Lutgarde Lynen

Combination therapy for visceral leishmaniasis

Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. We reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens. The first phase 2 results of combination regimens are promising, and have identified effective and safe regimens as short as 8 days. Several phase 3 trials are underway or planned in the Indian subcontinent and east Africa. The limited data available suggest that combination therapy is more cost-effective and reduces indirect costs for patients. Additional advantages are reduced treatment duration (8-17 days), with potentially better patient compliance and lesser burden on the health system. Only limited data are available on how best to prevent acquired resistance. Patients who are coinfected with visceral leishmaniasis and HIV could be a reservoir for development and spread of drug-resistant strains, calling for special precautions. The identification of a short, cheap, well-tolerated combination regimen that can be given in ambulatory care and needs minimal clinical monitoring will most likely have important public health implications. Effective monitoring systems and close regulations and policy will be needed to ensure effective implementation. Whether combination therapy could indeed help delay resistance, and how this is best achieved, will only be known in the long term.

Prevention of mother-to-child transmission of HIV and the health-related Millennium Development Goals: time for a public health approach

This article focuses on prevention of mother-to-child transmission (PMTCT) of HIV particularly in Malawi and discusses how the country is preparing to revise its policies for PMTCT of HIV and for antiretroviral therapy (ART) in response to WHOs 2010 guidelines. The authors propose offering all HIV-infected pregnant women lifelong ART which they see as a more feasible alternative to WHOs guidelines in addition to being more ethical. The article also describes the various benefits of their proposed plan and estimates the results and costs associated.

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea

BACKGROUND In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Unions Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Leishmaniasis in immunosuppressed individuals

Leishmaniasis is a vector-born chronic infectious disease caused by a group of protozoan parasites of the genus Leishmania. Whereas most immunocompetent individuals will not develop disease after Leishmania infection, immunosuppression is a well-established risk factor for disease. The most severe form is visceral leishmaniasis (VL), which is typically fatal if untreated. Whereas human immunodeficiency virus (HIV) co-infection (VL-HIV) was initially mainly reported from southern Europe, it is now emerging in other regions, including East Africa, India, and Brazil. VL has also been found in a wide range of non-HIV-related immunosuppressive states, mainly falling under the realm of transplantation medicine, rheumatology, haematology, and oncology. Clinical presentation can be atypical in immunosuppressed individuals, being easily misdiagnosed or mistaken as a flare-up of the underlying disease. The best diagnostic approach is the combination of parasitological and serological or molecular methods. Liposomal amphotericin B is the drug of choice. Treatment failure and relapse rates are particularly high in cases of HIV co-infection, despite initiation of antiretroviral treatment. Primary prophylaxis is not recommended, but secondary prophylaxis is recommended when the patient is immunosuppressed. Cutaneous leishmaniasis can have a number of particular features in individuals with immunosuppression, especially if severe, including parasite dissemination, clinical polymorphism with atypical and often more severe clinical forms, and even visceralization. Mucosal leishmaniasis is more common. Treatment of cutaneous and mucosal leishmaniasis can be challenging, and systemic treatment is more often indicated. With globally increased travel and access to advanced medical care in developing countries, the leishmaniasis burden in immunosuppressed individuals will probably continue to rise, warranting increased awareness and enhanced surveillance systems.

Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen.

BackgroundVitamin D is an important determinant of bone health and also plays a major role in the regulation of the immune system. Interestingly, vitamin D status before the start of highly active antiretroviral therapy (HAART) has been recently associated with HIV disease progression and overall mortality in HIV-positive pregnant women. We prospectively studied vitamin D status in HIV individuals on HAART in Belgium.We selected samples from HIV-positive adults starting HAART with a pre-HAART CD4 T-cell count >100 cells/mm3 followed up for at least 12 months without a treatment change. We compared 25-hydroxyvitamin D plasma [25-(OH)D] concentration in paired samples before and after 12 months of HAART. 25-(OH)D levels are presented using two different cut-offs: <20 ng/ml and <30 ng/ml.ResultsVitamin D deficiency was common before HAART, the frequency of plasma 25-(OH)D concentrations below 20 ng/ml and 30 below ng/ml was 43.7% and 70.1% respectively. After 12 months on HAART, the frequency increased to 47.1% and 81.6%.HAART for 12 months was associated with a significant decrease of plasma 25-(OH)D concentration (p = 0.001). Decreasing plasma 25-(OH)D concentration on HAART was associated in the multivariate model with NNRTI-based regimen (p = 0.001) and lower body weight (p = 0.008). Plasma 25-(OH)D concentrations decreased significantly in both nevirapine and efavirenz-containing regimens but not in PI-treated patients.ConclusionsVitamin D deficiency is frequent in HIV-positive individuals and NNRTI therapy further decreases 25-(OH)D concentrations. Consequently, vitamin D status need to be checked regularly in all HIV-infected patients and vitamin D supplementation should be given when needed.

Visceral Leishmaniasis and HIV Coinfection in East Africa.

Visceral Leishmaniasis (VL) is an important protozoan opportunistic disease in HIV patients in endemic areas. East Africa is second to the Indian subcontinent in the global VL caseload and first in VL-HIV coinfection rate. Because of the alteration in the disease course, the diagnostic challenges, and the poor treatment responses, VL with HIV coinfection has become a very serious challenge in East Africa today. Field experience with the use of liposomal amphotericin B in combination with miltefosine, followed by secondary prophylaxis and antiretroviral drugs, looks promising. However, this needs to be confirmed through clinical trials. Better diagnostic and follow-up methods for relapse and prediction of relapse should also be looked for. Basic research to understand the immunological interaction of the two infections may ultimately help to improve the management of the coinfection.

Evaluation of two tests based on the detection of histidine rich protein 2 for the diagnosis of imported Plasmodium falciparum malaria.

The ParaSight-F dipstick test (Becton Dickinson, USA) and the ICT Malaria Pf test (ICT, Australia) both detect histidine rich protein 2 (HRP-2), a water-soluble antigen expressed by Plasmodium falciparum trophozoites. The present study compared the diagnostic performance of both tests in persons returning to Belgium from countries endemic for malaria. During a period of 18 months both tests were performed on all patients returning from the tropics with a positive malaria blood film. Patients with fever without an obvious cause were used as controls. For the ParaSight-F test, considering P. falciparum trophozoites only, sensitivity was 95% and specificity 90%. Considering trophozoites of all species of Plasmodium, sensitivity was 71% and specificity 87%. Finally, considering patients with clinical malaria, the sensitivity of the test was 72% and specificity 87%. For the ICT Malaria Pf test, sensitivity was 95% and specificity 89% for P. falciparum trophozoites only, 71% and 86% for trophozoites of all species, and 72% and 87% for clinical malaria. Both tests gave highly comparable results. However, antigen detection assays cannot replace conventional microscopy in diagnosing imported malaria. Thick blood film examination is more sensitive and more specific, it allows estimation of parasitaemia and distinction between parasite growth stages, and it covers all species. Moreover, with treated patients the use of antigen tests might lead to problems in determining the efficacy of therapy.

An algorithm to optimize viral load testing in HIV-positive patients with suspected first-line antiretroviral therapy failure in Cambodia.

Objective:To develop an algorithm for optimal use of viral load testing in patients with suspected first-line antiretroviral treatment (ART) failure. Methods:Data from a cohort of patients on first-line ART in Cambodia were analyzed in a cross-sectional way to detect markers for treatment failure. Markers with an adjusted likelihood ratio <0.67 or >1.5 were retained to calculate a predictor score. The accuracy of a 2-step algorithm based on this score followed by targeted viral load testing was compared with World Health Organization criteria for suspected treatment failure. Results:One thousand eight hundred three viral load measurements of 764 patients were available for analysis. Prior ART exposure, CD4 count below baseline, 25% and 50% drop from peak CD4 count, hemoglobin drop of ≥1 g/dL, CD4 count <100 cells per microliter after 12 months of treatment, new onset of papular pruritic eruption, and visual analog scale <95% were included in the predictor score. A score ≥2 had the best combination of sensitivity and specificity and required confirmatory viral load testing for only 9% of patients. World Health Organization criteria had a similar sensitivity but a lower specificity and required viral load testing for 24.9% of patients. Conclusion:An algorithm combining a predictor score with targeted viral load testing in patients with an intermediate probability of failure optimizes the use of scarce resources.

Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study

Background Although stavudine (D4T) remains frequently used in low-income countries in Asia, associated long-term toxicity data are scarce. The aim of this study was to determine the long-term incidence of severe D4T-toxicity (requiring drug substitution) and associated risk factors in HIV-infected Cambodians up to six years on antiretroviral treatment (ART). Methodology/Principal Findings This is a retrospective analysis of an observational cohort, using data from an ART program with systematic monitoring for D4T-toxicity. Probabilities of time to D4T substitution due to suspected D4T toxicity (treatment-limiting D4T toxicity) were calculated, a risk factor analysis was performed using multivariate Cox regression modelling. Out of 2581 adults initiating a D4T-containing regimen, D4T was replaced in 276 (10.7%) patients for neuropathy, 14 (0.5%) for lactic acidosis and 957 (37.1%) for lipoatrophy. The main early side effect was peripheral neuropathy (7.0% by 1 year). After the first year, lipoatrophy became predominant, with a cumulative incidence of 56.1% and 72.4% by 3 and 6 years respectively. Older age (aHR 1.8; 95%CI: 1.4–2.3) and lower baseline haemoglobin (aHR 1.7; 95%CI: 1.4–2.2) were associated with the occurrence of neuropathy. Being female (aHR 3.8; 95%CI: 1.1–12.5), a higher baseline BMI (aHR 12.6; 95%CI: 3.7–43.1), and TB treatment at ART initiation (aHR 8.6; 95%CI: 2.7–27.5) increased the likelihood of lactic acidosis. Lipoatrophy was positively associated with female gender (aHR 2.3; 95%CI: 2.0–2.6), an older age (aHR 1.3; 95%CI: 1.1–1.4), and a CD4 count <200 cells/µL (aHR 1.3; 95%CI: 1.1–1.5). Conclusions Stavudine-based treatment regimens in low-income countries are associated with significant long-term toxicities, predominantly lipoatrophy. Close clinical monitoring for toxicity with timely D4T substitution is recommended. Phasing-out of stavudine should be implemented, as costs allows.

Five-year experience with scaling-up access to antiretroviral treatment in an HIV care programme in Cambodia.

Objectives  To evaluate a 5‐year HIV care programme (2003–2007) in the Sihanouk Hospital Center of HOPE, Phnom Penh, Cambodia.