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High Rate of Virologic Suppression with Raltegravir plus Etravirine and Darunavir/Ritonavir among Treatment-Experienced Patients Infected with Multidrug-Resistant HIV: Results of the ANRS 139 TRIO Trial
 
 
  "treatment with raltegravir, darunavir/ritonavir, and etravirine may be recommended for patients harboring multidrug-resistant virus"...."patients infected with highly-resistant HIV and who have few remaining treatment options may benefit from an antiretroviral therapy regimen containing raltegravir, etravirine, and darunavir/ritonavir and may achieve virologic suppression comparable to that of treatment-naive patients"
 
Raltegravir in CSF: "Raltegravir Concentrations in CSF Exceed The Median Inhibitory Concentration" - (09/20/09)
 
Darunavir in the CSF: "Darunavir Concentrations in CSF Exceed The Median Inhibitory Concentration" - (09/20/09)
 
from Jules: just a word on aging & complications- We are raising our awareness about concerns for cognitive impairment and other CNS diseases as patients age. We need intensive research to examine if drugs with greater CNS penetration, greater CPE scores according to Scott Letendre, improve cognitive impairment & other CNS diseases, particularly in patients >50 and >65 yrs old. If so, we need to understand how to optimize timing of the use of the regimens, so can we identify risk factors for cogitive impairment, perhaps better use of patient evaluation tests for cognitive impairment, frailty evaluations, diabetes & glucose intolerance can lead to cognitive impairment, early entry of HIV into the brain, what else leads to cognitive impairment?
 
"The TRIO trial is the first clinical trial whose a priori specific objective was to evaluate the efficacy and tolerability of a regimen containing 3 new agents for patients with highly resistant virus. The suppression rates found in our trial are higher than those found in any other study involving patients infected with multidrug-resistant HIV and approach the rates reported for antiretroviral-naive patients"....."At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/mL. The median CD4 cell count increase was 108 cells/mm3......."The antiretroviral regimen used in this study was generally well tolerated"....."The most frequent grade 3-4 laboratory abnormalities were elevated levels of creatine kinase (11 patients) and gamma-glutamyltransferase (4 patients). None of the laboratory abnormalities resulted in treatment discontinuation"....."in the TRIO trial, 90% of patients were given OBT in addition to the 3 fully active antiretroviral agents being evaluated, even though the drugs included in the OBT regimens were often considered to be ineffective.....In our analysis, however, we did not find any trends showing that OBT offers additional benefits."....."Recently, long-term virologic responses have dramatically increased among patients infected with multidrug-resistant virus [6, 10-12, 21-23]. The main reason for this improvement is a shift from the addition of 1 new agent to failing treatment regimens to the management of resistant HIV by providing patients with 2 or 3 new and active drugs. In a subgroup analysis of week 48 data from BENCHMRK 1 and 2, HIV-1 RNA levels were shown to decrease to <50 copies/mL in 89% of 44 patients who were naive to raltegravir, enfuvirtide, and darunavir/ritonavir and whose regimens included all 3 of these drugs"
 
"The guidelines for the use of antiretroviral agents for HIV-1-infected adults and adolescents state that virologic failure while receiving treatment can be defined by a confirmed HIV RNA level >400 copies/mL after 24 weeks or >50 copies/mL by 48 weeks [1]. Given the kinetics of the response of HIV-1 RNA levels to new investigational drugs, especially raltegravir, the question may now be raised about whether a stricter definition of virologic failure for treatment-naive and treatment-experienced patients should be used in clinical practice."

 
High Rate of Virologic Suppression with Raltegravir plus Etravirine and Darunavir/Ritonavir among Treatment-Experienced Patients Infected with Multidrug-Resistant HIV: Results of the ANRS 139 TRIO Trial
 
Clinical Infectious Diseases Nov 1 2009;49:1441-1449
 
Y. Yazdanpanah,1 C. Fagard,2 D. Descamps,3 A. M. Taburet,4 C. Colin,2 B. Roquebert,3 C. Katlama,5 G. Pialoux,6 C. Jacomet,10 C. Piketty,7 D. Bollens,8 J. M. Molina,9 G. Ch ne,2 and the ANRS 139 TRIO Trial Groupa
 
1Hopital Tourcoing, Lille School of Medicine, Lille, 2INSERM U897, Bordeaux, 3Hopital Bichat-Claude Bernard, 4Hopital Bicetre, Le Kremlin Bicetre, 5Hopital Pitie-Salpetriere, 6Hopital Tenon, 7Hopital Georges Pompidou, 8Hopital Saint Antoine, and 9Hopital Saint Louis and Universite de Paris Diderot Paris 7, Paris, and 10Hopital Clermont-Ferrand, Clermont-Ferrand, France
 
ABSTRACT
Background. The introduction of 2 or 3 fully active drugs in human immunodeficiency virus (HIV)-infected patients receiving failing antiretroviral therapy is a key determinant of subsequent treatment efficacy. The aim of this study was to assess the safety and efficacy of a regimen containing raltegravir, etravirine, and darunavir/ritonavir for treatment-experienced patients infected with multidrug-resistant HIV.
 
Methods. Patients enrolled in this phase II, noncomparative, multicenter trial were naive to the investigational drugs and had plasma HIV RNA levels >1000 copies/mL, a history of virologic failure while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI), >3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor (NRTI) mutations, and <3 darunavir and NNRTI mutations. The primary end point was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks.
 
Results. A total of 103 patients enrolled in the study. At baseline, genotypic resistance profiles showed a median of 4 primary protease inhibitor mutations, 1 NNRTI mutation, and 6 NRTI mutations. In addition to the investigational drugs, 90 patients (87%) received optimized background therapy that included NRTIs (86 patients) or enfuvirtide (12 patients). At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/mL. The median CD4 cell count increase was 108 cells/mm3. Grade 3 or 4 clinical adverse events were reported in 15 patients (14.6%). Only 1 patient discontinued the investigational antiretroviral regimen, because of an adverse event.
 
Conclusion. In patients infected with multidrug-resistant virus who have few remaining treatment options, the combination of raltegravir, etravirine, and darunavir/ritonavir is well tolerated and is associated with a rate of virologic suppression similar to that expected in treatment-naive patients.
 
The optimal choice for salvage therapy for human immunodeficiency virus (HIV)-infected patients has been shown to require at least 2, and preferably 3, fully active drugs [1]. However, until recently, clinicians treating patients infected with multidrug-resistant virus who were receiving failing combination antiretroviral therapy generally added only 1 new agent to optimized background therapy (OBT) regimens that did not contain any fully active agents. This approach, often necessary because of limited drug options, put patients at high risk of virologic failure and resistance to the new agent, as well as to other agents in the same class [2-4].
 
A new class of antiretroviral drugs, as well as 2 new drugs in previously available classes, recently and almost simultaneously became available for use in clinical practice. Raltegravir is the first HIV integrase inhibitor [5]. In the BENCHMRK randomized clinical trials, which were conducted involving HIV-infected patients with limited treatment options, 62.1% of patients taking raltegravir plus OBT achieved plasma HIV RNA levels <50 copies/mL at week 48 [6]. Darunavir, a new protease inhibitor, and etravirine, a new nonnucleoside reverse-transcriptase inhibitor (NNRTI), have both shown potent in vitro activity against multidrug-resistant strains of HIV-1 [7-9]. In the DUET 1 and 2 clinical trials, also conducted involving HIV-infected treatment-experienced patients, of the patients who took darunavir/ritonavir and etravirine plus OBT, 56.0% in DUET 1 and 62.0% in DUET 2 reached plasma HIV RNA levels <50 copies/mL at week 24 [10, 11].
 
Most studies conducted to date on the efficacy and safety of new antiretroviral drugs have involved the addition of only 1 new agent to an OBT regimen [6, 12]. The DUET trials evaluated the efficacy and safety of etravirine, but it was administered in combination with darunavir/ritonavir in both arms [10, 11]. Estimations of the efficacy and safety of a combination of 3 new drugs are lacking, especially for a population of treatment-experienced patients infected with multidrug-resistant HIV.
 
The objective of the Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS) 139 TRIO trial was to assess the 24-week virologic efficacy and safety of an antiretroviral regimen containing raltegravir, etravirine, and darunavir/ritonavir for HIV-1 infected patients who experienced failure of combination antiretroviral therapy and who were infected with multidrug-resistant virus. In this article, we report results of the primary outcome and the follow-up to 48 weeks.
 
Discussion
 
Patients infected with multidrug-resistant HIV who had few remaining treatment options showed high rates of virologic suppression and favorable immunological outcomes at 48 weeks with a combination antiretroviral therapy regimen containing raltegravir, etravirine, and darunavir/ritonavir. Moreover, this combination was well tolerated; most drug-related adverse events proved to be mild or moderate in severity.
 
Recently, long-term virologic responses have dramatically increased among patients infected with multidrug-resistant virus [6, 10-12, 21-23]. The main reason for this improvement is a shift from the addition of 1 new agent to failing treatment regimens to the management of resistant HIV by providing patients with 2 or 3 new and active drugs. In a subgroup analysis of week 48 data from BENCHMRK 1 and 2, HIV-1 RNA levels were shown to decrease to <50 copies/mL in 89% of 44 patients who were naive to raltegravir, enfuvirtide, and darunavir/ritonavir and whose regimens included all 3 of these drugs [24]. In a subgroup analysis of week 24 data from DUET 1 and 2, in which all patients received darunavir/ritonavir, 59% of 75 patients in DUET 1 and 73% of 80 patients in DUET 2 who were in the etravirine group and took enfuvirtide de novo reached HIV RNA level <50 copies/mL [10, 11]. The TRIO trial is the first clinical trial whose a priori specific objective was to evaluate the efficacy and tolerability of a regimen containing 3 new agents for patients with highly resistant virus. The suppression rates found in our trial are higher than those found in any other study involving patients infected with multidrug-resistant HIV and approach the rates reported for antiretroviral-naive patients [16, 25-27]. Although the patients enrolled in our study had fairly low HIV-1 RNA levels and high CD4 cell counts, virologic suppression did not differ by baseline HIV-1 RNA level or CD4 cell count. Therefore, the suppression rates found in the ANRS 139 TRIO trial are likely to be generalizable to all patients infected with multidrug-resistant HIV.
 
In this study, investigational drugs had a rapid antiretroviral effect, as reported in other studies investigating the efficacy of raltegravir plus OBT for treatment-naive and treatment-experienced patients [6, 28, 29]. The guidelines for the use of antiretroviral agents for HIV-1-infected adults and adolescents state that virologic failure while receiving treatment can be defined by a confirmed HIV RNA level >400 copies/mL after 24 weeks or >50 copies/mL by 48 weeks [1]. Given the kinetics of the response of HIV-1 RNA levels to new investigational drugs, especially raltegravir, the question may now be raised about whether a stricter definition of virologic failure for treatment-naive and treatment-experienced patients should be used in clinical practice.
 
Interestingly, in the TRIO trial, 90% of patients were given OBT in addition to the 3 fully active antiretroviral agents being evaluated, even though the drugs included in the OBT regimens were often considered to be ineffective. The drugs used in the OBT regimens were generally NRTIs. Because our sample size was small and a large proportion of patients achieved full virologic suppression, it was not possible to evaluate the additional benefit of adding an OBT or an active OBT (genotypic sensitivity score, >1) to the combination of raltegravir, etravirine, and darunavir/ritonavir. In our analysis, however, we did not find any trends showing that OBT offers additional benefits. Future clinical randomized trials involving patients infected with multidrug-resistant HIV-1 should confirm this finding. An AIDS Clinical Trials Group randomized trial involving treatment-experienced patients is currently ongoing, to determine the benefit of adding an NRTI to an antiretroviral regimen that includes new-generation drugs [30].
 
The antiretroviral regimen used in this study was generally well tolerated. Few serious or grade 3-4 events occurred, and only 1 led to treatment discontinuation. Because the TRIO trial did not have a control arm, it is difficult to identify which adverse events were related to the investigational drugs. Nevertheless, skin rash was one of the most frequent clinical adverse events, and clinicians often considered it to be related to the study treatment combination. DUET 1 and 2 found that skin rashes were more frequent in the etravirine treatment group than in the control group [10, 11]. In our study, skin rashes were mild to moderate and generally resolved with continued treatment, a finding consistent with DUET 1 and 2. The grade 4 skin rash observed in the patient who discontinued the investigational drugs was probably not related to etravirine. Creatine kinase elevation (11 patients) was the most frequent grade 3-4 laboratory adverse event. Although a recent case report acknowledged a case of severe rhabdomyolysis associated with raltegravir use [31], the proportion of patients with creatine kinase elevation in the BENCHMRK trials was not in the raltegravir treatment group than in the control group. In our study, all patients with creatine kinase elevations were asymptomatic, and none discontinued study treatment.
 
This study was designed as a single-arm clinical trial in which all patients received the 3 investigational drugs. This approach was used for a specific population of patients who harbored multidrug-resistant virus, to allow all trial participants, rather than only those fortunate enough to be randomized to receive a regimen containing 3 active agents, the chance to benefit from 3 fully active agents from multiple drug classes [4]. One may postulate that the absence of a control arm could make it more difficult to assess the effects of the investigational combination. However, we can compare virologic responses to the drug combinations used in TRIO with those to combinations used in previous trials that did not include TRIO's investigational drugs. Given the very high rate of virologic suppression in this study and the precision of our estimates, we believe that the benefits of this combination for patients infected with multidrug-resistant HIV are sufficiently great to make the interpretation of our results unambiguous [32]. Therefore, treatment with raltegravir, darunavir/ritonavir, and etravirine may be recommended for patients harboring multidrug-resistant virus, and the study results suggest that an additional randomized controlled trial would not be needed to evaluate this combination.
 
In conclusion, patients infected with highly-resistant HIV and who have few remaining treatment options may benefit from an antiretroviral therapy regimen containing raltegravir, etravirine, and darunavir/ritonavir and may achieve virologic suppression comparable to that of treatment-naive patients.
 
Results
 
Overall, 170 patients were screened from 9 May 2007 through 2 August 2007, and 103 patients were enrolled in the study (Figure 1). Of the 103 patients enrolled in the study, 100 (97%) were receiving therapy at week 24. Of the 3 patients who discontinued treatment, 1 experienced a grade 4 clinical adverse event, and 2 decided to stop taking the study drugs.
 
Patient baseline characteristics are shown in Table 1. The median duration of antiretroviral therapy before the study was 13 years (interquartile range [IQR], 11-15 years), and 44 patients (43%) had a history of an AIDS-defining event. The median CD4 cell count was 255 cells/µL (IQR, 132-351 cells/µL), and the median plasma HIV RNA level was 4.2 log10 copies/mL (IQR, 3.6-4.6 log10 copies/mL). Baseline genotypic sensitivity data showed that the median number of protease inhibitor mutations (primary mutations) was 4, the median number of NNRTI mutations was 1, and the median number of NRTI mutations was 6. Two patients (2%) had 3 etravirine mutations, and 36 patients (35%) had 3 primary darunavir mutations.
 
Throughout the treatment period, 86 patients (84%) received NRTI-containing OBT regimens, and 12 patients (12%) received enfuvirtide-containing OBT regimens. The median number of NRTIs contained in the OBT was 2 (IQR, 1-2). Ten of the 12 patients who received enfuvirtide were naive to the drug. For 54 (60%) of 90 patients who received an OBT, the genotypic sensitivity score of the OBT was <1 (Table 1).
 
At week 24, 93 patients (90%; 95% confidence interval, 85%-96%) had plasma HIV-1 RNA levels <50 copies/mL. At 4 and 12 weeks, 57 patients (55%) and 91 patients (88%), respectively, had plasma HIV-1 RNA levels <50 copies/mL (Figure 2). Among the 10 patients who had plasma HIV-1 RNA levels >50 copies/mL at week 24, there were 5 patients, including the 3 patients who discontinued treatment before week 24, who had HIV RNA levels 400 copies/mL. The 5 other patients had plasma HIV-1 RNA levels between 50 and 400 copies/mL. Among the 93 patients who had plasma HIV-1 RNA levels <50 copies/mL at week 24, 4 (4%) had a virologic rebound between weeks 24 and 48. At week 48, 89 patients (86%; 95% confidence interval, 80%-93%) had HIV-1 RNA levels <50 copies/mL.
 
Table 2 illustrates the proportion of patients who had plasma HIV-1 RNA levels <50 copies/mL at week 24, according to baseline characteristics. Virologic suppression did not differ according to baseline HIV-1 RNA levels, CD4 cell count, first use of enfuvirtide, or OBT genotypic sensitivity score. We retrospectively evaluated mutations associated with darunavir and etravirine, on the basis of the most current Stanford and ANRS algorithms [19, 20]. None of the patients were found to be resistant to darunavir at baseline, according to either the Stanford or ANRS algorithm. Resistance to etravirine was found among 3 patients (3%) by using the Stanford algorithm and 1 patient (1%) by using the ANRS algorithm. These patients all had plasma HIV-1 RNA levels <50 copies/mL at week 24.
 
Table 2. Patients with Human Immunodeficiency Virus Type 1 (HIV-1) RNA Levels <50 Copies/mL at Week 24, According to Baseline Characteristics in the ANRS 139 TRIO Trial

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The median change in log10 HIV-1 RNA copies/mL at week 48 was -2.4 (IQR, -2.9 to -1.9) (Figure 3). The median CD4 cell count increase from baseline to week 48 was 108 cells/mm3 (IQR, 58-169 cells/mm3). During the study period, 2 new AIDS-defining events (HIV encephalopathy and oesophageal candidiasis) occurred (2% of patients). One patient (1%) died due to a myocardial infarction after aortobifemoral bypass surgery.
 
Clinical adverse events and laboratory abnormalities reported throughout the duration of the study are shown in Table 3. Fifteen patients (14.6%) reported grade 3-4 clinical adverse events. Four of these events (3.9%) were considered to be drug-related, and 1 resulted in treatment discontinuation. The clinical adverse event that resulted in treatment discontinuation was a grade 4 skin rash with fever but without epidermal necrolysis. The investigator considered the adverse event to be probably related to raltegravir, because the symptoms recurred when the patient resumed use of raltegravir and the 3 NRTIs used at enrollment but did not recur when he resumed etravirine and darunavir/ritonavir. Five other patients (4.9%) reported skin rashes. The severity of the rashes was grade 1 in 3 patients and grade 2 in 2 patients. We found grade 3-4 laboratory abnormalities in 20 patients (19.4%). The most frequent grade 3-4 laboratory abnormalities were elevated levels of creatine kinase (11 patients) and gamma-glutamyltransferase (4 patients). None of the laboratory abnormalities resulted in treatment discontinuation.
 
Methods

 
Study design and study population. The ANRS 139 TRIO trial is a phase II, noncomparative, multicenter trial [13]. We recruited HIV-1-infected adults in 49 HIV clinics in France. Patients were eligible if they met the following inclusion criteria: plasma HIV-1 RNA level >1000 copies/mL; receiving stable combination antiretroviral therapy for >8 weeks before screening; naive to raltegravir, etravirine, and darunavir; >3 protease inhibitor resistance mutations at screening, as defined by the International AIDS Society-USA [14]; susceptibility to darunavir, as defined by version 16 of the ANRS resistance algorithm (3 mutations among the following: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V) [15]; and >3 nucleoside reverse-transcriptase inhibitor (NRTI) mutations, as defined by the International AIDS Society-USA [14]. Patients were also eligible if they had a history of virologic failure while receiving NNRTI-based therapy but were susceptible to etravirine at screening, on the basis of available data at the time the study was designed (3 NNRTI mutations among the following: A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T, and Y318F). Patients were not eligible if they had an AIDS-defining infection or cancer requiring chemotherapy at the time of screening or if they were pregnant, breast-feeding, or of child-bearing age. Other exclusion criteria included renal insufficiency (creatinine clearance level, <50 mL/min), hemoglobin level <7 g/dL, absolute neutrophil count <500 cells/µL, and platelet count <50,000 platelets/µL. Patients with chronic hepatitis B or C infection were eligible if (1) they did not have cirrhosis with Child-Pugh scores of B or C and (2) the observed concentrations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin were <3 times the upper limit of the normal range.
 
Written informed consent was obtained from all patients. The protocol was reviewed and approved by an ethics committee (Comite de Protection des Personnes) and competent health authorities (Agence Fran aise de Securite Sanitaire des Produits de Sante). The trial was conducted in accordance with the Declaration of Helsinki.
 
Study treatment. All patients received raltegravir (one 400-mg tablet twice daily), etravirine (two 100-mg tablets twice daily), and darunavir plus low-dose ritonavir (two 300-mg darunavir tablets plus 100 mg ritonavir twice daily). Physicians could also choose to give patients an OBT regimen that included NRTIs and/or enfuvirtide. All but 11 patients initiated the study drugs and the OBT regimen concurrently. These 11 patients began taking etravirine 7 days after initiation of raltegravir, darunavir/ritonavir, and OBT and were included in a planned pharmacokinetic substudy. Changes in OBT regimens were permitted throughout the duration of the study, to control the toxic effects of antiretroviral drugs.
 
Primary and secondary end points. The primary end point of the study was the proportion of patients reaching plasma HIV-1 RNA levels <50 copies/mL at week 24. The secondary end points were the proportion of patients who reached plasma HIV-1 RNA levels <50 copies/mL at week 48, the change in plasma HIV-1 RNA levels and CD4 cell counts from baseline through week 48, and drug tolerability. Results of additional secondary end points (change in drug susceptibility, proviral and circular HIV DNA evolution from baseline to week 48, and pharmacokinetic-pharmacodynamic association between raltegravir, etravirine, and darunavir) will be reported elsewhere.
 
Local laboratories assessed HIV-1 RNA levels and CD4 cell counts at screening, at enrollment (day 0), and at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. Protease and reverse-transcriptase genes were sequenced in centers affiliated with the ANRS Resistance Group but were analyzed in a central virology laboratory. Results of this analysis were used to determine the genotypic sensitivity scores of the OBT regimens. The genotypic sensitivity score represents the total number of antiretroviral drugs in the OBT regimen to which a patient's HIV was susceptible (score, 1), possibly susceptible (score, 0.5), or resistant (score, 0), according to version 16 of the ANRS algorithm [15].
 
We measured safety by conducting physical examinations and blood and urine tests at enrollment and during the study. An independent data and safety monitoring board reviewed available safety and efficacy data regularly.
 
Statistical analysis. The a priori primary efficacy hypothesis in this study was that the combination of raltegravir, etravirine, and darunavir/ritonavir would show a virologic efficacy similar to that of combination antiretroviral therapy for treatment-naive patients. On the basis of the results of the most recent studies conducted involving treatment-naive patients at the time the TRIO trial was designed [16, 17], our hypothesis was that if <60% of patients had virological suppression at 24 weeks, then the combination of 3 experimental agents for patients infected with multidrug-resistant virus would not be effective enough to warrant additional comparative trials. We would be able to conclude that the response rate at week 24 was at least 60% with an risk of 5% and a statistical power of 90% if the number of treatment failures among 90 patients did not exceed 28 [18].
 
Primary efficacy analyses were conducted on an intent-to-treat basis. They included all enrolled patients, regardless of whether they received at least 1 dose of the study medication. When HIV-1 RNA measurements were missing because patients had missed visits, they were recorded as treatment failures in the primary efficacy analyses. We examined the effects of baseline HIV-1 RNA level, CD4 cell count, and OBT use on the primary end point. For patients taking OBT, we also evaluated the impact of NRTI use, first enfuvirtide use, and the sensitivity of the OBT. Differences were assessed using Fisher's exact test for categorical variables. We tallied all adverse events from weeks 0 to 48. Investigators evaluated the association between the study regimen and each adverse event. The severity of clinical and laboratory abnormalities was graded according to the ANRS scale for grading severity of adverse events in adults. All statistical analyses were performed with SAS, version 9.1.3 service pack 2 (SAS Institute).
 
 
 
 
 
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