Herman G. Sprenger

Comparison of Changes in Bone Density and Turnover with Abacavir-Lamivudine versus Tenofovir-Emtricitabine in HIV-Infected Adults: 48-Week Results from the ASSERT Study

BACKGROUND Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. METHODS In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. RESULTS A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001). CONCLUSIONS This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy.

BACKGROUND Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

Nelfinavir and nevirapine side effects during pregnancy

Background:The risk of vertical transmission of HIV has been substantially reduced since the introduction of highly active antiretroviral therapy (HAART); however, the impact of taking HAART during pregnancy on the woman, the fetus and the infant is not yet understood. Objective:To assess and compare tolerability, safety and efficacy of nelfinavir- or nevirapine-containing HAART in a cohort of pregnant and non-pregnant HIV-infected women in the Netherlands. Design:Retrospective comparative study. Methods:In 15 centres specializing in HIV in the Netherlands, data on patient characteristics, HAART, adverse events, viral load response, mode of delivery and HIV status of the neonate were obtained from medical records of HIV-infected pregnant women who received HAART during pregnancy between January 1997 and June 2003. These data were compared with a control group of HIV-infected non-pregnant women that was obtained from the Dutch HIV-monitoring foundation database. Results:Data from 186 pregnant and 186 non-pregnant HIV-infected women using a nelfinavir- or nevirapine-containing regimen were analysed. The pregnant women were younger, used a nelfinavir containing regimen more often, had higher CD4 cell counts and lower HIV RNA levels. Nelfinavir-related gastrointestinal symptoms (P < 0.001), hyperglycaemia (P < 0.001) and nevirapine-related hepatotoxicity (P = 0.003) occurred more often during pregnancy. The risk of nevirapine-induced rash was not increased. No major adverse events occurred. Conclusion:Nelfinavir- or nevirapine-containing HAART regimens during pregnancy are well tolerated. Side effects of antiretroviral therapy are more frequent in pregnant than in non-pregnant women.

Relationship between Progression to AIDS and Thrombophilic Abnormalities in HIV Infection

BACKGROUND HIV-infected patients are at increased risk of venous and arterial thrombosis. We hypothesized that acquired thrombophilic abnormalities that could predispose to thrombosis are most pronounced in patients in advanced stages of HIV infection. METHODS We included 109 consecutive HIV-infected patients in the study and tested them twice for currently known thrombophilic abnormalities at an interval of at least 3 months (median, 3 months; range, 3-12 months). Detailed information was collected about the date of diagnosis of HIV infection, HIV treatment, and previous episodes of venous and arterial thrombosis. RESULTS After HIV infection was diagnosed, 16% of the patients experienced symptomatic thrombosis (venous, 10%; arterial, 6%). Repeated measurements established protein C deficiency in 9% of the patients, increased factor VIII concentrations in 41%, high fibrinogen concentrations in 22%, and free protein S deficiency in 60%. Median factor VIII concentrations were higher in patients with AIDS (CD4 cell counts <2 x 10(8)/L) than in patients with a non-AIDS-defining illness (2260 IU/L vs 1 490 IU/L; P < 0.001), whereas median free protein S concentrations were lower (450 IU/L vs 580 IU/L; P < 0.001). Developing AIDS was associated with increasing factor VIII concentrations and decreasing free protein S concentrations. Increasing factor VIII concentrations were correlated with increasing fibrinogen concentrations and decreasing free protein S concentrations. CONCLUSIONS Multiple acquired and persistent thrombophilic abnormalities are more frequently observed in HIV-infected patients than in the healthy population. The frequencies of these thrombophilic abnormalities increase with the progression to AIDS. These findings may contribute to the high prevalence of venous and arterial thrombosis in HIV-infected patients.

Treatment of poor prognosis epidemic Kaposi's sarcoma with doxorubicin, bleomycin, vindesine and recombinant human granulocyte-monocyte colony stimulating factor (rh GM-CSF).

The efficacy and toxicity of doxorubicin, bleomycin and vindesine in epidemic Kaposis sarcoma, and the role of rh GM-CSF in chemotherapy-induced neutropenia were evaluated in this Phase II study. Patients with progressive Kaposis sarcoma were eligible, and were staged according to ACTG criteria. Treatment consisted of 20 mg/m2 doxorubicin, and a fixed dose of 15 mg bleomycin and 4 mg vindesine every 2 weeks. All patients continued antiretroviral medication with severe myelosuppression, patients received subcutaneous 5 micrograms/kg rh GM-CSF (Leucomax) from days 2-12. Response and toxicity were measured according to ACTG and WHO criteria. 27 patients were evaluable, 25 patients classified as having a poor prognosis. The response rate was 70% (3 CR, 16 PR), the duration of response was 18 weeks (range 8-25) and the median survival 30 weeks (range 4-63+). The cause of death was mostly opportunistic infection. 4 patients died of pulmonary Kaposis sarcoma. The toxicity of this regimen was mainly myelosuppression and 13 patients were treated with rh GM-CSF. Complete recovery of the white blood cells occurred in seven of the 27 courses of rh GM-CSF (26%). No bacterial infections were recorded, but 5 patients (19%) developed an opportunistic infection during treatment. Peripheral neuropathy occurred in 16% of patients. Combination chemotherapy is effective in poor prognosis Kaposis sarcoma but has a shortlasting effect. The main toxicity of this treatment is severe myelosuppression which can be ameliorated by rh GM-CSF. It remains to be established whether rh GM-CSF is also able to reduce the incidence of opportunistic infections.

Rhodococcus equi Infection after Alemtuzumab Therapy for T-cell Prolymphocytic Leukemia

Rhodococcus equi, mainly known from veterinary medicine as a pathogen in domestic animals, can also cause infections in immunocompromised humans, especially in those with defects in cellular immunity. Alemtuzumab, an anti-CD52 monoclonal antibody, causes lymphocytopenia by eliminating CD52-positive cells. We report a patient in whom Rhodococcus equi infection developed after alemtuzumab therapy.

Impact of the HIV-1 env Genetic Context outside HR1-HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drugs target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy.

Active cytomegalovirus infection in patients with acute venous thrombosis : A case-control study

Infectious diseases have been associated with venous thrombosis (VT) [1]. Several case-studies described active cytomegalovirus infection in patients with VT [2-6]. In this case-control study, we detected five cases with active cytomegalovirus infection and VT, and none in the control group. All were female, below 37 years of age, and had another acquired risk factor for VT. This may imply that active cytomegalovirus infection contributes to a procoagulant state in young subjects with other mild risk factors for VT.

Venous thromboembolism in HIV-positive women during puerperium: a case series.

Several studies in the past few years suggested that HIV-infection is associated with an increased risk of venous thromboembolism. No data have been reported, however, on pregnancy and the postpartum period as possible additional risk factors for venous thromboembolism in HIV-infected women. We present a cohort of 41 consecutive pregnant HIV-infected women, wherein three cases (7.3%) had venous thromboembolism within 3 months postpartum. Annual incidence was 313 per 1000 person-years (95% confidence interval, 65-915). This risk is 120 fold higher than in HIV-positive controls, whereas the risk is 157-fold higher compared to HIV-negative pregnant women. Further clinical studies are warranted to assess its implications for pregnancy and postpartum management in HIV-infected women.

Comparison of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients

BACKGROUND Presently the semiquantitative pp65 cytomegalovirus (CMV) antigenemia test on white blood cells is often used for monitoring transplant patients for the appearance of active CMV infections. However, the need for immediate processing of the specimens and the lack of interlaboratory standardization of the test may sometimes be a disadvantage. OBJECTIVE The aim of this study was to investigate the value of the recently developed second version of the Murex Hybrid Capture (MHC) CMV-DNA assay (v 2.0) in comparison with the CMV-pp65 test. The MHC CMV-DNA assay is a quantitative solution hybridization antibody capture assay, using alkaline phosphatase conjugated antibodies and a chemiluminescent substrate. STUDY DESIGN 248 EDTA blood samples from 33 renal transplant patients and 32 samples from 22 other immunocompromised patients were tested by both the MHC CMV-DNA assay and the CMV-pp65 test. RESULTS The qualitative ( + or -) results of both tests showed an overall concordance of 81.4%. Calculations on the basis of discordancy analyses showed that the sensitivity, the specificity, and the positive and negative predictive values were 87.7, 98.3, 98.6, 85.2% for the MHC CMV-DNA assay and 76.6, 100, 100, 75.5% for the CMV-pp65 test. Comparison of the quantitative results of both tests systems showed a correlation coefficient of 0.837. In addition, retesting of 50 samples with the MHC-CMV-DNA assay showed an excellent reproducibility with a correlation coefficient of 0.992. All patients which were tested regularly (at least five samples) became either positive with both tests or with none of them. Neither test system detected CMV significantly earlier than the other one. Both tests became strongly positive in all transplant patients with symptomatic CMV infections, and both tests showed a rapid decline of CMV during subsequent antiviral treatment. CONCLUSION The quantitative Murex Hybrid Capture CMV-DNA assay (v 2.0) may become a valuable additional tool in CMV diagnosis. Further studies will be needed to support this preliminary judgement.