HIV-1 DNA genotypic resistance testing in virologically suppressed patients candidate for maintenance therapy. *J Virol Methods* 2018; **251**: 106-110.

518

519

520

45. Tzou PL, Kosakovsky Pond SL, Avila-Rios S et al. Analysis of unusual and signature APOBEC-mutations in HIV-1 pol next-generation sequences. *PLoS One* 2020; **15**: e0225352.

521

522

523

46. Morlat, C. Groupe d'experts pour la prise en charge du VIH. Résistance du VIH-1 aux antirétroviraux. 2016. *Prise en charge médicale des personnes vivant avec le VIH*. https://cns.sante.fr/wp-content/uploads/2017/02/experts-vih_resistance.pdf

524

525

526

47. Palich R, Teyssou E, Sayon S et al. Kinetics of Archived M184V Mutation in Treatment-Experienced Virally Suppressed HIV-Infected Patients. *J Infect Dis* 2022; **225**: 502-509.

527

528

529

530

48. Andreatta K, Willkom M, Martin R et al. Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I. *J Antimicrob Chemother* 2019; **74**: 3555-3564.

531

532

533

49. Santoro MM, Armenia D, Teyssou E et al. Virological efficacy of switch to DTG plus 3TC in a retrospective observational cohort of suppressed HIV-1 patients with or without past M184V: the LAMRES study. *J Glob Antimicrob Resist* 2022; **31**: 52-62.

534

535

536

537

50. Marcelin AG, Soulie C, Wirden M et al. The Virostar study: analysis of emergent resistance-associated mutations at first- or second-line HIV-1 virological failure with second-generation InSTIs in two- and three-drug regimens. *HIV Glasgow congress* 2022. Abstract P225.

538

539

540

51. Alidjinou EK, Deldalle J, Hallaert C et al. RNA and DNA Sanger sequencing versus next-generation sequencing for HIV-1 drug resistance testing in treatment-naïve patients. *Antimicrob Chemother* 2017; **72**: 2823-2830.
52. Skinner R, Nelson RR, Chin WW *et al*. The Delphi Method Research Strategy in Studies of Information Systems. *Commun Assoc Inf Syst* 2015; **37**: 31-63.
52. Skinner R, Nelson RR, Chin WW *et al*. The Delphi Method Research Strategy in Studies of Information Systems. *Commun Assoc Inf Syst* 2015; **37**: 31-63.
<figure><img src="image_1.png" /><figcaption>Figure 1: Modified Delphi process chart</figcaption></figure>
<figure><img src="image_2.png" /><figcaption>Figure 1: Modified Delphi process chart</figcaption></figure>
<table><caption>Table 1 – Characteristics of voters</caption><thead><tr><th>Characteristic</th><th>Virologists<br>(n = 21)</th><th>Clinicians<br>(n = 47)</th></tr></thead><tbody><tr><td>Age, median [IQR], years</td><td>46 [43-55]</td><td>56 [46-60.5]</td></tr><tr><td>Gender F/M, n (%)</td><td></td><td></td></tr><tr><td>Female</td><td>16 (76)</td><td>18 (38)</td></tr><tr><td>Male</td><td>5 (24)</td><td>29 (62)</td></tr><tr><td>Type of practice, n (%)</td><td></td><td></td></tr><tr><td>Full-time hospital workers</td><td>16 (76)</td><td>44 (94)</td></tr><tr><td>Part-time hospital workers</td><td>2 (10)</td><td>3 (6)</td></tr><tr><td>Others</td><td>3 (14)</td><td>-</td></tr><tr><td>Years of experience performing HIV DNA sequencing, median [IQR], years</td><td>10 [5-12]</td><td>-</td></tr><tr><td>Number of HIV DNA genotypes performed per year, median [IQR]</td><td>225 [42.5-425]</td><td>-</td></tr><tr><td>Years of experience in PLWH management, median [IQR], years</td><td>-</td><td>25 [15-31.5]</td></tr><tr><td>Number of PLWH seen per year, median [IQR]</td><td>-</td><td>270 [200-400]</td></tr><tr><td>Experience in HIV care-related activities in the past 5 years, n (%)</td><td></td><td></td></tr><tr><td>Conference abstract</td><td>16 (76)</td><td>39 (83)</td></tr><tr><td>Scientific article</td><td>16 (76)</td><td>35 (74)</td></tr><tr><td>Research project (not including this study)</td><td>21 (100)</td><td>43 (91)</td></tr><tr><td>Involved in training</td><td>17 (81)</td><td>38 (81)</td></tr><tr><td>Professional or associate group or member</td><td>16 (76)</td><td>38 (81)</td></tr><tr><td>Speaker at scientific events</td><td>11 (52)</td><td>32 (68)</td></tr></tbody></table>

DNA: desoxyribonucleic acid; F: Female; M: Male; PLWH: People living with HIV
<table><caption>Table 1 – Characteristics of voters</caption><thead><tr><th>Characteristic</th><th>Virologists<br>(n = 21)</th><th>Clinicians<br>(n = 47)</th></tr></thead><tbody><tr><td>Age, median [IQR], years</td><td>46 [43-55]</td><td>56 [46-60.5]</td></tr><tr><td>Gender F/M, n (%)</td><td></td><td></td></tr><tr><td>Female</td><td>16 (76)</td><td>18 (38)</td></tr><tr><td>Male</td><td>5 (24)</td><td>29 (62)</td></tr><tr><td>Type of practice, n (%)</td><td></td><td></td></tr><tr><td>Full-time hospital workers</td><td>16 (76)</td><td>44 (94)</td></tr><tr><td>Part-time hospital workers</td><td>2 (10)</td><td>3 (6)</td></tr><tr><td>Others</td><td>3 (14)</td><td>-</td></tr><tr><td>Years of experience performing HIV DNA sequencing, median [IQR], years</td><td>10 [5-12]</td><td>-</td></tr><tr><td>Number of HIV DNA genotypes performed per year, median [IQR]</td><td>225 [42.5-425]</td><td>-</td></tr><tr><td>Years of experience in PLWH management, median [IQR], years</td><td>-</td><td>25 [15-31.5]</td></tr><tr><td>Number of PLWH seen per year, median [IQR]</td><td>-</td><td>270 [200-400]</td></tr><tr><td>Experience in HIV care-related activities in the past 5 years, n (%)</td><td></td><td></td></tr><tr><td>Conference abstract</td><td>16 (76)</td><td>39 (83)</td></tr><tr><td>Scientific article</td><td>16 (76)</td><td>35 (74)</td></tr><tr><td>Research project (not including this study)</td><td>21 (100)</td><td>43 (91)</td></tr><tr><td>Involved in training</td><td>17 (81)</td><td>38 (81)</td></tr><tr><td>Professional or associate group or member</td><td>16 (76)</td><td>38 (81)</td></tr><tr><td>Speaker at scientific events</td><td>11 (52)</td><td>32 (68)</td></tr></tbody></table>

DNA: desoxyribonucleic acid; F: Female; M: Male; PLWH: People living with HIV
**Table 2 - Statements and cumulative voting results for virologists and clinicians**

For each statement, a total number of voters equaling 21 indicates that only virologists were invited to vote and a total number of voters different from 68, 61, or 21 indicates the use of the 'I don't know' option by voters during the second voting round.
**Table 2 - Statements and cumulative voting results for virologists and clinicians**

For each statement, a total number of voters equaling 21 indicates that only virologists were invited to vote and a total number of voters different from 68, 61, or 21 indicates the use of the ‘I don't know’ option by voters during the second voting round.
<table><thead><tr><th></th><th>STATEMENTS</th><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th></tr></thead><tbody><tr><td colspan="7">Clinical situations for the use of HIV DNA genotyping</td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>2.9% (2)</td><td>7.4% (5)</td><td>89.7% (61)</td><td>9</td><td>Strong consensus</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>2.9% (2)</td><td>13.2% (9)</td><td>83.8% (57)</td><td>8</td><td>Strong consensus</td></tr><tr><td>3</td><td>In the context of a patient who has achieved virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for clinical decision-making in the absence of usable or sufficiently informative RNA data.</td><td>5.9% (4)</td><td>13.2% (9)</td><td>80.9% (55)</td><td>8</td><td>Strong consensus</td></tr><tr><td>4</td><td>In the context of a patient with virological success, in the event of a decision to reduce or simplify sequential treatment (4 days out of 7 or 5 days out of 7) without changing the treatment molecules, prior genotyping on HIV DNA is not essential for the clinical decision, even in the absence of usable or sufficiently informative RNA data.</td><td>13.3% (8)</td><td>10% (6)</td><td>76.7% (46)</td><td>8</td><td>Strong consensus</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data, in the case of a patient with virological success, in the event of a decision to reduce/simplify to a treatment that reduces the number of ARV, prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>8.2% (5)</td><td>13.1% (8)</td><td>78.7% (48)</td><td>8</td><td>Strong consensus</td></tr><tr><td colspan="7">Techniques for performing HIV DNA genotyping</td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>5.3% (1)</td><td>5.3% (1)</td><td>89.5% (17)</td><td>9</td><td>Strong consensus</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or from blood cell pellets.</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current practice.</td><td>10.5% (2)</td><td>5.3% (1)</td><td>84.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>0% (0)</td><td>23.8% (5)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report any viral minority population detected for multidisciplinary discussions.</td><td>10% (2)</td><td>25% (5)</td><td>65% (13)</td><td>7.5</td><td>NO CONSENSUS</td></tr><tr><td colspan="7">Consideration of APOBEC mutations</td></tr><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M41I, M230I on reverse transcriptase) and/or stop codons.</td><td>1.9% (1)</td><td>13.2% (7)</td><td>84.9% (45)</td><td>8</td><td>Strong consensus</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are present, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>5.2% (3)</td><td>5.2% (3)</td><td>89.7% (52)</td><td>9</td><td>Strong consensus</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td></tr><tr><td colspan="7">Reporting of genotyping results</td></tr><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>4.4% (3)</td><td>17.2% (10)</td><td>80.9% (55)</td><td>8</td><td>Strong consensus</td></tr><tr><td>15</td><td>In a patient with virological success, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be considered for the</td><td>5% (3)</td><td>10% (6)</td><td>85% (51)</td><td>8</td><td>Strong consensus</td></tr></tbody></table>
<table><thead><tr><th></th><th>STATEMENTS</th><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th></tr></thead><tbody><tr><td colspan="7">Clinical situations for the use of HIV DNA genotyping</td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>2.9% (2)</td><td>7.4% (5)</td><td>89.7% (61)</td><td>9</td><td>Strong consensus</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>2.9% (2)</td><td>13.2% (9)</td><td>83.8% (57)</td><td>8</td><td>Strong consensus</td></tr><tr><td>3</td><td>In the context of a patient who has achieved virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for clinical decision-making in the absence of usable or sufficiently informative RNA data.</td><td>5.9% (4)</td><td>13.2% (9)</td><td>80.9% (55)</td><td>8</td><td>Strong consensus</td></tr><tr><td>4</td><td>In the context of a patient with virological success, in the event of a decision to reduce or simplify sequential treatment (4 days out of 7 or 5 days out of 7) without changing the treatment molecules, prior genotyping on HIV DNA is not essential for the clinical decision, even in the absence of usable or sufficiently informative RNA data.</td><td>13.3% (8)</td><td>10% (6)</td><td>76.7% (46)</td><td>8</td><td>Strong consensus</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data, in the case of a patient with virological success, in the event of a decision to reduce/simplify to a treatment that reduces the number of ARV, prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>8.2% (5)</td><td>13.1% (8)</td><td>78.7% (48)</td><td>8</td><td>Strong consensus</td></tr><tr><td colspan="7">Techniques for performing HIV DNA genotyping</td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>5.3% (1)</td><td>5.3% (1)</td><td>89.5% (17)</td><td>9</td><td>Strong consensus</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or from blood cell pellets.</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current practice.</td><td>10.5% (2)</td><td>5.3% (1)</td><td>84.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>0% (0)</td><td>23.8% (5)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report any viral minority population detected for multidisciplinary discussions.</td><td>10% (2)</td><td>25% (5)</td><td>65% (13)</td><td>7.5</td><td>NO CONSENSUS</td></tr><tr><td colspan="7">Consideration of APOBEC mutations</td></tr><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M41I, M230I on reverse transcriptase) and/or stop codons.</td><td>1.9% (1)</td><td>13.2% (7)</td><td>84.9% (45)</td><td>8</td><td>Strong consensus</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are present, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>5.2% (3)</td><td>5.2% (3)</td><td>89.7% (52)</td><td>9</td><td>Strong consensus</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td></tr><tr><td colspan="7">Reporting of genotyping results</td></tr><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>4.4% (3)</td><td>17.2% (10)</td><td>80.9% (55)</td><td>8</td><td>Strong consensus</td></tr><tr><td>15</td><td>In a patient with virological success, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be considered for the</td><td>5% (3)</td><td>10% (6)</td><td>85% (51)</td><td>8</td><td>Strong consensus</td></tr></tbody></table>
<table><thead><tr><th colspan="7">switch decision and subsequent follow-up.</th></tr></thead><tbody><tr><td colspan="7">ARV recycling</td></tr><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents <strong>low risk</strong> of virological failure over time.</td><td>7.4%<br>(5)</td><td>7.4%<br>(5)</td><td>85.3%<br>(58)</td><td>8</td><td><strong>Strong consensus</strong></td></tr><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination <strong>might present</strong> a risk of virological failure over time.</td><td>21.3%<br>(13)</td><td>14.8%<br>(9)</td><td>63.9%<br>(39)</td><td>7</td><td><strong>NO CONSENSUS</strong></td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using this ARV class.</td><td>1.7%<br>(1)</td><td>18.3%<br>(11)</td><td>80%<br>(48)</td><td>8</td><td><strong>Strong consensus</strong></td></tr><tr><td colspan="7">Test availability and delays</td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td>8.8%<br>(6)</td><td>7.4%<br>(5)</td><td>83.8%<br>(57)</td><td>9</td><td><strong>Strong consensus</strong></td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be sent to clinicians within 30 days.</td><td>6.6%<br>(4)</td><td>9.8%<br>(6)</td><td>83.6%<br>(51)</td><td>9</td><td><strong>Strong consensus</strong></td></tr></tbody></table>

ARV: Antiretrovirals; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine or Emtricitabine; PLWH: People living with HIV.
<table><thead><tr><th colspan="7">switch decision and subsequent follow-up.</th></tr></thead><tbody><tr><td colspan="7">ARV recycling</td></tr><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents <strong>low risk</strong> of virological failure over time.</td><td>7.4%<br>(5)</td><td>7.4%<br>(5)</td><td>85.3%<br>(58)</td><td>8</td><td><strong>Strong consensus</strong></td></tr><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination <strong>might present</strong> a risk of virological failure over time.</td><td>21.3%<br>(13)</td><td>14.8%<br>(9)</td><td>63.9%<br>(39)</td><td>7</td><td><strong>NO CONSENSUS</strong></td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using this ARV class.</td><td>1.7%<br>(1)</td><td>18.3%<br>(11)</td><td>80%<br>(48)</td><td>8</td><td><strong>Strong consensus</strong></td></tr><tr><td colspan="7">Test availability and delays</td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td>8.8%<br>(6)</td><td>7.4%<br>(5)</td><td>83.8%<br>(57)</td><td>9</td><td><strong>Strong consensus</strong></td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be sent to clinicians within 30 days.</td><td>6.6%<br>(4)</td><td>9.8%<br>(6)</td><td>83.6%<br>(51)</td><td>9</td><td><strong>Strong consensus</strong></td></tr></tbody></table>

ARV: Antiretrovirals; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine or Emtricitabine; PLWH: People living with HIV.
Table S1 – Consensus results according to voter groups
<caption>Table S1 – Consensus results according to voter groups</caption>
<table><thead><tr><th></th><th>STATEMENTS</th><th>Results<br>VIROLOGISTS</th><th>Results<br>CLINICIANS</th><th>CUMULATIVE<br>Results</th></tr></thead><tbody><tr><td colspan="5"><strong>Clinical situations for the use of HIV DNA genotyping</strong></td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>3</td><td>In the context of a patient who has achieved virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for the clinical decision in the absence of usable or sufficiently informative RNA data.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>4</td><td>In a virologically suppressed patient, in the event of a decision to reduce or simplify to a sequential treatment (4 days out of 7 or 5 days out of 7) without changing any ARV agents, prior genotyping on HIV DNA is not essential for clinical decision-making, even in the absence of usable or sufficiently informative RNA data.</td><td>Strong consensus</td><td>Good consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data in a virologically suppressed patient, in the event of a decision to reduce/simplify to a treatment that reduces the number of ARV, prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td colspan="5"><strong>Techniques for performing HIV DNA genotyping</strong></td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or blood cell pellets.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current clinical practice.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report any viral minority population detected for multidisciplinary discussions.</td><td>No Consensus</td><td>N.A.</td><td>NO CONSENSUS</td></tr><tr><td colspan="5"><strong>Consideration of APOBEC mutations</strong></td></tr><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M411, M230I on reverse transcriptase) and/or stop codons.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are detected, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td colspan="5"><strong>Reporting of genotyping results</strong></td></tr><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>15</td><td>In a virologically suppressed patient, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be</td><td>Strong consensus</td><td>Strong consensus</td><td>Strong consensus</td></tr></tbody></table>
<table><thead><tr><th></th><th>STATEMENTS</th><th>Results<br>VIROLOGISTS</th><th>Results<br>CLINICIANS</th><th>CUMULATIVE<br>Results</th></tr></thead><tbody><tr><td colspan="5"><strong>Clinical situations for the use of HIV DNA genotyping</strong></td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>3</td><td>In the context of a patient who has achieved virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for the clinical decision in the absence of usable or sufficiently informative RNA data.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>4</td><td>In a virologically suppressed patient, in the event of a decision to reduce or simplify to a sequential treatment (4 days out of 7 or 5 days out of 7) without changing any ARV agents, prior genotyping on HIV DNA is not essential for clinical decision-making, even in the absence of usable or sufficiently informative RNA data.</td><td>Strong consensus</td><td>Good consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data in a virologically suppressed patient, in the event of a decision to reduce/simplify to a treatment that reduces the number of ARV, prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td colspan="5"><strong>Techniques for performing HIV DNA genotyping</strong></td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or blood cell pellets.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current clinical practice.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report any viral minority population detected for multidisciplinary discussions.</td><td>No Consensus</td><td>N.A.</td><td>NO CONSENSUS</td></tr><tr><td colspan="5"><strong>Consideration of APOBEC mutations</strong></td></tr><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M411, M230I on reverse transcriptase) and/or stop codons.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are detected, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>Strong consensus</td><td>N.A.</td><td>STRONG<br>CONSENSUS</td></tr><tr><td colspan="5"><strong>Reporting of genotyping results</strong></td></tr><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>Strong consensus</td><td>Strong consensus</td><td>STRONG<br>CONSENSUS</td></tr><tr><td>15</td><td>In a virologically suppressed patient, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be</td><td>Strong consensus</td><td>Strong consensus</td><td>Strong consensus</td></tr></tbody></table>
<table><tbody><tr><td></td><td>considered for the treatment switch decision and subsequent follow-up.</td><td></td><td></td></tr><tr><td colspan="4"><strong>ARV recycling</strong></td></tr><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents <strong>low risk</strong> of virological failure over time.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination <strong>might present</strong> a risk of virological failure over time.</td><td><strong>Strong consensus</strong></td><td><strong>No consensus</strong></td><td><strong>NO CONSENSUS</strong></td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV agents of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using ARV agents of this class.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td colspan="4"><strong>Test availability and delays</strong></td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be given to clinicians within 30 days.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr></tbody></table>

N.A.: Not available; ARV: Antiretroviral; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine/Emtricitabine; PLWH: People living with HIV.
<table><tbody><tr><td></td><td>considered for the treatment switch decision and subsequent follow-up.</td><td></td><td></td></tr><tr><td colspan="4"><strong>ARV recycling</strong></td></tr><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents <strong>low risk</strong> of virological failure over time.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination <strong>might present</strong> a risk of virological failure over time.</td><td><strong>Strong consensus</strong></td><td><strong>No consensus</strong></td><td><strong>NO CONSENSUS</strong></td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV agents of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using ARV agents of this class.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td colspan="4"><strong>Test availability and delays</strong></td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be given to clinicians within 30 days.</td><td><strong>Strong consensus</strong></td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr></tbody></table>

N.A.: Not available; ARV: Antiretroviral; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine/Emtricitabine; PLWH: People living with HIV.
**Table S2 – Statements, detailed virologists’ and clinicians’ voting results, and
cumulative results for both groups**

For each statement, a total number of voters different from 21 for virologists and 40 or 47 for clinicians indicates the use of the ‘I don’t know’ option by voters during the second voting round.
**Table S2 – Statements, detailed virologists’ and clinicians’ voting results, and
cumulative results for both groups**

For each statement, a total number of voters different from 21 for virologists and 40 or 47 for clinicians indicates the use of the ‘I don’t know’ option by voters during the second voting round.
<table><thead><tr><th rowspan="2"></th><th rowspan="2">STATEMENTS</th><th colspan="5">VOTING SCORES FROM VIROLOGISTS</th><th colspan="5">VOTING SCORES FROM CLINICIANS</th><th rowspan="2">CUMULATIVE SCORES</th></tr><tr><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th></tr></thead><tbody><tr><td colspan="13" style="text-align: left; font-weight: bold;">Clinical situations for the use of HIV DNA genotyping</td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>4.8% (1)</td><td>0% (0)</td><td>95.2% (20)</td><td>9</td><td>Strong consensus</td><td>2.1% (1)</td><td>10.6% (5)</td><td>87.2% (41)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>4.8% (1)</td><td>4.8% (1)</td><td>90.5% (19)</td><td>9</td><td>Strong consensus</td><td>2.1% (1)</td><td>17.0% (8)</td><td>80.9% (38)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>3</td><td>In the context of a patient with virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for clinical decision-making in the absence of usable or sufficiently informative RNA data.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>9</td><td>Strong consensus</td><td>6.4% (3)</td><td>14.9% (7)</td><td>78.7% (37)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>4</td><td>In a virologically suppressed patient, in the event of a decision to reduce or simplify to a sequential treatment (4 days out of 7 or 5 days out of 7) without changing any ARV agents, prior genotyping on HIV DNA is not essential for the clinical decision, even in the absence of usable or sufficiently informative RNA data.</td><td>10% (2)</td><td>5% (1)</td><td>85.0% (17)</td><td>8</td><td>Strong consensus</td><td>15% (6)</td><td>12.5% (5)</td><td>72.5% (29)</td><td>8</td><td>Good consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data in a virologically suppressed patient, in the event of a desire to reduce/simplify towards a regimen that reduces the number of ARV agents prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td><td>7.5% (3)</td><td>17.5% (7)</td><td>75.0% (30)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td colspan="13" style="text-align: left; font-weight: bold;">Techniques for performing HIV DNA genotyping</td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>5.3% (1)</td><td>5.3% (1)</td><td>89.5% (17)</td><td>9</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or from blood</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr></tbody></table>
<table><thead><tr><th rowspan="2"></th><th rowspan="2">STATEMENTS</th><th colspan="5">VOTING SCORES FROM VIROLOGISTS</th><th colspan="5">VOTING SCORES FROM CLINICIANS</th><th rowspan="2">CUMULATIVE SCORES</th></tr><tr><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th><th>Scores 1-2-3 (n)</th><th>Scores 4-5-6 (n)</th><th>Scores 7-8-9 (n)</th><th>Median</th><th>Results</th></tr></thead><tbody><tr><td colspan="13" style="text-align: left; font-weight: bold;">Clinical situations for the use of HIV DNA genotyping</td></tr><tr><td>1</td><td>In the context of a therapeutic decision requiring genotyping data, when HIV RNA is not amplifiable, when cumulative HIV RNA genotyping is not available and/or in the event of an incomplete or unusable genotypic history, HIV DNA genotyping is recommended.</td><td>4.8% (1)</td><td>0% (0)</td><td>95.2% (20)</td><td>9</td><td>Strong consensus</td><td>2.1% (1)</td><td>10.6% (5)</td><td>87.2% (41)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>2</td><td>For the following therapeutic targets - reverse transcriptase, protease, integrase - HIV DNA sequencing has a good positive predictive value (excluding APOBEC mutations) and an imperfect negative predictive value.</td><td>4.8% (1)</td><td>4.8% (1)</td><td>90.5% (19)</td><td>9</td><td>Strong consensus</td><td>2.1% (1)</td><td>17.0% (8)</td><td>80.9% (38)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>3</td><td>In the context of a patient with virological success, in the event of a decision to reduce or simplify treatment to some long-acting regimens, prior genotyping on HIV DNA is useful for clinical decision-making in the absence of usable or sufficiently informative RNA data.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>9</td><td>Strong consensus</td><td>6.4% (3)</td><td>14.9% (7)</td><td>78.7% (37)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>4</td><td>In a virologically suppressed patient, in the event of a decision to reduce or simplify to a sequential treatment (4 days out of 7 or 5 days out of 7) without changing any ARV agents, prior genotyping on HIV DNA is not essential for the clinical decision, even in the absence of usable or sufficiently informative RNA data.</td><td>10% (2)</td><td>5% (1)</td><td>85.0% (17)</td><td>8</td><td>Strong consensus</td><td>15% (6)</td><td>12.5% (5)</td><td>72.5% (29)</td><td>8</td><td>Good consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>5</td><td>In the absence of usable or sufficiently informative RNA data in a virologically suppressed patient, in the event of a desire to reduce/simplify towards a regimen that reduces the number of ARV agents prior genotyping on HIV DNA may be useful for clinical decision-making.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td><td>7.5% (3)</td><td>17.5% (7)</td><td>75.0% (30)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td colspan="13" style="text-align: left; font-weight: bold;">Techniques for performing HIV DNA genotyping</td></tr><tr><td>6</td><td>In current practice, when the amount of DNA is very low, the performance (sensitivity, representativeness of viral populations) of HIV DNA genotyping is reduced.</td><td>5.3% (1)</td><td>5.3% (1)</td><td>89.5% (17)</td><td>9</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>7</td><td>In current practice, genotyping on HIV DNA can be performed either from whole blood, from the cells isolated from peripheral blood (PBMC) or from blood</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr></tbody></table>
<table><tr><td></td><td>cell pellets.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current clinical practice.</td><td>10.5% (2)</td><td>5.3% (1)</td><td>84.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>0% (0)</td><td>23.8% (5)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report to report any viral minority population detected for multidisciplinary discussions.</td><td>10% (2)</td><td>25% (5)</td><td>65% (13)</td><td>7.5</td><td>No Consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td></td></tr></table>

## Consideration of APOBEC mutations

<table><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M41I, M230I on reverse transcriptase) and/or stop codons.</td><td>0% (0)</td><td>9.5% (2)</td><td>90.5% (19)</td><td>8</td><td>Strong consensus</td><td>3.1% (1)</td><td>15.6% (5)</td><td>81.3% (26)</td><td>8.5</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are detected, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>4.8% (1)</td><td>0% (0)</td><td>95.2% (20)</td><td>9</td><td>Strong consensus</td><td>5.4% (2)</td><td>5.4% (2)</td><td>89.2% (33)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr></table>

## Reporting of genotyping results

<table><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>9</td><td>Strong consensus</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>15</td><td>In a virologically suppressed patient, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be considered for a treatment switch decision and subsequent follow-up.</td><td>4.8% (1)</td><td>14.3% (3)</td><td>81% (17)</td><td>8</td><td>Strong consensus</td><td>4.8% (1)</td><td>14.3% (3)</td><td>81% (17)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr></table>

## ARV recycling

<table><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents low risk of virological failure over time.</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>4.3% (2)</td><td>6.4% (3)</td><td>89.4% (42)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr></table>
<table><tr><td></td><td>cell pellets.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>8</td><td>Duplicate DNA genotyping increases performance (sensitivity, representativeness of viral populations) but is not possible in current clinical practice.</td><td>10.5% (2)</td><td>5.3% (1)</td><td>84.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>9</td><td>Sanger and ultra-deep sequencing can be used to perform HIV DNA genotyping.</td><td>0% (0)</td><td>23.8% (5)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr><tr><td>10</td><td>For ultra-high throughput DNA sequencing techniques (ultra-deep sequencing), with the current state of knowledge, the clinically relevant detection threshold is not defined. Nevertheless, it may be interesting to report to report any viral minority population detected for multidisciplinary discussions.</td><td>10% (2)</td><td>25% (5)</td><td>65% (13)</td><td>7.5</td><td>No Consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td></td></tr></table>

### Consideration of APOBEC mutations

<table><tr><td>11</td><td>Detection of the M184I mutation in HIV DNA is suggestive of the presence of a defective genome due to the APOBEC enzyme when it is associated with other suggestive mutations (e.g., M41I, M230I on reverse transcriptase) and/or stop codons.</td><td>0% (0)</td><td>9.5% (2)</td><td>90.5% (19)</td><td>8</td><td>Strong consensus</td><td>3.1% (1)</td><td>15.6% (5)</td><td>81.3% (26)</td><td>8.5</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>12</td><td>When resistance mutations attributable to APOBEC are detected, their significance should be interpreted with caution and based on the clinical context and treatment history.</td><td>4.8% (1)</td><td>0% (0)</td><td>95.2% (20)</td><td>9</td><td>Strong consensus</td><td>5.4% (2)</td><td>5.4% (2)</td><td>89.2% (33)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>13</td><td>The presence of resistance mutations attributable to APOBEC should be reported in the HIV DNA genotyping analysis.</td><td>9.5% (2)</td><td>4.8% (1)</td><td>85.7% (18)</td><td>8</td><td>Strong consensus</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>N.A.</td><td>STRONG CONSENSUS</td></tr></table>

### Reporting of genotyping results

<table><tr><td>14</td><td>The clinical interpretation of resistance mutations on HIV DNA genotyping should be discussed at multidisciplinary consultation meetings.</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>9</td><td>Strong consensus</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>15</td><td>In a virologically suppressed patient, the detection on HIV DNA genotyping of new resistance mutations (excluding APOBEC &amp; stop codons) previously undetected must be considered for a treatment switch decision and subsequent follow-up.</td><td>4.8% (1)</td><td>14.3% (3)</td><td>81% (17)</td><td>8</td><td>Strong consensus</td><td>4.8% (1)</td><td>14.3% (3)</td><td>81% (17)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr></table>

### ARV recycling

<table><tr><td>16</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC + 1 NRTI combination presents low risk of virological failure over time.</td><td>14.3% (3)</td><td>9.5% (2)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>4.3% (2)</td><td>6.4% (3)</td><td>89.4% (42)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr></table>
<table><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination might present a risk of virological failure over time.</td><td>19% (4)</td><td>4.8% (1)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>22.5% (9)</td><td>25% (10)</td><td>52.5% (21)</td><td>7</td><td>No consensus</td><td>NO CONSENSUS</td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV agents of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using ARV agents of this class.</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>8</td><td>Strong consensus</td><td>0% (0)</td><td>17.9% (7)</td><td>82.1% (32)</td><td>8</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td colspan="14">Test availability and delays</td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td>4.8% (1)</td><td>9.5% (2)</td><td>85.7% (18)</td><td>9</td><td>Strong consensus</td><td>10.6% (5)</td><td>6.4% (3)</td><td>83.0% (39)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be given to clinicians within 30 days.</td><td>4.8% (1)</td><td>4.8% (1)</td><td>90.5% (19)</td><td>9</td><td>Strong consensus</td><td>10.0% (4)</td><td>7.5% (3)</td><td>82.5% (33)</td><td>9</td><td>Strong consensus</td><td>STRONG CONSENSUS</td></tr></table>

N.A.: Not available; ARV: Antiretroviral; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine/Emtricitabine; PLWH: People living with HIV
<table><tr><td>17</td><td>In a patient with an undetectable viral load for at least one year, in the presence of a documented M184V substitution over the past five years, the use of a 2<sup>nd</sup> generation InSTI + XTC combination <strong>might present</strong> a risk of virological failure over time.</td><td>19% (4)</td><td>4.8% (1)</td><td>76.2% (16)</td><td>8</td><td><strong>Strong consensus</strong></td><td>22.5% (9)</td><td>25% (10)</td><td>52.5% (21)</td><td>7</td><td>No consensus</td><td>NO CONSENSUS</td></tr><tr><td>18</td><td>The use / recycling of NNRTIs in the event of documented resistance to ARV agents of this class is associated with a greater risk of virological failure, independently of the duration of undetectable viral load, especially in drug-reduction strategies using ARV agents of this class.</td><td>4.8% (1)</td><td>19% (4)</td><td>76.2% (16)</td><td>8</td><td><strong>Strong consensus</strong></td><td>0% (0)</td><td>17.9% (7)</td><td>82.1% (32)</td><td>8</td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td colspan="14"><strong>Test availability and delays</strong></td></tr><tr><td>19</td><td>HIV DNA genotypic tests should be accessible in clinical practice to all clinicians managing PLWH.</td><td>4.8% (1)</td><td>9.5% (2)</td><td>85.7% (18)</td><td>9</td><td><strong>Strong consensus</strong></td><td>10.6% (5)</td><td>6.4% (3)</td><td>83.0% (39)</td><td>9</td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr><tr><td>20</td><td>Reports of genotypic HIV DNA test results should be given to clinicians within 30 days.</td><td>4.8% (1)</td><td>4.8% (1)</td><td>90.5% (19)</td><td>9</td><td><strong>Strong consensus</strong></td><td>10.0% (4)</td><td>7.5% (3)</td><td>82.5% (33)</td><td>9</td><td><strong>Strong consensus</strong></td><td><strong>STRONG CONSENSUS</strong></td></tr></table>

N.A.: Not available; ARV: Antiretroviral; APOBEC: Apolipoproteins B mRNA editing enzyme; InSTI: Integrase Strand Transfer Inhibitor; XTC: Lamivudine/Emtricitabine; PLWH: People living with HIV
<table><caption>Table S3 – APOBEC context drug resistance mutations</caption><thead><tr><td>ARV class</td><td>Major resistance mutations</td></tr></thead><tbody><tr><td>PI</td><td>M46I, G73S, D30N</td></tr><tr><td>NRTI</td><td>D67N, M184I</td></tr><tr><td>NNRTI</td><td>M230I, E138K, G190E, G190S</td></tr><tr><td>InSTI</td><td>G163R, G163K, G140R, D232N, E138K, G140S, G118R, R263K</td></tr></tbody></table>

PI: Protease Inhibitor; InSTI: Integrase Strand Transfer Inhibitor
<table><caption>Table S3 – APOBEC context drug resistance mutations</caption><thead><tr><td>ARV class</td><td>Major resistance mutations</td></tr></thead><tbody><tr><td>PI</td><td>M46I, G73S, D30N</td></tr><tr><td>NRTI</td><td>D67N, M184I</td></tr><tr><td>NNRTI</td><td>M230I, E138K, G190E, G190S</td></tr><tr><td>InSTI</td><td>G163R, G163K, G140R, D232N, E138K, G140S, G118R, R263K</td></tr></tbody></table>

PI: Protease Inhibitor; InSTI: Integrase Strand Transfer Inhibitor