A randomized controlled trial of therapeutic drug monitoring in treatment-naive and -experienced HIV-1-infected patients. PharmAdapt: a randomized prospective study to evaluate the benefit of therapeutic monitoring of protease inhibitors: 12 week results. Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results. A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study. Results of a community-based antiretroviral treatment program for HIV-1 infection in Western Uganda. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. High rate of early virological failure with the once-daily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients. [Clinical trial comparing efficacy and safety of four highly active antiretroviral therapy (HAART) in antiretroviral-naive treatment with advanced HIV infection]. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons.
To improve the utility of therapeutic drug monitoring (TDM) by defining the proportion of patients with and predictors of above or below target protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) concentrations.
                This 48-week, multicenter, open-label clinical trial randomized patients to TDM versus standard of care (SOC). Serial pharmacokinetics, including a week-2 3-sample sparse collection, and expert committee TDM recommendations were given to TDM-arm patients' providers.
                Seventy-four (39%) of 190 patients had week-2 concentrations outside of targets and 122 (64%) of 190 had nontarget exposure at least once over 48 weeks. Providers accepted 75% of TDM recommendations. Among patients with below-target concentrations, more TDM-arm than SOC-arm patients achieved targets (65% vs. 45%; P = 0.09). Increased body weight and efavirenz or lopinavir/ritonavir use were significant predictors of nontarget concentrations. Patients at target and patients who achieved targets after TDM-directed dose modifications trended toward greater viral load reductions at week 48 than patients with below-target exposures (HIV RNA reductions: 2.4, 2.3, and 1.9 log10 copies/mL, respectively; P = 0.09).
                Most patients had nontarget PI and/or NNRTI concentrations over 48 weeks. TDM recommendations were well accepted and improved exposure. Patients below TDM targets trended toward worse virologic response. A randomized study to evaluate the usefulness of protease inhibitor (PI) therapeutic drug monitoring (TDM) in antiretroviral-experienced HIV-infected patients.
                In the control arm, treatment was modified according to genotypic resistance testing. In the TDM arm, therapy was modified on the basis of genotypic resistance testing and at week 8 according to PI plasma trough levels measured at week 4. The major endpoint was the change in HIV-RNA levels at week 12.
                A total of 183 patients, 96 in the control arm and 87 in the TDM arm, were included in the study. Low-dose ritonavir to enhance the associated PI was prescribed to 62.5% of patients in the control arm and 65.5% of patients in the TDM arm. Using our PI concentration targets, 17/81 patients (21%) in the TDM arm were considered to have suboptimal or partly optimal PI plasma levels at week 4. Physician and protocol-driven PI modifications were performed in 18/85 patients (23.5%) in the TDM arm, and in seven of 94 patients (7%) in the control arm (P < 0.01). Week 12 HIV RNA dropped 2 log10 copies/ml in the control arm and 1.7 log10 copies/ml in the TDM arm, respectively.
                We found no statistically significant difference between the TDM arm and control arm in virological outcome at week 12. The utility of TDM could be dependent on the presence of low-dose ritonavir as a booster and the antiretroviral experience of the studied population. Effective non-toxic target concentrations for resistant viruses have still to be determined.
                Copyright 2002 Lippincott Williams & Wilkins Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 <or=350 cells/mm(3) and HIV-1 RNA concentrations (viral load [VL]) greater than 30,000 copies per milliliter. Patients were randomized after reaching VL less than 50 copies per milliliter on two consecutive occasions between 12 and 24 weeks after start of zidovudine/lamuvidine and lopinavir/ritonavir combination. Eligible subjects switched to abacavir/lamivudine/zidovudine (TZV) or continued the PI-containing regimen. Here we present the 48-week data with virologic success rate (failure: VL > 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period. It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy.
                In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study.
                Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response.
                The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations. To compare the treatment outcomes and mortality in a rural community-based ART (CBART) program with a hospital-based ART program in the same district.
                The study design was a non-randomized cohort study consisting of 185 persons living with HIV (PLWHIV) in the CBART cohort and 200 PLWHIV in the hospital cohort. Eligibility for both cohorts was: being HIV-infected and eligible for ART, being treatment naïve, age 18 years or older, and being a resident of Rwimi sub-county. The intervention consisted of a community-based program which included weekly home visits to patients by trained volunteers who delivered antiretroviral drugs (ARVs), monitored and supported adherence to treatment, and identified and reported adverse reactions and other clinical symptoms. Outcome variables were compared to patients in a hospital-based cohort who received the standard care delivered to all other HIV patients in the hospital. The main outcome measures were HIV-1 RNA viral load (VL), CD4 cell count and mortality after six months of treatment.
                Successful ART treatment outcome as measured by virological suppression (VL<400 copies/ml) in the CBART cohort were similar to those in the hospital-based cohort (90.1% vs 89.3%, p=0.47). The median CD4 cell count increased significantly in both cohorts (community-based cohort 159 cells/microl vs 145 cells/microl in the hospital-based cohort). Mortality was not significantly different in both cohorts (community-based cohort 11.9%, hospital-based cohort 9.0%).
                The findings show that outcomes of a CBART intervention in a rural area compare favorably to outcomes of hospital-based care. If the study results are sustainable over a longer time period, this model could be considered for ART roll-out to impoverished rural/remote populations in Uganda and elsewhere. Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms.
                Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1-8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4-8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen.
                Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted. The combination of one non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors is a validated first-line antiretroviral (ARV) therapy. The once-daily combination of lamivudine, tenofovirDF and nevirapine has not been evaluated in a clinical trial.
                Randomized, open-label, multicentre, non-inferiority trial comparing lamivudine, tenofovirDF and nevirapine once daily (Group 2) with zidovudine/lamivudine and nevirapine twice daily (Group 1), in naive HIV-1-infected patients with a CD4 count <350/mm(3). We planned to enroll 250 patients.
                As of May 2006, 71 patients had been enrolled (35 in Group 1 and 36 in Group 2) and an unplanned interim analysis was done. The groups were comparable at baseline: median CD4 count was 195 and 191/mm(3) and median plasma viral load was 4.9 log(10) and 5.01 log(10), respectively, in Groups 1 and 2. Eight early non-responses (22.2%) were observed, all in Group 2, while two later viral rebounds occurred. Resistance genotypes for the nine Group 2 failing patients showed the mutations M184V/I (n = 3), K65R (n = 6), one or more NNRTI resistance mutations in all cases. At baseline, the nine Group 2 patients who failed had higher median plasma viral load (5.4 log(10)) and lower median CD4 count (110/mm(3)) than the other Group 2 patients (4.7 log(10), P = 0.002 and 223/mm(3), P = 0.004). Nevirapine trough concentrations were not different between the two groups, nor between patients with full viral suppression or those who failed in Group 2. Due to slow recruitment, and those results, the steering committee decided to stop the trial at 12 months.
                In ARV-naive HIV-1-infected patients, the once-daily lamivudine, tenofovirDF and nevirapine regimen resulted in a high rate of early virological failures. The reasons for the failures remain unclear. Comparison of efficacy and safety of four highly active antiretroviral therapy regimens (HAART) including two nucleoside analogues (NA) and a protease inhibitor (PI) in HIV positive patients with advanced infection and antiretroviral naive.
                Multicenter, randomized and open labeled clinical trial in ten community hospitals of Castilla-La Mancha and Madrid. Regimen 1 contains zidovudine (AZT), lamivudine (3TC) and indinavir (IDV) regimen 2 includes AZT, 3TC and ritonavir (RTV), regimen 3 was didanosine (DDI), estavudine (D4T) and IDV, and regimen 4 included DDI, D4T and RTV. Decrease in viral load of HIV (VC) has been assessed as primary endpoint and as secondary one, the increase of the numbers of CD4 lymphocytes, percentage of disease progression, adverse reactions and adherence. Measurements were made at baseline visit and at 6, 12, 24, 36 and 48 weeks.
                A total of 98 patients with a mean baseline CD4 count of 122 x 10(6)/l (range of 5-340) and a baseline viral load of 5.1 log copies/ml were included. At 48 weeks, a mean increase of the CD4 and decrease of the viral load without significant difference between the 4 regimens (103 cells/2.62 log in regimen 1; 169 cells/2.86 log in regimen 2; 171 cells/2.56 log in regimen 3 and 141 cells/1.71 log in regimen 4) were observed in the analysis of the patients in treatment. Treatment was discontinued due to adverse reactions: 24% in regimen 1, 48% in regimen 2, 26% in regimen 3 and 32% in regimen 4, without significant difference. Analyzing by PI groups, 41% of the patients with RTV and 25% of those with IDV discontinued treatment due to adverse effects. There was withdrawal from treatment due to disease progression in 7% of the RTV patients and in 9% of IDV patients.
                In the HIV positive patients with advanced infection, efficacy between the four regimens of HAART is similar, but there is a tendency to require more withdrawal due to adverse effects in the RTV group than in those of IDV, the two used as single PI. To compare long-term virologic, immunologic, and clinical outcomes in antiretroviral-naïve persons starting efavirenz (EFV)- versus nevirapine (NVP)-based regimens.
                The FIRST study randomized patients into three strategy arms: PI+NRTI, NNRTI+NRTI, and PI+NNRTI+NRTI. NNRTI was determined by optional randomization (NVP or EFV) or by choice. For this randomized substudy, the primary endpoint was HIV RNA >50 copies/mL after 8 months or death. Genotypic resistance testing was done at virologic failure (VF; HIV RNA >1,000 copies/mL at or after 4 months).
                228 persons (111 randomized to EFV, 117 to NVP) were followed for median 5 years. Rates per 100 person years for the primary endpoint were 41.2 (EFV) and 42.8 (NVP; p = .59). The percent of persons with HIV RNA <50 copies/mL was similar throughout follow-up (p = .24), as were average increases in CD4+ cells (p = .30). 423 persons declining the substudy chose EFV; 264 chose NVP. There were 915 persons in the combined cohort (randomized and choice). In the combined cohort, the risk of VF and VF with any NNRTI or NRTI resistance or resistance of any class was significantly less for EFV compared to NVP.
                EFV-based regimens as initial therapy resulted in a lower risk of VF and VF with resistance than did NVP-based regimens, although immunologic and clinical outcomes were similar.
Our review does not support routine use of ARV TDM in ARV-naive or -experienced patients on either boosted PI or NNRTI ART regimens. TDM in treatment-naive participants on a PI-based ART regimen, particularly if unboosted by ritonavir, may improve virological outcomes. Trials were underpowered with small sample sizes, short durations of follow-up and generally poor uptake of TDM recommendations. As these trials were conducted in higher income earning countries, results may not be generalisable to resource-limited countries where the burden of HIV is heaviest.