Quadruple nucleos(t)ide reverse transcriptase inhibitors-only regimen of tenofovir plus zidovudine/lamivudine/abacavir in heavily pre-treated HIV-1 infected patients: salvage therapy or backbone only?

BACKGROUND: We investigated the virologic and immunologic responses to a mono-class, nucleoside/nucleotide reverse transcriptase inhibitor - combination therapy consisting of tenofovir and zidovudine/lamivudine/abacavir in therapy experienced patients. METHODS: Retrospective study of 122 patients. Primary analysis was performed at 48 weeks. Virologic response was defined as viral load levels less than 400 copies/ml. RESULTS: About half of the patients had switched to tenofovir+ zidovudine/lamivudine/abacavir for simplification purposes or toxicity while the other half had experienced virologic failure. 80/122 (66%) responded. Median viral load decreased to 78 copies/ml at week 48; median CD4 count increased to 321 cells/mm(3). Of the 42 virologic failures, only 3 patients failed after week 24. 24/35 patients who had been on a non-suppressive zidovudine/lamivudine/abacavir-only regimen at baseline and added tenofovir to intensify, responded. 41/53 patients who switched from any nucleoside reverse transcriptase inhibitor-only regimen improved or maintained suppression. Genotypes were available for 85/122 patients. The only predictor of virologic failure was the combination 41L+210W+215Y/F mutational pattern. 16 of the patients who failed on tenofovir+ zidovudine/lamivudine/abacavir therapy selected new primary nucleoside reverse transcriptase inhibitor resistance mutations that they previously did not have. 48/85 (56%) patients with genotype tests had at least 3 (3-10; median 4) nucleoside reverse transcriptase inhibitor resistance-associated mutations in the past. CONCLUSIONS: Patients heavily pre-treated with nucleoside analogues may show response to mono-class tenofovir+ zidovudine/lamivudine/abacavir therapy despite having a history of failure with nucleoside reverse transcriptase inhibitors. Lower baseline viral load, higher baseline CD4 count were significant predictors for response. Archived 41L+210W+215Y/F mutational pattern was significantly associated with non-response.

Tenofovir comedication does not impair the steady-state pharmacokinetics of ritonavir-boosted atazanavir in HIV-1-infected adults.

OBJECTIVE: Our objective was to evaluate the steady-state pharmacokinetics of ritonavir-boosted atazanavir when coadministered with tenofovir in HIV-1-infected adult patients. DESIGN: Forty adult HIV-1-infected patients received either atazanavir/ritonavir 300/100 mg once daily and nucleoside reverse transcriptase inhibitors with (n = 20) or without (n = 20) tenofovir-disoproxil fumarate (tenofovir-DF) 300 mg once daily. Twenty-four-hour pharmacokinetics were assessed after at least 2 weeks of therapy according to a standardised therapeutic drug monitoring protocol. METHODS: Atazanavir/ritonavir plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and the geometric means of minimum and maximum concentrations (C(min), C(max)), the area under the time-concentration curve (AUC), half-life (t(1/2)) and total clearance (CL(tot)) were subject to a matched pairs-analysis. Patients' pairs were matched for gender, ethnicity, weight and Center for Disease Control and Prevention (CDC) status. RESULTS: The respective geometric means (90% CI) for atazanavir C(min), C(max) and AUC with tenfovir vs. without tenofovir were 405 (314-523) vs. 417 (304-572) ng/ml, 3,022 (2,493-3,664) vs. 2,817 (2,341-3,390) ng/ml and 34,822 (29,315-41,363) vs. 32,101 (26,206-39,321) ng x h/ml showing no significant differences between the groups. Atazanavir plasma concentrations measured at week 5 of therapy or later were lower than in the first 4 weeks (T-test for C(max), p = .080; AUC, p = .050 and CL(tot), p = .051). CONCLUSIONS: The coadministration of tenofovir-DF did not impair the plasma concentrations of ritonavir-boosted atazanavir in a pharmacokinetic analysis of patient pairs matched for gender, ethnicity, weight and CDC status.

Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen.

OBJECTIVE: Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options. DESIGN: Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV. METHODS: Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV). RESULTS: Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A (n=4) characterized by M184V without further regimen-associated mutations, group B (n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C (n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options. CONCLUSIONS: Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.

Pharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimen.

The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n=49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n=72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n=90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (Cmin and Cmax), area under the concentration-time curve under steady-state conditions (AUCss), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUCss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUCss was 22,794 versus 15,759 ng.h/ml (GM ratio [GMR]=1.45; P<0.05), the GM of the Cmax was 3,257 versus 2,331 ng/ml (GMR=1.40; P<0.05), and the GM of the Cmin was 438 versus 437 ng/ml (GMR=1.00); for ATV in groups 1 and 2, the GM of the AUCss was 39,154 versus 33,626 ng.h/ml (GMR=1.16), the GM of the Cmax was 3,488 versus 2,924 ng/ml (GMR=1.20), and the GM of the Cmin was 515 versus 428 ng/ml (GMR=1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.

The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy.

OBJECTIVES: To evaluate the virological, immunological and clinical responses to the boosted double protease inhibitor (PI) regimen combination of lopinavir/ritonavir and saquinavir ('LOPSAQ') without reverse transcriptase inhibitors (RTI) in HIV-positive patients who have few viable RTI treatment options. METHODS: Cohort study of 128 heavily pre-treated patients who were experiencing therapy failure on their current regimen due to RTI resistance and/or systemic toxicities. Patients with PI-resistance mutations or RTI toxicity underwent a structured treatment interruption (STI) (n=76) until virus reverted to wild-type or until resolution of toxicity symptoms. Baseline was defined as the time point when lopinavir/ritonavir plus saquinavir therapy was initiated. Virological response was defined as viral load<400 copies/mL at week 48. RESULTS: A total of 78 (61%) patients experienced a virological response to therapy (ITT). Median viral load at baseline was 5.06 log10 copies/mL; at week 48 median was 2.16 log10 copies. Median CD4 at week 48 was 280 cells/mm3 compared with 172 cells at baseline. At week 48, 78/128 patients were still on therapy. In univariable analyses, significant predictors of virological response included higher CD4 count (P<0.001), lower viral load (P=0.002), less PI-experience (P=0.006) at baseline and fewer PI-resistance mutations (P=0.043) at end of prior failing regimen; in the multivariable analysis only higher CD4 count at baseline (P=0.009) and fewer number of drugs previously taken (P=0.003) could be specified as independent predictors for response. CONCLUSIONS: The combination of lopinavir/ritonavir and saquinavir without RTIs is a potential option as salvage therapy for patients experiencing therapy failure due to RTI resistance or toxicity. This regimen may not be suitable for patients with very low baseline CD4 cell counts, very broad antiretroviral therapy experience or extensive PI-resistance mutations.

Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002.

BACKGROUND: Triple-combination antiretroviral therapy (CART) for human immunodeficiency virus infection has been in use for almost a decade, but the extent to which treatment success has changed is uncertain. We examined risk of initial virological failure of CART according to the year of starting therapy. METHODS: We included subjects from 5 complete clinic cohorts in Europe and Canada who started CART without previous antiretroviral therapy from 1996 to 2002 with 1 or more pre-CART viral load (VL) measurement and CD4 count. Based on the first VL measurement from 6 to 12 months after CART initiation, virological failure was defined as a VL of more than 500 copies/mL. We used the following 3 inclusion strategies: (1) including all subjects, with missing VL measurement counted as virological failure (n = 3825; strategy A); (2) including all subjects with VL measurement (n = 3120; strategy B); and (3) including all subjects receiving antiretroviral therapy at VL measurement (n = 2890; strategy C). RESULTS: From 1996 to 2002, risk of virological failure fell from 38.9% to 24.8% for strategy A, 28.4% to 12.0% for strategy B, and 22.8% to 8.2% for strategy C. Estimated relative reductions in risk (95% confidence interval) over the 7-year period, adjusted for cohort, demographic factors, pre-CART VL and CD4 count, and previous AIDS, were 48% (39%-56%), 64% (53%-73%), and 79% (69%-85%) for strategies A, B, and C, respectively. Reductions in risk were greatest from 1996 to 1999, with weaker trends subsequently. Trends remained but were attenuated after further adjustment for the starting regimen. CONCLUSIONS: Over a 7-year period of CART use in clinical practice, risk of initial virological failure of treatment has halved at least. These data suggest the trend is due to improvements in CART regimens and greater effectiveness of their use.

Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals.

Early prediction of suboptimal viral response to highly active antiretroviral therapy (HAART) is vital to prevent early development of drug resistance. We used logistic regression to predict the odds of achieving virologic suppression (<50 copies/mL) after 24 weeks of HAART in 656 antiretroviral-naive patients starting HAART at the J.W. Goethe University, Chelsea and Westminster, and Royal Free Hospitals according to their week 4 viral load. Therapy changes involving the switch of a single antiretroviral were assumed to have occurred for toxicity reasons and ignored. Because complete regimen changes or additions of new antiretrovirals could be due to virologic failure, patients were counted as virological failures at week 24. Three hundred sixty (84%) of 430 patients with viral loads of <1000 copies/mL, 106 (61%) of 175 with viral loads between 1001 and 10,000 copies/mL, 11 (37%) of 30 with viral loads between 10,001 and 100,000 copies/mL, and 5 (24%) of 21 with viral loads of >100,000 copies/mL at week 4 subsequently attained virologic suppression at 24 weeks. The odds of attaining virologic suppression at 24 weeks was 65% lower for every 1-log higher viral load at week 4 (odds ratio, 0.35; 95% confidence interval, 0.27-0.45). The proportion of patients with an undetectable viral load at 24 weeks among those who have not attained a viral load of <1000 copies/mL by 4 weeks is quite low. We suggest that this group of patients should be particularly closely monitored.

Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir.

OBJECTIVE: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. DESIGN: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. METHODS: Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. RESULTS: Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data. CONCLUSION: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Definition of loss of virological response in trials of antiretroviral drugs.

Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.