Wouter F. W. Bierman

HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review

Objective:To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy. Design and methods:Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios. Results:Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART [pooled odds ratio 1.48 (95% confidence interval 1.02–2.13, P = 0.037)]. Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72–1.53, P = 0.81)]. Conclusion:The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.

Presentation and diagnosis of imported schistosomiasis: relevance of eosinophilia, microscopy for ova, and serology.

BACKGROUND In nonendemic countries a steady rise in cases of imported schistosomiasis has been observed. The objective of this study was to describe the presentation of patients diagnosed with schistosomiasis in the Outpatient Department (OPD) for Tropical Diseases in the Academic Medical Center, Amsterdam, the Netherlands. METHODS In a retrospective study, patients with schistosomiasis from our OPD (1997-1999), including a subgroup of persons asking for screening for schistosomiasis and found positive, were analyzed. Diagnosis was based on freshwater exposure in an endemic area and positive serology for schistosomal antibodies. The following data were recorded: age, gender, country of birth, travel destination, symptoms, eosinophil count, and results of serology and stool and urine microscopy. RESULTS Seventy-eight patients (42 travelers, 16 expatriates, and 20 immigrants) were diagnosed with schistosomiasis; 47% were infected in southern Africa. Twenty-four percent had specific symptoms, 57% had eosinophilia, and in 17 patients (22%) Schistosoma ova were found. Eleven travelers suffered from Katayama syndrome. Of the subgroup of 42 persons screened for schistosomiasis, 15 (36%) had schistosomal antibodies; the majority of these persons (10/15 [67%]) were infected in southern Africa. CONCLUSION In our OPD schistosomiasis was diagnosed in about 26 patients per year, 3% of all new presentations. Infections were almost exclusively acquired in Africa. In travelers high eosinophilia was due to acute schistosomiasis; in immigrants it was due to concomitant helminthic infections. One of three people asking to be screened for schistosomiasis had schistosomal antibodies. Eosinophilia was indicative but an insufficient screening tool, and stool and urine microscopy for ova were not sensitive. Screening by serology is easy and reliable and the method of choice in asymptomatic persons with a history of freshwater exposure in a high-risk area.

Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium

BackgroundIntravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe.MethodsHospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated.ResultsOf the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain.ConclusionsData from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment.Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.

Protease inhibitors atazanavir, lopinavir and ritonavir are potent blockers, but poor substrates, of ABC transporters in a broad panel of ABC transporter-overexpressing cell lines

OBJECTIVES A possible mechanism for HIV therapy failure is the efflux of HIV drugs from viral target cells or certain body compartments by ATP-binding cassette (ABC) transporters, allowing ongoing viral replication. Here, we investigated the interaction between protease inhibitors (PIs) and ABC transporters. METHODS To explore the potential blocking capacity of PIs, we exposed cells overexpressing multidrug resistance 1 P-glycoprotein (MDR1 P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP) to established cytotoxic substrates with or without one of the PIs atazanavir, lopinavir or ritonavir. Furthermore, to assess whether PIs serve as substrates, cell growth-inhibitory effects of these PIs were evaluated on cells overexpressing 1 of 11 ABC transporters and their parental counterparts. RESULTS Atazanavir, lopinavir and ritonavir were highly effective in reversing resistance against established substrates in cells overexpressing MDR1 P-gp and MRP1, and, to a lesser extent, BCRP. Concurrently, however, PIs appeared to be relatively poor substrates for ABC transporters. Only a moderate level of resistance to atazanavir was observed in cells overexpressing MRP6 and MRP9 [resistance factor (RF): 2.0-2.6]. Cells overexpressing MDR1 P-gp, MRP3, MRP4 and MRP5 displayed low levels of resistance to atazanavir (RF: 1.3-1.7); MRP7- and MRP9-overexpressing cells to lopinavir (RF: 1.4-1.5); and MRP9-overexpressing cells to ritonavir (RF: 1.4). CONCLUSIONS PIs can act as potent blockers of MDR1 P-gp, MRP1 and BCRP, but they are poor substrates for 11 ABC transporters. Consequently, ABC transporters are unlikely to play a major role in PI failure, but still may contribute to drug-specific adverse events and drug-drug interactions.

Failure of Treatment with First-Line Lopinavir Boosted with Ritonavir Can Be Explained by Novel Resistance Pathways with Protease Mutation 76V

BACKGROUND Virological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment. METHODS Viral protease and the C-term part of Gag were sequenced. The observed mutations were introduced in a reference strain to investigate impact on protease inhibitor susceptibility and replication capacity. RESULTS A detailed longitudinal analysis demonstrated the selection of the M46I+L76V protease mutations in all 3 patients. The L76V conferred a solitary 3.5-fold increase in one-half the maximal inhibitory concentration to lopinavir but severely hampered viral replication. Addition of M46I, which did not confer any lopinavir resistance on its own, had a dual effect. It partly compensated for the loss in replication capacity and increased the one-half maximal inhibitory concentration to above the lower clinical cutoff (11-fold). Analysis of a large clinical database (>180,000 human immunodeficiency virus [HIV] sequences) demonstrated a significant association (Spearman rho, 0.93) between the increased presence of L76V in clinical samples (0.5% in 2000 to 3.4% in 2006) and lopinavir prescription over time. CONCLUSIONS The HIV protease substitution L76V, in combination with M46I, confers clinically relevant levels of lopinavir resistance and represents a novel resistance pathway to first-line lopinavir/r therapy.

Cutaneous Larva Migrans Acquired in Brittany, France

To the Editor: Hookworm-related cutaneous larva migrans is a parasitic dermatosis caused by the penetration of larvae, mostly of a dog or cat hookworm, into the epidermis of humans (1,2). This eruption is most commonly found in tropical and subtropical areas but was recently reported from western Europe, including Germany (3,4), England (5,6), Scotland (7), and southern France (8). We report a patient from the Netherlands who acquired hookworm-related cutaneous larva migrans while on a holiday in Brittany, France. A previously healthy 40-year-old man from the Netherlands traveled to Brittany, France, to visit from September 1 to September 15, 2008. He and his partner slept in tents, sometimes camping rough (not on designated camping sites or on private property), and they stayed in low-budget hotels. They spent a lot of time on several beaches along the Atlantic Ocean on the southern shore of Brittany (≈48°N). The weather during their stay was variable. The patient was frequently bitten by mosquitoes, especially on his feet. He had not traveled to the tropics before and did not own any pets. After his return to the Netherlands, the area around 2 presumed mosquito bites at the lateral side of his right foot became red, swollen, and itchy. This area evolved into a 1-cm pustule that later turned into a bulla. On November 10, he visited his general practitioner, who made a diagnosis of cellulitis and started the patient on amoxicillin/clavulanic acid 625 mg, 3×/day for 10 days. During antimicrobial drug treatment, skin inflammation improved, but after 2 days the patient noticed that an itching red streak had developed, extending from the lesions on the lateral side of the right foot to the whole width of the sole of the foot. The tip of the streak proceeded along the sole of the foot at the rate of 2 cm/day. On the fifth day, he was referred to our Tropical Diseases outpatient clinic. Physical examination showed 2 elevated, ulcerative lesions on the lateral side of the right foot, and from each originated an elevated serpiginous lesion (Figure, panels B and C). These were typical tortuous lesions 2 cm in width. One of the lesions ran across the whole sole of the right foot and was 14 cm in length (Figure, panels A and C). The medial end of the lesion was fervently erythematous. Based on clinical signs, we diagnosed the skin lesion as hookworm-related cutaneous larva migrans with secondary impetiginization. The patient was subsequently treated with a single oral dose of 12 mg ivermectin. The itch and the progression of the lesion halted instantly and the lesion disappeared during the following weeks. The larva was not extirpated and thus not further identified. Figure Right foot of a patient from Brittany, France, with a hookworm-related cutaneous larva migrans, showing an elevated serpiginous lesion on the sole of the foot (panels A, B) and ulcerative lesions at the origin of the lesions on the lateral side of the ... Hookworm-related cutaneous larva migrans is usually caused by Ancylostoma brasiliense, A. caninum or, rarely, Uncinaria stenocephala. These zoonotic hookworms need a high temperature and a moist environment to develop from an embryo to filariforme larva (1,2). Hookworm-related cutaneous larva migrans is typically a disorder of tropical and subtropical zones and it is rather common among tourists who visit tropical beaches. This was the first patient we had seen with this disease who became infected in western Europe. Apart from an exceptionally hot day on August 30 (maximum 26°C), the weather was not particularly warm during the summer of 2008 in Brittany; during the first 2 weeks of September the average minimum and maximum temperatures were 11°C and 17°C, respectively. Rainfall was moderate and humidity was ≈86% (9). However, the overall warmer climate, including warmer winters, might have created the conditions for zoonotic hookworm infections in humans in western Europe (10). Our patient may have been infected by U. stenocephala, a nematode of dogs that is common in temperate zones but rarely causes hookworm-related cutaneous larva migrans. An increase in ambient temperature might increase the incidence of these zoonotic infections in northern regions. Only 4 cases of hookworm-related cutaneous larva migrans were previously reported in France, all from southern regions (8). A northern spread of hookworm-related cutaneous larva migrans could thus point to expansion of the global distribution of the more tropical hookworms or altered conditions that favor the emergence of infection by a zoonotic hookworm such as U. stenocephala. Either explanation calls for screening of infection in cats and dogs and preventing pet animals and possibly stray animals from accessing beaches. Clinicians should be aware of the possibility of hookworm-related cutaneous larva migrans in patients who have traveled to western Europe and, in particular, those who have stayed on the beaches.

Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial

BACKGROUND The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART. METHODS We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months, and had CD4 nadirs of 200 cells per μL or higher, HIV RNA zeniths of 100 000 copies per mL or less, and no history of virological failure. Patients were randomly assigned (1:1), via a web-based block randomisation method (variable block sizes of 4 and 6), to switch to dolutegravir monotherapy (50 mg once a day) either immediately or after a delay of 24 weeks of continued combination ART. Randomisation was stratified by HIV RNA zenith (<50 000 copies per mL vs 50 000-99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828. FINDINGS Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI -5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation. INTERPRETATION Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy. FUNDING Erasmus Trustfonds.

Declining Hepatitis C Virus (HCV) Incidence in Dutch Human Immunodeficiency Virus-Positive Men Who Have Sex With Men After Unrestricted Access to HCV Therapy

Background Direct-acting antivirals (DAAa) cure hepatitis C virus (HCV) infections in 95% of infected patients. Modeling studies predict that universal HCV treatment will lead to a decrease in the incidence of new infections but real-life data are lacking. The incidence of HCV among Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) has been high for >10 years. In 2015 DAAs became available to all Dutch HCV patients and resulted in a rapid treatment uptake in HIV-positive MSM. We assessed whether this uptake was followed by a decrease in the incidence of HCV infections. Methods Two prospective studies of treatment for acute HCV infection enrolled patients in 17 Dutch HIV centers, having 76% of the total HIV-positive MSM population in care in the Netherlands. Patients were recruited in 2014 and 2016, the years before and after unrestricted DAA availability. We compared the HCV incidence in both years. Results The incidence of acute HCV infection decreased from 93 infections during 8290 person-years of follow-up (PYFU) in 2014 (11.2/1000 PYFU; 95% confidence interval [CI], 9.1-13.7) to 49 during 8961 PYFU in 2016 (5.5/1000 PYFU; 4.1-7.2). The incidence rate ratio of 2016 compared with 2014 was 0.49 (95% CI, .35-.69). Simultaneously, a significant increase in the percentage positive syphilis (+2.2%) and gonorrhea (+2.8%) tests in HIV-positive MSM was observed at sexual health clinics across the Netherlands and contradicts a decrease in risk behavior as an alternative explanation. Conclusions Unrestricted DAA availability in the Netherlands was followed by a 51% decrease in acute HCV infections among HIV-positive MSM.

Boceprevir, peginterferon and ribavirin for acute hepatitis C in HIV infected patients

BACKGROUND & AIMS Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy. METHODS We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint. RESULTS One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers. CONCLUSION With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495.

Yellow fever in a traveller returning from Suriname to the Netherlands, March 2017

A Dutch traveller returning from Suriname in early March 2017, presented with fever and severe acute liver injury. Yellow fever was diagnosed by (q)RT-PCR and sequencing. During hospital stay, the patient’s condition deteriorated and she developed hepatic encephalopathy requiring transfer to the intensive care. Although yellow fever has not been reported in the last four decades in Suriname, vaccination is recommended by the World Health Organization for visitors to this country.