Ignite Creation Date:
2024-05-06 @ 2:54 PM
Last Modification Date:
2024-10-26 @ 1:39 PM
Study NCT ID:
NCT04453436
Status:
UNKNOWN
Last Update Posted:
2020-07-24
First Post:
2020-06-27
Brief Title:
HIV Drug Resistance Among Individuals Failing TenofovirLamivudine and Dolutegravir First Line Regimen in Brazil
Sponsor:
Federal University of São Paulo
Organization:
Federal University of São Paulo
Study Overview
Official Title:
HIV Drug Resistance Profiles Among Individuals Failing TenofovirLamivudine and Dolutegravir First Line Regimen in Brazil
Status:
UNKNOWN
Status Verified Date:
2020-07
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Brazil was the first middle-income country to provide free and universal access to antiretroviral drugs to HIV infected individuals Since 2014 local guidelines recommend that all HIV infected individuals be started on therapy regardless of CD4 count Since January 2017 all patients are started on a DTG containing triple regimen As of November 2018 170000 individuals were receiving DTG through the public health system It is a public health priority to evaluate the risk of virologic failure and the subsequent development of INSTI resistance in these real-life settings Our preliminary data from Brazil indicated a high virologic failure rate of 8 after 18 months of treatment TLD Our central hypothesis is that TDR may be associated and contribute to virologic failure with DTG in clinical practice To test this central hypothesis we will identify PLWH failing DTG containing regimens in Brazil The insights generated with these studies will contribute to a more effective use of second generation INSTI in the future
Detailed Description:
SPECIFIC AIMS We are on the verge of the global rollout of the second-generation integrase strand-transfer inhibitor INSTI dolutegravir DTG as the World Health Organization WHO now recommends the combination of DTG 2 nucleoside reverse transcriptase inhibitors NRTIs as first- and second-line therapy As a result millions of people living with HIV PLWH will soon receive DTG In clinical trials which mainly included people infected with HIV-1 subtype B the combination of DTG 2 NRTIs demonstrated very high efficacy and acquired drug resistance was absent first-line treatment or very rare second-line treatment in the event of virologic failure It is not clear if this high efficacy and lack of acquired drug resistance can be extrapolated to clinical practice in low- and middle-income countries where the majority of PLWH live and where most infections are due to non-B subtypes Furthermore in the pivotal studies for initial treatment with DTG candidates harboring virus resistant to NRTIs met the exclusion criteria of these studies Although DTG failure in first line regimens in clinical trials reveal the absence of integrase resistance it is conceivable that mutations at other HIV genomic regions such as 5PPT nef could contribute to DTG lack of efficacy
Brazil was the first middle-income country to provide free and universal access to antiretroviral drugs to HIV infected individuals Since 2014 local guidelines recommend that all HIV infected individuals be started on therapy regardless of CD4 count Since January 2017 all patients are started on a DTG containing triple regimen As of November 2018 170000 individuals were receiving DTG through the public health system It is a public health priority to evaluate the risk of virologic failure and the subsequent development of INSTI resistance in these real-life settings Our preliminary data from Brazil indicated a high virologic failure rate of 8 after 18 months of treatment TLD Moreover acquired drug resistance was observed in first-line virologic failures 15 out of 84 investigated individuals A relatively high rate of transmitted drug resistance TDR was also observed among those 84 individuals 156 Our central hypothesis is that TDR may be associated and contribute to virologic failure with DTG in clinical practice To test this central hypothesis we will identify PLWH failing DTG containing regimens in Brazil a model country for large-scale DTG implementation where various HIV subtypes co-circulate The insights generated with these studies will contribute to a more effective use of second generation INSTI in the future
The specific aims of this proposal are as follows
1 Investigate the influence of Transmitted Drug resistance HIV clade profile and immunological and virological features among individuals failing first line regimen with Tenofovir3TC Dolutegravir after 24 weeks of treatment in Brazil
2 Determine the genotypic resistance profile among individuals failing first line regimen with Tenofovir3TC DTG after 24 weeks of treatment in Brazil
3 Determine which changes in the 3-PPT are observed in viruses from patients experiencing TLD failure and assess if this novel resistance pathway contributes to acquired drug resistance in clinical practice
The results from the proposed study can be used to optimize care of PLWH by improving treatment guidelines and drug resistance interpretation algorithms
RESEARCH PLAN SIGNIFICANCE The World Health Organization WHO recently changed the HIV treatment guidelines and now recommends the second-generation integrase strand-transfer inhibitor INSTI dolutegravir DTG 2 nucleoside reverse transcriptase inhibitors NRTIs as first- and second-line therapy for people living with HIV PLWH As a result millions of people living with HIV PLWH will soon receive DTG in low- and middle-income countries where the majority of PLWH live Considerations of the WHO for the transition from efavirenz-based regimens to DTG-based regimens are the high efficacy of DTG-based regimens the relatively low costs of producing generic DTG formulations and the low risk for baseline DTG resistance and acquired DTG resistance In clinical trials DTG 2 nucleoside reverse transcriptase inhibitors NRTIs demonstrated high efficacy in treatment naïve patients with viral suppression 50 cmL at week 48 in 90 FLAMINGO 88 SPRING-2 88 SINGLE and 82 ARIA of the participants with only 1-2 of data not in the window of 50 cmL Of major importance these trials showed that in the event of virologic failure no known resistance associated mutations RAMs could be detected in the integrase and reverse transcriptase gene Similarly DTG 2 NRTIs showed high efficacy in treatment experienced INSTI naïve PLWH and acquired drug resistance was rare5 However clinical trial participants are selected and closely monitored including extra doctors visits more frequent viral load measurements and genotypic resistance analyses and are switched more rapidly to other combination antiretroviral therapy cART in the event of virologic failure It is not clear if this high efficacy and lack of acquired drug resistance will carry on in clinical practice in low- and middle-income countries Therefore it is now a public health priority to evaluate the risk of virologic failure and subsequent development of INSTI resistance in real life settings in these countries We propose to perform such studies in Brazil a country with 860000 PLWH as this country already implemented DTG regimens and thus can serve as a model for other low- and middle-income countries
Preliminary data on efficacy and acquired drug resistance of DTG 2 NRTIs in Brazil
From January 2017 the recommended first-line regimen in Brazil is the fixed dose combination of generic tenofovir 300 mg plus lamivudine 300 mg combined with DTG 50 mg TLD In 2017 54175 PLWH started TLD as first-line regimen in Brazil and 26417 PLWH were switched from raltegravir-containing cART to TLD comprising 77 of individuals initiating cART in this country As shown in Figure 1 8 of individuals receiving TLD had a viral load 50 cmL after 18 months of treatment which is higher than expected based on clinical trial results In general from the 581064 individuals on treatment in Brazil as of December 2017 85 presented with viral loads 50 cmL Source MSSVSDepartamento de IST Aids e Hepatites Virais Brasil As of November 2018 170000 PLWH receive DTG in Brazil
Among 84 individuals who experienced virologic failure during first-line treatment with TLD 11 presented low level viremia 50-500 cmL In five patients 59 major resistance associated mutations were detected at IN 2 patients with R263Q one with G118R one with E138A and one with R263RK in IN plus K70EM184V in RT Six 71 additional individuals presented minor IN resistance mutations L74IM 2 cases G140RG163R V151A V151I T97A E157Q and M50I The prevalence of the polymorphic IN mutations L101I and T124A which are in vitro pathway for resistance were 535 and 464 respectively significantly higher than in Brazilian INSTI naïve patients Eight 95 patients presented TL RAM in the RT including 3 with K70EM184V Mutations not related to TLD eg TAMs NNRTI and PI were present in 256 of the patients significantly higher than in a representative national sample of 1568 antiretroviral naïve patients we have tested All these results are depicted in Table 1 Therefore the detection of IN and RT RAMs upon virologic failure indicates that selected resistance to first-line TLD is more common than what has been reported in clinical trials The apparent association between TLD failure in Brazil and TDR should be better evaluated as well as the role of IN polymorphic mutations that can emerge during DTG failure Together these results warrant further investigations of virologic failure and subsequent acquired INSTI resistance in this setting
Among 84 individuals who experienced virologic failure during first-line treatment with TLD 11 presented low level viremia 50-500 cmL In five patients 59 major resistance associated mutations were detected at IN 2 patients with R263Q one with G118R one with E138A and one with R263RK in IN plus K70EM184V in RT Six 71 additional individuals presented minor IN resistance mutations L74IM 2 cases G140RG163R V151A V151I T97A E157Q and M50I The prevalence of the polymorphic IN mutations L101I and T124A which are in vitro pathway for resistance were 535 and 464 respectively significantly higher than in Brazilian INSTI naïve patients Eight 95 patients presented TL RAM in the RT including 3 with K70EM184V Mutations not related to TLD eg TAMs NNRTI and PI were present in 256 of the patients significantly higher than in a representative national sample of 1568 antiretroviral naïve patients we have tested All these results are depicted in Table 1 Therefore the detection of IN and RT RAMs upon virologic failure indicates that selected resistance to first-line TLD is more common than what has been reported in clinical trials The apparent association between TLD failure in Brazil and TDR should be better evaluated as well as the role of IN polymorphic mutations that can emerge during DTG failure Together these results warrant further investigations of virologic failure and subsequent acquired INSTI resistance in this setting
APPROACH
Study design This is a prospective nested case control study comparing the baseline HIV profile of individuals experiencing virologic failure to TLD regimen after 24 weeks of treatment initiation cases to randomly selected 21 control individuals with viral load bellow detection limits 24 weeks after treatment initiation
Identification of PLWH who fail DTG in Brazil PLWH will be included at 5 large clinical sites in Brazil one collection site will be in the far South of Brazil where 85 of strains are subtype C the northeast of Brazil where 30 of samples are subtype F the city of Santos South-east of Brazil where 50 of strains are BF recombinant forms CRF_28 CRF_29 and unique recombinant forms Sao Paulo and Rio de Janeiro At each site a research nurse will identify PLWH that will initiate a TL D regimen and baseline samples will be collected and send to the Central Laboratory R Diaz PI after an informal consent At this time epidemiological virological and immunological data will be collected from each patient and stored in a Central database We expect to recruit 2500 patients initiating antiretroviral therapy in a 24-week period Those recruited patients will be oriented to perform a plasma viral load after 12 and 24 weeks of recruitment We expect that by week 24 8 of recruited individuals will reach the primary end point of the study which is the antiretroviral virologic failure and Blood samples from these individuals will be also sent to the Diaz laboratory for genotypic resistance testing
Cases and controls will be defined as
Cases HIV infected individuals with subtype C subtype F or BF recombinant forms who use TLD for at least 24 weeks and have a confirmed plasma viral load 200 copiesmL We expect to include samples from 200 individuals experiencing virologic failure as defined above
Controls HIV infected individuals with subtype C subtype F or BF recombinant forms who use TLD for at least 24 weeks and have a confirmed plasma viral load 50 copiesmL We will randomly select 400 samples from control individuals in order to characterize by genomic sequencing the HIV strains present at baseline before treatment initiation
Based on the total number of PLWH receiving DTG containing cART at these three sites our preliminary results showing a virologic failure rate of 8 and assuming that 10 will be lost to follow-up we will recruit 2500 PLWH in order to obtain 200 individuals experiencing virologic failure Based on our preliminary results it is safe to conservatively assume that 10 of these patients will harbor TDR at baseline
Coordination of inclusion of PLWH at the clinical sites
In Brazil all HIV infected individuals are entitled to free access to antiretroviral therapy As of November 2018 170000 individuals were receiving DTG through the public health system Participants for the present study will be recruited in 5 large clinical units all highly experienced in the conduct of multicenter studies In each site a specially dedicated research nurse will be hired Heshe will be responsible for identifying recruiting consenting and ensuring follow-up of study participants
Database management
A private repository will be set up on GitHub httpsgithubcom that will give access to remote researchers physicians and nurses and to Central coordination for data management and analysis at Diazs Retrovirology Laboratory We will prepare a short form in Excel format for the remote researchers to use to enter the data and serve as an electronic Case Report Form For every patient remote researchers will enter the needed data and all the entries will be combined into a database and bring the individuals files down onto our computers at the Retrovirology Lab to be stored offline The analyses will be performed by Dr James R Hunter from the Retrovirology Lab
Anticipated results and alternative approaches
We do not anticipate difficulties in recruiting the expected number of cases and controls Nonetheless expanding to other sites should not represent any major challenge This is because the laboratories in each of the five sites are responsible for performing viral loads for several primary care facilities in their respective cities Thus the same procedures could be expanded to recruit participants from primary care facilities located in the proximity of the main hospitals
Brazil was the first middle-income country to provide free and universal access to antiretroviral drugs to HIV infected individuals Since 2014 local guidelines recommend that all HIV infected individuals be started on therapy regardless of CD4 count Since January 2017 all patients are started on a DTG containing triple regimen As of November 2018 170000 individuals were receiving DTG through the public health system It is a public health priority to evaluate the risk of virologic failure and the subsequent development of INSTI resistance in these real-life settings Our preliminary data from Brazil indicated a high virologic failure rate of 8 after 18 months of treatment TLD Moreover acquired drug resistance was observed in first-line virologic failures 15 out of 84 investigated individuals A relatively high rate of transmitted drug resistance TDR was also observed among those 84 individuals 156 Our central hypothesis is that TDR may be associated and contribute to virologic failure with DTG in clinical practice To test this central hypothesis we will identify PLWH failing DTG containing regimens in Brazil a model country for large-scale DTG implementation where various HIV subtypes co-circulate The insights generated with these studies will contribute to a more effective use of second generation INSTI in the future
The specific aims of this proposal are as follows
1 Investigate the influence of Transmitted Drug resistance HIV clade profile and immunological and virological features among individuals failing first line regimen with Tenofovir3TC Dolutegravir after 24 weeks of treatment in Brazil
2 Determine the genotypic resistance profile among individuals failing first line regimen with Tenofovir3TC DTG after 24 weeks of treatment in Brazil
3 Determine which changes in the 3-PPT are observed in viruses from patients experiencing TLD failure and assess if this novel resistance pathway contributes to acquired drug resistance in clinical practice
The results from the proposed study can be used to optimize care of PLWH by improving treatment guidelines and drug resistance interpretation algorithms
RESEARCH PLAN SIGNIFICANCE The World Health Organization WHO recently changed the HIV treatment guidelines and now recommends the second-generation integrase strand-transfer inhibitor INSTI dolutegravir DTG 2 nucleoside reverse transcriptase inhibitors NRTIs as first- and second-line therapy for people living with HIV PLWH As a result millions of people living with HIV PLWH will soon receive DTG in low- and middle-income countries where the majority of PLWH live Considerations of the WHO for the transition from efavirenz-based regimens to DTG-based regimens are the high efficacy of DTG-based regimens the relatively low costs of producing generic DTG formulations and the low risk for baseline DTG resistance and acquired DTG resistance In clinical trials DTG 2 nucleoside reverse transcriptase inhibitors NRTIs demonstrated high efficacy in treatment naïve patients with viral suppression 50 cmL at week 48 in 90 FLAMINGO 88 SPRING-2 88 SINGLE and 82 ARIA of the participants with only 1-2 of data not in the window of 50 cmL Of major importance these trials showed that in the event of virologic failure no known resistance associated mutations RAMs could be detected in the integrase and reverse transcriptase gene Similarly DTG 2 NRTIs showed high efficacy in treatment experienced INSTI naïve PLWH and acquired drug resistance was rare5 However clinical trial participants are selected and closely monitored including extra doctors visits more frequent viral load measurements and genotypic resistance analyses and are switched more rapidly to other combination antiretroviral therapy cART in the event of virologic failure It is not clear if this high efficacy and lack of acquired drug resistance will carry on in clinical practice in low- and middle-income countries Therefore it is now a public health priority to evaluate the risk of virologic failure and subsequent development of INSTI resistance in real life settings in these countries We propose to perform such studies in Brazil a country with 860000 PLWH as this country already implemented DTG regimens and thus can serve as a model for other low- and middle-income countries
Preliminary data on efficacy and acquired drug resistance of DTG 2 NRTIs in Brazil
From January 2017 the recommended first-line regimen in Brazil is the fixed dose combination of generic tenofovir 300 mg plus lamivudine 300 mg combined with DTG 50 mg TLD In 2017 54175 PLWH started TLD as first-line regimen in Brazil and 26417 PLWH were switched from raltegravir-containing cART to TLD comprising 77 of individuals initiating cART in this country As shown in Figure 1 8 of individuals receiving TLD had a viral load 50 cmL after 18 months of treatment which is higher than expected based on clinical trial results In general from the 581064 individuals on treatment in Brazil as of December 2017 85 presented with viral loads 50 cmL Source MSSVSDepartamento de IST Aids e Hepatites Virais Brasil As of November 2018 170000 PLWH receive DTG in Brazil
Among 84 individuals who experienced virologic failure during first-line treatment with TLD 11 presented low level viremia 50-500 cmL In five patients 59 major resistance associated mutations were detected at IN 2 patients with R263Q one with G118R one with E138A and one with R263RK in IN plus K70EM184V in RT Six 71 additional individuals presented minor IN resistance mutations L74IM 2 cases G140RG163R V151A V151I T97A E157Q and M50I The prevalence of the polymorphic IN mutations L101I and T124A which are in vitro pathway for resistance were 535 and 464 respectively significantly higher than in Brazilian INSTI naïve patients Eight 95 patients presented TL RAM in the RT including 3 with K70EM184V Mutations not related to TLD eg TAMs NNRTI and PI were present in 256 of the patients significantly higher than in a representative national sample of 1568 antiretroviral naïve patients we have tested All these results are depicted in Table 1 Therefore the detection of IN and RT RAMs upon virologic failure indicates that selected resistance to first-line TLD is more common than what has been reported in clinical trials The apparent association between TLD failure in Brazil and TDR should be better evaluated as well as the role of IN polymorphic mutations that can emerge during DTG failure Together these results warrant further investigations of virologic failure and subsequent acquired INSTI resistance in this setting
Among 84 individuals who experienced virologic failure during first-line treatment with TLD 11 presented low level viremia 50-500 cmL In five patients 59 major resistance associated mutations were detected at IN 2 patients with R263Q one with G118R one with E138A and one with R263RK in IN plus K70EM184V in RT Six 71 additional individuals presented minor IN resistance mutations L74IM 2 cases G140RG163R V151A V151I T97A E157Q and M50I The prevalence of the polymorphic IN mutations L101I and T124A which are in vitro pathway for resistance were 535 and 464 respectively significantly higher than in Brazilian INSTI naïve patients Eight 95 patients presented TL RAM in the RT including 3 with K70EM184V Mutations not related to TLD eg TAMs NNRTI and PI were present in 256 of the patients significantly higher than in a representative national sample of 1568 antiretroviral naïve patients we have tested All these results are depicted in Table 1 Therefore the detection of IN and RT RAMs upon virologic failure indicates that selected resistance to first-line TLD is more common than what has been reported in clinical trials The apparent association between TLD failure in Brazil and TDR should be better evaluated as well as the role of IN polymorphic mutations that can emerge during DTG failure Together these results warrant further investigations of virologic failure and subsequent acquired INSTI resistance in this setting
APPROACH
Study design This is a prospective nested case control study comparing the baseline HIV profile of individuals experiencing virologic failure to TLD regimen after 24 weeks of treatment initiation cases to randomly selected 21 control individuals with viral load bellow detection limits 24 weeks after treatment initiation
Identification of PLWH who fail DTG in Brazil PLWH will be included at 5 large clinical sites in Brazil one collection site will be in the far South of Brazil where 85 of strains are subtype C the northeast of Brazil where 30 of samples are subtype F the city of Santos South-east of Brazil where 50 of strains are BF recombinant forms CRF_28 CRF_29 and unique recombinant forms Sao Paulo and Rio de Janeiro At each site a research nurse will identify PLWH that will initiate a TL D regimen and baseline samples will be collected and send to the Central Laboratory R Diaz PI after an informal consent At this time epidemiological virological and immunological data will be collected from each patient and stored in a Central database We expect to recruit 2500 patients initiating antiretroviral therapy in a 24-week period Those recruited patients will be oriented to perform a plasma viral load after 12 and 24 weeks of recruitment We expect that by week 24 8 of recruited individuals will reach the primary end point of the study which is the antiretroviral virologic failure and Blood samples from these individuals will be also sent to the Diaz laboratory for genotypic resistance testing
Cases and controls will be defined as
Cases HIV infected individuals with subtype C subtype F or BF recombinant forms who use TLD for at least 24 weeks and have a confirmed plasma viral load 200 copiesmL We expect to include samples from 200 individuals experiencing virologic failure as defined above
Controls HIV infected individuals with subtype C subtype F or BF recombinant forms who use TLD for at least 24 weeks and have a confirmed plasma viral load 50 copiesmL We will randomly select 400 samples from control individuals in order to characterize by genomic sequencing the HIV strains present at baseline before treatment initiation
Based on the total number of PLWH receiving DTG containing cART at these three sites our preliminary results showing a virologic failure rate of 8 and assuming that 10 will be lost to follow-up we will recruit 2500 PLWH in order to obtain 200 individuals experiencing virologic failure Based on our preliminary results it is safe to conservatively assume that 10 of these patients will harbor TDR at baseline
Coordination of inclusion of PLWH at the clinical sites
In Brazil all HIV infected individuals are entitled to free access to antiretroviral therapy As of November 2018 170000 individuals were receiving DTG through the public health system Participants for the present study will be recruited in 5 large clinical units all highly experienced in the conduct of multicenter studies In each site a specially dedicated research nurse will be hired Heshe will be responsible for identifying recruiting consenting and ensuring follow-up of study participants
Database management
A private repository will be set up on GitHub httpsgithubcom that will give access to remote researchers physicians and nurses and to Central coordination for data management and analysis at Diazs Retrovirology Laboratory We will prepare a short form in Excel format for the remote researchers to use to enter the data and serve as an electronic Case Report Form For every patient remote researchers will enter the needed data and all the entries will be combined into a database and bring the individuals files down onto our computers at the Retrovirology Lab to be stored offline The analyses will be performed by Dr James R Hunter from the Retrovirology Lab
Anticipated results and alternative approaches
We do not anticipate difficulties in recruiting the expected number of cases and controls Nonetheless expanding to other sites should not represent any major challenge This is because the laboratories in each of the five sites are responsible for performing viral loads for several primary care facilities in their respective cities Thus the same procedures could be expanded to recruit participants from primary care facilities located in the proximity of the main hospitals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None