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Primary HIV-1 drug resistance in Abidjan (Côte d'Ivoire): a genotypic and phenotypic study

Toni, Thomas d'Aquina; Masquelier, Bernardb; Bonard, Dominiquea; Faure, Murielb; Huët, Charlottec; Caumont, Anneb; Roques, Pierred; Dabis, Françoise; Salamon, Rogere; Fleury, Hervé*; and the Primo-CI/PAC-CI Study Group

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aCentre Intégré de recherches Biocliniques à Abidjan (CIRBA), Abidjan, Côte d'Ivoire; bLaboratoire de Virologie, CHU de Bordeaux, Bordeaux, France; cPAC-CI Programme, Abidjan, Côte d'Ivoire; dCIRMF, Franceville, Gabon; eUnité INSERM 330, Université Victor Segalen Bordeaux 2, Bordeaux, France.

The two first authors contributed equally to this study.

*Participants are listed in the Appendix.

Sponsorship: This study was supported by the ANRS (Agence Nationale de Recherches sur le SIDA, Paris, France).

This study was presented in part at the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, USA, 4–8 February 2001 [Abstract 457].

Received: 27 July 2001;

revised: 24 August 2001; accepted: 25 September 2001.

We studied the impact of HIV-1 genetic diversity on antiretroviral susceptibility and the prevalence of primary HIV-1 resistance in a cohort of seroconverters in Abidjan. Despite an extensive variation in the protease and reverse transcriptase genes, most of the isolates seemed to conserve a full susceptibility to antiretroviral drugs. Minor variations of nevirapine susceptibility should be investigated in a context of the potential wide use of this drug for preventing mother-to-child transmission.

Mutations within the reverse transcriptase (RT) and protease genes, conferring resistance to the different antiretroviral drugs, can be detected in drug-naive, recently infected patients. Recent reports have evaluated the prevalence of antiretroviral-resistant HIV-1 in primary infected patients at between 5 and 16% in developed countries [1–3].

In Africa, the access to antiretroviral treatments is still limited, as a result of economic and logistical factors. Few data are available concerning primary resistance in HIV-infected African patients and the impact of HIV-1 subtype non-B diversity on antiretroviral susceptibility [4,5]. We decided to study the HIV-1 diversity in relation to a putative primary resistance in the Primo-CI cohort of HIV-1-infected seroconverters in Abidjan, Côte d'Ivoire.

Regulars, volunteers and unpaid blood donors at the National Blood Bank were enrolled into the Primo-CI cohort when they presented an HIV-1 infection or a dual HIV-1+2 infection, with a previous negative HIV1+2 serology in the past 3 years [6]. All virological analyses of this study were performed on the first plasma sample corresponding to entry into the cohort.

The RT and protease genotype was determined using the ANRS (Agence Nationale de Recherches sur le SIDA, France) consensus method [7]. The env (region C2V3) gene was sequenced and the nucleotide sequences of RT, prot, and env were submitted to phylogenetic analysis as previously described [8]. Drug sensitivity assays were performed using a single-cycle recombinant virus assay (Phenoscipt, Viralliance, Paris, France), as previously described [9,10].

A total of 99 patients were consecutively enrolled into the study between June 1997 and August 2000. They were predominantly male, in their early 30s, single, with a medium to high level of education. The median time between the estimated date of seroconversion and inclusion was 9.4 months.

The phylogenetic study revealed that most of the isolates (82/99, 83%) clustered with the recombinant form CRF02 AG, in concordance with previous reports [11,12]. Nine strains belonged to HIV-1 subtype A. Other viruses were found to have divergent sequences: one virus was a recombinant form A(pol)-F2 (env), four clustered with the CPX (CRF06) sequences for at least one of the three regions studied. Three isolates formed an isolate cluster for their RT sequences.

No major protease inhibitor resistance mutation was seen in the 99 patients. Polymorphisms K20I/R and M36I/L in the protease were detected in 94 and 96% of patients, respectively. Other mutations at codons involved in protease inhibitor resistance were present with decreasing frequencies: L63A/H/P/S/V (27%), L10I/V (13%), V77I (1%), V82I (2%), and A71R (1%). Two patients had an asparagin insertion in the protease gene, between codons 36/37 and 37/38. This confirms previous reports of frequent protease polymorphisms in non-B subtypes of HIV [13–15].

No primary nucleoside reverse transcriptase inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutation was noticed after sequencing the RT gene from 98 patients. Two out of 98 (2%) and 60 out of 81 (74%) patients, respectively, presented with the RT polymorphisms V106I and V245Q/K/R at positions potentially implicated in NNRTI resistance. Fifteen out of 98 patients (15%) presented with a I135T mutation, which has been described to code for low-level resistance to nevirapine.

Phenotypic results for 13 isolates representative of the diversity are expressed in Table 1. A 6.9-fold reduction of susceptibility to nelfinavir was detected in one isolate, with an asparagin insertion in the protease between positions 36 and 37. Another sample with the I135T RT mutation showed a 4.2-fold resistance to nevirapine. Other frequent genotypic patterns (e.g. 20I plus 36I in the protease gene) were not associated with any decrease in sensitivity to antiretroviral drugs.

Table 1
Table 1
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The absence of mutations coding for high-level resistance to antiretroviral drugs has to be interpreted with regard to the characteristics of the enrolled patients. We supposed that these patients had been infected through heterosexual contacts with antiretroviral-naive, HIV-infected partners, because antiretroviral therapy is still an exception for people living with HIV in Abidjan [4]. The delay between HIV infection and blood sampling for genotype is also a crucial factor for detecting primary resistance to antiretroviral drugs. In our study, we searched for primary resistance after a median time of 9.4 months, which makes an underestimation possible. However, 33% of patients were included less than 6 months after the estimated date of infection, and no primary mutation was detected in this group.

The polymorphisms in the protease and in the RT were rarely found to be correlated with any phenotypic resistance to antiretroviral drugs in our patients. However, we found reduced sensitivity to nelfinavir for a CRFO2 virus with an insertion between codons 36 and 37 of the protease. Considering the variability in the RT gene, the most interesting genotypic changes concerned two amino acids at positions 135 and 245, previously shown to be correlated with a low-level resistance to NNRTI in treatment-naive patients [16]. The high prevalence of these changes found in our study should continue to be investigated in the context of a potentially wide use of nevirapine for preventing mother-to-child transmission of HIV-1 [17]. Interestingly, a low-level phenotypic resistance to nevirapine was found in a virus sharing the I135T mutation. The clinical significance of low-level resistance to nevirapine has to be investigated in further studies.

In the protease and in the RT genes, various polymorphisms were detected at codons not previously involved in resistance to antiretroviral drugs. Our phenotypic results do not plead for a role of these substitutions, and of the genotypic changes detected at secondary mutation loci in the protease gene, as determinants of primary drug resistance.

In conclusion, this study showed an excellent overall susceptibility to antiretroviral drugs of HIV-1 from drug-naive, well documented seroconverters, including those most recently infected in Abidjan. These results provide baseline data in a pre-therapeutic context, and are one more argument to argue for access to antiretroviral agents in Africa. Further studies will then be needed to document the evolution of HIV-1 quasispecies in African treated patients.

Thomas d'Aquin Tonia

Bernard Masquelierb

Dominique Bonarda

Muriel Faureb

Charlotte Huëtc

Anne Caumontb

Pierre Roquesd

François Dabise

Roger Salamone

Hervé Fleuryb

and the Primo-CI/PAC-CI Study Group*

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Acknowledgements

The authors would like to thank all the patients who participated in the study. Special thanks to Yann Louis (Visible Genetics) for supplying genotypic kits and to Valérie Birac for excellent technical assistance.

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References

1. Chaix ML, Harzic M, Masquelier B, et al. Prevalence of genotypic drug resistance among french patients infected during the year 1999. In:8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, USA, 4–8 February 2001 [Abstract 755].

2. Little SJ, Routy JP, Daar ES, et al. Antiretroviral drug susceptibility and response to initial therapy among recently HIV-infected subjects in north America. In:8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, USA, 4–8 February 2001 [Abstract 756].

3. Yerly S, Race E, Vora S, et al. HIV drug resistance and molecular epidemiology in patients with primary infection. In:8th Conference on Retroviruses and Opportunistic Infections. Chicago, IL, USA, 4–8 February 2001 [Abstract 754].

4. Adje C, Cheingsong R, Roels TH. et al. High prevalence of genotypic and phenotypic HIV-1 drug-resistant strains among patients receiving antiretroviral therapy in Abidjan, Cote d'Ivoire. J Acquir Immune Defic Syndr 2001, 26: 501–506.

5. Weidle PJ, Kityo CM, Mugyenyi P. et al. Resistance to antiretroviral therapy among patients in Uganda. J Acquir Immune Defic Syndr 2001, 26: 495–500.

6. Salamon R, Marimoutou C, Ekra D, et al. Clinical and biological evolution of HIV-1 seroconverters in Abidjan, Côte d'Ivoire, 1997–2000. J Acquir Immune Defic Syndr 2001, in press.

7. Descamps D, Calvez V, Izopet J. et al. Prevalence of resistance mutations in antiretroviral naive HIV-1 chronic infected patients in 1998: a French national study. AIDS 2001, 15: 1777–1782.

8. Caumont A, Hoang Lan NT, Vy Uyen NT. et al. Sequence analysis of env C2/V3, gag p17/p24, and pol protease regions of 25 HIV type 1 isolates from Ho Chi Minh City, Viet Nam. AIDS Res Hum Retroviruses 2001, 17: 1285–1291.

9. Race E, Dam E, Obry V, Paulous S, Clavel F. Analysis of human immunodeficiency virus type 1 cross-resistance to protease inhibitors in patients failing on combination therapies using a rapid single-cycle recombinant virus assay. AIDS 1999, 13: 2061–2068.

10. Masquelier B, Race E, Tamalet C. et al. Genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 variants with insertions or deletions in the reverse transcriptase (RT): multicenter study of patients treated with RT inhibitors. Antimicrob Agents Chemother 2001, 45: 1836–1842.

11. Ellenberg D, Pieniazek D, Nkengasong JN. et al. Genetic analysis of human immunodeficiency virus in Abidjan, Ivory Coast reveals predominance of HIV type 1 subtype A and introduction of subtype G. AIDS Res Hum Retroviruses 1999, 15: 3–9.

12. Nkengasong JN, Luo CC, Abouya L. et al. Distribution of HIV-1 subtypes among HIV-seropositive patients in the interior of Côte d'Ivoire. J Acquir Immune Defic Syndr 2000, 23: 430–436.

13. Becker-Pergola G, Kataaha P, Johnston-Dow L, Fung S, Jackson JB, Eshleman SH. Analysis of HIV type 1 protease and reverse transcriptase in antiretroviral drug-naive Ugandan adults. AIDS Res Hum Retroviruses 2000, 16: 807–813.

14. Vergne L, Peeters M, Mpoudi-Ngole E. et al. Genetic diversity of protease and reverse transcriptase sequences in non-subtype-B human immunodeficiency virus type 1 strains: evidence of many minor drug resistance mutations in treatment-naive patients. J Clin Microbiol 2000, 38: 3919–3925.

15. Pieniazek D, Rayfield M, Hu DJ. et al. Protease sequences from HIV-1 group M subtypes A–H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide. HIV Variant Working Group. AIDS 2000, 14: 1489–1495.

16. Brown AJ, Precious HM, Whitcomb JM. et al. Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites. J Virol 2000, 74: 10269–10273

17. Guay LA, Musoke P, Fleming T. et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999, 354: 795–802.

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Appendix

The Primo-CI Study Group is organized as follows:

Principal investigators: Prs L. Montagnier and R. Salamon

Epidemiological coordination: Pr F. Dabis, Dr C. Marimoutou, Dr C. Huët

Clinical coordination: Dr A. Minga

Biological coordination: Drs D. Bonard and F. Rouet

Data management: Ms G. Gourvellec

Field team: Dr L. Siransy-Bogui (blood bank), Dr D. Ekra (epidemiology), Drs H. Abe, I. Coulibaly, L. Dohoun, and A. Yao (clinic), Dr P. Combe, Mr G. Dahourou, Mrs M Enouf, Mr E. Nerrienet and Mr TA. Toni (laboratory), and Mr S. Ouedraogo (monitoring and data management). Cited Here...

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