Retrospective study of the prevalence of acquired drug resistance after failed antiretroviral therapy in Libya

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Nader Shalaka¹

¹Department of Infectious Diseases, Tripoli University Hospital, University Road, Ain Zara, Tripoli, Libya (Correspondence to Nader Shalaka: This email address is being protected from spambots. You need JavaScript enabled to view it.; This email address is being protected from spambots. You need JavaScript enabled to view it.).

Abstract

Background: The increasing rate of drug-resistant HIV mutations in Libya and other African countries threatens the efficacy of antiretroviral therapy (ART), thus necessitating urgent regional strategies to combat resistance and improve treatment outcomes.

Aim: To characterize the frequency and pattern of acquired HIV drug resistance mutations in patients showing ART failure while using non-nucleoside reverse transcriptase inhibitors (NNRTI) prescribed by the Department of Infectious Diseases at Tripoli University Hospital, Libya.

Methods: We collated retrospective data on 128 people living with HIV, aged 18 years or above, who experienced first-line treatment failure at Tripoli University Hospital, Libya, from 2014 to 2017. We analysed the extant HIV amino acid sequences to identify resistance mutations using algorithms from the Stanford University HIV drug resistance database.

Findings: All included cases had at least one resistance mutation (n = 128; 100%) and 119 (93%) had both nucleoside reverse transcriptase inhibitors (NRTI) and NNRTI mutations. M184V/I was the most common NRTI mutation (n = 119; 93%) while K103N was the most common NNRTI mutation (n = 100; 78%). Thymidine analog mutations were detected in 51 cases (40%); featuring T215Y, D67N and M41L. Predicted full susceptibility was highest for Tenofovir (66.4%), followed by Etravirine (60%).

Conclusion: We detected high level drug resistance and associated mutations among people living with HIV. Implementing drug regimens with high genetic barriers to resistance, coupled with rigorous monitoring and surveillance of HIV resistance development, could help mitigate such resistance in the future.

Keywords: HIV/AIDS, anti-retroviral therapy, treatment failure, drug resistance, Libya

Citation: Shalaka N. Retrospective study of the prevalence of acquired drug resistance after failed antiretroviral therapy in Libya. East Mediterr Health J. 2024;30(7):470–481. https://doi.org/10.26719/2024.30.7.470.

Received: 23/10/2023; Accepted: 23/05/2024

Copyright © Authors 2024; Licensee: World Health Organization. EMHJ is an open access journal. This paper is available under the Creative Commons Attribution Non-Commercial ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo).

Background

By the end of 2022, approximately 39 million people globally were living with HIV, with 29.8 million receiving antiretroviral therapy (ART) (1). This represents a significant increase from the 7.7 million accessing treatment in 2010; however, the long-term success of ART is increasingly threatened by the emergence of drug-resistant mutations, potentially leading to treatment failure (2).

In developing countries, lack of laboratory monitoring, including quantification of HIV viral load, delays recognition of ART failure with the consequence of large accumulations of resistance mutations, limiting options for second-line treatment and increasing the rates of morbidity and mortality (3,4). National shortages of ARTs further complicate (5) and limit access to first-line ARTs with high genetic barrier to resistance, resulting in delayed treatment success (6).

In Libya, the national HIV programme, established in the late 1990s, recommended a first-line ART regimen comprising a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Efavirenz or Nevirapine) combined with a nucleoside reverse transcriptase inhibitor (NRTI) backbone of Lamivudine and Zidovudine or Abacavir. Despite more than 20 years of national data on the types of HIV services provided in Libya, there are virtually no data on resistance mutations of HIV isolates from patients who failed a first-line ART (7). Also, little is known about circulating HIV genotypes among people living with HIV in Libya.

Given the current political instability and healthcare infrastructure limitations in Libya, conducting prospective research on HIV drug resistance presents significant challenges. In this context, retrospective analysis of electronically stored data offers valuable insights into the characteristics and extent of drug resistance among people living with HIV in Libya. Studying local data on HIV drug resistance prevalence and specific mutations in Libya can inform the development of national, evidence-based treatment guidelines tailored to the Libyan context. This could improve patient outcomes and maximize the effectiveness of available medications. Understanding HIV drug resistance in Libya can contribute to broader public health initiatives in the Middle East and North Africa, allowing for more effective regional responses to the HIV epidemic and the potential cross-border spread of resistant strains.

This study aimed to describe the pattern of acquired HIV drug resistance mutations found in patients exhibiting treatment failure while on NNRTI-based therapies from 2014 through 2017. It describes the potential effects of drug resistant mutation on second-line antiretroviral therapy

Methods

Study design and population

This study was designed as a retrospective, descriptive analysis of electronically stored patient data on HIV drug resistance for persons living with HIV after documented failure of NNRTI-based ART, who were treated at the hospital from January 2014 to December 2017.

Tripoli University Hospital is a tertiary referral hospital that provides specialist medical services to patients from Tripoli and other cities in the western and central regions of Libya. The Department of Infectious Diseases provides specialist HIV management as an ambulatory care as well as a 14-bed capacity ward dedicated to the management of inpatients with HIV/AIDS.

We collated data on HIV-positive adults who attended HIV care at our department and experienced first-line ART failure between 2014 and 2017, ensuring the data remained anonymous and retrospective to protect participant confidentiality and comply with ethical standards.

Case data was selected from the electronic record database using the following inclusion criteria: (i) 18 years or older at the time of ART failure; (ii) virological failure, which was defined as a viral load of more than 1000 copies per millilitre on 2 consecutive measurements (8); and (iii) patient was regularly on NNRTI-based ART for at least 6 months prior to HIV resistance testing. We excluded patient data for: (i) patients receiving protease inhibitors as antiretroviral therapy; (ii) irregular use of antiretroviral therapy; and (iii) patients with HIV viral loads of less than 1000 copies per millilitre.

Data collation and preparation for analysis

We collated anonymous study data from electronic patient files using a standard data collection form. For patients diagnosed with first-line ART failure between 2014 and 2017, we anonymously collected variables such as age, gender, and HIV risk factors. We gathered data on ART regimen, duration on ART, HIV viral load, CD4 counts at the time of ART failure, and targeted HIV amino acid sequences and drug resistance mutations for each case.

Immunologically advanced HIV infection was defined as CD4 counts of less than 200 cells per microliter (8). Analysis of HIV sequences to identify drug resistance mutations and determine HIV subtypes was performed using algorithms from the Stanford University HIV Drug Resistance Database (v8; https://hivdb.stanford.edu/).

Ethics

The study was approved by the ethics review board of Tripoli University Hospital (Approval no. IDD-2018-07). The review board waived written informed consent because the study involved collecting anonymous retrospective data, ensuring no direct harm to participants and no public availability of individually identifiable information.

Data analysis

We performed all statistical analysis using R version 4.0.2 (9). We chose to use median and interquartile range (IQR) to summarize our quantitative variables and used the Mann–Whitney U-test for bivariate analysis. We represented categorical variables (grouped quantitative and qualitative variables) using frequency tables and percentages of the total. For these variables, we used either Chi-squared or Fisher's exact tests for low sample sizes (Tables 1,2,3). All analyses were 2-sided and P-values of < 0.05 were considered statistically significant.

Results

Patient characteristics

Table 1 summarizes the demographics and basic disease data. A total of 128 cases were included in this study (men=87; 68%). The median age at the time of HIV diagnosis was 33 years with a median of 30.6 months of ART use before treatment failure. Compared to men, women tended to be younger at the time of HIV diagnosis (29.3 vs. 33.2; P= 0.02).

HIV and ART characteristics

All sequenced HIV isolates were group M and circulating recombinant form 02 subtype (CRF02). At the time of ART failure, 109 (85%) of cases were on an Efavirenz-based regimen and 71 (55.5%) had Zidovudine as the NRTI backbone. Seventy-four (57.8%) cases had advanced HIV with CD4 counts of less than 200 (median=136; IQR=39-280), and 100 (78%) had HIV viral loads of more than 10 000 copies per ml.

Prevalence and pattern of HIV drug resistance mutations

All study participants (n=128; 100%) had at least one resistance mutation, with a median of 5 drug resistant mutations per case. One hundred and twenty-seven (99%) had at least one NNRTI resistance mutation while 119 (93%) had both NRTI and NNRTI resistance mutations, with a median of 2 NRTI and 2 NNRTI mutations per case. M184V/I was the most frequently detected NRTI mutation (n=119; 93%) followed by T215Y/F/S (n=40; 31.3%) and L74V/I (n=30; 23.4%), while only one case had a Q151M mutation. The most frequently detected NNRTI mutations were K103N (n= 100; 78%), G190A (n=17; 13.3%), Y181C (n=15; 11.7%), K101E (n=14; 11%), and V108I (n=32; 25%). Thymidine analog mutations (TAMs) were detected in 51 cases (40%). The most frequently detected TAMs were T215Y (n=28; 55%), D67N (n=22; 43%) and M41L (n=20; 39%). Twenty-two cases (43%) had 3 or more TAMs.

Prevalence of drug resistance mutations by drug exposure

Figures 1 and 2 present resistance mutation profiles according to prescribed ART regimen. At the time of treatment failure, cases who were on Zidovudine were more likely to have M41L (χ2=4.6; p =0.03), D67N (χ2=8.8; P =0.002), T215F/Y (χ2=21; P

The potential impact of resistance mutations on predicted drug susceptibility

The predicted susceptibility to all NNRTIs and NRTIs at the time of ART failure is presented in Figure 3. The predicted full NRTI susceptibility was highest for Tenofovir (n=85; 66.4%) and Zidovudine (n=79; 61.7%). Participants who received non-zidovudine-based ART retained better susceptibility to other NRTIs than those failing zidovudine-based ART (n=50; 87.7% vs. n=29; 40.8% retained susceptibility to Zidovudine (P

The proportion of cases with resistance to all 3 NRTIs (Zidovudine, Abacavir, and Tenofovir), including second-line regimens, was 3% (n=4) and 6% in NNRTIs (including second-generation) (n=8). Tables 2 and 3 summarize detected NRTI and NNRTI-resistance mutations and their effects on both NRTI and NNRTI drug susceptibility in 128 cases from 2014 to 2017.

Discussion

This study provides the first insights into HIV subtypes and drug resistance mutations among patients with first-line ART failure in Libya. All HIV isolates were group M, subtype CRF02, aligning with findings from West and Central Africa (10) but differing from the diverse subtypes in the Middle East and North Africa (11). Subtype B predominates in Morocco (12), while Algeria (13), Tunisia (14) and Egypt (15) show various subtypes and CRFs. Understanding HIV genetic diversity is crucial for local epidemic tracking, ART response and resistance surveillance (16,17,10).

We found that 100% of HIV sequences had at least one drug resistance mutation at first-line ART failure. This high drug resistance mutation prevalence is similar to reports from Tunisia (83%) (18), Kenya (82%) (19), South Africa (85-90%) (20-21) and sub-Saharan Africa (70%) (22). High drug resistance mutation rates can diminish ART efficacy, limit therapeutic options, increase transmitted resistance risks, complicate management and reduce control over AIDS-related outcomes (23–24,3–4). Low CD4 counts and high viral loads suggest prolonged treatment failure before diagnosis (26).

The M184V mutation was prevalent (93%), similar to other settings (19,20), likely due to widespread Lamivudine use, which is still used despite resistance (27). Zidovudine regimens were more likely to select TAMs at ART failure (53.8% vs. 22.8%; P

NRTI cross-resistance variations were noted; non-Zidovudine ART retained better susceptibility to other NRTIs than Zidovudine-based ART [87.7% vs 40.8% to Zidovudine (P

For second-generation NNRTIs, 38 (29.7%), 9 (7%), and 36 (28%) of our cases had high-level resistance to Rilpivirine, Etravirine, and Doravirine, respectively. Only 41 (32%), 77 (60.2%), and 33 (25.8%) cases would benefit from these drugs as fully active in salvage regimens, respectively. Resistance levels to second-generation NNRTIs were similar to findings in Thailand (33) and South Africa (32,36), making them less viable options for inclusion in second-line regimens under Libyan guidelines.

Our study has limitations. Firstly, the study was retrospective, and some parts of the data were missing for some of the cases. Secondly, the study included only patients on ART who completed resistance testing, and this may have underestimated the prevalence of drug resistant mutations among patients who were lost to follow-up, stopped ART or died. Thirdly, it is possible that drug resistant mutations were underestimated among patients with HIV viral loads below 1000 copies/ml. As there was no pre-existing baseline data on the prevalence of resistance before initiating first-line ART, all detected drug resistant mutations were assumed to be acquired after initial treatment failure.

Conclusion

This study documents a high prevalence of HIV drug resistance after failing an NNRTI-based ART at Tripoli University Hospital in Libya. We highlight the need to improve first-line treatment outcomes and to reduce the risk of developing HIV drug resistance via inaccurate or ineffective service delivery. The Libyan national HIV programme needs to address drug resistance by including drugs with a high genetic barrier to resistance (such as Dolutegravir-based ART) in first-line ART regimens. It also needs to improve HIV treatment adherence strategies and closely monitor for increases in treatment failures due to drug resistance. Libya also needs structured HIV virologic monitoring programmes. Timely virologic monitoring and prompt switch to second-line ART could limit the accumulation of drug resistance and enable successful future virologic suppression. In addition, Libyan national HIV service delivery requires assistance in capacity-building, including improving diagnostic laboratory infrastructure, training and recruitment of qualified laboratory personnel and training physicians in the latest evidenced-based HIV medical care and management.

Acknowledgments

The author would like to thank our colleagues for their insightful comments and suggestions.

Funding: None.

Conflicting interest: None declared.

Étude rétrospective de la prévalence de la pharmacorésistance acquise après l’échec d’un traitement antirétroviral en Libye

Résumé

Contexte : Le taux croissant de mutations du VIH pharmacorésistantes en Libye et dans d'autres pays d'Afrique menace l'efficacité du traitement antirétroviral (TAR), d'où le besoin urgent de mettre en place des stratégies régionales pour combattre la résistance et améliorer les résultats thérapeutiques.

Objectif : Caractériser la fréquence et le schéma des mutations du VIH pharmacorésistantes acquises chez les patients présentant un échec du TAR tout en utilisant des inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) prescrits par le Département des maladies infectieuses de l'hôpital universitaire de Tripoli, en Libye.

Méthodes : Nous avons rassemblé des données rétrospectives sur 128 personnes vivant avec le VIH, âgées de 18 ans ou plus, qui avaient connu un échec de traitement de première intention à l'hôpital universitaire de Tripoli (Libye), de 2014 à 2017. Nous avons analysé les séquences existantes d'acides aminés du VIH afin d'identifier les mutations de résistance à l'aide d'algorithmes issus de la base de données sur la pharmacorésistance du VIH de l'Université de Stanford.

Résultats : Tous les cas inclus présentaient au moins une mutation de résistance (n = 128 ; 100 %) et 119 (93 %) montraient à la fois des mutations aux inhibiteurs nucléosidiques de la transcriptase inverse (INTI) et aux INNTI. La M184V/I était la mutation la plus fréquente pour les INTI (n = 119 ; 93 %) tandis que pour les INNTI (n = 100; 78 %), la K103N était la plus fréquente. Des mutations des analogues de la thymidine ont été détectées dans 51 cas (40 %), représentées par les mutations T215Y, D67N and M41L. La sensibilité totale prédite était la plus élevée pour le ténofovir (66,4 %), suivi de l'étravirine (60 %).

Conclusion : Nous avons détecté des niveaux élevés de pharmacorésistance et de mutations associées chez les personnes vivant avec le VIH. La mise en œuvre de schémas thérapeutiques présentant de fortes barrières génétiques à la résistance, associée à un suivi et à une surveillance rigoureux du développement de la résistance du VIH, pourrait contribuer à atténuer cette résistance à l'avenir.

دراسة استرجاعية لمعدل انتشار المقاومة المكتسبة للأدوية بعد فشل العلاج بمضادات الفيروسات القهقرية في ليبيا

نادر شلاكه

الخلاصة

الخلفية: هناك زيادة في معدل طفرات فيروس العوز المناعي البشري المقاومة للأدوية في ليبيا وغيرها من البلدان الأفريقية، وهذه الزيادة تهدد فاعلية العلاج بمضادات الفيروسات القهقرية، ما يعني الحاجة الملحة إلى استراتيجيات إقليمية لمكافحة المقاومة وتحسين حصائل العلاج.

الأهداف: هدفت هذه الدراسة الى توصيف تواتر ونمط طفرات مقاومة فيروس العوز المناعي البشري المكتسبة للأدوية لدى المرضى الذين تظهر عليهم علامات فشل العلاج بمضادات الفيروسات القهقرية، وذلك أثناء استخدام المثبطات المنتسخة العكسية اللانوكليوزيدية التي وصفها لهم قسم الأمراض المعدية في مستشفى طرابلس الجامعي بليبيا.

طرق البحث: جمعنا بيانات استرجاعية عن 128 مصابًا بفيروس العوز المناعي البشري، لا يقل سن الواحد منهم عن 18 عامًا، ممن عانوا من فشل علاج الخط الأول في مستشفى طرابلس الجامعي بليبيا، من عام 2014 إلى عام 2017. وقد حللنا تسلسلات الأحماض الأمينية لفيروسات العوز المناعي البشري الموجودة لتحديد طفرات المقاومة باستخدام خوارزميات من قاعدة بيانات جامعة ستانفورد لمقاومة فيروس العوز المناعي البشري للأدوية.

النتائج: كان لدى جميع الحالات المُدرَجة طفرة مقاومة واحدة على الأقل (بعدد 128؛ 100%) ولدى 119 حالة (93%) طفرة في مقاومة كلٍّ من المثبطات المنتسخة العكسية النوكليوزيدية والمثبطات المنتسخة العكسية اللانوكليوزيدية. وكانت طفرة M184V/I أكثر طفرات المثبطات المنتسخة العكسية النوكليوزيدية شيوعًا (بعدد 119؛ 93%) في حين كانت طفرة K103N أكثر طفرات المثبطات المنتسخة العكسية اللانوكليوزيدية شيوعًا (بعدد 100؛ 78%). وقد اكتُشفت طفرات نظائر الثيميدين في 51 حالة (40%)؛ تضمنت T215Y وD67N وM41L. وكان توقُّع الحساسية التامة أعلى ما يكون في حالة تينوفوفير (66.4%)، يليه إيترافيرين (60%).

الاستنتاجات:رصدنا ارتفاع مستوى مقاومة الأدوية، وما يرتبط بها من طفرات بين المتعايشين مع فيروس العوز المناعي البشري. ويمكن أن يساعد تنفيذ أنظمة دوائية ذات حواجز جينية عالية تحول دون المقاومة، إلى جانب الرصد والمراقبة الدقيقين لتطور مقاومة فيروس العوز المناعي البشري، على التخفيف من حدة هذه المقاومة في المستقبل.

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