Linda Harrison

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

Comparison of 5-mg and 10-mg Loading Doses in Initiation of Warfarin Therapy

Warfarin levels are monitored by measuring the prothrombin time, which responds to reductions in levels of three vitamin K-dependent clotting factors: factors II, VII, and X [1, 2]. During the first 48 hours of treatment, the anticoagulant effect of warfarin is caused mainly by a reduction in the activity of factor VII, which has a half-life of 6 hours. In contrast, the antithrombotic effect of warfarin (which is thought to be caused primarily by a reduction in the activity of factor II) is delayed for as long as 60 hours [3, 4]. Therefore, during the first 48 hours of therapy, the anticoagulant and antithrombotic effects of warfarin may be dissociated. In addition, because the half-life of the vitamin K-dependent anticoagulant protein, protein C, is similar to that of factor VII [5], the early anticoagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a procoagulant effect (which results from reduction of protein C) [6]. Warfarin treatment is often initiated with a 10-mg loading dose and then reduced to a level that maintains the international normalized ratio (INR) within the therapeutic range. An alternative approach is to start warfarin therapy at a dose of 5 mg, which is the average dose required to maintain an INR of 2.0 to 3.0. Although a 10-mg loading dose produces a more rapid increase in the prothrombin time, this effect is caused largely by a decrease in factor VII levels and therefore may not produce a more rapid antithrombotic effect. The 10-mg loading dose has three potential short-comings. First, if heparin is discontinued as soon as the INR reaches the therapeutic range, thrombus extension may occur. This is because the antithrombotic effect of warfarin may not yet have manifested. Second, elderly or vitamin K-deficient patients may be exposed to an unnecessary risk for bleeding [7-12]. Third, protein C levels can be excessively decreased before the full antithrombotic effect of warfarin has been completely expressed through the reduction of factor II. On the basis of these considerations, we did a study to compare the relative effects of 5- and 10-mg loading doses of warfarin on four surrogate laboratory markers of efficacy and safety. Methods Patients with no contraindications to warfarin who required anticoagulation (target INR, 2.0 to 3.0) were invited to participate in the trial between June and November 1994 at The Hamilton Civic Hospitals (Ontario, Canada). Enrollment was targeted at 50 patients. All patients gave written, informed consent, and the study was approved by the local internal review board. Patients were assigned by random number table to receive warfarin at an initial dose of 5 or 10 mg. Subsequent doses were determined on the basis of nomograms that were developed before the study began through an iterative process. Because the study used laboratory outcomes, patients and health care professionals were not blinded to treatment assignments. Patients were followed for a maximum of 108 hours, during which time they received five doses of warfarin. Blood samples were taken before warfarin therapy was initiated, 12 hours after the first dose of warfarin, and at 24-hour intervals for 5 days. Blood was collected into vacuum-sealed containers that contained 0.102 mol of buffered sodium citrate per liter. To obtain platelet-free plasma, the sample was double centrifuged at 1700 g and frozen at 70C for batch assays [13]. The prothrombin time was measured using Thromborel S (International Sensitivity Index 1.06, Behring Diagnostics, Kanata, Ontario, Canada) and reported as an INR [14]. Heparin does not increase the prothrombin time in patients receiving both warfarin and heparin if this thromboplastin reagent is used. Factors II, VII, IX, and X were assayed by using the one-stage clotting method [15]. Protein C levels were measured by using a functional clotting assay (Dade International, Mississauga, Ontario, Canada) [16]. Treatment of supratherapeutic INRs with vitamin K was left to the discretion of the attending physician. The outcome measures were the time required to achieve an INR of 2.0 to 3.0, the proportion of INR values greater than 3.0, the time course for reductions in levels of factors II and X, and the time course for reduction in protein C levels. Additional data included levels of factors VII and IX. Results Fifty-one consecutive patients were enrolled in the trial. Two were excluded after one dose of warfarin: One died, and one required cardiac catheterization. Twenty-five patients were randomly assigned to receive a 10-mg loading dose of warfarin; 24 were assigned to receive a 5-mg loading dose. The two groups did not differ in age; weight; or frequency of acute thromboembolism, cancer, or surgery during or immediately before the study period. Forty-eight patients received concomitant heparin therapy for all or part of the study period. Beginning on study day 2, the dose of warfarin was adjusted using a nomogram. Warfarin doses in the two groups were similar except on days 1 and 2. The 10-mg group achieved an INR greater than 2.0 statistically significantly sooner than did the 5-mg group (Table 1). At 36 hours, 11 of 25 patients (44% [CI, 34% to 54%]) in the 10-mg group had INRs of 2.0 or greater compared with 2 of 24 patients (8% [CI, 3% to 14%]) in the 5-mg group (P = 0.005). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) had INRs greater than 3.0 compared with none of 23 patients in the 5-mg group (P = 0.002). Five patients (4 in the 10-mg group and 1 in the 5-mg group) received vitamin K. These patients had INRs of 4.8 to 9.3 and received 0.5 to 2.0 mg of vitamin K subcutaneously. No patient bled. Table 1. International Normalized Ratios for Patients Assigned to Receive a 5- or 10-mg Loading Dose of Warfarin* Levels of factors II and X declined slowly, and no substantial differences were seen between the 5-and 10-mg groups. In contrast, levels of factor VII and protein C decreased more rapidly and were statistically significantly lower in the 10-mg group than in the 5-mg group at 36 and 60 hours (Figure 1). Figure 1. Plasma levels of coagulation factors in patients receiving a 10-mg (striped bars) or 5-mg (white bars) loading dose of warfarin for each of six time points assessed. top middle bottom Discussion We compared the relative effects of 5- and 10-mg loading doses of warfarin. The time course of reduction in levels of factor II was used as a surrogate end point for clinical efficacy, and excessive elevation of the prothrombin time and unopposed reduction in protein C levels were used as surrogate end points for safety. Patients who received a 10-mg loading dose of warfarin achieved INRs greater than 2.0 more rapidly than did patients who received a 5-mg loading dose. However, because this change in the INR was entirely caused by the early reduction of factor VII levels in the 10-mg group, it may not reflect an antithrombotic effect of warfarin, which is thought to result from a reduction in factor II levels. Two separate experimental observations in rabbits support this idea: The first is the early report of a 5-day delay in achieving an antithrombotic effect with warfarin, although the prothrombin time was first prolonged into the therapeutic range and the level of factor VII was markedly reduced after 2 days of treatment [17]. This observation provides the rationale for overlapping heparin and warfarin therapy for 5 days during the initiation of anticoagulant therapy [17, 18]. The second is the finding that the antithrombotic effect of warfarin is abrogated by the infusion of factor II and (to a lesser extent) factor X [18]. In our study, the rate of reduction in levels of factor II and factor X activity were similar in the 5- and 10-mg groups. On the other hand, the 10-mg loading dose was associated with a significantly more rapid decrease in protein C activity (which decreased before levels of factors X and II were substantially reduced) than that seen in the 5-mg group and an excessive prolongation of the INR. The combination of markedly reduced protein C levels and near-normal levels of factors II and X over the first 2 days of warfarin therapy could produce a hypercoagulable state, and excessive prolongation of the INR could create a higher risk for bleeding. Our study is limited because we used surrogate markers for efficacy and safety. A much larger trial using clinical outcome measures is needed to determine whether the surrogate markers that we used are clinically relevant. Nevertheless, our findings suggest that both regimens result in a therapeutic INR in most patients by day 5 of treatment. From Hamilton Civic Hospital, McMaster University, and The Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.

First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial

BACKGROUND Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. METHODS In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. FINDINGS Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. INTERPRETATION Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. FUNDING Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study

BACKGROUND For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings. METHODS A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715. FINDINGS Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes. INTERPRETATION In settings with extensive NRTI resistance but no available resistance testing, our data support WHOs recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity. FUNDING National Institutes of Health.

HIV type-1 drug resistance in antiretroviral treatment-naive adults infected with non-B subtype virus in the United Kingdom.

BACKGROUND There is an increasing prevalence of non-B subtype HIV type-1 (HIV-1) infections in Europe, reflecting patterns of migration. We examined the characteristics of HIV-1 drug resistance in antiretroviral treatment (ART)-naive individuals migrating to the UK. METHODS Resistance tests reported to the UK HIV Drug Resistance Database between 2001 and 2006 were included. Demographic data were obtained via linkage to national databases. Resistance was defined as ≥ 1 drug resistance mutation. Non-B HIV-1 subtype was used as a surrogate marker of infection acquired outside the UK. Logistic regression was used to examine the association between demographics and the prevalence of resistance. RESULTS Overall, 196/4,291 (4.6%) samples with non-B subtype showed resistance compared with 745/6,435 (11.6%) samples for subtype B. Among non-B subtypes, the prevalence of resistance decreased over time (6.0% in 2001-2003 to 3.2% in 2006) and was independently associated with later calendar year of sampling (P=0.001). Resistance was confined mainly to one ART class (85%); non-nucleoside reverse transcriptase inhibitor resistance was more common in subtype C (47%) compared with non-B non-C subtypes (29%; P=0.02). M184V was more common in non-B subtypes (non-B 30% versus B 5%; P<0.001) and T215 variants were more common in subtype B (non-B 10% versus B 49%; P<0.001). CONCLUSIONS In ART-naive individuals living in the UK, but who are likely to have acquired HIV-1 abroad, we observed a downward trend in resistance over time, which is surprising in light of ART roll-out in resource-limited settings. Reassuringly, resistance was mainly confined to one drug class; however, patterns of resistance differed by subtype, with some evidence of possible undisclosed prior therapy in non-B subtypes.

Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age

Background:The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier. Design/methods:We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved (

No relationship between drug transporter genetic variants and tenofovir plasma concentrations or changes in glomerular filtration rate in HIV-infected adults

/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa:

Using CD4 Percentage and Age to Optimize Pediatric Antiretroviral Therapy Initiation

7500)/YLS as ‘very cost-effective,’ interventions with ICERs below 3× gross domestic product/YLS as ‘cost-effective,’ and interventions leading to longer life expectancy and lower lifetime costs as ‘cost-saving’. Results:Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs (

HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years,

CCR5-Δ32 Heterozygosity, HIV-1 Reservoir Size, and Lymphocyte Activation in Individuals Receiving Long-term Suppressive Antiretroviral Therapy

44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective. Conclusions:On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.