Preemptive Therapy Prevents Cytomegalovirus End-Organ Disease in Treatment-Naïve Patients with Advanced HIV-1 Infection in the HAART Era

<div><p>Background</p><p>The efficacy of preemptive therapy against cytomegalovirus (CMV) infection remains unknown in treatment-naïve patients with advanced HIV-1 infection in the HAART era.</p><p>Methods</p><p>The subjects of this single-center observation study were126 treatment-naïve HIV-1 infected patients with positive CMV viremia between January 1, 2000 and December 31, 2006. Inclusion criteria were age more than 17 years, CD4 count less than 100/μl, plasma CMV DNA positive, never having received antiretroviral therapy (ART) and no CMV end-organ disease (EOD) at first visit. The incidence of CMV-EOD was compared in patients with and without preemptive therapy against CMV-EOD. The effects of the CMV preemptive therapy were estimated in uni- and multivariate Cox hazards models.</p><p>Results</p><p>CMV-EOD was diagnosed in 30 of the 96 patients of the non-preemptive therapy group (31%, 230.3 per 1000 person-years), compared with 3 of the 30 patients of the preemptive therapy group (10%, 60.9 per 1000 person-years). Univariate (HR = 0.286; 95%CI, 0.087–0.939; p = 0.039) and multivariate (adjusted HR = 0.170; 95%CI, 0.049–0.602; p = 0.005) analyses confirmed that CMV-EOD is significantly prevented by CMV preemptive therapy. Multivariate analysis showed that plasma CMV DNA level correlated significantly with CMV-EOD (per log10/ml, adjusted HR = 1.941; 95%CI, 1.266–2.975; p = 0.002). Among the 30 patients on preemptive therapy, 7 (23.3%) developed grade 3–4 leukopenia. The mortality rate was not significantly different between the two groups (p = 0.193, Log-rank test).</p><p>Conclusions</p><p>The results indicate that preemptive therapy lowers the incidence of CMV-EOD by almost 25%. Preemptive therapy for treatment-naïve patients with CMV viremia is effective, although monitoring of potential treatment-related side effects is required.</p></div

Flow diagram of patient selection.

<p>ART, antiretroviral therapy; ATV, atazanavir; DRV/r, ritonavir-boosted darunavir; ATV/r, ritonavir-boosted atazanavir.</p

Clinical presentation of AHC patients (n = 32).

<p>Data are number (%) of patients or median [range] values.</p><p>*Time between AHC diagnosis and HCV clearance (weeks).</p>¶<p>Data of 6 patients not available for analysis.</p>†<p>Data of 5 patients not available for analysis.</p>‡<p>Data of 1 patient not available for analysis.</p

Histological findings in needle liver biopsy specimen from the patient who showed null-response (Table 3).

<p>The pre-treatment biopsy specimen obtained at 13 weeks after AHC diagnosis showed stage 2 fibrosis (F2) according to the classification of chronic hepatitis C (New Inuyama Classification). (A and B) Formation of bridging fibrosis by fibrous and cellular expansion in the portal tract. (C) Magnified view showing centrilobular piece-meal necrosis (green arrow), acid folic body (yellow arrow) and spotty necrosis (red arrow). (A) Hematoxylin-eosin stain, x100, (B) Silver impregnation stain, x100, (C) Hematoxylin-eosin stain, x400. PEG-IFN: pegylated interferon, RBV: ribavirin, AHC: acute C hepatitis.</p

Pharmacokinetics of Rifabutin in Japanese HIV-Infected Patients with or without Antiretroviral Therapy

<div><p>Objective</p><p>Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection.</p><p>Methods</p><p>Plasma concentrations of rifabutin and its biologically active metabolite, 25-<i>O</i>-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5–63) of rifabutin use.</p><p>Results</p><p>The mean C_max and AUC_0–24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean C_max and AUC_0–24 of 25–<i>O</i>-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing.</p><p>Conclusion</p><p>Rifabutin dose of 150 mg every other day combined with lopinavir-ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART.</p><p>Trial registration</p><p>UMIN-CTR (<a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E" target="_blank">https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E</a>) UMIN000001102</p></div

Comparison of patients of the SVR and non-SVR groups.

<p>Data are number (%) of patients or median [range] values.</p><p>*Time between AHC diagnosis and initiation of therapy (months).</p>¶<p>Time between initiation of therapy and HCV clearance (weeks).</p><p>ART, antiretroviral therapy; UD, undetectable; PEG-IFN+RBV, pegylated interferon plus ribavirin; SVR, sustained viral response; EVR, early viral response; RVR, rapid viral response.</p

Kaplan-Meier curve showing time to the diagnosis of nephrolithiasis.

<p>ATV/r, ritonavir-boosted atazanavir; DRV/r, ritonavir-boosted darunavir.</p

Pharmacokinetic parameters for rifabutin and 25-<i>O</i>-desacetyl rifabutin.

a<p>By the Mann Whitney's <i>U</i> test.</p>b<p>In Group I, AUC_24–48 is assumed the same as AUC_0–24 and AUC_0–48 is calculated as double of AUC_0–24 for comparison with Group II.</p><p>C_max, maximum plasma concentration; AUC, area under the curve; T_max, time of C_max; CI, confidence interval.</p

Mean plasma concentrations-versus-time plots of rifabutin (A), 25-<i>O</i>-desacetyl rifabutin (B), and rifabutin plus 25-<i>O</i>-desacetylrifabutin (C).

<p>Nine patients of Group I received 300 mg of rifabutin and 7 patients of Group II received 150 mg of rifabutin every other day with lopinavir/ritonavir-containing antiretroviral therapy. <i>Solid circles:</i> Group I, <i>open circles:</i> Group II. Data are mean ±1 standard errors. Dotted line in Figure C represents data of Group I during 0–24 hour for reference. RBT, rifabutin; PI/r, ritonavir-boosted protease inhibitor.</p

Characteristics of study subjects.

a<p>By Fisher's exact test for categorical data and Mann Whitney's U test for continuous variables.</p><p>cART, combination antiretroviral therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IU, international unit.</p