Successful use of protease inhibitors in HIV-infected haemophilia patients

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group.
Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 × 10⁶/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.     

Long‐term follow‐up of 11 protease inhibitor (PI)‐naïve and PI‐treated HIV‐infected patients harbouring virus with insertions in the HIV‐1 protease gene

Objectives

Amino acid insertions in the protease gene have been reported rarely, and mainly in patients receiving protease inhibitors (PIs). The aim of the study was to assess the long‐term viro‐immunological follow‐up of HIV‐infected patients harbouring virus with protease insertions.

Methods

Cases of virus exhibiting protease insertions were identified in routine resistance genotyping tests. Therapeutic, immunological and virological data were retrospectively collected.

Results

Eleven patients harbouring virus with a protease gene insertion were detected (prevalence 0.24%), including three PI‐naïve patients. The insertions were mainly located between codons 33 and 39 and associated with surrounding mutations (M36I/L and R41K). The three PI‐naïve patients were infected with an HIV‐1 non‐B subtype. Follow‐up of these PI‐naïve patients showed that the insert‐containing virus persisted for several years, was archived in HIV DNA, and displayed a reduced viral replicative capacity with no impact on resistance level. Of the eight PI‐experienced patients, 63% were infected with HIV‐1 subtype B; one had been antiretroviral‐free for 5 years and seven were heavily PI‐experienced (median duration of follow‐up 24 months; range 10–62 months). The protease insertion was selected under lopinavir in four patients and under darunavir in one, in the context of major PI‐resistance mutations, and following long‐term exposure to PIs. The insert‐containing virus persisted for a median of 32 months (range 12–62 months) and displayed no specific impact on phenotypic resistance level or viral replicative capacity.

Conclusion

Our data, obtained during long‐term follow‐up, show that insertions in the protease gene do not seem to have an impact on resistance level. This finding supports the recommendation of PI‐based regimens, although further work is required to confirm it.     

The long-term pharmacokinetics and safety of adding low-dose ritonavir to a nelfinavir 1,250 mg twice-daily regimen in HIV-infected patients

OBJECTIVES: To evaluate the long-term pharmacokinetics and safety of adding ritonavir 100 mg twice-daily to a nelfinavir 1250 mg twice-daily regimen in HIV-infected patients. METHODS: This was a prospective, randomized, open-label, controlled 24-week study. Sixteen patients receiving a nelfinavir 1250 mg twice-daily regimen with plasma viral load <1000 HIV-1 RNA copies/mL were randomized to continue treatment or to have ritonavir 100 mg twice-daily added. Safety, including fasting lipid levels, was evaluated at weeks 4, 12 and 24. Patients who were randomized to have ritonavir added (n=9) participated in three 12-h pharmacokinetic evaluations at baseline, week 4 and week 24. RESULTS: Increases in median nelfinavir steady-state plasma concentrations at 12 h (C(12)) from 512 to 773 ng/mL [median difference 450 ng/mL; 95% confidence interval (CI) 116--1510 ng/mL] and in median active nelfinavir metabolite M 8 C(12) from 107 to 603 ng/mL (median difference 545 ng/mL; 95% CI 370--891) were seen after the addition of low-dose ritonavir (baseline to week 24). There were no differences between the nelfinavir or M 8 pharmacokinetic parameters at weeks 4 and 24. No significant changes or differences in the concentration of fasting total cholesterol, low-density lipoprotein (LDL) cholesterol or total triglycerides or in the occurrence of adverse events were observed within or between the two groups. CONCLUSIONS: Nelfinavir and especially M 8 concentrations are increased when low-dose ritonavir is added to a nelfinavir-containing regimen. The combination seems to be safe and the nelfinavir/ritonavir regimen could be an option in patients with low nelfinavir+M 8 concentrations.     

Interactions between protease inhibitors and acid-reducing agents: a systematic review

OBJECTIVE: The purpose of this article is to provide a systematic review of the available pharmacokinetic and clinical data on drug interactions between protease inhibitors (PIs) and acid-reducing agents, and their clinical relevance. METHODS: A literature search was performed using Medline and EMBASE, abstracts of the previous 2 years of major conferences were searched and the drug information service of the manufacturer of every currently available PI was contacted. All data were summarized, and verified by at least two authors. RESULTS: A total of 1231 references were identified, 22 of which were studies of pharmacokinetic interactions between PIs and acid-suppressive agents and a further 12 of which provided pharmacokinetic and/or clinical data. CONCLUSIONS: Many pharmacokinetic studies show a lack of a drug interaction between at least one acid-reducing agent and most PIs. Little clinical information is available, except on interactions between atazanavir and acid-reducing agents. This is probably a consequence of the complexity of the interaction.     

Correlates of high hepatitis C virus RNA load in a cohort of HIV‐negative and HIV‐positive individuals with haemophilia

Summary. Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV‐RNA load. Correlates of high HCV‐RNA load in individuals with haemophilia are largely unknown. Among 1266 interferon naïve HCV‐infected individuals with haemophilia, we compared those with high (>2 × 10⁶ HCV‐RNA copies/mL) to lower viral load, overall and stratifying on HIV co‐infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Overall, high HCV load was independently associated with longer duration of HCV infection (P_trend = 0.0001), body mass index ≥25 kg/m² (OR = 1.4, 95% CI = 1.1–1.9), and HIV co‐infection (OR = 1.4, 95% CI = 1.0–1.8). Among 795 HIV‐negative participants, high HCV‐RNA load was associated with older age at HCV acquisition (OR = 1.9 for >15 years vs≤2 years, P_trend = 0.008), and lower AST/platelet ratio (P_trend = 0.01), in addition to longer duration of HCV infection (P_trend = 0.0008), and body mass index ≥25 kg/m² (OR = 1.6, P = 0.005). Among 471 HIV‐positive individuals, anti‐retroviral therapy (ART) was the only variable associated with high HCV‐RNA load (OR = 1.8, CI = 1.1–2.9 for combination ART; OR = 1.8, CI = 0.9–3.4, for other ART vs no treatment). High HCV‐RNA load with haemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end‐stage liver disease.     

Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series

In July 1996 the Food and Drug Administration (FDA) alerted healthcare providers about 15 case reports of spontaneous bleeding episodes in HIV-positive haemophiliacs taking HIV protease inhibitors. In order to characterize the bleeding associated with HIV protease inhibitor therapy, the FDA's spontaneous adverse event reporting system was searched through 28 February 1997. The bleeding episode reporting rate for persons with haemophilia was compared for HIV protease inhibitors and zidovudine, and the characteristics of haemorrhagic events were compared between individuals with and without haemophilia. There was a substantial predominance of bleeding episodes for haemophiliacs taking HIV protease inhibitors (39 of 67; 58%) as compared with zidovudine (two of 63; 3.2%). A comparison of 39 reports of bleeding in haemophiliacs with 28 in non-haemophiliacs revealed similarities in time to event and type of HIV protease inhibitor implicated, but differences were present concerning location of bleeding and outcome. A greater proportion of haemophiliacs had resolution of their bleeding following discontinuation of their HIV protease inhibitor and recurrence of bleeding following rechallenge, as compared with non-haemophiliacs. HIV-positive haemophiliacs appear to be at an elevated risk of bleeding while taking HIV protease inhibitors, but these medications may predispose all individuals to such complications.     

Dipeptidyl peptidase‐4 inhibitors: pharmacokinetics,efficacy, tolerability and safety in renal impairment

The dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a new class of blood glucose‐lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP‐4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large‐scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP‐4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP‐4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.     

Long‐term (96‐week) follow‐up of antiretroviral‐naïve HIV‐infected patients treated with first‐line lopinavir/ritonavir monotherapy in the MONARK trial*

Background

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.

Methods

A total of 136 antiretroviral‐naïve patients, with a CD4 cell count above 100 cells/μL 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).

Results

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.

Conclusion

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.     

A case of emphysematous pyelonephritis in a patient with rheumatoid arthritis taking corticosteroid and low‐dose methotrexate

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic synovial inflammation. Patients with RA have increased risk of infection; this is related to RA itself or the adverse effects of medication. In this report, we describe a case of emphysematous pyelonephritis in a patient with RA associated with AA amyloidosis and steroid‐induced diabetes mellitus who was taking corticosteroid and low‐dose methotrexate.