Differences in marketed prices of antiretrovirals raises questions about the fairness of pricing medicines of significant public health importance such as dolutegravir (DTG). In view of the reduced prices of generically available efavirenz (EFV), there is a need to determine if previous conclusions on DTG's cost-effectiveness need to be re-assessed Lowest list prices of DTG were extracted from national drug price or reimbursement databases for 52 countries. Price was recorded as US$ per person-year (ppy). We compared the price of DTG to minimum costs of production and reduced prices of EFV, as well as assessed the correlation with gross domestic product (GDP) per capita and HIV epidemic size in three income classification groups ('high', 'upper middle-income', 'lower middle or low-income'). Annual prices of DTG ranged from $27 per person-year in Georgia to $20,130 in the USA. Within each income group, there was no observable relationship between DTG prices, GDP per capita and HIV epidemic size. Median price in countries excluded from voluntary licensing agreements ($8718) was >140 times higher than countries included ($60). Price of DTG was >500% higher than EFV in many countries. Three full economic evaluations from high-income settings that compared DTG against EFV all used branded drug prices of EFV-based regimens as cost inputs to evaluate DTG's cost-effectiveness. This study highlights the wide disparity in prices of DTG across countries, even when segregated by similar income levels. The cost-effectiveness of DTG versus EFV should be re-evaluated now that low-cost generic EFV has become widely available.
Introduction The effectiveness of antiretroviral therapy (ART) is assessed by measuring CD4 cell counts and viral load. Recent studies have questioned the added value of routine CD4 cell count measures in patients who are virologically suppressed. Methods We systematically searched three databases and two conference sites up to 31 October 2014 for studies reporting CD4 changes among patients who were on ART and virologically suppressed. No geographic, language or age restrictions were applied. Results and discussion We identified 12 published and 1 unpublished study reporting CD4 changes among 20,297 virologically suppressed patients. The pooled proportion of patients who experienced an unexplained, confirmed CD4 decline was 0.4% (95% CI 0.2–0.6%). Results were not influenced by duration of follow‐up, age, study design or region of economic development. No studies described clinical adverse events among virologically suppressed patients who experienced CD4 declines. Conclusions The findings of this review support reducing or stopping routine CD4 monitoring for patients who are immunologically stable on ART in settings where routine viral load monitoring is provided.
Background: Protease inhibitor monotherapy is an attractive treatment option for HIV-infected subjects. Data assessing neuropsychiatric events with the use of protease inhibitor monotherapy are sparse. Methods: Clinician- and patient-reported neuropsychiatric events were assessed over 48 weeks in HIV-infected subjects on stable antiretroviral therapy, with a plasma HIV RNA <50 copies/mL, randomised to commence on a one to one basis darunavir/ritonavir (800/100 mg once daily) alone (DRVrMono) or with nucleoside analogues (DRVrNRTI). Patient-reported events were assessed by the Functional Assessment of HIV Infection (FAHI) questionnaire and included an assessment of cognitive function. Results: Of 256 subjects enrolled, clinician-reported grade 1–4 adverse events of the nervous system (all cause) were seen in 16% of patients in each treatment arm. FAHI questionnaires were completed by 206 subjects at 48 weeks. No differences in cognitive functioning or other FAHI scores were observed between study treatment groups: Cognitive Functioning score [mean (SD)] 8.9 (2.4) and 9.0 (2.6) in DRVrMono arm and 8.8 (2.6) and 8.9 (2.8) in DRVrNRTI arm at baseline and week 48, respectively (P value for difference = .76). Conclusion: In this exploratory analysis, no differences in the evolution of neuropsychiatric adverse events over 48 weeks are observed in HIV-infected subjects randomised to switch antiretroviral therapy to darunavir/ritonavir with or without nucleoside reverse transcriptase inhibitors.
To the Editors: The standard method of indirectly calculating low density lipoprotein (LDL) levels, using the Friedewald equation, may underestimate the number of patients with grade 3 elevations of LDL in the ARTEMIS (TMC114-C211) and TITAN (TMC114-C214) trials. This was a particular problem for patients treated with lopinavir/ritonavir, which raises triglycerides above levels, where the Friedewald equation can normally be used. LDL is an important marker of cardiovascular risk and can be measured either directly or indirectly. Current National Cholesterol Education Program (NCEP) treatment guidelines recommend maintaining LDL levels at least below 130 mg/dL (<3.4 mmol/L), and preferably below 100 mg/dL (<2.6 mmol/L), for those with a high risk of cardiovascular disease.1 In HIV clinical trials, LDL elevations are normally reported by the AIDS Clinical Trials Group grading scale.2 Grade 3 elevations of LDL (above 190 mg/dL or 4.9 mmol/L) are considered high enough to justify starting cholesterol lowering drugs, even for patients with a low (<1%) 10-year risk of cardiovascular disease.1 Direct measurement of LDL cholesterol, using ultracentrifugation and precipitation, (known as “beta quantification”) is cumbersome and time consuming and requires expensive instrumentation and trained personnel.3 LDL cholesterol can also be calculated indirectly using the Friedewald equation4: This equation assumes that virtually all plasma triglyceride is carried on VLDL and that the cholesterol to triglyceride ratio of VLDL is constant at around 5:1. The Friedewald equation is not valid if triglyceride levels are above 400 mg/dL (>4.52 mmol/L). For patient samples with these high triglyceride levels, the LDL value is not normally reported.4 Therefore, if drugs raise triglyceride levels, use of the Friedewald equation may miss important elevations in LDL cholesterol. In previous clinical trials, lopinavir/ritonavir has been shown to elevate triglyceride levels more than other antiretrovirals.5-8 The ARTEMIS trial evaluated lopinavir/ritonavir versus darunavir/ritonavir 800/100 mg OD in treatment-naive patients, in combination with tenofovir/emtricitabine.7 The TITAN trial evaluated lopinavir/ritonavir versus darunavir/ritonavir 600/100 mg twice a day in treatment-experienced patients with HIV-1 RNA >1000 copies per milliliter, in combination with optimized nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor combinations.8 In both trials, fasting lipid data were collected at baseline and through 48-96 weeks of randomized treatment. LDL was calculated using the Friedewald equation, and then either (1) excluding LDL data from patients with triglyceride levels above 400 mg/dL or (2) setting triglycerides equal to 400 mg/dL for those with higher levels. Results from this analysis are shown in Table 1: the percentage of patients with grade 3 elevations in LDL was analyzed by treatment arm and time in the ARTEMIS and TITAN trials.TABLE 1: Percentage of Patients With Grade 3 Elevations in LDL Cholesterol, Calculated by Friedewald Equation in the ARTEMIS and TITAN TrialsIn ARTEMIS, the darunavir/ritonavir arm led to significantly lower mean triglyceride levels at week 48 (142 mg/dL or 1.6 mmol/L) and remained below the NCEP guidelines for intervention. In the lopinavir/ritonavir arm, mean triglycerides rose to 195 mg/dL (2.2 mmol/L) at Week 48, which was above the NCEP levels for intervention. There were 179 patient visits in the lopinavir/ritonavir arm with no LDL calculated owing to high triglycerides versus 48 such patient visits in the darunavir/ritonavir arm. In the lopinavir/ritonavir arm, patients with missing LDL levels at week 48 had mean total cholesterol of 6.0 mmol/L, versus 4.8 mmol/L for those with available LDL levels. In the TITAN trial, the darunavir/ritonavir arm also led to significantly lower triglyceride levels at week 48 (221 mg/dL or 2.5 mmol/L) versus lopinavir/ritonavir (283 mg/dL or 3.2 mmol/L). In both the ARTEMIS and TITAN trial, imputing triglycerides of 400 mg/dL (4.51 mmol/L) for patients with higher triglyceride levels resulted in more grade 3 elevations in LDL being identified compared with using the normal Friedewald equation (Table 1). The percentage of patients with grade 3 elevations in LDL was higher in both arms when calculated with the modified method but particularly in the lopinavir/ritonavir arm. In summary, the Friedewald equation, used to calculate LDL in the ARTEMIS and TITAN trials, underestimated the number of patients with LDL elevations because LDL was not reported for patient samples with triglyceride levels above 400 mg/dL. A significant percentage of these patients may have LDL levels high enough to need intervention with lipid-lowering drugs. Analysis of the AIDS Clinical Trials Group 5087 trial has also showed that the Friedewald equation underestimates the actual levels of LDL for HIV-infected individuals with high triglyceride levels.9 In both the TITAN and ARTEMIS trials, the Friedewald equation missed fewer grade 3 LDL elevations for the darunavir/ritonavir arm, which raised triglycerides less. Assuming a value of 400 mg/dL for triglyceride levels above this level allows the identification of more patients with LDL grade 3 elevations. This is an approximation, and probably overestimates the LDL level, because the triglyceride fraction of the Friedewald equation has been set to a lower level than is measured. For patients with triglycerides above 400 mg/dL (4.51 mmol/L), the best alternative is direct measurement of LDL using beta quantification. Mark Nelson, MD* Ralph DeMasi, PhD† Christiane Moecklinghoff, MD‡ Andrew M. Hill, PhD§∥ *St. Stephens Centre, Chelsea and Westminster Hospital, London, United Kingdom †Department of Statistics, Tibotec Research and Development, Yardley, PA. ‡Clinical Research, Janssen-Cilag, Mechelen, Belgium §Pharmacology Research Laboratories, University of Liverpool, Liverpool, United Kingdom ∥Tibotec Research and Development, Mechelen, Belgium
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).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).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).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.
Abstract Background Molnupiravir has been recently approved in the United Kingdom for the treatment of COVID-19 for showing promising survival benefits in clinical trials. This analysis will estimate and compare potential generic minimum costs of molnupiravir as well as observe countries eligible for pricing discounts as agreed by Merck and The Medicines Patent Pool (MPP). Methods Drug prices were searched for molnupiravir using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability. Trends of molnupiravir drugs prices were also evaluated for the last 6-month period. Mean daily COVID-19 diagnosis rates were calculated for the countries eligible for voluntary licensing. Results Molnupiravir can be generically manufactured at the very low per-course cost of $9.00. Over the past 6 months, prices of molnupiravir have fallen significantly, and when comparing reported international prices, we found wide variations between countries. Only 9% of diagnosed patients worldwide were in the countries eligible for voluntary licensing. Conclusions Prices of molnupiravir range from $20 to $750 per course. Only 9% of worldwide COVID-19 diagnoses are made in countries covered by voluntary licenses. Middle income countries not eligible for voluntary licensing may need to issue compulsory licenses to secure access to molnupiravir at affordable prices.
Summary The field of hepatitis C ( HCV ) therapy is moving inexorably towards a time when interferon is no longer part of routine HCV treatment. 2015 will see at least two interferon‐free directly acting antiviral ( DAA ) treatments licensed in Europe and the USA . For those parts of the world that can afford it, this will mean the potential for treatment of those who have either failed interferon‐based therapy or have been unable to tolerate the side‐effects that commonly accompany treatment.
Lifestyle changes and statins are the cornerstones in management of dyslipidaemia in patients with HIV infection. Replacement of an antiretroviral therapy (ART) component is a proposed therapeutic strategy to reduce cardiovascular risk. In dyslipidaemic patients with HIV infection, we assessed the efficacy of replacing boosted protease inhibitor (bPI) or efavirenz (EFV) by etravirine (ETR) as an alternative to statin therapy.A prospective, open-label, multicentre, 12-week study of patients with HIV infection on ART including bPI or EFV, and statin treatment. Four weeks after statin interruption, bPI or EFV was switched to ETR (400 mg, 8 weeks) if serum low-density lipoprotein cholesterol (LDL-C) was ≥ 3 mM. The primary endpoint was the proportion of patients on ETR with no indication for statin treatment at study completion. Serum levels of HIV RNA, lipids and biomarkers of cardiovascular disease were also measured. (ClinicalTrials.gov: NCT01543035).The 31 included patients had a HIV-1 RNA < 50 copies/mL (median age, 52 years; median CD4, 709 cell/mL; median LDL-C, 2·89 mM), 68% were on EFV, and 32% were on bPI. At week 4, 27 patients switched to ETR. At study completion, 15 patients (56%) on ETR did not qualify for statin treatment. After the ETR switch, serum levels of the cardiovascular biomarkers sICAM and MCP1/CCL2 decreased by 11·2% and 18·9%, respectively, and those of CCL5/RANTES and tissue inhibitor of metalloproteinase-1 increased by 14·3% and 13·4%, respectively, indicating reduced cardiovascular risk. There were no notable treatment-related adverse events.Replacing bPI or EFV by ETR is a viable strategy to obviate primary prevention statin treatment.
Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.
Objective To determine the correlation between ritonavir (RTV) dose and the degree of enhancement of saquinavir (SQV) exposure. Methods Combined analysis of pharmacokinetic data at steady state obtained from two open‐label, randomized, parallel‐group, multiple‐dose, single‐centre studies involving healthy volunteers. Plasma samples for SQV assay were obtained from 97 healthy subjects following multiple dosing of a range of SQV (400–1800 mg) plus RTV (100–400 mg) dosages for 13–14 days. The pharmacokinetics of SQV were derived by model‐independent, noncompartmental methods. Data were analysed by multivariate regression of log transformed C min and C max (geometric means) of SQV dosage as the dependent variable and independent variables of SQV and RTV dosage. Ritonavir was fitted as both a continuous and a categorical variable. Results There is a strong effect of any dose of RTV on C max and C min of SQV ( P < 0.0001 for both parameters), but no greater effect of higher vs. lower RTV dosages on either parameter ( C max : P =0.4373; C min : P =0.3393). Higher SQV dosage correlates linearly with higher C max ( P =0.0093) and C min ( P =0.0010), but the effects of increasing SQV dosages are less than with the addition of any RTV dose. Conclusions RTV enhances SQV concentrations to increase C max and C min . This effect is similar for RTV dosages of 100–400 mg twice daily. Based on this concept of ‘mini‐dose’ RTV, once‐daily dosing of 1600 mg SQV/100 mg RTV and twice‐daily 1000 mg SQV/100 mg RTV are currently being evaluated in clinical trials.
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