#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Genotyping and outcomes of presumptive second line ART failure cases switched to third line or maintained on second line ART in Mumbai, India


Authors: Naresh Gill aff001;  Rafael Van den Bergh aff002;  Khine Wut Yee Kyaw aff003;  Chinmay Laxmeshwar aff001;  Mrinalini Das aff001;  Sarthak Rastogi aff001;  Miriam Arago Galindo aff001;  Homa Mansoor aff001;  Stobdan Kalon aff001;  Petros Isaakidis aff004
Authors place of work: Médecins Sans Frontières, Mumbai, India aff001;  Médecins Sans Frontières, Brussels, Belgium aff002;  International Union Against Tuberculosis and Lung diseases, Mandalay, Myanmar aff003;  Southern Africa Medical Unit (SAMU), Médecins Sans Frontières, Cape Town, South Africa aff004
Published in the journal: PLoS ONE 14(11)
Category: Research Article
doi: https://doi.org/10.1371/journal.pone.0225631

Summary

Background

HIV programs are increasingly confronted with failing antiretroviral therapy (ART), including second-line regimens. WHO has provided guidelines on switching to third-line ART. In a Médecins Sans Frontières clinic in Mumbai, India, receiving referred presumptive second-line ART failure cases, an evidence-based protocol consisting of viral load (VL) testing, enhanced adherence counselling (EAC) and genotype for switching was implemented.

Objective

To document the outcome and genotype of presumptive second-line ART failure cases switched to third-line or maintained on second-line ART.

Design

Retrospective cohort study of patients referred between January 2011 and September 2017.

Results

The cases (n = 120) were complex with median 9.2 years of ART exposure, poor adherence at baseline, and exposure to multiple ART regimens other than recommended by WHO. Out of 90 evaluated cases, 39(43%) were maintained on second-line ART. Forty-nine (54%) were ever switched to third-line ART. Twelve months virological suppression was 72% in the second-line and 93% in the third-line ART cohort, while retention in care was 80% and 94% respectively. Genotyping showed 62% resistance for PIs, and 52% triple class resistance to NRTIs, NNRTIs and PIs. Resistance was noted for the new class of integrase inhibitors, and for different drugs without any documented previous exposure to the same drug.

Conclusion

Adopting WHO guidelines on switching ART regimens and provision of EAC can prevent unnecessary switching/exposure to third-line ART regimens. Genotyping is urgently required in national HIV programs, which currently use only the exposure history of patients for switching to third-line ART regimens.

Keywords:

Viral load – India – Antimicrobial resistance – HIV epidemiology – Mutation detection – Genotyping

Introduction

HIV infection is a global health problem. Since the beginning of the epidemic, more than 70 million people have been infected with the virus. Globally, about 36.9 million people were reported to be living with HIV and AIDS (PLHA) at the end of 2017 and 59% were on antiretroviral therapy (ART) [1]. The Sustainable Development Goals defines an ambition to end the HIV epidemic by 2030 [2]. UNAIDS has set the ambitious 90-90-90 targets, aiming for 90% testing coverage, linkage to treatment, and viral suppression by 2020 [3]. While emphasis has been placed on meeting the first two 90s, it is essential the third 90 is also acted upon simultaneously in order to end the pandemic. In order to reach the third target (90% of all people on ART achieving viral suppression), it is essential that PLHA; 1) receive appropriate treatment regimens, including second and third line ART regimens in the case of therapeutic failure, 2) are not exposed to such regimens unnecessarily, and 3) receive adherence counselling and other support throughout their treatment.

An important element in meeting this target is the World Health Organization (WHO) recommendation of integrating routine HIV viral load (VL) testing in HIV programs, to monitor the response to ART and detect treatment failure in a timely manner [4]. However, access to routine VL testing along with enhanced adherence counseling is not keeping pace with ART scale-up, mainly due to prohibitive costs and lack of availability [57]. Drug sensitivity testing too is not yet a standard component of care, especially in resource-limited settings, despite the considerable threat that resistance poses to the HIV control efforts that have been realized over the past years [8,9].

India is one such country struggling to upscale its HIV program. It was home to nearly 2.1 million PLHA in 2016, the third largest number of PLHA in the world after South Africa and Nigeria [10]. Under the National AIDS Control Program, India started providing free ART in 2004 and gradually scaled up its activities in terms of facilities for treatment and number of beneficiaries [11]. ART centres provided first-line ART to 997,000 (47.5% of 2.1 million) PLHA and second line ART to 15,500 PLHA. Third-line ART was rolled out in 2016 at Centers of Excellence across India and up until September 2016, 109 PLHA had been switched to third line ART [11,12]. Although under the national HIV program, the ART centers provide free ART services, large numbers of patients still receive care from private providers for various reasons, including a lack of privacy, perceived low quality of care, and long waiting times in the public system [13,14].

WHO has defined treatment failure as consistently high VL measurements (>1000 copies of RNA/ml) while receiving adherence support for a minimum duration of 3 months in between two high VL tests [15]. However, under the national program in India, the decision to switch to third-line ART for second-line ART failure is made by a clinical expert panel at the Centers of Excellence, on the basis of a single viral load measurement (the test is repeated after 1 month if the VL is between 1000–10000 copies of RNA/ml, to rule out blips), an adherence assessment, and previous ART exposure history. Additionally, testing for antiretroviral (ARV) drug resistance by genotyping is not done [16].

Cases of presumptive second-line treatment failure/ARV resistance, without clear guidance on whether a switch in regimen is truly needed, are thus becoming increasingly common [11]. This is not without risk, as a delayed switch to second and third line ART regimens increases the risk of unfavourable outcomes, cross-resistance to even unexposed antiretroviral drugs, and primary transmission of resistant HIV subtypes in the community. An unnecessary switch to third-line ART regimens increases the risk of development of resistance against this last line of defence against HIV and increases the economic burden on the national program.

In order to answer the need for VL testing, resistance testing/genotyping, and in general appropriate provision of third-line ART treatment in Mumbai, India, the medical humanitarian non-governmental organization Médecins Sans Frontières (MSF) started providing these services at its HIV clinic in 2011. To document the strengths and challenges of this program, we undertook a study to 1) describe the socio-demographic and clinical profile of presumptive second-line ART failure cases, 2) describe the one-year retention in care and viral suppression among patients maintained on second-line ART and those switched to third-line ART treatment, and 3) document the genotypic resistance profiles.

Methods

Study design

This was a retrospective cohort study using routinely collected program data.

Setting

In India, Maharashtra is the second most populous state with over 112 million inhabitants. In 2016, Maharashtra had more than 329,000 PLHA, and 25% of these were in the Mumbai. The Mumbai Districts AIDS Control Society in 2015 had 75,220 PLHA registered and 46,232 (61%) were active in care [17,18]. In Mumbai, second-line ART was available at all 16 ART centres. However, the decision to start second-line ART can only be made by two ART Plus centres (King Edward Memorial Hospital and Lokmanya Tilak Municipal Hospital) and the Centre of Excellence at Sir J.J. Group of Hospitals. Third-line ART in public sector was available only at the Centre of Excellence at Sir J. J. Group of Hospitals. Numbers of patients accessing treatment through the private sector are unknown.

In Mumbai, MSF has provided free ART services since 2006, and introduced third-line ART in January 2011. Referrals of presumptive second-line ART failure cases are received from private as well as public ART centres. The case definitions and treatment protocols used in the MSF clinic are shown in Table 1.

Tab. 1. Operational definitions and treatment protocols used in MSF Clinic.
Operational definitions and treatment protocols used in MSF Clinic.

On referral, presumptive second-line ART failure cases are evaluated by a team of doctors, nurses, counsellors and a psychiatrist, who assess the adequacy of the treatment regimen, the adherence profile, and HIV-VL. Three sessions of enhanced adherence counselling (EAC) are offered to patients with VL >1000 copies of RNA/ml over a period of 3 months. If the post-EAC VL is higher than the cut-off value of 1000 copies of RNA/ml, then genotyping is advised. If genotyping confirms resistance, then the patient is switched to an optimal third-line ART regimen. However, if the genotype report is available at the time of referral and is suggestive of resistance to second-line ART drugs, then third-line ART may be initiated immediately and continued with treatment literacy support and EAC.

Study population

The study population comprised all PLHA referred to the MSF clinic in Mumbai for presumptive second-line ART failure, between January 2011 and September 2017. To assess the 12 month virological suppression, a subset of patients referred up until June 2016 was considered.

Data collection and variables

The basic socio-demographic and clinical variables (ART regimens, ART duration, CD4 count, VL at referral/baseline and follow-up) were extracted from patient files and electronic database (FUCHIA version 1.7.1.1661 software, Epicentre-MSF, Paris, France) [24]. Cases were assessed for whether their ART regimens were standard in comparison with existing WHO guidelines; as well as for adherence, opportunistic infections and comorbidities. Genotyping was interpreted based on the Stanford HIV database [25].

For programmatic outcome, a censor date of 30th September 2017 was used. The possible outcomes were: alive on second-line ART, alive on third-line ART, transferred out, lost to follow-up, and died.

Analysis and statistics

Data from the FUCHIA software was exported and analysed in EpiData Analysis software (v2.2.2.185, EpiData Association, Odense, Denmark) and SPSS (Release 20, 2011; IBM Inc., Chicago, IL, USA). All categorical variables were described using frequency tables and proportions, and associations with confirmed failure status were assessed by chi2 test; p-value, relative risk and 95% confidence interval were reported on. A p-value<0.05 was considered statistically significant.

Ethics

Ethics approval was obtained from the Ethics Advisory Group of The Union, Paris, France (EAG No: 40/17).The study met the criteria for a posteriori analysis of routinely collected clinical data and thus did not require MSF Ethics Review Board full review. It was conducted with permission of the Medical Director, Operational Centre Brussels, MSF.

Results

Patient characteristics

During the study period a total of 120 patients were referred for presumptive second-line ART failure. Their baseline characteristics are shown in Table 2: 73 (61%) patients belonged to the age group 16–45 years, 89 (74%) were male, 44 (37%) had been on ART for >10 years, and 67 (56%) had CD4 count<200 cells/mm3. For 48 (40%) cases, VL at referral was suppressed, and 62 (52%) patients were on non-standard ART regimens at the time of referral.

Tab. 2. Baseline characteristics of presumptive second line ART failure cases referred to a Médecins Sans Frontières clinic in Mumbai, India, January 2011-September 2017 (n = 120).
Baseline characteristics of presumptive second line ART failure cases referred to a Médecins Sans Frontières clinic in Mumbai, India, January 2011-September 2017 (n = 120).

Retention in care and virological suppression

In the sub-cohort of 92 patients referred till June 2016, the patient flow is described in Fig 1. Ninety patients underwent baseline VL testing. After performing the baseline VL testing, EAC, and post-counselling VL testing, 39 (43%) patients were kept on second-line ART. Among these, 6 and 12 months retention in care was 35 (90%) and 31 (79%) respectively, while virological suppression among tested was 22 of 34 (65%) and 21 of 29 (72%) respectively. Among patients switched to third-line ART at any point in time, 46 (94%) were retained both at 6 and 12 months; 38 of 46 (83%) and 38 of 41 (93%) were virologically suppressed at 6 and 12 months respectively.

Patient flow, retention in care and viral suppression at 6 and 12 months among presumptive second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-June 2016.
Fig. 1. Patient flow, retention in care and viral suppression at 6 and 12 months among presumptive second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-June 2016.
* 1 SL Cohort patient were not tested at 6 months. ** 2 SL cohort patient were not tested at 12 month. SL- Second Line, LFU- Lost to Follow Up, TO- Transfer Out, EAC- Enhanced Adherence Counselling, VL- Viral Load.

Genotyping

Among 61 patients referred with presumptive second-line ART failure who had undergone genotyping for ARV drug resistance, 10% did not show any resistance and were susceptible to all ART classes (NRTI, NNRTI and PI), while 29 (52%) showed resistance to all three ARV classes (Table 3). PI resistance was seen among 37 (62%) cases. Detailed information about mutations is provided in Table 4.

Tab. 3. Drug resistance mutation patterns among second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-September 2017.
Drug resistance mutation patterns among second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-September 2017.
Tab. 4. Major mutations on participants tested for drug resistance ART cases in the MSF clinic between January 2011 and September 2017.
Major mutations on participants tested for drug resistance ART cases in the MSF clinic between January 2011 and September 2017.

Intra-class cross-resistance was observed. Among NRTI drugs, resistance without previous exposure to same drug was observed among 31% of the cases for Abacavir, 20% for Stavudine, and 7% for both Tenofovir and Zidovudine; and among NNRTIs 26% for Efavirenz and 12% for Nevirapine. For PIs, 12% resistance without previous exposure to the same drug was observed for Lopinavir and 5% for Atazanavir (Fig 2).

Resistance patterns in presence and absence of previous exposure to specific ARV drugs among second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-September 2017.
Fig. 2. Resistance patterns in presence and absence of previous exposure to specific ARV drugs among second line ART failure cases referred to a MSF clinic in Mumbai, India, January 2011-September 2017.
TDF- Tenofovir, AZT- Zidovudine, ABC-Abacavir, D4T- Stavudine, EFV (Efavirenz), NVP -Nevirapine, LPV- Lopinavir, ATV- Atazanavir, DRV-Darunavir, RAL- Raltegravir, EVG- Elvitegravir, DTG- Dolutegravir.

Among the third-line drugs, resistance without previous exposure to the same drug was observed among 2/9 cases for Raltegravir and 4/52 cases for Darunavir. Of the 6 resistance tests for Dolutegravir, 2 (33%) showed low resistance without any history of exposure.

Discussion

This study represents a cohort of presumptive second-line ART failure in adults in Mumbai treated under routine programmatic conditions. The referred cases could be considered complex, with 4 out of 10 patients having been on ART for more than 10 years; more than half on non-standard ART regimens previously, and almost half with a poor adherence at baseline. The socio-demographic and clinical profile of the patients referred to the MSF clinic for presumptive second-line ART failure was comparable to that described in the limited number of studies on similar cohorts: male predominance (60–78%), a median age of 42 years and a duration of ART exposure of 8–10 years have been documented previously [2628].

Twelve month retention in care and viral suppression exceeded 70% among those who were maintained on second line ART and 90% in the switched group (on third line ART). Genotyping information suggested a worrying picture, with significant proportions of patients showing intra-class cross-resistance to ARVs they had not been exposed to, and with resistance observed against the integrase inhibitor class of drugs from the third-line ART regimens.

Our results support the importance of the adherence counselling in managing presumptive failure cases, as recommended by WHO [22]. Through this process, more than half of the referred cases were initially maintained on second-line ART despite the presumptive second-line failure, and more than 7 in 10 patients were still retained in care on second-line at 12 months. These indicators are comparable to existing cohort studies on second-line ART treatment [29,30], though no other studies were found to focus on a presumptive failure cohort. This is also in line with other studies documenting the retention in care after EAC in general in India and sub-Saharan Africa [26,31]. Switching to third-line ART should be based on the confirmation by consecutive high viral loads, ensuring adherence through multiple EAC sessions, and genotype results.

Third-line ART as the last line of defence against HIV was highly effective in this cohort, with over 90% retention and viral suppression at 12 months post-switching, similar to other studies [26,27]. High level of resistance against PIs, in excess of the lower levels (8–25%) documented elsewhere [3134] but similar to those documented specifically among second-line ART failure cases (58–73%) were noted [27,28]. The triple class resistance to NRTIs, NNRTIS and PIs in more than half of the cases undergoing genotyping is worrying. In particular the presence of resistance to the new class of integrase inhibitors, albeit in a small sample size, is a major concern [35]. Finally, the existence of resistant genotypes for certain drugs even among patients without exposure to those drugs (either through cross-resistance or incomplete records of previous exposure) has major implications for the national program, as the third-line ART regimens provided through the program are designed only based on the previous exposure profile of patients. In absence of genotyping data, it seems highly likely that third-line ART regimens containing ARVs to which the patient already has resistance might be selected.

Strengths of the study include the fact that the MSF clinic provides all ART services free of cost to its beneficiaries, and hence the patient profile likely reflects that found in both the public and private health systems. Additionally, while sample sizes were relatively small and precluded a full risk factor analysis, our study represents a large cohort benefiting from genotyping and/or on third-line ART in India. A relative weakness of the study was its retrospective nature, which did not allow inclusion of key variables such as the exact start date of previous ART regimens or objective measures of adherence. Additionally, previous ARV exposures were either self-reported or were based on documents provided by patients, and it cannot be excluded that these records were incomplete. However, as the public health system also bases its design of third line regimens on self-reported or self-produced evidence of previous regimens, the implications of our observations are not affected by this study weakness.

Our study carries a number of implications. First, EAC and genotying can lead to maintaining a sizeable proportion of presumptive failure cases on second-line ART. The uptake and rigorous implementation of the EAC model is strongly encouraged.

Second, the presence of substandard regimens among more than half of all patients is indicative of the heterogeneous prescription practices that patients are exposed to over their lifelong exposure to ART. Substandard regimens compromise future treatment options for failing PLHA, especially third-line ART.

Third, the study highlights a particular urgency to make genotyping available through the national program, as documented past exposure does not seem sufficiently accurate to design an appropriate third-line regimen. Further research, possibly investigating the cost-effectiveness of genotyping is needed.

In conclusion, our study illustrates the complex challenge of providing care for presumptive second-line ART failure cases: patients with extended treatment history, substandard regimens, and poor adherence. Provision of EAC and adopting the WHO guidance on treatment switch must be encouraged. The implementation of genotyping to further guide when to switch regimens is urgently required.


Zdroje

1. UNAIDS. Global HIV & AIDS statistics—2018 fact sheet | UNAIDS [Internet]. [cited 14 Dec 2018]. Available: http://www.unaids.org/en/resources/fact-sheet

2. United Nations. Sustainable Development Goals [Internet]. 2015.

3. UNAIDS. 90-90-90 An ambitious treatment target to help end the AIDS epidemic [Internet]. 2014. Available: http://www.unaids.org/Sites/Default/Files/Media_Asset/90-90-90_En_0.Pdf

4. World Health Organization. Policy Brief: Consolidated guidelines on the use of Antiretroviral Drugs for treating and preventing HIV infection: What’s New. 2015. doi: 10.1017/CBO9781107415324.004

5. Isaakidis P, Gupta S, Das M, Ferrer D, Nalinikanta R, Reid T, et al. HIV viral load messages should go viral in India. Lancet HIV. Elsevier Ltd; 2015;2: e414–e415. doi: 10.1016/S2352-3018(15)00180-0 26423648

6. Roberts T, Cohn J, Bonner K, Hargreaves S. Scale-up of Routine Viral Load Testing in Resource-Poor Settings: Current and Future Implementation Challenges. Clin Infect Dis. 2016;62: 1043–1048. doi: 10.1093/cid/ciw001 26743094

7. World Health Organization. The Availability and use of HIV diagnostics: A 2012–2013 who survey in Low and middle income countries. 2014.

8. Kumarasamy N, Krishnan S. Beyond first-line HIV treatment regimens. Curr Opin HIV AIDS. 2013;8: 586–590. doi: 10.1097/COH.0000000000000004 24100872

9. Van Vaerenbergh K. Study of the impact of HIV genotypic drug resistance testing on therapy efficacy. Verh K Acad Geneeskd Belg. 2001;63: 447–73. 11813503

10. National AIDS Control Organisation. National Strategic Plan for HIV/AIDS and STI,2017. New Delhi; 2017.

11. Department of Health & Family Welfare. NACO Annual Report 2016–17. New Delhi; 2017.

12. UNAIDS. South Africa | UNAIDS [Internet].

13. Ramchandani SR, Mehta SH, Saple DG, Vaidya SB, Pandey VP, Vadrevu R, et al. Knowledge, Attitudes, And Practices of Antiretroviral Therapy among HIV-Infected Adults Attending Private And Public Clinics in India. AIDS Patient Care STDS. 2007;21: 129–142. doi: 10.1089/apc.2006.0045 17328662

14. MINISTRY OF HEALTH AND FAMILY WELFARE. Report of the National Commission on Macroeconomics and Health. 2005.

15. World Health Organisation. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach [Internet]. 2013. 978 92 4 150572 7

16. Ministry of Health and Family Welfare. Guidelines for provision of third line ART inder National AIDS Control Programme. New Delhi; 2016. p. 2.

17. Mumbai District AIDS Control Society. Care & Support and Treatment (CST) [Internet].

18. Maharashtra State AIDS Control Society. ART [Internet].

19. National AIDS Control Organisation. Training modules for Medical Officers on HIV care and Treatment. New Delhi; 2007.

20. World Health Organization. HIV TREATMENT AND CARE. 2015.

21. World Health Organization. Antiretroviral therapy for HIV Infection in adults and adolescents. World Health Organization. Geneva; 2010.

22. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Heal Organ. 2016; 155 p.

23. World Health Organization. Consolidated Guidelines on HIV prevention, diagnosis, treatment and care for key populations-2016 update. 2016.

24. O’Brien DP, Venis S, Greig J, Shanks L, Ellman T, Sabapathy K, et al. Provision of antiretroviral treatment in conflict settings: the experience of Médecins Sans Frontières. Confl Health. 2010;4: 12. doi: 10.1186/1752-1505-4-12 20553624

25. STANFORD HIV DRUG RESISTANCE DATABASE Major HIV-1 Drug Resistance Mutations Major Non-Nucleoside RT Inhibitor (NNRTI) Resistance Mutations. 2017.

26. Khan S, Das M, Andries A, Deshpande A, Mansoor H, Saranchuk P, et al. Second-line failure and first experience with third-line antiretroviral therapy in Mumbai, India. Glob Heal …. 2014;1: 1–10. doi: 10.1136/amiajnl-2014-002841

27. Pujari SN, Makane A, Lodha A, Bele V, Joshi K. Short-term effectiveness and safety of third-line antiretroviral regimens among patients in Western India. J Acquir Immune Defic Syndr. 2014;65: e82–4. doi: 10.1097/QAI.0b013e3182a6104a 24442229

28. Saravanan S, Vidya M, Balakrishnan P, Kantor R, Solomon SS, Katzenstein D, et al. Viremia and HIV-1 drug resistance mutations among patients receiving second-line highly active antiretroviral therapy in Chennai, Southern India. Clin Infect Dis. 2012;54: 995–1000. doi: 10.1093/cid/cir967 22323567

29. Schoffelen AF, Wensing AMJ, Tempelman HA, Geelen SPM, Hoepelman AIM, Barth RE. Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa. doi: 10.1371/journal.pone.0058526

30. Wilhelmson S, Reepalu A, Tolera Balcha T, Jarso G, Björkman P. Retention in care among HIV-positive patients initiating second-line antiretroviral therapy: a retrospective study from an Ethiopian public hospital clinic. Glob Health Action. Taylor & Francis; 2016;9: 29943. doi: 10.3402/gha.v9.29943 26765104

31. Fox MP, Berhanu R, Steegen K, Firnhaber C, Ive P, Spencer D, et al. Intensive adherence counselling for HIV-infected individuals failing second-line antiretroviral therapy in Johannesburg, South Africa. Trop Med Int Heal. 2016;21: 1131–1137. doi: 10.1111/tmi.12741 27383454

32. Svärd J, Mugusi S, Mloka D, Neogi U, Meini G, Mugusi F, et al. Drug resistance testing through remote genotyping and predicted treatment options in human immunodeficiency virus type 1 infected Tanzanian subjects failing first or second line antiretroviral therapy. PLoS One. Public Library of Science; 2017;12: e0178942. doi: 10.1371/journal.pone.0178942 28582463

33. Gupta A, Saple DG, Nadkarni G, Shah B, Vaidya S, Hingankar N, et al. One-, Two-, and Three-Class Resistance among HIV-Infected Patients on Antiretroviral Therapy in Private Care Clinics: Mumbai, India. AIDS Res Hum Retroviruses. 2010; doi: 10.1089/aid.2009.0102 20063995

34. Sinha S, Shekhar RC, Ahmad H, Kumar N, Samantaray JC, Sreenivas V, et al. Prevalence of HIV drug resistance mutation in the northern Indian population after failure of the first line antiretroviral therapy. Curr HIV Res. 2012;10: 532–8. doi: 10.2174/157016212802429785 22716105

35. Blanco J-L, Varghese V, Rhee S-Y, Gatell JM, Shafer RW. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis. Oxford University Press; 2011;203: 1204–14. doi: 10.1093/infdis/jir025 21459813


Článek vyšel v časopise

PLOS One


2019 Číslo 11
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#