Evaluation de l'implantation d'un programme de 3ème ligne pour des sujets infectés par le VIH au Cambodge

par Phearavin Pheng

Projet de thèse en Santé publique - épidémiologie

Sous la direction de Laurence Meyer.

Thèses en préparation à université Paris-Saclay , dans le cadre de École doctorale Santé Publique , en partenariat avec Service de Santé Publique du GH Hôpitaux Universitaires de Paris Sud (laboratoire) et de Faculté de médecine (référent) depuis le 22-10-2019 .


  • Résumé

    My research project aims to conduct a programmatic evaluation of a third line regimen implementation containing darunavir/r, dolutegravir and optimized NRTI in Cambodia based on the ANRS 12374 3DICAM study, that has been accepted for funding by the National Agency for HIV/AIDS Research (ANRS) in France. The 3DICAM study is a phase II non-comparative multicenter pilot prospective study; the first inclusions started in October 2018. The duration of inclusion was initially planned to be 12 months and patients will be followed during 12 months after treatment initiation. Patients > 15 years old at inclusion, who had failed a non nucleosidic reverse transcriptase inhibitor (NNRTI)-based first-line regimen and a PI- based second- line regimen after 3 months of adherence boosting and infected with a viral strain intermediate or fully resistant to ATV/r AND/OR resistant to both retrovir (AZT), abacavir (ABC) and tenofovir (TDF) will be enrolled. Three objectives are identified for this PhD thesis: Objective 1: To assess the one year clinical and virological outcomes of a third-line regimen combining DRV/r, DTG and optimized NRTI, in Cambodian HIV-infected adults, who failed a PI-based second-line regimen after 3 months of BAC (boosted adherence counseling), with evidence of intermediate or fully resistance to atazanavir (ATV) and/or resistance to all NRTI. The specific objectives are to 1/ assess the virological effectiveness at 6 and 12 months after treatment switch; 2/ assess the clinical and immunological effectiveness (morbidity events, frequency of IRIS, immune restoration); 3/ assess safety and adherence of this regimen; 4/ assess the effectiveness of switching DRV/r from 600/100 twice daily to 800/100 once daily for patients with plasma HIV1 RNA < 40 copies/mL at 6 months. a) Statistical methods  Calculation of number of patients needed The calculation of sample size was as follows in the protocol approved by ANRS and the Cambodian Ethics Committee: “With a sample size of 45 patients, we could conclude that the success rate is at least 60% if the total number of failures does not exceed 12 (alpha=0.05, power=0.90). Among the 3500 Cambodian patients on PI-based second line regimen, and according to the results of the ANRS 2PIKAM study, we expect than 5% of patients (n=175) failed their current ART regimen and one third of them (n=60) will need third-line regimen as proposed in the 3DICAM study. With a 10% refusal rate, we anticipate to enroll 54 patients.  Analysis plan - Description of the subjects characteristics at inclusion (including sociodemographic characteristics, medical history, CD4 cell count and plasma viral load). These variables will be described by their median and interquartile range, mean and standard deviation, or frequencies (%), as appropriate. - Primary outcome The percentage, and its 95% confidence interval, of patients with plasma HIV-1 RNA < 40 copies/mL at 6 months will be given, in a FDA snapshot analysis (patients who had stopped treatment and patients lost to follow-up will be considered in virological failure). An analysis stratified on the level of plasma HIV-RNA at inclusion (thresholds of 4 and 5 Log copies/mL) will also be performed. Comparisons of the percentage of subjects with plasma HIV-1 RNA <40 copies/mL at 6 months, by the characteristics at inclusion, will be done by a Chi2 test or Fisher exact test, as appropriate. - Secondary outcomes Virological outcome: The percentage, and its 95% confidence interval, of patients with plasma HIV-1 RNA < 40 copies/mL at 12 months will be given, in a FDA snapshot analysis (patients who had stopped treatment and patients lost to follow-up will be considered in virological failure). The immune restoration: The level of CD4 cell count reached at 6 months and 12 months will be described by median and interquartile range, and mean and standard deviation. The percentages of subjects with a CD4 level > 350 cells/mm3 or > 500 cells/mm3 will also be given at each of these times. The results will be given overall, and by group (according to whether subjects switched or not at M6 from DRV/r 600/100 twice daily to DRV/r 800/100 once daily). The increase in CD4 cell count will also be analyzed by the difference of the value at M6 with that at inclusion, and then by the difference between M12 and M6 (median, interquartile interval, mean and standard deviation). The analysis will be performed on the available data (without any imputation of missing data). A sensitivity analysis will be also carried out, with data censored at treatment discontinuation. Patients with IRIS: The percentage and its 95% confidence interval of subjects with IRIS will be given. Treatment discontinuation during the first year: The probability of discontinuation of treatment and its 95% confidence interval, as well as the median time to the occurrence of treatment discontinuation, will be determined using a Kaplan Meier analysis, to take into account censored data due to loss of follow-up. The analysis will be performed overall, and by group, the time of follow-up since inclusion will be taken into account in the analysis. An analysis will also be performed among those who switched at 6 months, with time of follow-up since M6 that will be considered in the analysis. Occurrence of grade 3-4 adverse events (ANRS grading table): The percentage and its 95% confidence interval of subjects who had presented at least once a grade 3-4 adverse event will be given. The incidence rate of grade 3-4 adverse event and its 95% confidence interval will also be determined, overall, and by group. The type of side effects will be detailed, overall, and by group. Adherence of third-line regimen combination: The percentage and its 95% confidence interval of subjects with adherence > 90% during one year will be given. Frequency of switch from DRV/r 600/100 twice daily to DRV/r 800/100 once daily at 6 months: The percentage and its 95% confidence interval of subjects who switched at 6 months will be given. Effectiveness of switching DRV/r from 600/100 twice daily to 800/100 once daily: The percentage and its 95% confidence interval, of subjects with plasma HIV-RNA < 40 copies/mL at 12 months, among those switched from 600/100 twice daily to 800/100 once daily, will be given. Objective 2: To study pharmacokinetic (PK) parameters of DRV/r and DTG As no data exist to date on PK parameters on recent ART drugs in Asian patients, we plan to: • Estimate plasma exposure and pharmacokinetic parameters (Cmax, Cmin and AUC) of DRV/r 600/100 twice daily, DRV/r 800/100 once daily and DTG 50 mg once daily in the 20 first included patients; • Conduct an intra-patient comparison of the 2 dosing regimens of DRV/r. • Plasma darunavir concentration: The plasma darunavir concentration will be described (median, interquartile interval, mean, standard deviation) at week 4 in all subjects, at week 30 in the subjects having switched at M6 DRV/r from 600/100 twice daily to 800/100 once daily, and in case of occurrence of coinfection tuberculosis during follow-up, at 2 weeks after Rifampicin initiation. Study Flowchart Objective 3: To conduct a cost-analysis of third-line regimen implementation in Cambodia We also planned: • To conduct a cost analysis of the global strategy for a third-line program in Cambodia (with and without DRV dose reduction after 6 months of treatment); • To generate a base of evidence to inform policy around the implementation of national HIV/AIDS third line program; • To assess separately the indirect costs of its implementation for patients and providers. It is a great challenge for Cambodia to assess the effectiveness of a third-line regimen, as DRV/r and DTG are now available as WHO pre-qualified generic drug at low affordable prices. If this combination is proven to be effective, NCHADS will be able to complete the guidelines and to provide scientific information for the neighboring countries.

  • Titre traduit

    Programmatic assessment of a third line regimen implementation including darunavir/ritonavir, dolutegravir and optimized NRTI for HIV-infected subjects in Cambodia


  • Résumé

    My research project aims to conduct a programmatic evaluation of a third line regimen implementation containing darunavir/r, dolutegravir and optimized NRTI in Cambodia based on the ANRS 12374 3DICAM study, that has been accepted for funding by the National Agency for HIV/AIDS Research (ANRS) in France. The 3DICAM study is a phase II non-comparative multicenter pilot prospective study; the first inclusions started in October 2018. The duration of inclusion was initially planned to be 12 months and patients will be followed during 12 months after treatment initiation. Patients > 15 years old at inclusion, who had failed a non nucleosidic reverse transcriptase inhibitor (NNRTI)-based first-line regimen and a PI- based second- line regimen after 3 months of adherence boosting and infected with a viral strain intermediate or fully resistant to ATV/r AND/OR resistant to both retrovir (AZT), abacavir (ABC) and tenofovir (TDF) will be enrolled. Three objectives are identified for this PhD thesis: Objective 1: To assess the one year clinical and virological outcomes of a third-line regimen combining DRV/r, DTG and optimized NRTI, in Cambodian HIV-infected adults, who failed a PI-based second-line regimen after 3 months of BAC (boosted adherence counseling), with evidence of intermediate or fully resistance to atazanavir (ATV) and/or resistance to all NRTI. The specific objectives are to 1/ assess the virological effectiveness at 6 and 12 months after treatment switch; 2/ assess the clinical and immunological effectiveness (morbidity events, frequency of IRIS, immune restoration); 3/ assess safety and adherence of this regimen; 4/ assess the effectiveness of switching DRV/r from 600/100 twice daily to 800/100 once daily for patients with plasma HIV1 RNA < 40 copies/mL at 6 months. a) Statistical methods  Calculation of number of patients needed The calculation of sample size was as follows in the protocol approved by ANRS and the Cambodian Ethics Committee: “With a sample size of 45 patients, we could conclude that the success rate is at least 60% if the total number of failures does not exceed 12 (alpha=0.05, power=0.90). Among the 3500 Cambodian patients on PI-based second line regimen, and according to the results of the ANRS 2PIKAM study, we expect than 5% of patients (n=175) failed their current ART regimen and one third of them (n=60) will need third-line regimen as proposed in the 3DICAM study. With a 10% refusal rate, we anticipate to enroll 54 patients.  Analysis plan - Description of the subjects characteristics at inclusion (including sociodemographic characteristics, medical history, CD4 cell count and plasma viral load). These variables will be described by their median and interquartile range, mean and standard deviation, or frequencies (%), as appropriate. - Primary outcome The percentage, and its 95% confidence interval, of patients with plasma HIV-1 RNA < 40 copies/mL at 6 months will be given, in a FDA snapshot analysis (patients who had stopped treatment and patients lost to follow-up will be considered in virological failure). An analysis stratified on the level of plasma HIV-RNA at inclusion (thresholds of 4 and 5 Log copies/mL) will also be performed. Comparisons of the percentage of subjects with plasma HIV-1 RNA <40 copies/mL at 6 months, by the characteristics at inclusion, will be done by a Chi2 test or Fisher exact test, as appropriate. - Secondary outcomes Virological outcome: The percentage, and its 95% confidence interval, of patients with plasma HIV-1 RNA < 40 copies/mL at 12 months will be given, in a FDA snapshot analysis (patients who had stopped treatment and patients lost to follow-up will be considered in virological failure). The immune restoration: The level of CD4 cell count reached at 6 months and 12 months will be described by median and interquartile range, and mean and standard deviation. The percentages of subjects with a CD4 level > 350 cells/mm3 or > 500 cells/mm3 will also be given at each of these times. The results will be given overall, and by group (according to whether subjects switched or not at M6 from DRV/r 600/100 twice daily to DRV/r 800/100 once daily). The increase in CD4 cell count will also be analyzed by the difference of the value at M6 with that at inclusion, and then by the difference between M12 and M6 (median, interquartile interval, mean and standard deviation). The analysis will be performed on the available data (without any imputation of missing data). A sensitivity analysis will be also carried out, with data censored at treatment discontinuation. Patients with IRIS: The percentage and its 95% confidence interval of subjects with IRIS will be given. Treatment discontinuation during the first year: The probability of discontinuation of treatment and its 95% confidence interval, as well as the median time to the occurrence of treatment discontinuation, will be determined using a Kaplan Meier analysis, to take into account censored data due to loss of follow-up. The analysis will be performed overall, and by group, the time of follow-up since inclusion will be taken into account in the analysis. An analysis will also be performed among those who switched at 6 months, with time of follow-up since M6 that will be considered in the analysis. Occurrence of grade 3-4 adverse events (ANRS grading table): The percentage and its 95% confidence interval of subjects who had presented at least once a grade 3-4 adverse event will be given. The incidence rate of grade 3-4 adverse event and its 95% confidence interval will also be determined, overall, and by group. The type of side effects will be detailed, overall, and by group. Adherence of third-line regimen combination: The percentage and its 95% confidence interval of subjects with adherence > 90% during one year will be given. Frequency of switch from DRV/r 600/100 twice daily to DRV/r 800/100 once daily at 6 months: The percentage and its 95% confidence interval of subjects who switched at 6 months will be given. Effectiveness of switching DRV/r from 600/100 twice daily to 800/100 once daily: The percentage and its 95% confidence interval, of subjects with plasma HIV-RNA < 40 copies/mL at 12 months, among those switched from 600/100 twice daily to 800/100 once daily, will be given. Objective 2: To study pharmacokinetic (PK) parameters of DRV/r and DTG As no data exist to date on PK parameters on recent ART drugs in Asian patients, we plan to: • Estimate plasma exposure and pharmacokinetic parameters (Cmax, Cmin and AUC) of DRV/r 600/100 twice daily, DRV/r 800/100 once daily and DTG 50 mg once daily in the 20 first included patients; • Conduct an intra-patient comparison of the 2 dosing regimens of DRV/r. • Plasma darunavir concentration: The plasma darunavir concentration will be described (median, interquartile interval, mean, standard deviation) at week 4 in all subjects, at week 30 in the subjects having switched at M6 DRV/r from 600/100 twice daily to 800/100 once daily, and in case of occurrence of coinfection tuberculosis during follow-up, at 2 weeks after Rifampicin initiation. Study Flowchart Objective 3: To conduct a cost-analysis of third-line regimen implementation in Cambodia We also planned: • To conduct a cost analysis of the global strategy for a third-line program in Cambodia (with and without DRV dose reduction after 6 months of treatment); • To generate a base of evidence to inform policy around the implementation of national HIV/AIDS third line program; • To assess separately the indirect costs of its implementation for patients and providers. It is a great challenge for Cambodia to assess the effectiveness of a third-line regimen, as DRV/r and DTG are now available as WHO pre-qualified generic drug at low affordable prices. If this combination is proven to be effective, NCHADS will be able to complete the guidelines and to provide scientific information for the neighboring countries.