Michael Norton

Université de Montpellier 1, Montpelhièr, Languedoc-Roussillon, France

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Publications (27)85.17 Total impact

  • Pat A. Tookey · Claire Thorne · Jean van Wyk · Michael Norton
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    ABSTRACT: Background The National Study of HIV in Pregnancy and Childhood (NSHPC) conducts comprehensive population-based surveillance of pregnancies in women with HIV infection in the United Kingdom/Ireland. Use of antepartum antiretroviral therapy (ART) for prevention of mother-to-child transmission (MTCT) and to treat maternal infection, if required, is standard practise in this population; lopinavir/ritonavir (LPV/r) is commonly used. The study objective was to examine the use of LPV/r among pregnant women with HIV infection to describe maternal and foetal outcomes. Methods The NSHPC study collected maternal, perinatal and paediatric data through confidential and voluntary obstetric and paediatric reporting schemes. Pregnancies reported to the NSHPC by June 2013, due to deliver 2003–2012 and with LPV/r exposure were included in this analysis, using pregnancy as the unit of observation. Results Four thousand eight hundred sixty-four LPV/r-exposed pregnancies resulting in 4702 deliveries in 4118 women were identified. Maternal region of birth was primarily sub-Saharan Africa (77 %) or United Kingdom/Ireland (14 %). Median maternal age at conception was 30 years. LPV/r was initiated preconception in 980 (20 %) and postconception in 3884 (80 %) pregnancies; median duration of antepartum LPV/r exposure was 270 and 107 days, respectively. Viral load close to delivery was <50 copies/mL in 73 % and <1000 copies/mL in 94 % of women. 63 % of deliveries were by caesarean section (elective, 62 %; emergency, 38 %). Among singleton live births, 13 % were <37 weeks of gestation (2.5 % <32 weeks) and 15 % had birth weight <2500 g (2.3 % <1500 g). MTCT rates were 1.1 (2003–2007) and 0.5 % (2008–2012). 134 live born children (2.9 %) had ≥1 congenital abnormality. Conclusions The results of this analysis using real-world data from a large number of pregnant women with HIV infection in the United Kingdom and Ireland who received LPV/r-containing ART regimens demonstrate that these regimens have a good safety profile and are effective for viral suppression during pregnancy, with associated low rates of MTCT.
    No preview · Article · Dec 2015 · BMC Infectious Diseases
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    ABSTRACT: Increased access to successful antiretroviral therapy (ART) is necessary in order to achieve an AIDS-free generation. Importantly, slightly over half of the people living with HIV are women. Small studies have described many barriers to accessing treatment and care among women living with HIV. This cross-sectional, non-interventional, epidemiological study assessed the prevalence of barriers to accessing care for women living with HIV across 27 countries, divided into four global regions. HIV-positive women attending routine clinical visits were offered the opportunity to participate in the study. Data describing the study sites and demographic characteristics of the participating women were collected. Participating women filled out questionnaires including the Barriers to Care Scale (BACS) questionnaire, on which they reported the extent to which they found each of the 12 potential barriers to accessing health care problematic. A total of 1931 women living with HIV were included in the study: 760 from Western Europe and Canada (WEC), 532 from Central and Eastern Europe (CEE), 519 from Latin America (LA), and 120 from China. The mean age of participating women was 40.1 ± 11.4 years. A total of 88.2% were currently taking ART. A total of 81.8% obtained HIV treatment under a government health plan. The most prevalent barrier to care was community HIV/AIDS stigma. Community HIV/AIDS knowledge, lack of supportive/understanding work environments, lack of employment opportunities, and personal financial resources were also highly prevalent barriers to accessing care. These findings indicate that, more than 30 years after the start of the AIDS epidemic, stigma is still a major issue for women living with HIV. Continued efforts are needed to improve community education on HIV/AIDS in order to maximize access to health care among women living with HIV.
    No preview · Article · Jul 2015 · AIDS Care
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    ABSTRACT: Inhibition of the cytochrome p450 3A4 enzyme system leads to increases in plasma concentrations of coadministered antiretroviral agents - a concept known as pharmacokinetic boosting. Ritonavir and cobicistat are potent inhibitors of cytochrome p450 3A4. Ritonavir was initially developed as an HIV protease inhibitor, but is currently used primarily as a pharmacokinetic boosting agent for other HIV and hepatitis C protease inhibitors. Cobicistat is a boosting agent for the integrase inhibitor elvitegravir and the protease inhibitors atazanavir and darunavir. Phase III data showed that atazanavir + cobicistat + tenofovir/emtricitabine had non-inferior efficacy and resulted in similar CD4 T-cell count increases to atazanavir + ritonavir + tenofovir/emtricitabine. The tolerability, gastrointestinal, and lipid profile of the cobicistat-containing regimen was comparable with the ritonavir-containing regimen. Primary HIV protease resistance mutations were not selected in either ritonavir or cobicistat arm virologic failures. Cobicistat-containing regimens have consistently shown higher serum creatinine increases and creatinine clearance decreases compared with ritonavir, and accurate assessment of glomerular filtration in the presence of cobicistat could only be made by using exogenous markers such as iohexol. Drugs contraindicated with cobicistat are consistent with those contraindicated with ritonavir-containing protease inhibitor regimens with respect to cytochrome p450 3A interactions. Information in this review may help clinicians assess the benefits and limitations of currently available pharmacokinetic enhancers when selecting the most appropriate treatment for their patients.
    No preview · Article · Jan 2015 · AIDS reviews
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    ABSTRACT: Introduction During pregnancy, LPV/r is a common anchor drug employed to treat the mother's HIV-1 infection in addition to reducing the risk of mother-to-child transmission (MTCT). The National Study of HIV in Pregnancy and Childhood (NSHPC) conducts a comprehensive population-based surveillance of HIV infection in pregnant women exposed to antiretroviral therapy (ART) in the UK and Ireland; in 2003–2012 over a third of pregnancies reported to the NSHPC involved exposure to LPV/r. Methods We undertook a retrospective were descriptive analysis of individual NSHPC patient data, using pregnancy as the unit of observation. Clinical outcomes for pregnancies reported by June 2013, where women were exposed to LPV/r and due to deliver between January 2003 and December 2012, are described. Results A total of 4864 LPV/r exposed pregnancies in 4118 women were identified. These resulted in 4702 deliveries with 4759 live and 46 stillborn infants. Seventy five percent of women were born in sub-Saharan Africa, 13% in the UK or Ireland. Median maternal age at conception was 30 years. Nine hundred and eighty (20%) pregnancies were conceived while taking LPV/r, with a median duration of LPV/r exposure of 270 days. A total of 3884 (80%) pregnancies initiated LPV/r after conception, with a median duration of LPV/r exposure of 107 days. Viral load (VL) close to delivery was available for 4083/4702 (87%) deliveries, with VL <50 c/mL in 73% and <1000 c/mL in 94% of women. VL by timing of LPV/r initiation is shown in Table 1. Sixty three percent of deliveries were by C-section, of which 62% were classified as elective and 38% as emergency. Among singleton liveborn infants, 13% were born prior to 37 weeks gestation (2.5% <32 weeks) and 15% had birth weight <2500 g (2.3% <1500 g). HIV infection status was available for 4039 (89%) singleton infants. For the periods 2003–2007 and 2008–2012, MTCT rates were 1.1% (95% CI 0.6–1.6) and 0.5% (95% CI 0.2–0.8) respectively. Hundred and thirty four live born children (2.8%) had at least one congenital abnormality reported. Conclusions In the NSHPC database, in women exposed to LPV/r during pregnancy in the UK and Ireland, MTCT rates are low and continue to decline, and are similar to rates in the entire NSHPC cohort of women with diagnosed HIV [1]. The congenital abnormality rate is comparable with that reported for the uninfected population in this geographic region.
    Preview · Article · Nov 2014 · Journal of the International AIDS Society
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    ABSTRACT: Aim: To assess renal function changes among 172 treatment-naive subjects treated with lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) or LPV/r plus tenofovir/emtricitabine in the PROGRESS study, a prospective, randomized controlled trial. Patients & methods: Serum creatinine, creatinine clearance and chronic kidney disease category were compared between groups. Results: Mean change from baseline to week 96 in creatinine clearance was smaller with LPV/r plus RAL versus LPV/r plus tenofovir/emtricitabine (-1.4 vs -7.3 ml/min; p = 0.035). Chronic kidney disease category improvement was more frequent and the mean increase in serum creatinine was smaller for the LPV/r plus RAL group. Differences in estimated renal function were also detected when the analysis was performed according to baseline demographics. Conclusion: Smaller renal function declines were observed with LPV/r plus RAL. The results from this study warrant further evaluation of the renal safety profile of nucleotide reverse transcriptase inhibitor-sparing regimens.
    No preview · Article · Aug 2014 · Future Virology
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    ABSTRACT: CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV-positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients ≥18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART-experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART-experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted.
    Full-text · Article · Jul 2014 · AIDS Care
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    ABSTRACT: Aim: Data describing the safety and efficacy of antiretroviral therapy (ART) in HIV-infected patients aged 50 years are limited. We evaluated the effect of age on safety, efficacy and tolerability in patients aged <50 and 50 years receiving lopinavir/ritonavir (LPV/r)-containing ART. Methods: End points from AbbVie Inc. (IL, USA) or AIDS Clinical Trials Group randomized clinical trials in adults using LPV/r 800/200 mg/day as part of a three-drug regimen (follow-up 48 weeks) were evaluated using a random-effects meta-analysis (virologic efficacy; intent-to-treat; noncompleter = failure) or pooled data (other end points). Results: A total of 2608 patients (2294.3 patient-years of follow-up) from ten trials were included: 2248 patients (86.2%) <50 years of age and 360 (13.8%) 50 years of age. Demographics and baseline characteristics were similar between age groups. At week 48, 64.9 and 67.8% of patients <50 and 50 years, respectively, had plasma HIV-1 RNA <50 copies/ml (random effects meta-analysis p = 0.992). Mean change from baseline in CD4(+) T-cell count was +193.9 and +163.5 cells/l (<50 and 50 years, respectively; p < 0.001). Smaller proportions of patients <50 years of age discontinued due to adverse events (AEs)/HIV-related events (4.9 vs 9.4%; p = 0.001) and reported moderate-to-severe treatment-related AEs (30.5 vs 36.4%; p = 0.027) compared with patients 50 years of age. Conclusion: This analysis suggests LPV/r-anchored three-drug therapy in patients 50 years of age leads to comparable rates of virologic suppression, with a smaller increase in absolute CD4(+) T cells and increased AEs, including discontinuations associated with AEs compared with patients <50 years of age.
    No preview · Article · Apr 2014 · Future Virology
  • A Hermes · L Fredrick · M Martinez · R Rode · M Pasley · M Norton · A Nilius

    No preview · Article · Jun 2013 · Journal of the International AIDS Society
  • R D'Amico · C Wegzyn · W Richter · C Lin · J Beron · Y Hu · L Fredrick · B Saget · M Guion · M Norton

    No preview · Article · Jun 2013 · Journal of the International AIDS Society
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    ABSTRACT: Purpose of the study: The prevalence of neurocognitive impairment (NCI) in people living with HIV has previously been reported between 20-50%, with prevalence rates of depression reported between 12-71%. The primary objective of the CRANIum study was to describe the prevalence of a positive screen for NCI and depression/anxiety in an HIV-1-infected adult population, comparing ARV-naïve and -experienced patients. Here we present an ethnicity analysis of the CRANIum data. Methods: The study was an epidemiologic, cross-sectional study that included HIV-1-infected patients >18 years old attending a routine clinic visit. One-third of patients were ART-naïve, one-third on a PI/r- and one-third on a NNRTI-based regimen. The Brief Neurocognitive Screen (BNCS) was used to screen for NCI. It consists of the Digit Symbol and Trailmaking A and B tests. A standard deviation of >1 on 2 tests or >2 on 1 test was considered a positive screen for NCI. The Hospital Anxiety and Depression Scale (HADS) was used to screen for anxiety (HADS-A) and depression (HADS-D). HADS is self-administered and consists of 14 items (7 HADS-A, 7 HADS-D) scored between 0 to 3. A score of ≥8 was considered as a positive screen for either condition. Summary of results: 2859 evaluable patients were included from 15 countries. Baseline characteristics are shown in table 1 (*p < 0.05 as compared with Caucasian group). Overall, 41.4% of patients had a positive screen for NCI, 33.3% for anxiety and 15.7% for depression. Results by ethnicity are shown in figure 1. Conclusions: In this large epidemiologic study, the overall prevalence of a positive screen for NCI was high. In particular, the rate in black patients was nearly double that of the overall study population. This finding needs to be interpreted in light of differences in demographics and disease characteristics between ethnic groups. The overall prevalence of a positive screen for depression in HIV-infected patients was nearly double what has previously been reported in the non-HIV-infected population in Europe when utilizing a similar screening tool, with no significant differences between identified ethnic groups. These results support a strategy of regular screening for, and clinical management of NCI, depression, and anxiety in all HIV-infected patients, with specific focus on NCI in the black population.
    No preview · Article · Nov 2012 · Journal of the International AIDS Society
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    ABSTRACT: Purpose: Women comprise ≯50% of HIV-infected patients, yet safety, tolerability, and efficacy data in women taking antiretrovirals (ARVs) are limited. Lopinavir/ ritonavir (LPV/r)-anchored regimens are globally the most widely prescribed HIV-1 protease inhibitor regimens. The objective was to investigate the safety and efficacy of LPV/r-based therapy in women. Methods: A database query yielded all available data in HIV-1-infected subjects receiving LPV/r-based triple-ARV regimens from randomized clinical trials lasting ≥48 weeks from Abbott or Abbott-supported AIDS Clinical Trials Group studies. Efficacy (HIV-1 RNA levels, CD4+ T-cell counts) and safety and tolerability (treatment discontinuation, treatment-related adverse events [AE], and clinical laboratory abnormalities) at 48 weeks were assessed for total women, women by age (≥50, <50 years) and body mass index (BMI; <25, ≥25 to <30, ≥30 kg/m2), and sex. Results: Nine hundred ninety-two women initiated LPV/r-based therapy (of whom 79.2% were ARV-naïve), with 83.6% completing 48 weeks of treatment. There were 75.5% of women who achieved a threshold of HIV RNA <400 copies/mL by intent-to-treat, non-completer equals failure (ITT, NC = F) analysis, with a mean ± SE CD4+ T-cell count increase of 191.6 ± 4.92 cells/mm3 from baseline. Women aged ≥50 versus <50 years had higher incidence of moderate-to-severe treatment-related AEs and certain laboratory abnormalities, better virologic response (HIV RNA <400 copies/mL by ITT, NC = F), similar immunologic responses, and similar overall incidence of treatment discontinuations. Higher incidences of certain moderate-to-severe treatment-related AEs and laboratory abnormalities occurred in women with BMI ≥30 kg/m2; however, no effect of BMI on efficacy or discontinuation was observed. Conclusions: LPV/r-based regimens were efficacious and well-tolerated in women without marked differences based on age and BMI categories evaluated.
    No preview · Article · Nov 2012 · HIV Clinical Trials
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    ABSTRACT: Abstract Alternative combinations of antiretrovirals (ARVs) are desired to increase treatment options for HIV-infected patients. PROGRESS was a randomized, open-label, 96-week pilot study comparing a regimen of lopinavir/ritonavir (LPV/r) 400/100 mg twice daily in combination with either raltegravir (RAL) 400 mg twice daily or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily in ARV-naive adults. A total of 206 subjects were randomized and treated (LPV/r+RAL, N=101; LPV/r+TDF/FTC, N=105). Demographics and baseline characteristics were similar across treatment groups. At 96 weeks, 66.3% of subjects receiving LPV/r+RAL and 68.6% of subjects receiving LPV/r+TDF/FTC were responders (plasma HIV-1 RNA levels<40 copies/ml) by the FDA time to loss of virologic response (FDA-TLOVR) algorithm (p=0.767). Mean CD4(+) T cell increases through 96 weeks were similar between treatment groups (LPV/r+RAL=281 cells/mm(3), LPV/r+TDF/FTC=296 cells/mm(3), p=0.598). Safety and tolerability were generally similar between groups. The LPV/r+RAL regimen resulted in greater increases in peripheral fat, but not trunk fat, compared with LPV/r+TDF/FTC. There was a statistically significantly greater mean reduction in estimated glomerular filtration rate from baseline to week 96 in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (-7.33 ml/min vs. -1.43 ml/min; p=0.035). The LPV/r+TDF/FTC group had a statistically significant (p<0.001) mean percent decrease from baseline to week 96 in bone mineral density, which was significantly different from the mean percent change in the LPV/r+RAL group (-2.48% vs. +0.68%, p<0.001). These efficacy and safety observations support further evaluation of the LPV/r+RAL regimen.
    No preview · Article · Jun 2012 · AIDS research and human retroviruses
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    ABSTRACT: There is growing interest in studying age-related diseases, such as coronary artery disease (CAD) and resulting myocardial infarction (MI) in HIV-infected patients. While some cohort studies indicate that several antiretrovirals (ARVs), including the protease inhibitor lopinavir/ ritonavir (LPV/r), are associated with an increased relative risk (RR) of MI, other studies show a reduction of MI and CAD in subjects taking ARVs when compared with HIV+ patients not taking ARV therapy. This manuscript reviews data from Abbott-sponsored clinical trials and pharmacovigilance reporting system. A systematic search was performed to retrieve cases of MI and CAD in Abbott’s clinical trial and pharmacovigilance safety databases. The rates of MI and CAD, and risk factors for the events were reviewed in detail. The rate of MI and CAD per 1,000 patient treatment years (PTY) was 1.24 (95% CI = 0.40 - 2.90) and 2.74 (95% CI = 1.37 - 4.90), respectively, for subjects taking LPV/r during clinical trials. The frequency of pharmacovigilance reports of MI and CAD were 2.9 per 100,000 PTY and 3.6 per 100,000 PTY, respectively. Most subjects who had MI and CAD events had multiple baseline risk factors. Relatively few subjects experienced MI or CAD during Abbott-sponsored clinical trials of LPV/r. Analysis of clinical trial and pharmacovigilance data did not indicate an increased risk of MI or CAD associated with LPV/r compared with the general population. In general, the subjects that experienced MI or CAD had known traditional risk factors suggesting that addressing modifiable risk factors could decrease the risk of MI or CAD. ARVs have not been thoroughly studied in subjects at high risk for MI and CAD, and further studies of this population could identify whether starting ARVs affects the incidences of cardic events in subjects with many traditional risk factors
    No preview · Article · Apr 2012 · International journal of clinical pharmacology and therapeutics
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    ABSTRACT: Background Antiretroviral therapy is associated with adverse events (AEs). The most frequently reported AE associated with lopinavir/ritonavir (LPV/r) containing regimens is diarrhea. The objective of this meta-analysis is to describe the incidence, prevalence, and duration of diarrhea in individuals taking LPV/r. Methods This is a meta-analysis of Abbott-conducted clinical trials. Inclusion criteria included prospective randomized clinical trials with the LPV/r tablet formulation and had AE data (moderate/severe diarrhea) available through 48 weeks of treatment. Results Three trials (total 1469 participants) met the inclusion criteria. In all, 11.2% of participants reported moderate/severe diarrhea by week 8, with median time to resolution of 7.4 weeks. The overall 48-week incidence of moderate/severe diarrhea was 15.5%. The discontinuation rate due to moderate/severe diarrhea was 1.3%. Conclusions Moderate/severe diarrhea occurred in less than 1 in 6 participants taking LPV/r, typically started in the first 8 weeks of treatment and infrequently resulted in premature discontinuation.
    No preview · Article · Apr 2012 · Journal of the International Association of Physicians in AIDS Care (JIAPAC)
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    ABSTRACT: Aims: Several studies reported similar virologic responses for lopinavir/ritonavir (LPV/r) 800/200 mg once-daily (q.d.)-containing regimens or LPV/r 400/100 mg twice-daily (b.i.d.)-containing regimens in antiretroviral-naive patients. However, the virologic response in patients with baseline viral loads ≥100,000 copies/ml and gastrointestinal adverse events (AEs) sometimes favored b.i.d. dosing, whereas hypertriglyceridemia may be less frequent with q.d. dosing. This meta-analysis compared the efficacy and tolerability of these two dosing strategies. Materials & methods: Random effects meta-analysis models, in all patients and subgroups with baseline plasma HIV-1 RNA ≥100,000 copies/ml and CD4 + T-cell counts <200 cells/l, assessed virologic efficacy (HIV-1 RNA <50 copies/ml and time to virologic failure) and prespecified AEs incidence between q.d. and b.i.d. dosing strategies. Descriptive analysis of the pharmacokinetic/pharmacodynamic relationship and resistance development was performed. Results: No difference was found between the two strategies in virologic efficacy, to virologic failure, or AEs in the overall or subgroup populations. Numerical but nonstatistically significant differences in discontinuations due to AEs (2.4%; 95% CI:-0.7-5.5; p = 0.132) favored b.i.d. over q.d. dosing in the overall population. Conclusion: Virologic efficacy, treatment durability and tolerability were similar between the two dosing strategies in the overall and subgroup populations. The LPV/r dosing strategy should be individualized according to patient need.
    No preview · Article · Jan 2012 · Future Virology
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    ABSTRACT: Antiretroviral therapy has decreased the rate of HIV-related mortality and extended the life span of HIV patients. Current guidelines recommend the use of a 3-drug regimen, such as two nucleoside reverse transcriptase inhibitors and a protease inhibitor, boosted by ritonavir. Osteoporosis can be associated with the HIV disease itself or with antiretroviral therapy. Many trials have been conducted employing a single drug regimen to simplify antiretroviral therapy but few studies assessed the effect of the single drug regimen on bone mineral density (BMD). The objectives of the study were to assess and compare the relative (%) changes in lumbar spine and hip BMD over 48 weeks in HIV patients treated with mono or triple antiretroviral regimens The study was conducted using data from a randomized trial (MONARK) conducted in 136 antiretroviral-naïve HIV patients (89 men and 47 women) comparing the antiviral efficacy of a single-drug protease inhibitor regimen of lopinavir/ritonavir (LPV/r) versus LPV/r in combination with zidovudine (ZDV) and lamivudine (3TC). Lumbar spine and total hip BMD were assessed in 100 patients by dual-energy X-ray absorptiometry at baseline and 48 weeks. 48 week-BMD data were available for 43 patients (mean age 37years) with a mean baseline lumbar spine Z-score of -0.1 in the LPV/r monotherapy group and for 25 patients (mean age 35.8years) with a mean baseline lumbar spine Z-score of -0.2 in the LPV/r+ZDV+3TC group. After 48weeks, lumbar spine BMD significantly decreased by 4.4% (-5.1% to -2.1%, P≤0.001) in the LPV/r group and by 4.0% (-5.0% to -1.7%, P≤0.0001) in the LPV/r+ZDV+3TC group. There was no significant difference in BMD changes between the two groups. These results suggest that bone loss is observed 48 weeks after the initiation of antiretroviral therapy, whether the patients receive a single- or triple-drug antiretroviral regimen.
    No preview · Article · May 2011 · Bone
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    ABSTRACT: Given the decline in mortality among HIV-infected patients, it has become increasingly important to consider delayed disease-related and/or anti-HIV therapy-related adverse effects, such as lipodystrophy, when choosing initial therapy. Data from the MONARK trial allowed for comparison of the potential lipodystrophic effects of lopinavir/ritonavir (LPV/r) monotherapy with those of triple therapy with LPV/r plus zidovudine (ZDV) and lamivudine (3TC). This was a randomized, open-label, multinational study that included 136 antiretroviral-naive HIV-infected patients. A portion of study patients underwent evaluations of limb and trunk fat tissue by dual-energy x-ray absorptiometry at baseline and after 48 weeks of treatment (and 96 weeks in some patients). Sixty-three patients had paired absorptiometry data at baseline and week 48 (13 patients at week 96). At week 48, median change in limb fat was -63 g on LPV/r monotherapy versus -703 g on LPV/r + ZDV/3TC triple therapy (p=0.014). The proportion of patients with fat loss (>20% loss in limb fat) was significantly lower with LPV/r monotherapy (4.9% versus 27.3%; p=0.018). Changes in trunk fat did not differ significantly between treatments. Nonetheless, limb fat and trunk fat varied in the same direction with both treatments. The decrease in arm lean mass was also significantly less in patients receiving LPV/r monotherapy. Only treatment type emerged as a significant predictor of fat loss (odds ratio, 7.06; 95% CI, 1.11-78.69). These results suggest that LPV/r, and possibly other protease inhibitors, may not be the main contributor to lipoatrophy in HIV-infected patients receiving triple therapy.
    No preview · Article · Jan 2011 · Current HIV research
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    ABSTRACT: Patterns of HIV-1 protease inhibitor (PI) resistance-associated mutations (RAMs) and effects on PI susceptibility associated with the L76V mutation were studied in a large database. Of 20,501 sequences with ≥1 PI RAM, 3.2% contained L76V; L76V was alone in 0.04%. Common partner mutations included M46I, I54V, V82A, I84V, and L90M. L76V was associated with a 2- to 6-fold decrease in susceptibility to lopinavir, darunavir, amprenavir, and indinavir and a 7- to 8-fold increase in susceptibility to atazanavir and saquinavir.
    Full-text · Article · Nov 2010 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients. A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56). At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96. By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.
    Full-text · Article · Sep 2009 · HIV Medicine
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    ABSTRACT: The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society-USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.
    Full-text · Article · Jun 2009 · Antimicrobial Agents and Chemotherapy