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Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients
Abstract
Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed.
TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a >or= 1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm.
For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/mul; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved >or= 1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P <or= 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18-39% of TMC114/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59-75 versus 12 cells/mul (TMC114/r versus CPI: P <or= 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups.
TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks.
... Eighteen randomized controlled trials (totaling 7963 patients) comprising 47 ART comparison groups were retrieved [15][16][17][18][19][27][28][29][30][31][32][33][34][35][36][37][38][39] (Fig. 1 and Table 1). We also identified another 10 publications reporting extension results (referring to the previously selected RCTs that presented results in more advanced follow-up periods in time, i.e., 48 and 96 weeks) and 15 studies reporting subgroup analyses (Additional file 3: Table S2). ...
... The 18 RCTs assessed the efficacy and safety of nine new ARVs:ENF [15,39], TPV [16,28], DAPD [36], DRV [17,29,37], ETV [30][31][32], RAL [18,38], MVC [19,33], VIC [27,34], and DTG [35] (Table 1). Eleven of those studies (61%) were characterized as phase III trials and seven as phase IIb studies. ...
... Two studies [16,28] adopted genotypic sensitivity scores, six used phenotypic scores [15,30,31,[37][38][39], and five studies used both methods, which resulted in an overall sensitivity score [18,19,27,33,35]. The remaining studies did not provide data on the method chosen for the detection of viral resistance [17,29,32,34,36]. ...
Background
The World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some controversy remains as to the best combinations of ART for experienced HIV-1-infected patients. Therefore, we conducted a systematic review and meta-analysis to (i) assess the efficacy of third-line therapy for adults with HIV/AIDS based on randomized controlled trials (RCT) that adopted the “new antiretroviral (ARV) + optimized background therapy (OBT)” approach and (ii) address the key issues identified in WHO’s guidelines on the use of third-line therapy.
Methods
MEDLINE, EMBASE, LILACS, ISI Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials were searched for RCTs assessing third-line ARV therapy that used an OBT approach between 1966 and 2015. Data was extracted using an Excel-structured datasheet based on the Consolidated Standards of Reporting Trials (CONSORT) recommendations. The primary outcome of this meta-analysis was the proportion of patients reaching undetectable HIV RNA levels (< 50 copies/mL) at 48 weeks of follow-up. Included studies were evaluated using the Cochrane’s Risk of Bias assessment tool. Summarized evidence was rated according to the GRADE approach.
Results
Eighteen trials assessing 9 new ARV + OBT combinations defined as third-line HIV therapy provided the efficacy data: 7 phase IIb trials and 11 phase III trials. Four of the 18 trials provided extension data, thus resulting in 14 trials providing 48-week efficacy data. In the meta-analysis, considering the outcome regarding the proportion of patients with a viral load below 50 copies/ml at 48 weeks, 9 out of 14 trials demonstrated the superiority of the new combination being studied (risk difference = 0.18, 95% CI 0.13–0.23). The same analysis stratified by the number of fully active ARVs demonstrated a risk difference of 0.29 (95% CI 0.12–0.46), 0.28 (95% CI 0.17–0.38) and 0.17 (95% CI 0.10–0.24) respectively from zero, one, and two or more active drugs strata. Nine of the 18 trials were considered to have a high risk of bias.
Conclusions
Efficacy results demonstrated that the groups of HIV-experienced patients receiving the new ARV + OBT were more likely to achieve viral suppression when compared to the control groups. However, most of these trials may be at a high risk of bias. Thus, there is still not enough evidence to stipulate which combinations are the most effective for therapeutic regimens that are to be used sequentially due to documented multi-resistance.
... 34 Clinical Studies: Treatment Efficacy Treatment-experienced adult patients POWER (Performance of TMC114/r When Evaluated in treatment-Experienced patients with PI resistance) 1 and POWER 2 were randomized, multicentre, 144 weeks phase IIb studies that compared the efficacy and safety of darunavir plus low-dose ritonavir versus investigator-select control PIs. The first 24 week of POWER 1 and 2 were partially blinded dose-finding studies, 63,64 followed by openlabel phases at 48, 6 96, 65 144 weeks. 66 POWER 3 is an analysis of two Phase IIb, noncomparative, open-label, 144-week trials in patients treated with darunavir/r 600/100 mg bid. ...
... The treatment was discontinued in case of: virological failure defined as viral load reduction 0.5 log 10 copies/ml at week 8; 1.0 log 10 copies/ml at or beyond week 12 or an increase of 0.5 log 10 copies/ml above nadir; tolerability and toxicity causes The primary efficacy end point was confirmed viral load reduction 1.0 log 10 copies/ml or more from baseline (time-to-loss of virological response [TLOVR] algorithm). 6,[63][64][65][66][67][68] The secondary efficacy end points were the proportion of patients reaching viral loads less than 50 and 400 copies/ml (TLOVR), change in HIV-RNA and CD4 cell count from baseline. Safety and tolerability were also continuously assessed. ...
... The efficacy and safety analyses were based on the intent-to-treat (ITT) population which included all those who had received at least one dose of the study medication. 6,7,63,64 The combined 46, 98, 144 analysis included only patients who received boosted DRV/r 600/100 mg bid or boosted PI from randomization subgroup. 6,64,65 In POWER 1, 63 and 2, 64 after 24 weeks of treatment more patients treated with DRV/r achieved the primary end point than those treated with PI group. ...
Darunavir is an oral peptidomimetic HIV-1 protease inhibitor with antiretroviral activity against wild type HIV strains and HIV strains with protease inhibitor mutations. Ritonavir-boosted darunavir is rapidly absorbed and it has a higher bioavailability than unboosted darunavir. In HIV infected adults, the pharmacokinetic profile of darunavir showed that the drug concentrations are similar in the age range between 18 to 65 years and unaffected by the presence of moderate renal or hepatic function impairment. Darunavir chemical structure provides a strong interaction between the drug and HIV-1 protease and accounts for its potent antiretroviral activity and high genetic barrier to the development of resistance. The efficacy, safety and tolerability of darunavir have been widely dem- onstrated in HIV-infected treatment-experienced and naive adult patients and it’s use has been labelled in this population. Recently, upon the approval of the Food and Drug Administration, a 75 mg darunavir’s tablet formulation has been licensed for the treatment of HIV-infected children and adolescents in the age range between 6 to 17 years.
... In clinical studies, darunavir is administered together with low-dose ritonavir (darunavir/ritonavir). Published results from one phase IIa clinical study and two phase IIb studies indicate that darunavir/ritonavir has potent antiviral activity in PI-experienced patients [75][76][77] . In the 24-week, dose-finding portion of two large, randomized, controlled, 144-week phase IIb studies (POWER 1 [TMC114-C213] and POWER 2 [TMC114-C202]), patients were nucleoside reverse transcriptase inhibitor (NRTI)-experienced, nonnucleoside reverse transcriptase inhibitor (NNRTI)-experienced, and PI-experien ced, had at least one primary PI mutation (according to the IAS-USA guidelines) and had viral load ≥ 1,000 co pies/ml at screening 76,77 . ...
... Published results from one phase IIa clinical study and two phase IIb studies indicate that darunavir/ritonavir has potent antiviral activity in PI-experienced patients [75][76][77] . In the 24-week, dose-finding portion of two large, randomized, controlled, 144-week phase IIb studies (POWER 1 [TMC114-C213] and POWER 2 [TMC114-C202]), patients were nucleoside reverse transcriptase inhibitor (NRTI)-experienced, nonnucleoside reverse transcriptase inhibitor (NNRTI)-experienced, and PI-experien ced, had at least one primary PI mutation (according to the IAS-USA guidelines) and had viral load ≥ 1,000 co pies/ml at screening 76,77 . Both studies were of similar design. ...
... The baseline characteristics showed that patients in the POWER 2 study had somewhat more advanced disease (longer duration of infection, lower baseline CD4 and higher viral load), more patients had virus resistant to all commercially available PIs (71 vs. 63%), and a greater percentage of patients had three or more primary PI mutations (66 vs. 56%) than in the POWER 1 study 77 . In both studies, darunavir/ritonavir plus OBR was shown to be significantly more effective than investigator-selected PI(s) plus OBR for both suppression of HIV-1 RNA and increase in CD4 cell count. ...
The current effectiveness of HAART in the management of HIV infection is compromised by the emergence of extensively cross-resistant strains of HIV-1, requiring a significant need for new therapeutic agents. Due to its crucial role in viral maturation and therefore HIV-1 replication and infectivity, the HIV-1 protease continues to be a major development target for antiretroviral therapy. However, new protease inhibitors must have higher thresholds to the development of resistance and cross-resistance. Research has demonstrated that the binding characteristics between a protease inhibitor and the active site of the HIV-1 protease are key factors in the development of resistance. More specifically, the way in which a protease inhibitor fits within the substrate consensus volume, or "substrate envelope", appears to be critical. The currently available inhibitors are not only smaller than the native substrates, but also have a different shape. This difference in shape underlies observed patterns of resistance because primary drug-resistant mutations often arise at positions in the protease where the inhibitors protrude beyond the substrate envelope but are still in contact with the enzyme. Since all currently available protease inhibitors occupy a similar space (in spite of their structural differences) in the active site of the enzyme, the specific positions where the inhibitors protrude and contact the enzyme correspond to the locations where most mutations occur that give rise to multidrug-resistant HIV-1 strains. Detailed investigation of the structure, thermodynamics, and dynamics of the active site of the protease enzyme is enabling the identification of new protease inhibitors that more closely fit within the substrate envelope and therefore decrease the risk of drug resistance developing. The features of darunavir, the latest FDA-approved protease inhibitor, include its high binding affinity (Kd = 4.5 x 10-12 M) for the protease active site, the presence of hydrogen bonds with the backbone, and its ability to fit closely within the substrate envelope (or consensus volume). Darunavir is potent against both wild-type and protease inhibitor-resistant viruses in vitro, including a broad range of over 4,000 clinical isolates. Additionally, in vitro selection studies with wild-type HIV-1 strains have shown that resistance to darunavir develops much more slowly and is more difficult to generate than for existing protease inhibitors. Clinical studies have shown that darunavir administered with low-dose ritonavir (darunavir/ritonavir) provides highly potent viral suppression (including significant decreases in HIV viral load in patients with documented protease inhibitor resistance) together with favorable tolerability. In conclusion, as a result of its high binding affinity for and overall fit within the active site of HIV-1 protease, darunavir has a higher genetic barrier to the development of resistance and better clinical efficacy against multidrug-resistant HIV relative to current protease inhibitors. The observed efficacy, safety and tolerability of darunavir in highly treatment-experienced patients makes darunavir an important new therapeutic option for HIV-infected patients.
... In addition, the combination of DRV and potentiating drugs significantly reduces the risk of viral resistance, thus contributing to improved efficacy [160,161]. The efficacy and safety of DRV administered alone or in combination therapy have been demonstrated in numerous studies [162][163][164][165]. The results showed that DRV significantly improved the virological and immunological response compared to other PIs and was also well tolerated. ...
... DRV is strongly bound to plasma proteins in a proportion of approximately 95%, binding in particular to plasma α1-acid glycoprotein [153,167]. It can also be detected in cervical-vaginal fluid [171], sperm [163,172], and cerebrospinal fluid [13,173,174]. Following intravenous administration, the volume of distribution of DRV alone was 88.1 ± 59.01 (mean ± DS) and increased to 131 ± 49.9 l (mean ± DS) in the presence of 100 mg RTV twice daily. ...
A major challenge in the management of antiretroviral therapy (ART) is to improve the 11 patient's adherence, reducing the burden caused by the high number of drugs that compose the 12 treatment regimens for human immunodeficiency virus positive (HIV+) patients. Selection of the 13 most appropriate treatment regimen is responsible for therapeutic success and aims to reduce vire-14 mia, increase the immune system response capacity, and reduce the incidence rate and intensity of 15 adverse reactions. In general, protease inhibitor (PI) is one of the pillars of regimens, and darunavir 16 (DRV), in particular, is frequently recommended, along with low doses of enzyme inhibitors as co-17 bicistat (COBI) or ritonavir (RTV), by the international guidelines. The potential of clinically signif-18 icant drug interactions in patients taking COBI or RTV is high due to the potent inhibitory effect on 19 cytochrome CYP 450, which attracts significant changes in the pharmacokinetics of PIs. Regardless 20 of the patient or type of virus, the combined regimens of DRV/COBI or DRV/RTV are available to 21 clinicians, proving their effectiveness, with a major impact on HIV mortality/morbidity. This study 22 presents current information on the pharmacokinetics, pharmacology, drug interactions, and ad-23 verse reactions of DRV; it not only compares the bioavailability, pharmacokinetic parameters, im-24 munological and virological responses, but also the efficacy, advantages, and therapeutic disad-25 vantages of DRV/COBI or DRV/RTV combinations. 26
... 4 Results from studies on ritonavir-boosted darunavir have shown efficacy and safety benefits over ritonavir-boosted lopinavir and atazanavir. [5][6][7][8][9] However, darunavir has traditionally not been considered as a substitute for these protease inhibitor combinations in LMICs because of its higher cost. 3 Darunavir is the only protease inhibitor with the optimal dose established in trials of individuals highly pretreated for HIV with antiretrovirals. ...
... 3 Darunavir is the only protease inhibitor with the optimal dose established in trials of individuals highly pretreated for HIV with antiretrovirals. In the POWER studies, [8][9][10] for the subset of participants harbouring virus phenotypically sensitive to darunavir, no difference in HIV RNA reductions was measured between the 400 mg once-daily dose and higher doses up to 600 mg twice daily. POWER 1 and 2 were randomised phase 3b studies done over 48 weeks, and had low numbers of patients (110 participants in the darunavir group and 120 in the non-darunavir protease inhibitor group), which, although favouring the darunavir group for both efficacy and safety, might have obscured efficacy differences within the group. ...
Background:
Pilot studies suggest that ritonavir-boosted darunavir could show high efficacy at doses below those currently approved. We investigated whether switch to 400 mg of darunavir boosted with 100 mg ritonavir once daily could show equivalent efficacy to continuation of ritonavir-boosted lopinavir (a protease inhibitor commonly used in low-income and middle-income countries) for individuals with HIV RNA suppression.
Methods:
In the WRHI 052 study, a randomised, parallel-group, open-label, non-inferiority phase 3 trial, adults who were HIV-1 positive were enrolled in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. Eligible participants were 18 years or older, who tolerated ritonavir-boosted lopinavir in combination with two nucleoside analogues (standard of care) for 6 months or more, and had plasma HIV-1 RNA of less than 50 copies per mL within 60 days of enrolment. We randomly assigned participants (1:1), using a computer-generated randomisation plan, to switch to darunavir (400 mg) boosted with ritonavir (100 mg) once daily or remain on ritonavir-boosted lopinavir (800 mg [plus 200 mg ritonavir]), with nucleoside analogues left unchanged. The primary endpoint was the proportion of patients with less than 50 HIV-1 RNA copies per mL at week 48 (US Food and Drug Administration snapshot algorithm; non-inferiority margin -4%). Primary and safety analyses included participants receiving at least one dose of darunavir boosted with ritonavir. This trial is registered with ClinicalTrials.gov, number NCT02671383.
Findings:
Between June 30, 2016, and June 15, 2017, 148 participants were assigned to ritonavir-boosted darunavir 400 mg and 152 continued on their lopinavir-containing regimen. Four (3%) patients in the darunavir group and three (2%) in the lopinavir group discontinued before week 48. At week 48, darunavir was non-inferior to lopinavir for the primary outcome (142 [96%] of 148 participants on darunavir had <50 HIV-1 RNA copies per mL vs 143 [94%] of 152 participants on lopinavir; difference 1·9% [95% CI -3·4 to 7·3]), with a predefined margin of -4%. More participants taking darunavir (30 [20%] participants) had drug-related adverse events than those on lopinavir (eight [5%]), but the adverse events were generally asymptomatic and resolved when switching back to lopinavir. Elevated liver transaminase in three (1%; one symptomatic) darunavir participants led to study withdrawal; all transaminase elevations resolved on restarting lopinavir.
Interpretation:
Low-dose ritonavir-boosted darunavir might be a safe and efficacious switch option to maintain HIV suppression for patients on lopinavir. However, an adequately powered and designed study in viraemic participants is needed.
Funding:
South African Medical Research Council, United States Agency for International Development, and US National Institute of Allergy and Infectious Diseases.
... However, the backbone components of these PI-based regimens were not taken into account for this analysis. Reviewing these studies individually, none separately evaluated the different NRTI backbones, and several excluded use of abacavir altogether [8][9][10][15][16][17][18][19][20][21][22]. ...
... While the median number of viral load assessments was comparable while receiving the initial ABC/3TC ? PI regimen (darunavir vs. non-darunavir median [IQR] viral load laboratory values: 4 [3][4][5][6][7][8] vs. 5 [3][4][5][6][7][8][9]; p = 0.09), the large disparities in total follow-up time resulted in far more viral load assessments for the intent-to-treat analysis in the non-darunavir PI treatment group (7 [3][4][5][6][7][8][9][10][11][12][13][14] vs. 12 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]; p \ 0.0001). ...
Background and Objectives
The standard of care for HIV treatment is a three-drug regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor (PI) or an integrase strand transfer inhibitor. Darunavir boosted with ritonavir (DRV/r) is the only preferred PI in the US Department of Health and Human Services (DHHS) HIV treatment guidelines for antiretroviral-naïve patients, recommended in combination with tenofovir/emtricitabine for antiretroviral-naïve patients. For treatment-experienced and certain antiretroviral-naïve patients, abacavir and lamivudine (ABC/3TC) in combination with DRV/r is considered an effective and tolerable alternative, despite limited research on the effectiveness of this particular combination. This study evaluated virologic outcomes in treatment-experienced patients taking ABC/3TC + DRV/r compared to treatment-experienced patients taking ABC/3TC with any other PI.
Methods
Treatment-experienced HIV-infected patients initiating their first regimen containing ABC/3TC in combination with any PI in the year 2005 or later were selected from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort, a prospective observational cohort reflecting routine medical care. Viral load measurements taken during follow-up were compared between patients taking ABC/3TC + DRV/r and ABC/3TC with a PI other than DRV/r. Logistic regression models were fit to assess the association between regimen exposure and viral load suppression.
Results
A total of 151 patients initiating ABC/3TC + DRV/r and 525 patients initiating ABC/3TC + a non-darunavir PI were included. Patients in both treatment groups had comparable clinical indicators (viral load, CD4) at baseline. A regimen of ABC/3TC + DRV/r was more likely to be prescribed in the later years of the study period, leading to a shorter median follow-up in the DRV/r treatment group (as-treated analysis: 14 vs. 17 months, p = 0.04; intent-to-treat analysis: 33 vs. 68 months, p < 0.001). Multivariable logistic regression models accounting for year of regimen initiation, among other factors, indicated no statistically significant differences in achieving an undetectable viral load for patients taking DRV/r with ABC/3TC compared with other PIs, both in the as-treated (odds ratio [95 % confidence interval]: 0.84 [0.53–1.34]) and intent-to-treat analyses (0.82 [0.48–1.40]). Patients in both treatment groups also showed similar reductions in viral load (median darunavir vs. non-darunavir: −23.0 vs. −23.0 copies/mL; p = 0.72) and gains in CD4 T cell counts (median darunavir vs. non-darunavir: 106 vs. 108 cells/mm³; p = 0.59] while being treated with the regimen of interest.
Conclusions
Patients receiving ABC/3TC + DRV/r appear to experience similar treatment benefit to patients taking ABC/3TC with other PIs in terms of achieving suppression, as well as absolute reductions in viral load and CD4 lymphocyte gains.
... Darunavir (DRV) is the preferred PI, but must be coadministered with a pharmacokinetic (PK) booster, either ritonavir (RTV) or cobicistat (COB), to maximize exposure. Standard dosages include DRV/RTV 800/100 mg every 24 h (q24h) or DRV/ COB 800/150 mg q24h for PI-naïve patients [3] (or those pretreated with PIs but with no known resistance mutations) [4], and DRV/RTV 600/100 mg every 12 h (q12h) for patients presenting with PI resistance mutations [5][6][7][8]. One of the main advantages of DRV is its high genetic barrier to resistance as it binds to a highly conserved domain of the viral protease [9][10][11]. ...
Background and objectivesProtease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations.Methods
Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated.ResultsOur model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC50 in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients.Conclusions
These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017.
... However, it has a poor oral bioavailability of approximately 37% due to its low hydrophilicity and its first pass metabolism by intestinal and hepatic CYP3A enzymes [11]. DRV is administered in combination with RTV, however this combination may lead to DDI , causing adverse effects such as liver disorders and hypersensitivity reactions [40,41]. Based on these findings, the Madgulkar group developed SLN of DRV, taking advantage of the properties associated with lipid nanoparticles of enhancing drug solubility and forming stable dispersion [42]. ...
Introduction: Antiretroviral therapy (ART) has led to a significant reduction in HIV-1 morbidity and mortality. Many antiretroviral drugs (ARVs) are metabolized by cytochrome P450 (CYP) pathway, and majority of these drugs are also either CYP inhibitors or inducers and few possess both activities. These CYP substrates, when used for HIV treatment in the conventional dosage form, have limitations such as low systemic bioavailability, potential drug-drug interactions, and short half-lives. Thus, an alternative mode of delivery is needed in contrast to conventional ARVs.
Areas covered: In this review, we summarized the limitations of conventional ARVs in HIV treatment, especially for ARVs which are CYP substrates. We also discussed the preclinical and clinical studies using the nanotechnology strategy to overcome the limitations of these CYP substrates. The preclinical studies and clinical studies published from 2000 to February 2019 were discussed.
Expert opinion: Since preclinical and clinical studies for prevention and treatment of HIV using nanotechnology approaches have shown considerable promise in recent years, nanotechnology could become an alternative strategy for daily oral therapy as a future treatment.
... Another example is DRV, a CYP inhibitor from the PIs. DRV has poor oral bioavailability (37%), metabolizes in the liver by CYP enzymes, and may lead to liver diseases and skin rashes [95,96]. Desai et al. demonstrated that solid lipid nanoparticles loaded DRV has fourfold increased permeability than DRV plain drug [97]. ...
Introduction: Drugs used in HIV treatment; all protease inhibitors, some non-nucleoside reverse transcriptase inhibitors, and pharmacoenhancers ritonavir and cobicistat can inhibit cytochrome P450 (CYP) enzymes. CYP inhibition can cause clinically significant drug-drug interactions (DDI), leading to increased drug exposure and potential toxicity.
Areas covered: A complete understanding of pharmacodynamics and CYP-mediated DDI is crucial to prevent adverse side effects and to achieve optimal efficacy. We summarized the pharmacodynamics of all the CYP inhibitors used for HIV treatment, followed by a discussion of drug interactions between these CYP inhibitors and other drugs, and a discussion on the effect of CYP polymorphisms. We also discussed the potential advancements in improving the pharmacodynamics of these CYP inhibitors by using nanotechnology strategy.
Expert opinion:
The drug-interactions in HIV patients receiving ARV drugs are complicated, especially when patients are on CYP inhibitors-based ART regimens. Therefore, evaluation of CYP-mediated drug interactions is necessary prior to prescribing ARV drugs to HIV subjects. To improve the treatment efficacy and minimize DDI, novel approaches such as nanotechnology may be the potential alternative approach. However, further studies with large cohort need to be conducted to provide strong evidence for the use of nano-formulated ARVs to effectively treat HIV patients.
... These results are consistent with a subset analysis of the POWER 1 and 2 studies in patients with HIV strains susceptible to darunavir, which showed similar virological response rates with once-daily darunavir/r 400/100 and 800/100 mg (78% and 74%, respectively, at week 24). [28][29] In addition, clinical trials of darunavir/r in PI-naive or -experienced patients have shown no correlation between PK exposure to darunavir and plasma HIV RNA suppression, when HIV-1 was susceptible to darunavir, suggesting that the optimal dose of darunavir in patients with a susceptible strain is as yet unknown. 30,31 It is also reassuring that preliminary PK data reported from the ANRS 165 Darulight study showed a similar AUC of darunavir at the dose of 800/100 or 400/100 mg, with an increase in ritonavir AUC with the low darunavir dose probably because of lower induction on ritonavir. ...
Objectives:
To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs.
Design:
A multicentre, Phase II, non-comparative, single-arm, open-label study.
Setting:
Tertiary care hospitals in France.
Subjects:
One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs.
Primary outcome measure:
Proportion of patients with treatment success: plasma HIV RNA level ≤50 copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis.
Results:
At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%-96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation.
Conclusions:
In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks.
... In the post-authorisation information on darunavir, we found no clear reference to the final reports of the three pivotal trials [23][24][25]. Possibly a pooled analysis of these results satisfied the specific obligation, providing information on the resistance to darunavir in HIV patients heavily treated with other antiretroviral drugs. Similarly, we could not find any clear statement on the submission of an open-label extension of previous studies in combination with low-dose ritonavir. ...
This paper examines conditional approvals that allow the marketing of medicines with unsettled benefit-risk profiles in the European Union.
We identified medicines that had received conditional approval from the European Medicines Agency in the period January 2006-June 2015. We searched the reasons and bases for approvals, the median time to address the specific obligations imposed in order to cover the information gap and allow regular authorisations, and their extent of fulfilment.
Of the 26 products conditionally authorised two were withdrawn for commercial reasons, ten were switched to regular approval, and 14 are still under conditional approval. Conditional approval was granted mainly to medicinal products intended for seriously debilitating disease or life-threatening disease. The median time to address the specific obligations was four years (range 0.2 to 7.7). There were delays or discrepancies in the fulfilment of these obligations in more than one third of the authorisation procedures.
In most cases there was limited evidence supporting the positive benefit-risk balance at the time of approval. Delays or discrepancies in the fulfilment of obligations allow medicinal products with unsettled benefit-risk profiles onto the market for several years. This should be taken into account when further early or step-wise licensing strategies are considered.
Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
... 12 Two randomized, controlled, phase IIb studies, POWER-1 (USA) and -2 (Europe), brought darunavir to the forefront of attention and led to an accelerated approval of darunavir for use in combination with ritonavir in adults with HIV strains that are resistant to other PIs. [13][14][15] In Romania the need for safety and efficacy data for darunavir used in subtype F HIV-1 ART-experienced patients was the starting point of this project. The primary aim of the current national multi-center prospective study was to evaluate the efficacy (CD4 cell count, viral load, and treatment compliance) of DRV/r and other ARV medications under marketed conditions in subtype F HIV-1 infected, treatment-experienced subjects in routine clinical practice in Romania. ...
Introduction:
The aim of the study was to assess the safety and efficacy of darunavir (Prezista(®)) used in subtype F human immunodeficiency virus - type 1 (HIV-1) infected, antiretroviral therapy (ART)-experienced patients in Romania in routine clinical practice.
Methods:
This was a post-authorization, open-label, one-cohort, non-interventional, prospective study conducted at multiple sites in Romania to assess efficacy (CD4 cell count, viral load, and treatment compliance) and safety ([serious] adverse events, clinical laboratory evaluation, and vital signs) of darunavir in combination with low-dose ritonavir (DRV/r) and other antiretroviral (ARV) medications in subtype F HIV-1 infected subjects in naturalistic settings. Seventy-eight subjects were recruited by 9 investigational sites and received 600/100 mg DRV/r twice daily.
Results:
Treatment with DRV/r administered with other ARV medications resulted in the expected, statistically relevant improvement of CD4 cell count and viral load in subjects eligible for such treatment. In addition, adherence to treatment was high and the treatment-emergent safety profile observed during this study was consistent with the established safety profile of darunavir.
Conclusion:
DRV/r administered in combination with other ARV medications in subtype F HIV-1 infected subjects in naturalistic settings proved to be an effective and safe treatment in Romania.
Trial registration:
NCT01253967.
... In randomized controlled trials comparing regimens containing newer drugs (approved since 2005) to background regimens consisting of conventional drugs optimized through the use of resistance tests, the newer drug regimens more effectively suppressed viral load and increased CD4 counts. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Newer drugs are particularly useful when used in combination. Epidemiological data from Western Europe in 2000 indicate that 32% of patients had exhausted all available drug options; in 2008 this proportion had decreased to 1%, in large part due to the availability of newer antiretroviral drugs. ...
Newer antiretroviral drugs provide substantial benefits but are expensive. We determined the cost-effectiveness of using antiretroviral drugs in combination for patients with multi-drug resistant HIV disease.
We built a cohort state-transition model representing treatment-experienced patients with low CD4 counts, high viral load levels, and multi-drug resistant virus. We estimated the effectiveness of newer drugs (those approved in 2005 or later) from published randomized trials. We estimated other parameters from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of two newer drugs and one conventional drug, compared to three conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness.
Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared to conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting three newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued.
In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior.
... The safety and efficacy of DRV/r at 600/100 mg twice daily have been also established in treatment-experienced patients in the POWER 1 and 2 trials at 24 [10][11][12][13] and 48 [14] weeks. DRV/r was generally well tolerated, with no clear dose-response relationship for the safety parameters there were evaluated. ...
... Patients who received tipranavir-ritonavir (TPV/r) with an optimized background regimen have achieved and maintained more treatment response than patients who received investigator selected comparator PIs (CPIs) with optimized background regimens [9]–[11]. Similarly, patients who received darunavir-ritonavir (DRV/r) with optimized background regimens also achieved and maintained more treatment response than patients who received CPIs-ritonavir based regimens [12]–[18]. ...
The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of
Heavily treatment-experienced (HTE) persons with HIV have limited options for antiretroviral therapy and face many challenges, complicating their disease management. There is an ongoing need for new antiretrovirals and treatment strategies for this population. We reviewed the study designs, baseline characteristics, and results of clinical trials that enrolled HTE persons with HIV. A PubMed literature search retrieved articles published between 1995 and 2020, which were grouped by trial start date (1995–2009, N = 89; 2010–2014, N = 3; 2015–2020, N = 2). Clinical trials in HTE participants markedly declined post-2010. Participant characteristics and study designs showed changes in trends over time. As treatment strategies for HTE persons with HIV progress, we must look beyond virologic suppression to consider the broader needs of this complex heterogeneous population.
Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains. Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose. The t 1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir. An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas. Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable. For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required. This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals.
Background:
This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum.
Methods:
Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography (HPLC). Target darunavir area under the concentration time curve (AUC) was >70% (43.6 mcg*hr/mL) of median AUC (62.3 mcg*hr/mL) in non-pregnant adults on twice daily darunavir-ritonavir 600/100 mg.
Results:
Twenty-four women were included in the analysis. Darunavir AUC0-12 was lower with the increased dose during the second [(geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88; p=0.055)] and third trimesters (GMR 0.64 (IQR 0.55-0.73; p=<0.001) compared to postpartum. Darunavir apparent clearance was higher in during the second (GMR 1.77 (IQR 1.24-2.51; p=0.039) and third trimesters (GMR 2.01 (IQR 1.17-2.35; p=<0.001) compared to postpartum. Similarly, ritonavir AUC0-12 was lower during the third trimester (GMR 0.65 (IQR 0.52-0.82; p=0.007) compared to postpartum, while its apparent clearance was higher during the third trimester (GMR 1.53 (IQR 1.22-1.92; p=0.008) compared to postpartum. No major drug-related safety concerns were noted.
Conclusion:
Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared to 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.
Introduction: Darunavir (DRV) was the last approved protease inhibitor (PI) and has been extensively used for the treatment of HIV in both naïve and experienced subjects due to its high genetic barrier and efficacy. The introduction in clinical practice of integrase strand transfer inhibitors limited its role in the management of naïve subjects and in antiretroviral treatment simplification strategies. However, recent data from trials that have investigated the new DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) combination showed an excellent efficacy and tolerability of this coformulation both in naïve patients and in those with viral suppression, making D/C/F/TAF a new option for the treatment of HIV infection.
Areas covered: The authors present and discuss the efficacy and safety data of DRV when used in antiretroviral-naïve, multiexperienced subjects and in the setting of treatment deintensification in subjects with viral suppression. Moreover, the authors evaluate the recent data from two different Phase III trials on D/C/F/TAF both in treatment-naïve and virologically suppressed subjects.
Expert opinion: Although novel antiretroviral drugs may become available over time, DRV continues to represent a valuable option for multiexperienced subjects and has a role in simplification regimens. In addition, the convenience of D/C/F/TAF coformulation may be useful for the future management of HIV-infected subjects.
Background:
Darunavir/ritonavir is a potent PI with a high genetic barrier and pharmacological robustness favourably investigated as monotherapy. Whether darunavir could be dose reduced in the context of monotherapy deserves investigation.
Methods:
Patients with HIV suppressed viraemia (plasma viral load <50 copies/mL for 12 months) under ART who had switched to darunavir/ritonavir monotherapy at 600/100 mg/day between 2013 and 2015 were included in this observational 48 week single-centre study. The primary outcome was the proportion of patients with virological success (defined as plasma viral load <50 copies/mL) at week 24. Secondary outcomes included treatment strategy success and resistance.
Results:
Thirty-one patients were included with the following baseline characteristics [median (IQR)]: age 52 years (47-57), CD4+ 649 cells/mm3 (463-813), ART duration 16.3 years (9.2-22.3), nadir CD4+ 195 cells/mm3 (144-261) and duration of HIV suppression 7.8 years (4.8-9.7). Prior to switch, ART consisted of PI monotherapy for 28 of 31 patients [darunavir/ritonavir 800/100 mg/day (n = 26), lopinavir/ritonavir (n = 1) and atazanavir/ritonavir (n = 1)] and a triple drug regimen for 3 of 31 patients. Within the 48 weeks of follow-up, no virological failure occurred and two patients discontinued 600/100 mg of darunavir/ritonavir due to side effects at week 16 and 40, leading to a virological suppression rate of 100% (95% CI = 89-100) at weeks 24 and 48. Strategy success rates were 96.8% (95% CI = 83.3-99.9) at week 24 and 93.5% (95% CI = 78.6-99.2) at week 48. Median (IQR) Ctrough values of 800/100 mg of darunavir/ritonavir and 600/100 mg of darunavir/ritonavir were 1537 ng/mL (1286-1724) and 1255 ng/mL (873-2161), respectively.
Conclusions:
A lower dose of darunavir/ritonavir used as monotherapy (600/100 mg/day) was highly effective in virologically suppressed HIV-infected patients. Further studies are needed to confirm these data.
Darunavir has a low oral bioavailability (37%) due to its lipophilic nature, metabolism by cytochrome P450 enzymes and P-gp efflux. Lipid nanoparticles were prepared in order to overcome its low bioavailability and to increase the binding efficacy of delivery system to the lymphoid system. Darunavir-loaded lipid nanoparticles were prepared using high-pressure homogenization technique. Hydrogenated castor oil was used as lipid. Peptide, having affinity for CD4 receptors, was grafted onto the surface of nanoparticles. The nanoparticles were evaluated for various parameters. The nanoparticles showed size of less than 200 nm, zeta potential of − 35.45 mV, and a high drug entrapment efficiency (90%). 73.12% peptide was found conjugated to nanoparticles as studied using standard BSA calibration plot. Permeability of nanoparticles in Caco-2 cells was increased by 4-fold in comparison to plain drug suspension. Confocal microscopic study revealed that the nanoparticles showed higher uptake in HIV host cells (Molt-4 cells were taken as model containing CD4 receptors) as compared to non-CD4 receptor bearing Caco-2 cells. In vivo pharmacokinetic in rats showed 569% relative increase in bioavailability of darunavir as compared to plain drug suspension. The biodistribution study revealed that peptide-grafted nanoparticles showed higher uptake in various organs (also in HIV reservoir organs namely the spleen and brain) except the liver compared to non-peptide-grafted nanoparticles. The prepared nanoparticles resulted in increased binding with the HIV host cells and thus could be promising carrier in active targeting of the drugs to the HIV reservoir.
The present investigation aimed to study the effect of particle size of solid lipid nanoparticles (SLNs) on oral bioavailability of Darunavir. High pressure homogenization technique was used to prepare SLNs. Three different sized SLNs loaded with Darunavir were developed with mean particle sizes of around 100 nm, 200 nm and 500 nm respectively. The in-vivo pharmacokinetics in rats showed a significant increase in oral bioavailability of Darunavir from all the three formulations in comparison to plain drug suspension and reference tablet. The results revealed insignificant difference between SLNs of 100 and 200 nm and these had significantly higher bioavailability in comparison to SLNs of 500 nm. However, more number of homogenization cycles is required for obtaining 100 nm and thus we selected 200 nm as an optimum size for oral bioavailability enhancement of Darunavir. The optimized SLN formulation was stable for a period of 6 months at 25±2ºC/60±5% RH.
Background:
The possibility of incorporating generics into combination antiretroviral therapy and breaking apart once-daily single-tablet regimens (STRs), may result in less efficacious medications and/or more complex regimens with the expectation of marked monetary savings. A modeling approach that assesses the merits of such policies in terms of lifelong costs and health outcomes using adherence and effectiveness data from real-world U.S. settings.
Methods:
A comprehensive computer-based microsimulation model was developed to assess the lifetime health (life expectancy and quality adjusted life-years-QALYs) and economic outcomes in HIV-1 infected patients initiating STRs compared with multiple-table regimens including generic medications where possible (gMTRs). The STRs considered included tenofovir disoproxil fumarate/emtricitabine and efavirenz or rilpivirine or elvitegravir/cobicistat. gMTRs substitutions included each counterpart to STRs, including generic lamivudine for emtricitabine and generic versus branded efavirenz.
Results:
Life expectancy is estimated to be 1.301 years higher (discounted 0.619 QALY gain) in HIV-1 patients initiating a single-tablet regimen in comparison to a generic-based multiple-table regimen. STRs were associated with an average increment of $26,547.43 per patient in medication and $1,824.09 in other medical costs due to longer survival which were partially offset by higher inpatients costs ($12,035.61) with gMTRs treatment. Overall, STRs presented incremental lifetime costs of $16,335.91 compared with gMTRs, resulting in an incremental cost-effectiveness ratio of $26,383.82 per QALY gained.
Conclusions:
STRs continue to represent good value for money under contemporary cost-effectiveness thresholds despite substantial price reductions of generic medications in the U. S.
Highly active antiretroviral therapy (HAART) is a therapeutic intervention developed by clinicians and researchers in order to fight the HIV pandemic. It has contributed to a significant reduction in AIDS-related mortality and allowed many previously bed-ridden patients to live healthier, more productive lives. Until the advent of HAART in 1996, a diagnosis of HIV infection was considered a death sentence. A decade later, the disease has been transformed into a serious, yet potentially manageable, medical condition for thousands of people living with HIV/AIDS in the developed world — almost overnight creating a generation of ‘HIV Survivors’ — and forged a global movement to ensure that its Lazarus-like benefit reaches millions more in the developing world. This book reviews the achievements of HAART over the past decade and explores the challenges that may arise in the future. It recounts key landmarks in the development and introduction of HAART from the perspective of clinicians, researchers, economists, sociologists, and public policy experts, including the co-discoverers of HIV, Luc Montagnier and Robert Gallo. It explores the evolution of the disease, the evolution of HIV treatment, and the economic, social, and public policy impacts of both HIV and the introduction of HAART.
Introduction:
Cobicistat-boosted darunavir is a boosted protease inhibitor in a fixed-dose combination to be approved for the treatment of human immunodeficiency virus type1 infection. It contains darunavir, a well-known protease inhibitor with a good efficacy and safety profile, and the new pharmacokinetic enhancer cobicistat. The convenience of this combination in a single pill makes this compound easier to take, thus improving adherence. Areas covered: PubMed and www.clinicaltrials.gov were searched with the term "darunavir/cobicistat" for all clinical trials conducted up to date, as well as for those ongoing and to be opened in the near future as well as for pharmacology data. A review of abstracts from major infectious diseases (particularly those dedicated to human immunodeficiency disease) and pharmacology conferences from 2010 to 2015 was also conducted. Expert opinion: improving adherence, particularly by minimizing pill burden with convenient formulations (i.e., fixed-dose combination), is one of the major objectives of modern antiretroviral treatment of patients with human immunodeficiency virus disease. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels for several antiretrovirals. Darunavir co-administered with low-dose ritonavir, in combination with other antiretrovirals, is recommended in several guidelines for treatment of patients with human immunodeficiency disease. Darunavir/cobicistat fixed-dose combination allows for a once-daily treatment regimen with a reduced pill burden. This new co formulation makes this compound easier to take, thus improving adherence.
IntroductionDiscoverySynthesisFormulationPreclinical DevelopmentClinical DevelopmentFuture DirectionsConclusions
References
Maximizing ART efficiency is of growing interest. This study assessed the efficacy, safety, pharmacokinetics and economics of a darunavir dose-reduction strategy.
This was a multicentre, randomized, open-label clinical trial in HIV-infected patients with plasma HIV-1 RNA <50 copies/mL while receiving triple ART including 800 mg of darunavir once daily. Participants were randomized to continue 800 mg of darunavir (DRV800) or to 600 mg of darunavir (DRV600), both once daily. Treatment failure was defined as two consecutive HIV-1 RNA determinations >50 copies/mL or discontinuation of study treatment by week 48. The study was registered at https://www.clinicaltrialsregister.eu (trial number 2011-006272-39).
Fifty participants were allocated to each arm. The mean (SD) CD4+ T cell count at baseline was 562 (303) cells/mm(3) and HIV-1 RNA had been <50 copies/mL for a median (IQR) of 106.9 (43.4-227.9) weeks before enrolment. At week 48 no treatment failure had occurred in 45/50 (90%) DRV600 patients and in 47/50 (94%) DRV800 patients (difference -4%; 95% CI lower limit, -12.9%). When only patients with virological data were considered, that endpoint was met by 45/48 (94%) in the DRV600 arm and 47/49 (96%) in the DRV800 arm (difference -2.2%; 95% CI lower limit, -9.6%). Darunavir exposure was similar in the two arms. The average reduction in annual cost per successfully treated DRV600-arm patient was US$7273.
The efficacy of a darunavir daily dose of 600 mg seemed to be similar to the efficacy of the standard 800 mg dose in virologically suppressed HIV-infected patients on triple ART. This strategy can potentially translate to substantial savings in the cost of care of HIV-infected patients.
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Background
The currently approved dose of darunavir/ritonavir is 800/100 mg once daily for PI-naïve patients, and 600/100 mg twice daily for PI-pretreated patients. However, in DRV-sensitive patients at baseline in the POWER 1/2 trials, similar rates of HIV RNA suppression (1 log reduction) were achieved with doses ranging from 400/100 mg once daily to 600/100 mg twice daily. In previously virologically suppressed patients, a reduced dose of DRV (600/100 QD) is non-inferior to the standard dose (800 mg QD)[1] and DRV concentrations in plasma and CSF are similar in patients receiving the above different doses [1, 2].
Methods
Twelve treatment-naïve patients were started on darunavir/ritonavir 600/100mg once daily, with TDF/FTC (8) or ABC/3TC (4). Seven patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (2), ABC/3TC (2), NVP (1), AZT/3TC (1). One was on monotherapy with DRV. Seven treatment-experienced patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (5), ABC/3TC (1), RAL (1).
Results
Of the 12 naïve patients (mean baseline HIV RNA 134,024 log10 copies/mL, range 4,256-397,932), 11 had HIV RNA <20 c/mL after a mean 27.4 months of follow-up (range 12–33). Mean PK level was 2,920 ng/mL (1,268–4,562). One patient had virological failure after 14 months (HIV RNA 39,300 copies/mL); no mutations were detected and after introduction of DRV/r 600 mg b.i.d., he returned aviremic. All switched patients maintained HIV RNA suppression (<20 c/mL) for a mean of 32.8 months (range 21-54). PK level was available for one patient only (Ctrough 3,442 ng/mL). Of the treatment-experienced patients (mean baseline HIV RNA 24,167 log10 copies/mL, range 112–111,426), five maintained HIV RNA suppression for a mean of 46.2 months (range 31–67). One patient interrupted HAART for three months and then restarted it, the latest HIV RNA level being 628 copies/mL after five weeks of therapy. One patient failed after 42 months (HIV RNA 3,930 copies/mL); after intensification (DRV/r 600 twice daily), he returned aviremic. PK levels were available for three patients (mean 2,502 ng/mL; range 844–4,518).
Conclusions
In this pilot study of 26 patients, use of DRV/r at 600/100 mg OD dose led to sustained HIV RNA suppression in 23 patients with acceptable PK exposures to DRV. Large non-inferiority trials are warranted to establish its efficacy.
Darunavir is a synthetic non-peptidic protease inhibitor that has been shown to be extremely potent against wild-type HIV, and it is an important component of highly active antiretroviral treatment (HAART), which is considered as one of the most significant advances in the field of HIV therapy. However, there are some concerns about darunavir quality control. Darunavir shows pseudo-polymorphism: in different ambient conditions one pseudo-polymorphic form can change to another. This behavior of darunavir is problematic because the dosage form is exposed to different ambient conditions around the world, since HIV/AIDS is prevalent globally. Issues around differences in the solubility and effects that different forms of darunavir can cause are of concern, and a more stable form is preferable. Important investigations of darunavir such as dissolution behavior, polymorphism, stability and degradation studies, and the impact of that on the quality of the product are being conducted by our working group. A cure for HIV/AIDS remains a long-term commitment, and there is much yet to achieve. This article discusses, by a critical review of the literature, the impact of the use of darunavir in the treatment of HIV-infected patients, its physical-chemical properties, the analytical methods to determine it, and challenges that remain in order to ensure the quality and stability of darunavir.
The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.
Objectives:
The study aimed to investigate the incidence of and associated factors with skin rashes among HIV-infected Taiwanese patients who received once-daily darunavir (DRV) boosted by ritonavir (RTV) (800/100 mg) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs).
Methods:
We reviewed the medical records of HIV-infected patients who switched to once-daily DRV/RTV-containing regimens between January 2012 and November 2013. Patients who switched from 2 NRTIs plus non-NRTI (nNRTI) or other protease inhibitor (PI) to 2 NRTIs plus PIs other than DRV were chosen as comparators.
Results:
During the study period, 238 patients who switched to once-daily DRV/RTV-containing regimens (Group A) and 178 patients who switched from 2 NRTIs plus nNRTI or other PI to 2 NRTIs plus PI other than DRV/RTV (Group B) were included. There were no differences between Groups A and B in most of the baseline characteristics. Compared with Group B in which 7 (3.9%) developed rashes after switch to PI other than DRV, 26 patients (10.9%) in Group A developed rashes after a median interval of 14 days of starting DRV/RTV-containing regimens (P = 0.009). In multivariate analysis, patients with a history of rashes related to the previous nNRTI-containing regimens before starting DRV/RTV-containing regimens were more likely to develop rashes with an adjusted odds ratio of 3.53 (95% confidence interval, 1.45-8.62).
Conclusions:
Once-daily regimens containing DRV/RTV is associated with a higher rate of adverse cutaneous reactions than other PI-containing regimens in HIV-infected Taiwanese, especially in those who have a history of rashes to nNRTI-containing regimens before switch to DRV/RTV-containing regimens.
The latest HIV-1 protease inhibitor (PI) darunavir (Prezista™) has a high genetic barrier to resistance development and is active against wild-type HIV and HIV strains no longer susceptible to some older PIs. Ritonavir-boosted darunavir, as a component of antiretroviral therapy (ART), is indicated for the treatment of HIV-1 infection in adult and paediatric patients (aged ≥3 years), with or without treatment experience (details vary depending on region of approval). Several open-label or partially-blinded trials have evaluated the efficacy of ritonavir-boosted darunavir ART regimens for up to 192 weeks in these settings. In treatment-naïve adults, once-daily boosted darunavir was no less effective in establishing virological suppression than once- or twice-daily boosted lopinavir, yet was more effective at maintaining suppression long term. Moreover, treatment-experienced adults with no darunavir resistance-associated mutations (RAMs) had no less effective viral load suppression with once-daily than with twice-daily boosted darunavir. In treatment-experienced adults, including some with multiple major PI RAMs, twice-daily boosted darunavir was more effective than twice-daily boosted lopinavir or boosted control PIs in reducing viral load, and provided virological benefit as part of a salvage regimen in those with few remaining treatment options. Boosted darunavir also reduced viral load when administered once-daily in treatment-naïve adolescents or twice-daily in treatment-experienced children and adolescents. Boosted darunavir is generally well tolerated, with gastrointestinal disturbances and lipid abnormalities among the most common tolerability issues. It has a lipid profile more favourable than that of boosted lopinavir in terms of total cholesterol and triglyceride changes and, when administered once daily, its lipid effects are generally similar to those of boosted atazanavir. Thus, boosted darunavir is a useful option for the ART regimens of adult and paediatric patients with HIV-1 infection.
Introduction:
Published data addressing the effectiveness of darunavir-ritonavir (DRV/r)-based therapy for multiexperienced patients in developing countries are scarce. This study evaluated the 48-week virologic and immunologic effectiveness of salvage therapy based on DRV/r for the treatment of multidrug-experienced HIV-1-infected adults in Brazil.
Materials and methods:
A multicenter retrospective cohort study was carried out with multidrug-experienced adults who were on a failing antiretroviral therapy and started a DRV/r-based salvage therapy between 2008 and 2010. The primary effectiveness end point was the proportion of patients with virologic success (plasma HIV-1 RNA <50 copies/mL at week 48).
Results:
At 48 weeks, 73% of the patients had HIV-RNA <50 copies/mL and a mean increase of 108 CD4 cells/mm(3). Higher baseline viral load, lower baseline CD4 count, younger age, and 3 or more DRV/r-associated resistance mutations were significantly predictive of virologic failure. Concomitant use of raltegravir was strongly associated with virologic success.
Conclusion:
The use of DRV/r-based regimens for salvage therapy is an effective strategy in the clinical care setting of a developing country.
There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited. AIM:: To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response.
Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated.
DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found.
In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.
Darunavir was approved in 2006 by the US FDA for patients harboring HIV-1 resistant to more then one protease inhibitor. It belongs to the second generation of protease inhibitors with potent activity against viral strains to all currently available protease inhibitors. Darunavir should always be co-administrated with low-dose ritonavir and with food. Current guidelines suggest that the goal of therapy in all HIV infected patients, including heavily experienced, is full viral suppression. Treatment options for patients infected with multidrug resistant HIV are limited. The results of clinical trials demonstrated that darunavir is effective and well tolerated. The POWER-1, 2, and 3 trials that used DRV/r showed that the compound had a potent effect in heavily pretreated patients. Ongoing studies in treatment-naïve and treatment-experienced will provide more data on the safety and efficacy of darunavir.
Autoimmune hepatitis is a rare clinical entity characterized by interface hepatitis, hypergammaglobulinaemia and circulating antibodies. The coexistence of AIH and HIV infection has been reported previously in only 7 cases in the literature. This paper describes a case of a patient with HIV infection, on ARV therapy who developed an icteric hepatitis. Diagnostic challenges and difficulties are presented with comparison to previously described cases.
Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.
Correspondencia: Unidad de Enfermedades Infecciosas. Consorcio Hospital General Universitario. Avda. Tres Cruces, s/n. 46014 Valencia. España.
The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronisation with κ-carrageenan or microcrystalline cellulose (MCC) as pelletisation aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2±3.5h from MCC pellets (1301±301μm) and 6.1±0.7min from κ-carrageenan pellets (966±136μm). In contrast to κ-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300mg dose were more than 60-fold higher when formulated with κ-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (Frel) was 155% with κ-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in κ-carrageenan pellets, likely due to their better disintegration behavior.
Darunavir (formerly known as TMC 114) is a protease inhibitor that was approved by the US FDA in June 2006 for use in treatment-experienced patients, with markedly greater virological and immunological benefits compared with the standard of care. It is dosed twice daily with food and requires boosting with ritonavir. It has demonstrated virological efficacy in vivo, with activity against protease inhibitor-resistant HIV, and in treatment-naive patients in clinical studies with up to 48-week follow-up in combination with an optimized background regimen. Darunavir used with low-dose ritonavir is a largely well-tolerated protease inhibitor with proven efficacy.
The potential for once-daily use of darunavir in combination with low-dose ritonavir (darunavir/ritonavir) in antiretroviral-naive patients has been evaluated in the Phase III ARTEMIS trial. This followed the demonstration of sustained efficacy and a favorable safety profile of darunavir/ritonavir 600/100 mg twice daily in patients with a broad range of treatment experience in the Phase IIb POWER and Phase III TITAN studies. The 48-week primary analysis of ARTEMIS demonstrated that once-daily darunavir/ritonavir 800/100 mg was noninferior to lopinavir/ritonavir, given either 400/100 mg twice daily or 800/200 mg every day, in treatment-naive, HIV-1-infected patients (84 vs 78% of patients, respectively, had confirmed plasma HIV-1 RNA less than 50 copies/ml by per-protocol time-to-loss of virologic response at week 48). In patients with baseline HIV RNA more than 100,000 copies/ml, darunavir/ritonavir achieved higher response rates than lopinavir/ritonavir (79 vs 67%; p <0.05). In addition to being at least as effective as lopinavir/ritonavir, once-daily darunavir/ritonavir had tolerability advantages compared with lopinavir/ritonavir, including lower incidences of grade 2-4 gastrointestinal adverse events (mainly diarrhea), and triglyceride and total cholesterol elevations. These benefits, along with the convenience of once-daily darunavir/ritonavir 800/100 mg and its low propensity to the development of resistance, suggest darunavir/ritonavir is a valuable treatment option for treatment-naive patients.
Darunavir is a new protease inhibitor (PI) active against wild-type and drug-resistant HIV-1 strains and has recently been approved for use in treatment-experienced adult patients. The main clinical trials, POWER and TITAN, have been conducted in treatment-experienced, HIV-1-infected patients. The Phase Mb POWER 1 and 2 trials compared the efficacy and safety of darunavir plus low-dose ritonavir (darunavir/ritonavir) with currently available Pls in highly treatment-experienced patients receiving an optimized background regimen. At 24 and 48 weeks in POWER 1 and 2, patients receiving darunavir/ritonavir had significantly higher efficacy responses than those receiving currently available Pis (45 vs 10% of patients reached a viral load <50 copies/ml at week 48). The highest responses were observed with the darunavir/ritonavir 600/100 mg twice daily dose (also evaluated in the POWER 3 analysis), which was selected for the subsequent Phase III TITAN study. TITAN evaluated darunavir/ritonavir 600/100 mg twice daily in comparison with lopinavir/ ritonavir in early treatment-experienced, lopinavir-naive patients. For the primary end point of a viral load of less than 400 copies/ml, darunavir/ritonavir was noninferior to lopinavir/ritonavir (77 vs 68%; 95% confidence interval [Ci]: 2-16); for a viral load of less than 50 copies/ml, darunavir/ritonavir was again noninferior to the lopinavir/ ritonavir group (71 vs 60%; 95% CI: 3-19). Both regimens were well tolerated, although discontinuations due to diarrhea and liver and lipid abnormalities were less frequent in the darunavir/ritonavir group. Darunavir/ritonavir has been shown to be effective in patients with a broad range of treatment experience and has the potential to become used across the HIV treatment spectrum, including in antiretroviral-naive patients.
Five years after its initial approval, an overwhelming amount of pivotal data has come out on darunavir/ritonavir. It is the only antiretroviral that has been registered at two different doses, 800/100 mg once‑daily or 600/100 mg twice‑daily, allowing its administration throughout the entire course of HIV disease, from naive subjects without any HIV‑1 resistance to heavily treatment‑experienced subjects with widespread triple‑class family resistance. Its binding affinity is more than 100‑fold higher compared to other protease inhibitors, which poses extreme difficulties for wild‑type viruses to develop in vitro resistance to darunavir. It is a preferred option for initial therapy as no subjects developing virologic failure select darunavir resistance mutations in this scenario. It is the default protease inhibitor for early and advanced salvage regimens in subjects with virologic failure. The once‑daily darunavir dose has demonstrated non‑inferior efficacy against the twice‑daily dose in early stages of virologic failure in pretreated subjects without darunavir mutations, both doses retaining the genetic barrier against resistance seen in treatment‑naives. With a high potency, superior genetic barrier to HIV‑1 resistance development, and favorable pharmacokinetics, it meets the optimal requirements for being a candidate for once‑daily antiretroviral monotherapy - a challenging proof‑of‑concept in HIV medicine. It has demonstrated non‑inferior efficacy at 48 weeks against triple therapy in selected pretreated patients with suppressed plasma viremia, without evolution of protease resistance being seen up to 144 weeks. The present article summarizes the clinical implications of the key data on efficacy of darunavir.
Background:
ODIN (once-daily darunavir in treatment-experienced patients) was a 48-week, phase III, randomized, open-label trial comparing once-daily (qd) darunavir/ritonavir (DRV/r) 800/100 mg with twice-daily (bid) DRV/r 600/100 mg, both with an optimized background regimen [OBR; at least two nucleoside reverse transcriptase inhibitors (NRTIs)], in treatment-experienced, HIV-1-infected adults with no DRV resistance-associated mutations (RAMs) at screening. Week 48 analyses of virological response by subgroups are reported.
Methods:
A total of 590 patients were randomized to receive qd (n=294) or bid (n=296) DRV/r. Virological response (HIV-1 RNA <50 copies/mL) was assessed according to: screening HIV-1 RNA (≥ or <50000 copies/mL), CD4 cell count, prior protease inhibitor (PI) use, number of active NRTIs in the OBR, presence of mutations (primary PI mutations, PI RAMs or M184V/I), gender, age, race, HIV-1 clade and adherence.
Results:
Baseline characteristics were well balanced between arms and across subgroups. Response rates were comparable between qd and bid DRV/r treatments for all subgroups examined. Response rates were 78.4 and 76.8% in the qd and bid treatment arms, respectively, in patients with baseline HIV-1 RNA ≤ 50000 copies/mL and 52.8% in both arms in those with > 50000 copies/mL. Response rates for the qd and bid treatment arms by baseline CD4 cell count were also similar (69.6 vs. 65.2% for <200 cells/μL; 72.2 vs. 74.8% for 200- <350 cells/μL; 77.0 vs. 74.3% for ≥ 350 cells/μL).
Conclusions:
DRV/r administered either qd or bid provided effective treatment for antiretroviral treatment-experienced patients with no DRV RAMs, with comparable response rates across all subgroups studied. Low patient numbers in specific subgroups may limit interpretation of these specific subgroup results.
To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.
The safety and antiviral activity of lopinavir (Lpv), a protease inhibitor (PI) coformulated with ritonavir (Rtv) to enhance
its pharmacokinetic properties, were evaluated in 70 patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA
levels of 1000–100,000 copies/mL on a first PI-containing regimen. Patients were randomized to substitute only the PI with
Lpv/Rtv, 400/100 mg or 400/200 mg twice daily. On day 15, nevirapine (200 mg 2×/day) was added, and nucleoside reverse-transcriptase
inhibitors were changed. Despite a >4-fold reduction in phenotypic susceptibility to the preentry PI in 63% of patients, mean
plasma HIV-1 RNA levels declined by 1.14 log10 copies/mL after 2 weeks of Lpv/Rtv. At week 48, 86% of subjects receiving treatment had plasma HIV-1 RNA levels of <400 copies/mL;
76% had levels <50 HIV-1 RNA copies/mL (intent-to-treat: 70% and 60%, respectively). Mean CD4 cell counts increased by 125
cells/µL. Three patients discontinued therapy for drug-related adverse events.
The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor.
Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24.
A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group.
The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.
Tenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor.
To evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients.
A prospective, randomized, double-blind study conducted at 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study.
Patients were randomized to receive either tenofovir DF (n = 299) or stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz.
Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48.
In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, -10.4% to 1.5%), exceeding the predefined -10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P =.06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n = 170] vs +134 mg/dL for stavudine [n = 162], P<.001), total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], P<.001), and high-density lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P =.003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, P<.001). The number of bone fractures and the renal safety profile were similar between the 2 groups.
Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.
To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options.
Multicentre cohort study.
Six large HIV treatment centres in southeast England.
All individuals seen for care between 1 January 1996 and 31 December 2002.
Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden.
Information is available on 16,593 individuals (13,378 (80.6%) male patients, 10,340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10,207 of the 16,593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of "viral load failure" with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3.
The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.
The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 muM (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naive and PI-experienced patients with HIV.
The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started receiving highly active antiretroviral therapy (HAART).
The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death.
Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P<.0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval [CI], 14%-54%; P<.0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up [PYFU], respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%-56%; P<.0001).
The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigation.