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.

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.

Mesenteric vein thrombosis associated with primary cytomegalovirus infection: a case report.

In the past few years several studies have supported an interplay between cytomegalovirus infections and a prothrombotic state. We describe a case of primary cytomegalovirus infection in an immunocompetent adult that was complicated with mesenteric vein thrombosis. Transient protein C deficiency, lupus anticoagulant and activated protein C resistance were found, in combination with a heterozygous prothrombin G20210A mutation. We discuss the possible mechanisms of cytomegalovirus-related venous thrombosis.

Yield of yearly routine physical examination in HIV-1 infected patients is limited: A retrospective cohort study in the Netherlands.

BACKGROUND: Routine physical examinations might be of value in HIV-infected patients, but the yield is unknown. We determined the diagnoses that would have been missed without performing annual routine physical examinations in HIV-infected patients with stable disease. METHODS: Data were collected from the medical records of 299 HIV-1-infected patients with CD4 count >350 cells/mm3 if not using combination antiretroviral therapy (cART), or CD4 count >100 cells/mm3 and undetectable viral load if using cART. We defined the diagnoses that would have been missed without performing routine physical examinations on annual check-ups in 2010. Exclusion criteria were hepatitis B/C co-infection, start/ switch of cART < 24 weeks, pregnancy, and transgenderism. RESULTS: 215 patients (72%) had positive findings: lipodystrophy (30%), lymphadenopathy (16%) and hypertension (8.4%) were the most common. Two-thirds of all findings were not new or were based on complaints indicating a physical examination even if not routinely scheduled. For 24 patients (8.0%) the routine physical examination led to the finding of a new diagnosis: six-all men who have sex with men (MSM)-had a concurrent sexually transmitted infection, eight had hypertension, and ten others had a large variety of diagnoses. A total atrioventricular block with bradycardia was the most clinically relevant finding. CONCLUSIONS: Annual physical examinations of HIV-infected patients with stable disease brought few new diagnoses that would have been missed without performing a routine examination. Our results suggest that standard assessments could be restricted to six-monthly measuring blood pressure in all patients and annually performing anogenital and digital rectal examination on MSM.

Skin advanced glycation end products in HIV infection are increased and predictive of development of cardiovascular events.

OBJECTIVE: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection. DESIGN: Single-centre prospective cohort study. METHODS: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age-matched healthy volunteers. RESULTS: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; P < 0.001). In multivariate regression analysis, rSAF was associated with nadir CD4 cell count less than 200 cells/µl (ß -0.274; P = 0.01), smoking (ß 0.240; P = 0.03), and men who have sex with men (MSM) (ß 0.202; P = 0.07). CVD events occurred in six patients (7%). In Cox regression analysis including age, SAF, smoking, diabetes, hypertension and CKD, SAF (P = 0.01), and (Wet Medisch-wetenschappelijk Onderzoek met mensen; WMO) CKD (P = 0.03) remained as independent predictors of CVD events. CONCLUSION: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4 cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events.

Cost-effectiveness of antenatal HIV-testing: reviewing its pharmaceutical and methodological aspects.

This paper reviews the pharmacoeconomic aspects of antenatal testing for HIV. HIV is a retrovirus which is transmitted among humans through sexual contact, infected blood or blood products (needle sharing or percutaneous accidents) and from mother to child (vertical transmission). Vertical transmission from the HIV-infected mother can occur in utero during and after delivery, through breastfeeding. Effective interventions available to reduce the risk of vertical transmission include: pharmacotherapy prior, during and after delivery; voluntary caesarean section; and replacing breastfeeding by bottle-feeding [1,2]. The existence of these effective interventions underlies the need to detect yet undiagnosed HIV-infection in pregnancy through antenatal testing. Contemporary pharmacotherapy consists of a combination of three or more antiretroviral drugs, also referred to as highly-active antiretroviral therapy (HAART). For newly detected HIV-infected mothers, the Centers for Disease Control suggests the use of a zidovudine-comprising combination with one other nucleoside analogue reverse transcriptase inhibitor and a protease inhibitor (PI) [3]. As HIV in pregnancy may be asymptomatic, structured antenatal HIV-testing therefore seems to offer an attractive prevention strategy. Two broad types of approaches exist: selective or targeted testing versus universal testing. The availability of effective - but expensive - combination therapies since 1996 has greatly enhanced the importance of pharmacoeconomic assessments in the field of HIV-infection. Treatment of the mother will incur additional costs but will also make any programme more effective. Furthermore, avoiding children becoming infected with HIV will also incur monetary benefits, as children are also being treated with HAART. In summary, the background of antenatal HIV-testing has undergone major changes compared with the early 1990s. This review of the pharmacoeconomics of antenatal HIV-testing followed a systematic approach as it was performed according to prespecified criteria, allowing valid comparisons in methodologies and findings of those studies that have yet been conducted in this area.

A systematic review of a single-class maintenance strategy with nucleoside/nucleotide reverse transcriptase inhibitors in HIV/AIDS.

BACKGROUND: Single-drug class regimens with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are generally not recommended as initial therapy because they are inferior compared with therapy with two NRTIs plus efavirenz. However, triple-NRTI combinations can be useful in specific circumstances such as in tuberculosis coinfection, pregnancy or dyslipidaemia. Here, we review the potential of such combinations to maintain viral suppression after induction of suppression by standard combination antiretroviral therapy (cART) and to evaluate the trade-off of NRTI-only regimens for metabolic control. METHODS: We conducted a systematic search of the literature in two databases from 1 January 1998 up to 1 March 2013: Medline, through the search engine PubMed, and Embase. RESULTS: A total of 11 randomized controlled trials (RCTs) with 2,105 patients and 3 observational studies with 2,639 patients were included. Studies including patients with mono- or dual-NRTI treatment before start of effective cART showed a tendency to higher failure rate because of resistance based on archived viral mutations. In studies with ART-naive subjects before start of cART, triple-NRTI combination showed virological activity comparable to two NRTIs plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor in all RCTs, but not in one cohort study. Switching improved serum lipids significantly. CONCLUSIONS: Of the studied triple-NRTI combinations only abacavir/lamivudine/zidovudine was sufficiently potent. Triple-NRTI maintenance after successful induction with two-class cART appeared successful in treatment-naive subjects and remains a useful option in specific circumstances, especially when other drugs are not available or drug interactions are an issue.

Unusual cluster of HIV type 1 dual infections in Groningen, The Netherlands.

In 2007, 14 Dutch men having sex with men (MSM) filed a criminal case against three other men, accusing them of administering sedative drugs, sexual abuse, and deliberate subcutaneous injections with HIV-1-infected blood. Medical files showed that 9 of 17 men presented with an acute HIV-1 infection syndrome during 2006-2007. Two men were not infected with HIV. Analysis of viral strains in the 12 MSM and the three alleged donors showed that one donor and six recipients were double infected with two distinct HIV-1 subtype B strains, while another five recipients and one donor were single infected with either strain. Two men were infected with unrelated strains. The finding of multiple double infections with very similar HIV-1 strains is without precedent.

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 drug's 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.

Pegylated interferon-α monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C.

BACKGROUND: Despite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-α [PEG-IFN-α] monotherapy or in combination with ribavirin) is still under debate. METHODS: A total of 23 HIV-infected patients were prospectively diagnosed with acute HCV and treated with PEG-IFN-α2a monotherapy (180 µg/week) for 24 or 48 weeks. Add-on ribavirin was allowed from week 4 of therapy onwards. There were three patients who were not included for different reasons. Blood samples were routinely drawn for viral load measurement and IL28B polymorphism analysis. RESULTS: Spontaneous viral clearance occurred in 1 (4%) patient. Nineteen patients (13 genotype 1 and 6 genotype 4) received treatment with PEG-IFN-α monotherapy (3 with add-on ribavirin) resulting in a rapid virological response (HCV RNA<50 IU/ml at week 4) in 7 (37%) patients. A sustained virological response (SVR) was reached in 7 (37%) patients, whereas 9 (47%) patients were null-responders to treatment (that is, <2 log10 drop in HCV RNA at week 12 of therapy). The unfavourable G allele of the IL28B polymorphism rs8099917 was detected in 66% of the non-responders. In case of re-emergence of HCV viraemia after treatment discontinuation, sequence analysis of quasispecies confirmed an HCV relapse in 3 patients while 2 patients were re-infected by their previously non-responding partner. CONCLUSIONS: PEG-IFN-α monotherapy resulted in a low SVR rate and a high percentage of null-response, whereas non-SVR was associated with a polymorphism in the IL28B gene (rs8099917).

[Drug interaction caused by communication problems. Rhabdomyolysis due to a combination of itraconazole and simvastatin]. / Geneesmiddelinteractie door communicatieproblemen. Rabdomyolyse door de combinatie van itraconazol en simvastatine.

A 58-year-old man, who spoke very little Dutch, had various symptoms and used several drugs including simvastatin. He was prescribed itraconazole for onychomycosis. Simvastatin was concurrently replaced with pravastatin to prevent drug interactions. However, the interaction still occurred when the pravastatin ran out, and the patient resumed taking simvastatin on his own initiative. Myalgia and muscle weakness developed after one week. The general practitioner found a strongly elevated creatine kinase level in the blood. The patient required hospitalisation for severe rhabdomyolysis. He was treated with an infusion of an ample quantity of physiological saline solution and made a full recovery. Due to the elevated risk of toxic interactions, doctors should beware of communication problems in complex patients and avoid new prescriptions not strictly required.

Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands.

BACKGROUND: We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type-1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. METHODS: Treatment-naive adults reaching plasma viral load (pVL)<400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL≥400 copies/ml following prior suppression to <400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). RESULTS: For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P<0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P<0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). CONCLUSIONS: HIV-1-infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients.

Two donor-related infections in a heart transplant recipient: one common, the other a tropical surprise.

BACKGROUND: Infection is the most frequent complication after heart transplantation (HTx). In this report and brief literature review we present a recipient who some 6 weeks post-HTx had two donor-related infections: a "common" primary cytomegalovirus (CMV) infection and, simultaneously, a highly unusual donor-related Strongyloides stercoralis infection. METHODS: The parasite was discovered by chance in a skin biopsy. CMV was treated with ganciclovir and the strongyloidiasis was cured with two courses of anti-helminthic therapy--initially with ivermectine and albendazol and, in response to eosinophilia, with ivermectine monotherapy. The patient's recovery was further complicated by two successive rejection episodes, a relapse of the CMV syndrome and a novel influenza A/H1N1 infection. These episodes were treated with steroids, ganciclovir and oseltamivir, respectively. RESULTS: It took almost 9 months before a permanent IgG anti-CMV response was seen. At 13 months post-HTx, coronary angiography showed only slight vessel wall abnormalities. At present, the patient is back at home and in good condition. CONCLUSION: Until now, only 4 recipient-derived strongyloidiasis cases have been described in post-HTx patients, all diagnosed by autopsies. This is the first report of a donor-related Strongyloides infection in a patient after HTx.

Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results.

Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.