Boosted Protease Inhibitor Monotherapy Research Articles

Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial

Despite satisfactory efficacy of WHO-recommended second-line antiretroviral treatment for patients with HIV in low-income countries, the need for simplified, low-cost, and less-toxic maintenance strategies remains high. We compared boosted protease inhibitor monotherapy with dual therapy with boosted protease inhibitor plus lamivudine in patients on second-line antiretrovial therapy (ART). We did a multicentre, randomised, parallel, open-label, superiority, trial in the HIV services of five hospitals in sub-Saharan Africa (Yaoundé, Cameroon; Dakar, Senegal; and Bobo Dioulasso, Burkina Faso). We recruited patients from the long-term, post-trial cohort of the ANRS 12169/2LADY study that compared the efficacy of three second-line combinations based on boosted protease inhibitors. Participants for our study were HIV-1 infected with multiple mutations including M184V, at first-line failure, aged 18 years and older, on boosted protease inhibitor plus two nucleoside reverse transcriptase inhibitors (NRTI) for at least 48 weeks with at least 48 weeks follow-up in the 2LADY trial, with two viral load measurements of less than 200 copies per mL in the previous 6 months, CD4 counts of more than 100 cells per μL, adherence of at least 90%, and no change to ART in the past 3 months. We randomly assigned participants (1:1) to receive either monotherapy with their boosted protease inhibitor (once-daily darunavir 800 mg [two 400 mg tablets] boosted with ritonavir 100 mg [one tablet] or coformulation of lopinavir 200 mg with ritonavir 50 mg [two tablets taken twice per day]) or to boosted protease inhibitor plus once-daily lamivudine 300 mg (one 300 mg tablet or two 150 mg tablets). Computer-generated randomisation was stratified by study site and viral load at screening (< 50 copies per mL, and 50-200 copies per mL), and concealed from study personnel throughout the inclusion period. After randomisation, treatment allocation was not masked from clinicians or patients]. Patients had follow-up visits at weeks 4 and 12, and every 3 months until 96 weeks; if viral load exceeded 500 copies per mL at any visit, NRTI (tenofovir and lamivudine) were reintroduced into treatment. The primary outcome was the proportion of participants who had treatment failure at 96 weeks in the intention-to-treat analysis, where treatment failure was defined as one of the following: a confirmed viral load of more than 500 copies per mL, reintroduction of NRTI, or interruption of boosted protease inhibitor. We designed the study to detect a difference of 12% between groups in the primary outcome, with an expected 20% of patients having treatment failure in the monotherapy group. This study is registered with ClinicalTrials.gov, number NCT01905059. Between March 5, 2014, and Jan 26, 2015, 265 participants were assigned to receive monotherapy (133) or boosted protease inhibitor plus lamivudine (132). At week 48, an independent data safety monitoring board reviewed data, and advised discontinuation of the monotherapy group because the number of failures had exceeded the expected 20%; therefore results here are for week 48. At this point, treatment failure occurred in four (3·0%; 95% CI 0·8-7·6) of 132 participants on dual therapy and 33 (24·8%; 17·7-33·0) of 133 participants on monotherapy (relative risk 8·2, 95% CI 3·0-22·5; odds ratio 10·6, 95% CI 3·6-42·1). The difference between groups (21·8%, 95% CI 13·9-29·7; p<0·0001) showed superiority of dual therapy compared with monotherapy. We recorded 46 severe adverse events of grade 3 or 4 (29 in the monotherapy group, 17 in the boosted protease inhibitor plus lamivudine group); one event in the montherapy group (intoxication resulting from co-administration of ritonavir-boosted lopinavir with an ergotamine derivate) was deemed related to study drug. Two participants in the monotherapy group and one in the dual therapy group died, all from causes not related to study drugs or procedures (one from complications from gastric cancer surgery, one in a work accident, and one from a lung disease of unknown cause). After viral suppression with boosted protease inhibitor plus NRTI in second-line ART, maintenance therapy with boosted protease inhibitor plus lamivudine was associated with a high rate of success, despite the presence of M184V mutations at first-line treatment failure. Results indicated that boosted protease inhibitor monotherapy cannot be recommended for these patients. Agence National de Recherche sur le Sida et les hépatites and Janssen Pharmaceutica.

One Year Follow-Up of Darunavir/Cobicistat Monotherapy in Pretreated HIV Patients

Introduction: Boosted protease inhibitor monotherapy (PI/r ) : Darunavir/ritonavir (DRV/r) or Lopinavir/ritonavir (LPV/r) monotherapy is only provided in the major treatment guidelines in pre-treated HIV patients to prevent toxicity associated with nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs), reduce costs and simplify antiretroviral treatment. To start PI/r monotherapy, according to GESIDA g uidelines 2016, patients need to meet the following criteria: absence of chronic hepatitis B, plasma viral load <50 copies/ mL for at least 6 months and absence protease inhibitors mutations or previous virologic failures to PI/r. Currently, there are no studies that evaluate the efficacy and safety of DRV/COBI monotherapy. Methods: This prospective study analyzed pretreated HIV patients with DRV/r monotherapy that were switched to DRV/COBI monotherapy. The aim of the study is to describe the effectiveness and safety of the DRV/COBI monotherapy. Results: A total of 78 patients were evaluated. In total 11.53% (9/78) patients developed blips (Plasma viral load: 50-200 copies/ml) in our study and four patients had a viral load ≥ 200 copies/mL. Twelve patients (15.38%) switched to another antiretroviral treatment, so at week 48 only 66 of the 78 patients continued with DRV/COBI monotherapy. Three patients continued with blips at week 48. Despite blips, virological rebounds and switch in treatments, 95.45% (63/66) of the patients with DRV/COBI monotherapy were maintained with a viral load <37 copies/mL at week 48 of the follow-up. In addition, there had been a slight increase in the CD4+ T cell count at week 48 of follow up. As for safety, there were no significant differences in lipid profile, liver function (transaminases) and renal function between DRV/r and DRV/COBI monotherapy. Conclusions: DRV/COBI monotherapy seems to be effective and safe (lipid profile, liver and kidney function). However, it will be necessary to design specific studies comparing DRV/r vs DRV/COBI monotherapy to confirm these results.

Antiretroviral treatment initiation does not differentially alter neurocognitive functioning over time in youth with behaviorally acquired HIV.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18–24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 <350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.

Protease inhibitor monotherapy is effective in controlling human immunodeficiency virus 1 shedding in the male genital tract

Cross-sectional study comparing seminal human immunodeficiency virus type 1 (HIV-1) shedding in patients receiving boosted protease inhibitor monotherapy (mtPI/rtv) (n = 66) versus triple therapy (TT) (n = 61). Seminal HIV-1 shedding rates in patients with undetectable plasma HIV-RNA were 16.0% on mtPI/rtv compared with 28.6% on TT (p 0.173). Aviraemic status and time on viral suppression were independently associated with lack of seminal HIV-1 shedding. During TT, non PI/rtv-based regimens were associated with a better control of HIV infection in semen despite similar time on viral suppression. The use of mtPI/rtv in well-controlled patients is not associated with increased seminal HIV excretion compared with TT.

Switching from tenofovir containing regimens to boosted protease inhibitor monotherapy: Impact on renal function

ObjectiveTo evaluate the effect on creatinine clearance (CG-CrCl, Cockcroft–Gault equation) of switching to boosted protease inhibitor (PI) monotherapy in patients receiving a triple drug antiretroviral regimen containing TDF. MethodsAll patients who had received a TDF-containing regimen for at least one year and had been switched to PI monotherapy were included. A rapid decrease in CG-CrCl during exposure to TDF was defined as a decrease in CG-CrCl at least five times higher than the expected due to age (0.4ml/min/year by the years of exposure to TDF). In this subgroup of patients, we considered improvement if the last value of CG-CrCl on PI monotherapy was 10% higher than the last value of CG-CrCl before switching to PI monotherapy. A multivariate logistic regression was constructed to identify factors associated to renal improvement after switching to bPI monotherapy. Results64 patients included. The median (IQR) annual change in CG-CrCl during PI monotherapy was significantly lower than the median (IQR) annual change while exposed to TDF [−0.9 (−4.7 to +2.8) ml/min vs. −4 (−8 to −1) ml/min, p=0.001]. 44 patients experienced a rapid decline during TDF exposition. After switch to PI monotherapy, 15/44 (34%, 95% CI: 21–50%) had an improved CG-CrCl and 16/44 (36%, CI 23–52%) experienced a further decline in CG-CrCl. The only variable associated to CG-CrCl improvement was a more rapid CG-CrCl decline in the last year of exposure to TDF. ConclusionSwitching to PI monotherapy partially reversed CG-CrCl decrease associated to TDF use, especially in patients with a more rapid decline while receiving TDF.

Desafíos de lopinavir/ritonavir en la cronicidad de la infección por virus de la inmunodeficiencia humana

Combination antiretroviral therapy (ART) has increased patient survival, which is currently similar to that of the general population in western countries. However, ART is unable to completely restore normal health, given the persistence of chronic immune activation. Human immunodeficiency virus (HIV) infection has become a chronic disease and 50% of patients will soon be older than 50 years. Currently, there is a debate on the possibility of accelerated aging in the HIV-infected population. An overlap has been observed between chronic inflammation, age-related comorbidities, lifestyle, and the long-term toxicity of ART. ART-related toxicity can encourage the development of comorbidities, especially cardiovascular and renal complications, while toxicity-especially that of thymidine analogs-can also contribute to inflammation and aging. Evidence is available on simplification strategies with boosted protease inhibitor monotherapy aiming to avoid or reduce potential or demonstrated toxicity. Currently, studies are underway of dual therapy strategies with lopinavir/ritonavir (LPV/r) with distinct antiretroviral agents. The studies with the largest samples are those with raltegravir and lamivudine. The GARDEL trial has demonstrated that dual therapy with LPV/r plus a generic drug such as lamivudine is non-inferior to triple therapy in treatment- naïve patients. All of the above indicates the response to the challenge posed to LPV/r by the chronic phase of the disease and by the need to reduce costs.

Lipid changes in HIV-patients switching to the coformulated single tablet FTC/RPV/TDF (Eviplera®). Efficacy and safety analysis. GeSida Study 8114.

IntroductionRilpivirine (RPV) has a better lipid profile than efavirenz (EFV) in naïve patients [1]. Switching to RPV may be convenient for many patients, while maintaining a good immunovirological control [2]. The aim of this study was to analyze lipid changes in HIV-patients at 24 weeks after switching to Eviplera® (emtricitabine/RPV/tenofovir disoproxil fumarate [FTC/RPV/TDF]).Materials and MethodsRetrospective, multicentre study of a cohort of asymptomatic HIV-patients who switched from a regimen based on 2 nucleoside reverse transcriptase inhibitors (NRTI)+protease inhibitor (PI)/non nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir boosted PI monotherapy to Eviplera® during February-December, 2013; all had undetectable HIV viral load for ≥3 months prior to switching. Patients with previous failures on antiretroviral therapy (ART) including TDF and/or FTC/3TC, with genotype tests showing resistance to components of Eviplera®, or who had changed the third drug of the ART during the study period were excluded. Changes in lipid profile and cardiovascular risk (CVR), and efficacy and safety at 24 weeks were analyzed.ResultsAmong 305 patients included in the study, 298 were analyzed (7 cases were excluded due to lack of data). Men 81.2%, mean age 44.5 years, 75.8% of HIV sexually transmitted. 233 (78.2%) patients switched from a regimen based on 2 NRTI+NNRTI (90.5% EFV/FTC/TDF). The most frequent reasons for switching were central nervous system (CNS) adverse events (31.0%), convenience (27.6%) and metabolic disorders (23.2%). At this time, 293 patients have reached 24 weeks: 281 (95.9%) have continued Eviplera®, 6 stopped it (3 adverse events, 2 virologic failures, 1 discontinuation) and 6 have been lost to follow up. Lipid profiles of 283 cases were available at 24 weeks and mean (mg/dL) baseline vs 24 weeks are: total cholesterol (193 vs 169; p=0.0001), HDL-c (49 vs 45; p=0.0001), LDL-c (114 vs 103; p=0.001), tryglycerides (158 vs 115; p=0.0001), total cholesterol to HDL-c ratio (4.2 vs 4.1; p=0.3). CVR decreased (8.7 vs 7.5%; p= 0.0001). CD4 counts were similar to baseline (653 vs 674 cells/µL; p=0.08), and 274 (96.8%) patients maintained viral suppression.ConclusionsAt 24 weeks after switching to Eviplera®, lipid profile and CVR improved while maintaining a good immunovirological control. Most subjects switched to Eviplera® from a regimen based on NNRTI, mainly EFV/FTC/TDF. CNS adverse events, convenience and metabolic disorders were the most frequent reasons for switching.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Central Nervous System HIV Infection in “Less-Drug Regimen” Antiretroviral Therapy Simplification Strategies

Less-drug regimens (LDR) refer to combinations of either two antiretroviral drugs or ritonavir-boosted protease inhibitor (PI) monotherapy. They may represent a simplification strategy in patients with persistently suppressed human immunodeficiency virus (HIV) viremia, with the main benefits of reducing drug-related toxicities and costs. Systemic virological efficacy of LDR is slightly lower as compared with combined antiretroviral therapy (cART), but patients with failure do not usually develop drug resistance and resuppress HIV replication after reintensification. A major concern of LDR is the lower efficacy in the virus reservoirs, especially in the central nervous system (CNS), where viral compartmentalization and independent evolution of infection may lead to CNS viral escape, often associated with neurologic symptoms. The authors reviewed studies of virological and functional CNS efficacy of LDR, particularly of boosted PI monotherapy regimens, for which more information is available. Symptomatic viral CSF escape was observed mainly in PI/r monotherapy patients with plasma failure and low nadir CD4+ cell counts, and resolved upon reintroduction of triple drug cART, whereas asymptomatic viral failure in CSF was not significantly more frequent in patients on PI/r monotherapy compared with patients on standard cART. In addition, there was no difference in functional outcomes between PI monotherapy and cART patients, irrespective of CSF viral escape. More data are needed on the CNS effect of dual ART regimens and, in general, on long-term efficacy of LDR. Simplification with LDR may be an attractive option in patients with suppressed viral load, if they are well selected and monitored for potential CNS complications.

Higher vitamin D levels in HIV‐infected out‐patients on treatment with boosted protease inhibitor monotherapy

We investigated the vitamin D status of patients receiving frequently used types of combination antiretroviral therapy (cART), including boosted protease inhibitor (PI) monotherapy. For this cross-sectional study, out of 450 HIV-infected patients followed in the Hospital Severo Ochoa (Madrid, Spain), we selected 352 patients for whom vitamin D levels had been measured (January 2009 to December 2010). We collected the following data: demographics, cART duration, main cART regimen, viral load (VL), CD4 cell count, and concentrations of 25(OH)-vitamin D [25(OH)-D], parathyroid hormone (PTH), albumin and calcium. Vitamin D status cut-off points were: (1) deficiency (vitDd): 25(OH)-D < 20 ng/mL; (2) insufficiency (vitDi): 25(OH)-D from 20 to 29.99 ng/mL; and (3) optimal (vitDo): 25(OH)-D ≥ 30 ng/mL. The percentages of patients with vitDd, vitDi and vitDo were 44, 27.6 and 28.5%, respectively. Twenty-nine out of 30 (96.7%) Black patients had vitDd or vitDi, vs. 71.6% in the global sample (P < 0.001). Former injecting drug users (IDUs) had a higher prevalence of vitDo (P < 0.001) than patients in other transmission categories. Among patients with vitDd, vitDi and vitDo, the proportions of patients with a VL ≤ 50 HIV-1 RNA copies/mL were 77.4, 68 and 91%, respectively (P < 0.0001). Of the cART regimens, only boosted PI monotherapy was associated with significant differences in vitamin D levels (P = 0.039). Multivariate logistic regression analysis showed an increased risk of vitDi or vitDd associated with the following variables: Black vs. Caucasian ethnicity [odds ratio (OR) 10.6; 95% confidence interval (CI) 1.2-94; P = 0.033]; heterosexual (OR 2.37; 95% CI 1.13-4.93; P = 0.022) or men who have sex with men (MSM) (OR 3.25; 95% CI 1.25-8.50; P = 0.016) transmission category vs. former IDU; and VL > 50 copies/mL (OR 2.56; 95% CI 1.10-7.25; P = 0.040). A lower risk of vitamin D insufficiency or deficiency was found in patients on boosted PI monotherapy vs. no treatment (OR 0.08; 95% CI 0.01-0.6; P = 0.018). Our data show an increased risk of vitamin D deficiency or insufficiency in patients with detectable VL and a Black ethnic background. Among cART regimens, boosted PI monotherapy was associated with a lower risk of vitamin D deficiency or insufficiency. The more favourable vitamin D status in former IDUs was probably attributable to a higher frequency of outdoor jobs in this group of patients.

Antiretroviral treatment switch strategies for lowering the costs of antiretroviral therapy in subjects with suppressed HIV-1 viremia in Spain.

BackgroundThe current economic recession in European countries has forced governments to design emergency measures to reduce spending on drugs, including antiretroviral therapy (ART). Switching antiretroviral drugs for others that have the same efficacy and safety profile at a lower cost (cost-reduction measures, CRM) could prove to be a valid means of generating savings.MethodsDescriptive study of prospective consensus-based CRM undertaken in 2011 in a Catalonian hospital HIV unit among patients with prolonged plasma HIV-1 RNA <50 copies/mL.ResultsDuring the study period, we made 673 switches (87.5% more than the previous year), of which 378 (56.2%) were CRM (16% of all patients treated), leading to a savings of €87,410/month. Switching tenofovir/emtricitabine for abacavir/lamivudine was the most common CRM (129, 31.3%), followed by simplification to boosted protease inhibitor monotherapy (bPImono, 102, 26%). The CRM that generated the greatest saving were switching to bPImono (38%), withdrawal or replacement of raltegravir (24%), switching tenofovir/emtricitabine for abacavir/lamivudine (13%), and switching to nevirapine (5%). Cost savings with CRM were slightly higher than those achieved with medication paid for by clinical trial sponsors (€80,333/month) or through discount arrangements (€76,389/month).ConclusionProactively switching antiretroviral therapy in selected treated patients with sustained virological suppression can generate significant cost savings in pharmacy spending in developed countries. These findings have implications for decision makers in designing safe strategies that maintain HIV-1 suppression at lower costs.

Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan-European expert panel meeting.

While the introduction of combination highly active antiretroviral therapy (HAART) regimens represents an important advance in the management of human immunodeficiency virus (HIV)-infected patients, tolerability can be an issue and the use of several different agents may produce problems. The switch of combination HAART to ritonavir-boosted protease inhibitor (PI) monotherapy may offer the opportunity to maintain antiviral efficacy while reducing treatment complexity and the risks of toxicity. Current European AIDS Clinical Society (EACS) guidelines recognise ritonavir-boosted PI monotherapy with twice-daily lopinavir/ritonavir or once-daily darunavir/ritonavir as a possible option in patients who have intolerance to nucleoside reverse transcriptase inhibitors, or for treatment simplification. Clinical trials data for PI boosted monotherapy are encouraging, showing substantial efficacy in the majority of patients; however, further data are required before this approach can be recommended as a routine treatment. Available data indicate that the most suitable candidates for the use of boosted PI monotherapy are long-term virologically suppressed patients who have demonstrated good adherence to antiretroviral therapy, who do not have chronic hepatitis B, have no history of treatment failure on PIs and are able to tolerate low-dose ritonavir.

Boosted protease inhibitor monotherapy as a maintenance strategy

We aimed to determine the effectiveness of boosted protease inhibitor monotherapy (BPIMT) initiated as a maintenance strategy in routine care and identify predictive factors of failure. Observational study in the FHDH-ANRS CO4 cohort. Five hundred and twenty-nine virologically suppressed individuals switched to BPIMT in the period 2006-2010, 75% had at least 12 and 49% at least 24 months of follow-up. Virological failure (two consecutive HIV-RNA > 50 copies/ml or one HIV-RNA > 50 copies/ml followed by BPIMT discontinuation) and treatment failure (virological failure, antiretroviral reintensification or death) were analysed separately. At baseline, 11% were protease inhibitor-naive, median duration on combined antiretroviral therapy was 84 months and median duration of suppressed viremia was 38 months. Nine percent had a history of virological failure, while on a protease inhibitor-containing regimen, and rates of virological failure were higher among those individuals [adjusted hazard ratio, 1.6; 95% confidence interval (CI), 0.9-2.9]. Compared to individuals with less than 1 year of sustained virological suppression before the switch to BPIMT, those with longer duration were less likely to experience virological failure [hazard ratio, 0.7; (95% CI, 0.4-1.2) and 0.6 (95%CI, 0.4-0.9)] for a duration of 12-23 months and 24 months or more, respectively. Rates of failure were similar for BPIMT with lopinavir-ritonavir (RTV) or darunavir-RTV, but increased for BPIMT with atazanavir-RTV. Same risk factors were associated with treatment failure. The safety and efficacy of a maintenance strategy with BPIMT in a routine care setting matched the results of randomized clinical trials. A longer duration since last virological rebound before switching to BPIMT was associated with a decreased risk of subsequent failure.

Prolonged treatment with boosted protease inhibitor monotherapy is not associated with a higher rate of neurocognitive impairment than triple drug ART

Purpose of the studyTo investigate if boosted protease inhibitor monotherapy is associated with a higher risk of neurocognitive impairment (NCI).MethodsHIV‐infected patients from two hospitals in Madrid (Spain) without concomitant major neurocognitive confounders, currently receiving for ≥1 year lopinavir/ritonavir (LPV) or darunavir/ritonavir (DRV) as monotherapy or with two N(t)RTIs were included if they had prolonged (≥1 year) plasma viral suppression (&lt;50 c/mL, single blip allowed). Patients underwent full neurocognitive assessment (7 domains) by two psychologists blinded to the treatment group. NCI was defined as per 2007 Frascati criteria using demographically adjusted normative scores. Rates of NCI and the association between NCI and boosted protease inhibitor monotherapy, adjusted by significant confounders, were analyzed. Two categories of monotherapy duration were considered: short‐term (1–2 years) and long‐term (2–9 years). We evaluated as potential confounding variables: demographics, HIV risk factor, AIDS, CD4 (nadir/current), smoking, alcohol/illicit drug use, prior medical, neurological and psychiatric disease, HCV coinfection, years of ART, prior blips, time with HIV viral suppression, type of protease inhibitor, lipids and HOMA index.Summary of results191 patients (89.5% Caucasian) were included (Table 1). Triple therapy (n=95) Monotherapy (n=96) p value Male. n (%) 70 (73.7) 70 (72.9) 0.91 Former IVDU. n (%) 30 (31.6) 34 (35.4) 0.85 MSM. n (%) 29 (30.5) 30 (31.3) 0.85 Age. Median (IQR) 44.7 (40.6–48.4) 47.4 (44.8–51.4) &lt;0.01 Years of education. Mean (SD) 11.3 (4.1) 10.4 (4.4) 0.13 Prior neurologic disease. N (%) 12 (12.6) 10 (10.4) 0.63 Prior psychiatric disease. n (%) 19 (20.0) 24 (25.0) 0.44 Current or past use of illicit drugs. n (%) 49 (53.6) 46 (47.9) 0.66 HCV coinfection (past or active) 43 (47.3) 43 (45.3) 0.54 Years of ART. Median (IQR) 10.7 (4.8–15.7) 14.1 (10.7–15.9) 0.01 Years of monotherapy. Median (IQR) Not applicable 2.3 (1.7–3.2) Not applicable Years suppressed (&lt;50 c/mL). Median (IQR) 4.8 (2.9–8.9) 7.5 (4.5–10.0) &lt;0.01 No prior blip 63 (66.3) 61 (63.5) 0.17 Currently on LPV. n (%) 70 (73.7) 53 (55.2) &lt;0.01 Currently on DRV. n (%) 25 (26.3) 43 (44.8) &lt;0.01 CPE score (2010). Median (IQR) 7 (7–7) 3 (3–3) Not applicable CD4 cell nadir. Median (IQR) 153 (49–255) 182 (76–288) 0.11 CD4 cell current. Median (IQR) 560 (440–754) 629.5 (476–845.5) &lt;0.05 Proportion (95% CI) with NCI: Overall: 27.2% (20.9–33.6, all asymptomatic or mild). Triple therapy: 31.6 (22.1–41.0). 1–2 years of monotherapy (n=40): 25.0 (11.3–38.7). 2–9 years of monotherapy (n=56): 21.4 (10.5–32.3) No differences in rates of NCI were found by treatment group (p=0.38). In our regression model confounding variables for NCI were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by those variables the odds ratio (95% CI) for NCI of patients receiving boosted protease inhibitor monotherapy monotherapy during 1–2 years was 0.85 (0.29–2.50) and for 2–9 years was 0.40 (0.14–1.15).ConclusionsBoosted protease inhibitor monotherapy, regardless of duration, was not associated with a higher rate of neurocognitive impairment than triple drug ART. These results call into question the ability of neuropenetrance scores to predict the neuroefficacy of antiretroviral regimens in HIV‐infected patients with adequate blood viral suppression.

Potential for simplification of HIV treatment with boosted protease inhibitor monotherapy

Previous studies have evaluated the simplification of HIV treatment with ritonavir-boosted protease inhibitor monotherapy, demonstrating acceptable efficacy and advantages such as avoidance of the adverse effects of reverse transcriptase inhibitors. To achieve the best results, patients should be appropriately selected for this therapy. The purpose of this study was to estimate the proportion of HIV patients suitable for boosted protease inhibitor monotherapy according to clinical trial criteria. Setting The study was conducted in the outpatient hospital pharmacy service of the Complejo Hospitalario de Navarra in northern Spain. A retrospective analysis was performed on data from 635 adults on antiretroviral therapy. The eligibility criteria were: (1) >18 years of age; (2) prior triple-drug antiretroviral regimen; (3) durability of current treatment >18 months; (4) viral load <400 copies/mL over the 18 months before evaluation and <50 copies/mL over the last 6 months; (5) CD4 count ≥250 cells/μL; (6) CD4 count nadir >100 cells/μL; (7) no previous virological failure under prior protease inhibitor-based regimen; (8) absence of co-infection with hepatitis B virus; (9) absence of HIV-related neurological disease; and (10) adherence >95 %. The average cost of the current treatment was calculated for patients who met all criteria, as well as the potential economic impact of simplification to monotherapy. Number of patients meeting all criteria for simplification to monotherapy according to clinical trial standards. One hundred and three patients (16.5 %) met the clinical trial criteria for protease inhibitor monotherapy. One hundred and fifty patients (24 %) failed to fulfil only one of the conditions. Fifty-four percent of the patients who met all of the criteria had been treated for more than 10 years. The average saving per patient per year was <euro>2,850-<euro>3,400. This treatment strategy represents a realistic, albeit minority, option. Fulfilment of the above conditions should be the basis for simplification to protease inhibitor monotherapy, though the final decision depends on clinical criteria and patient preferences assessed by the attending physician. Further studies are needed to confirm long-term safety and efficacy.

A Pilot, Prospective, Open-Label Simplification Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Once-Daily Lopinavir-Ritonavir Monotherapy in HIV-HCV Coinfected Patients: The MONOCO Study

Background: A safe, effective, easy-to-dose antiretroviral therapy that minimizes hepatic complication risk is essential in optimizing HIV-HCV treatment. Nucleoside-sparing boosted protease inhibitor monotherapy may achieve this goal. Methods: A prospective, open-label pilot simplification study of once-daily lopina-vir/ritonavir (LPV/r) monotherapy in HIV-HCV coinfected patients was conducted in patients on HAART with undetectable HIV RNA for ≥6 months. The primary outcome was maintenance of HIV RNA <50 copies/mL through week 48. HIV RNA, immune measures, metabolic markers, and pharmacokinetics were assessed. Results: Twenty participants received once-daily LPV/r monotherapy. Mean baseline age was 46.9 years and CD4 467 cells/L. By per protocol analysis, 71.4% (95% CI, 45.4-88.3) remained on once-daily LPV/r monotherapy with virologic suppression at week 48. Virologic breakthrough (HIV RNA >50 copies/mL on 2 consecutive measures) occurred in 7 patients (mean standard error [SE] time to breakthrough, 38.3 [4.8] weeks). Resuppression occurred with improved adherence in 2 partici-pants and improved adherence plus addition of nucleosides in 2 others. LPV C min was <1 mg/L in 8 patients and was associated with virologic breakthrough in 2 cases but with no development of resistance. No clinically significant changes in CD4, lipids, or glucose were noted. Three participants developed transient ≥5-fold liver enzyme elevations. None of 9 severe adverse events were LPV/r- or liver-related. Six discontinued participation for withdrawal of consent (n=1), poor adherence (n=3), or drug intolerance (n=2). Conclusions: Once-daily LPV/r monotherapy in HIV-HCV coinfected individuals offers a safe and effective approach to the management of the HIV infection, with a predictable pharmacokinetic profile.

Similar Evolution of Cellular HIV-1 DNA Level in Darunavir/Ritonavir Monotherapy versus Triple Therapy in MONOI –ANRS136 Trial over 96 Weeks

BackgroundA higher proportion of intermittent viremia (to have a HIV-1 RNA viral load>50 copies/mL not confirmed) was reported in the boosted protease inhibitor monotherapy arm in some studies including MONOI trial, and that could have an impact on the replenishment of the HIV-1 DNA reservoirs. The HIV-1 DNA level is an interesting marker which reflects the size of cellular HIV reservoir. Our objectives were to study the impact of 96 weeks of Darunavir/ritonavir monotherapy versus a triple standard combination on the HIV-1 blood reservoir and factors associated with HIV-1 plasma DNA at baseline in MONOI trial sub-study.Methodology/Principal FindingsThis sub-study is focused on 160 patients (79 patients in monotherapy arm and 81 in tritherapy arm) for whom blood cells were available both at baseline and at week 96 (W96). Baseline HIV-1 plasma DNA was associated with CD4 nadir, pre therapeutic HIV-1 RNA viral load and baseline HIV-1 RNA measured by ultrasensitive assay. A similar median delta HIV-DNA was observed between D0 and W96 in both arms; 0.35 log copies/106 leucocytes in monotherapy arm versus 0.51 log copies/106 leucocytes in tritherapy arm.Conclusion/SignificanceDespite a higher proportion of intermittent viremia in monotherapy arm, a similar evolution of cellular HIV-1 DNA level was observed between mono and triple therapy arm.Trial RegistrationClinicalTrials. gov NCT00421551 <NCT00421551>

Protease inhibitor monotherapy

The present review focuses on recent data about boosted protease inhibitor monotherapy for maintenance of HIV virological suppression. Until recently most of the trials of boosted protease inhibitor monotherapy have studied lopinavir/ritonavir monotherapy. These trials showed a slightly inferior efficacy of lopinavir/ritonavir monotherapy than that of lopinavir/ritonavir and two nucleosides. Two clinical trials [Monotherapy in Europe with TMC114 (MONET) and Monotherapy inhibitor protease (MONOI)] have shown that darunavir/ritonavir monotherapy has also a slightly lower efficacy for maintenance of virological suppression than darunavir/ritonavir with two nucleosides. The risk of resistance development is minimal and patients who fail this strategy can be re-suppressed again by adding nucleosides or switching to a triple therapy regimen without having lost therapeutic options. MONOI has also shown limb fat recovery in patients receiving darunavir/ritonavir monotherapy and good penetration of darunavir in the seminal fluid. There are still conflicting views about the ability of boosted protease inhibitor to protect the central nervous system from HIV replication. There are no randomized clinical trials showing a higher risk of discordant HIV replication in the cerebrospinal fluid in patients exposed to monotherapy. There are insufficient data of monotherapy with atazanavir/ritonavir. There currently is no consensus about the role of boosted protease inhibitor monotherapy for the treatment of HIV infection. It is clear that suppression can be maintained in a large proportion of patients without exposing patients to a substantial risk of resistance development, but the precise role of this strategy is still undefined.

Virological findings from the SARA trial: boosted PI monotherapy as maintenance second-line ART in Africa

Background: The SARA trial recently demonstrated a non-inferior CD4 response, over median follow-up of 60 weeks, with a boosted protease inhibitor monotherapy (bPImono) maintenance second-line regimen compared with continuous combination therapy (CT), suggesting this approach could maintain effectiveness whilst improving tolerability and decreasing costs [International AIDS Conference 2010, LBPE16]. Analysis of virological response and genotypic drug resistance is reported here. Methods: Eligible participants in the DART trial who received 24 weeks of lopinavir/ritonavir-containing second-line CT were randomised to maintain current CT or to reduce to bPImono within a nested pilot trial (SARA). No real-time virology was performed, but stored plasma samples from time at switch to second-line, randomisation after 24 weeks of second-line, and 24 weeks after randomisation were assayed for HIV-1 RNA viral load (VL) by Roche Amplicor v1.5. Genotypic resistance was assessed on samples with VL >1000 c/ml at this latest time point, along with paired samples at switch to second-line. All analyses are intention-to-treat. Results: 192 participants were randomised to CT (n=95) or bPImono (n=97). 77% (135/173) had VL 1000 c/ml at week 24, 12 (2 CT, 10 bPImono) have been assessed genotypically. IAS major PI mutations at week 24, not present at switch to second-line, were detected in 2 bPImono participants only. One participant (VL=3600 c/ml) had I54V only, the other (VL=1490 c/ml) M46IM+V82AV. Both isolates were considered fully susceptible to darunavir. Conclusions: In this study based on retrospective virological testing, bPImono following 24 week second-line induction was associated with an increase in low level viraemia, although generally in the absence of PI resistance. Longer-term trials are required before definitive conclusions can be drawn about the effectiveness of PI monotherapy in populations without access to virological monitoring. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-O20 Cite this article as: Pillay et al.: O214. Virological findings from the SARA trial: boosted PI monotherapy as maintenance second-line ART in Africa. Journal of the International AIDS Society 2010 13(Suppl 4):O20. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112833/

Incorrect attribution of cerebrospinal fluid HIV-1 virological escape and lymphocytic meningitis to lopinavir/ritonavir monotherapy

We respectfully disagree with many of the interpretations of the case reported by de Truchis et al. [1] entitled ‘Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy’. The title is misleading. Many readers might interpret that ‘escape’ means that HIV replication was suppressed in blood and active in the cerebrospinal fluid (CSF). This is not the case as the patient at the time of presentation had active replication both in blood and CSF. The patient was inadequately treated with lopinavir/ritonavir monotherapy. Authors do not emphasize enough that, as recommended in the European AIDS Clinical Society (EACS) guidelines [2], patients infected with protease inhibitor-resistant isolates should not be treated with lopinavir/ritonavir monotherapy. All the trials of protease inhibitor monotherapy have excluded patients who might be infected with HIV isolates resistant to protease inhibitors. It is interesting, however, that in Truchis et al.[1] case, virological suppression was achieved during 18 months despite intermediate resistance to lopinavir/ritonavir. Once again, this finding supports the extremely high genetic barrier to resistance of boosted protease inhibitors. Virological failure and lymphocytic meningitis is wrongly attributed to the use of lopinavir/ritonavir monotherapy. It is very likely that the reduction of plasmatic and CSF levels of lopinavir/ritonavir concentrations possibly caused by orlistat would have not changed if the patient had been treated with two analogs and lopinavir/ritonavir with similar clinical consequences and with the additional possible development of resistance to nucleosides. The authors claim discordant viral evolution in CSF without adequate data. There is no CSF sample to prove that an isolate with 54V was also present in CSF at the time the first resistance testing was performed in plasma. An alternative explanation is disappearance of 54V both in plasma and CSF owing to insufficient drug pressure caused by low levels of lopinavir/ritonavir. Nevertheless, discordant viral evolution in the CSF and higher viral loads in CSF than in plasma have also been described in patients receiving triple therapy [3]. The authors incorrectly quote Monotherapy Switzerland Thailand (MOST) study of Gutmann et al.[4] as supporting evidence of a higher risk of discordant replication in CSF in patients treated with boosted protease inhibitor monotherapy. In the MOST study, all six patients with neurological symptoms had virological failure both in blood and CSF. The authors mention the studies of Gutmann et al. [4] and Katlama et al. [5] as evidence of a higher risk of HIV encephalitis in patients treated with monotherapy but omit to mention that this complication also occurs in patients treated with triple therapy [3]. Until we have a randomized clinical trial that systematically evaluates CSF replication in patients treated with boosted protease inhibitor monotherapy versus triple therapy, claims of ‘a higher risk of virological escape under protease inhibitor monotherapy’ would not be based on adequate evidence. Finally, we recommend that clinicians closely follow the EACS guidelines [2] before switching patients to boosted protease inhibitor monotherapy.