First-line tuberculosis treatment with double-dose rifampicin is well tolerated.

OBJECTIVE: To compare the occurrence of unfavourable treatment and safety outcomes of double-dose rifampicin (RMP; 20 mg/kg/d, intervention) with standard dose (10 mg/kg/d, control) in a first-line tuberculosis (TB) treatment regimen for smear-positive TB patients in Bangladesh.DESIGN: This was a randomised clinical trial. The primary efficacy and safety endpoints were the occurrence of an unfavourable treatment outcome (death, failure, relapse or loss to follow-up) and the occurrence of any serious drug-related adverse event (SAE).RESULTS: In primary efficacy analysis, among 343 control and 347 intervention patients, respectively 15.5% and 11.8% had an unfavourable outcome. In safety analysis, among 349 intervention and 352 control patients, respectively 4.3% and 2.6% experienced an SAE. These differences were not significant. There was a significantly lower occurrence of SAEs, explained by a lower occurrence of hepatic toxicity, in a RMP double-dosed but erroneously HZE (isoniazid+pyrazinamide+ethambutol) under-dosed subgroup.CONCLUSIONS: Our findings show that there is no statistically significant difference in terms of efficacy and safety between standard and double-dose RMP. An accidental finding (related to dosage levels of the standard regimen) suggests that high-dose RMP is potentially a lesser cause of hepatotoxicity. Larger trials with more power, or trials with at least a triple-dose might be needed to clearly see the effect of high-dose RMP on unfavourable outcomes.

Principles for constructing a tuberculosis treatment regimen: the role and definition of core and companion drugs.

Current World Health Organization guidelines for the formulation of treatment regimens for multidrug-resistant tuberculosis (MDR-TB) pay too little attention to the microbiological activity of anti-tuberculosis drugs. Here, we draw lessons from the pioneering work done on shorter MDR-TB treatment regimens and the current knowledge of the bactericidal and sterilizing properties of the drugs to inform the composition of treatment regimens for MDR-TB. We propose to reserve the term 'core drug' for the one drug in a regimen that contributes most to relapse-free cure. The core drug has both moderate to high bactericidal and sterilizing activity, is given throughout treatment, is well tolerated, and has no cross-resistance with the core drug used in the previous regimen. Currently used core drugs include rifampicin in the first-line 6-month regimen, and fourth-generation fluoroquinolones and bedaquiline in regimens for drug-resistant TB. All other drugs are 'companion drugs', used to avert treatment failure due to acquired drug resistance against the core drug. Some also help further reduce the risk of relapse. Moreover, toxic drugs should be avoided if there is an alternative. A regimen must always include the core drug, plus at least one companion drug with high bactericidal activity, a second bactericidal companion drug, plus two sterilizing companion drugs.

Factors Associated with Prevalent Tuberculosis Among Patients Receiving Highly Active Antiretroviral Therapy in a Nigerian Tertiary Hospital.

BACKGROUND: Tuberculosis (TB) causes significant morbidity/mortality among human immunodeficiency virus-infected individuals in Africa. Reducing TB burden in the era of highly active antiretroviral therapy (HAART) is a public health priority. AIM: We determined the factors associated with prevalent TB among patients receiving HAART. SUBJECTS AND METHODS: We conducted a cross-sectional study of adult patients who had received HAART for ≥12 weeks in a Nigerian tertiary hospital. Patients whose TB diagnosis predated HAART were excluded from the study. Pre-HAART data were collected from the clinic records, whereas post-HAART data were obtained through medical history, physical examination, and laboratory investigations. Standard TB screening/diagnostic algorithms as applicable in Nigeria were used. Logistic regression analysis was used to determine factors independently associated with prevalent TB. RESULTS: about 65.8% (222/339) were women. The mean age was 41.1 (10.0) years and 23.6% (73/339) had past history of TB. The prevalence of active TB was 7.7% (26/339). Among these patients, 42.3% (11/26) had pulmonary TB, 34.6% (9/26) had disseminated TB, whereas 23.1% (6/26) had only extra-pulmonary disease. Only 45% (9/20) of patients with pulmonary involvement had positive sputum smear. Factors independently associated with prevalent TB were lower social class (adjusted odds ratio [aOR]: 31.7; 95% confidence interval [CI]: 1.1-1417.3), HAART non-adherence (aOR125.5; 95% CI: 9.6-1636.3), baseline CD4 <200cells/µl (aOR31.0; 95%CI: 1.6-590.6), previous TB (aOR13.8; 95% CI: 2.0-94.1), and current hemoglobin <10 g/dl (aOR10.3; 95% CI: 1.1-99.2). CONCLUSION: Factors associated with prevalent TB were a lower social class, HAART non-adherence, severe immunosuppression before HAART initiation, previous TB, and anemia post-HAART. TB case finding should be intensified in these high-risk groups.

Factors Associated with Prevalent Tuberculosis Among Patients Receiving Highly Active Antiretroviral Therapy in a Nigerian Tertiary Hospital

Background: Tuberculosis (TB) causes significant morbidity/mortality among human immunodeficiency virus­infected individuals in Africa. Reducing TB burden in the era of highly active antiretroviral therapy (HAART) is a public health priority.Aim: We determined the factors associated with prevalent TB among patients receiving HAART.Subjects and Methods: We conducted a cross­sectional study of adult patients who had received HAART for ≥12 weeks in a Nigerian tertiary hospital. Patients whose TB diagnosis predated HAART were excluded from the study. Pre­HAART data were collected from the clinic records, whereas post­HAART data were obtained through medical history, physical examination, and laboratinvestigations.StandardTBscreening/diagnostic algorithms as applicable in Nigeria were used. Logistic regression analysis was used to determine factors independently associated with prevalent TB.Results: about 65.8% (222/339) were women. The mean age was 41.1 (10.0) years and 23.6% (73/339) had past history of TB. The prevalence of active TB was 7.7% (26/339). Among these patients, 42.3% (11/26) had pulmonary TB, 34.6% (9/26) had disseminated TB, whereas 23.1% (6/26) had only extra­pulmonary disease. Only 45% (9/20) of patients with pulmonary involvement had positive sputum smear. Factors independently associated with prevalent TB were lower social class (adjusted odds ratio [aOR]: 31.7; 95% confidence interval [CI]: 1.1­1417.3), HAART non­adherence (aOR125.5; 95% CI: 9.6­1636.3), baseline CD4 <200cells/µl (aOR31.0; 95%CI: 1.6­590.6), previous TB (aOR13.8; 95% CI: 2.0­94.1), and current hemoglobin <10 g/dl (aOR10.3; 95% CI: 1.1­99.2).Conclusion: Factors associated with prevalent TB were a lower social class, HAART non­adherence, severe immunosuppression before HAART initiation, previous TB, and anemia post­HAART. TB case finding should be intensified in these high­risk groups

Systematic screening for drug-resistant tuberculosis with Xpert(®) MTB/RIF in a referral hospital in Cambodia.

SETTING: Limited access to drug susceptibility testing (DST) in referral hospitals contributes to delayed detection of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVE: To document the impact of identifying rifampicin (RMP) resistance using Xpert(®) MTB/RIF on time to diagnosis and time to treatment, and evaluate its performance under programmatic conditions. METHODS: Using a prospective observational study, we screened presumptive MDR-TB cases with Xpert and solid culture/conventional DST. RMP resistance was confirmed using a line-probe assay (LPA). We recorded diagnostic and treatment delays. We performed rpoB gene sequencing post hoc to resolve discordant RMP susceptibilities. RESULTS: We screened 299 of 345 presumptive MDR-TB individuals, and identified 44 Xpert RMP-resistant cases: 16/165 (10%) were new and 28/136 (20%) retreated. The median time to diagnosis was 2 days (Xpert) vs. an additional 6 with LPA; the median time to treatment was 14 days. Confirmatory LPA on 39/44 revealed 27 concordant, 6 discordant and 6 invalid results. Xpert RMP resistance was confirmed in respectively 24/30 (80%) and 21/23 (91%) by phenotypic DST and rpoB sequencing. CONCLUSION: Screening presumptive MDR-TB patients with Xpert enabled rapid diagnosis and treatment of MDR-TB. Xpert performed well, provided appropriate risk assessment was done. Rapid confirmatory testing added little to clinical decision making. Our findings support the latest World Health Organization guidelines to abandon confirmatory LPA in favour of repeat Xpert when in clinical doubt, pending phenotypic DST.

Is frontloaded sputum microscopy an option in active tuberculosis case finding?

SETTING: Active tuberculosis (TB) case finding (ACF) in Phnom Penh, Cambodia using light-emitting diode fluorescence microscopy (FM). OBJECTIVE: To evaluate the smear-positive yield of frontloaded (same-day) smear microscopy in ACF. DESIGN: All presumptive TB cases screened through ACF were asked to provide three sputum specimens: two spot specimens on Day 1 and a morning specimen on Day 2 (spot-spot-morning, SSM). Laboratory technicians blinded to previous results read the smears using FM. We considered only SSM series with at least one positive smear to calculate the proportion of TB cases missed and to determine the difference between the spot-spot (SS) and spot-morning (SM) approach. RESULTS: Of 4616 presumptive TB patients enrolled, 3306 provided three sputum samples. Of 2957 (89.4%) who followed the SSM approach, 188 (6.4%) were smear-positive: 177 on SM and 160 on SS. The incremental yield of the second sputum sample was 18.1% for SM vs. 9.4% for SS. Relative to any smear-positive case detected by SSM, 28/188 (14.9%, 95%CI 10.1-20.8) TB cases would be missed by SS vs. 11/188 (5.9%, 95%CI 3.0-10.2) by SM. The difference in the proportion of missed TB patients was 9.0% (P = 0.006). CONCLUSION: ACF frontloaded sputum microscopy is inferior in terms of smear-positive yield: the SS approach would have missed a significant proportion of smear-positive TB.

Syphilis reinfections pose problems for syphilis diagnosis in Antwerp, Belgium - 1992 to 2012.

Persons with multiple syphilis reinfections may play an important role in syphilis transmission. We analysed all syphilis tests carried out for people attending the HIV/sexually transmitted infection (STI) clinic at the Institute of Tropical Medicine, Antwerp, Belgium, from 1992 to 2012 to evaluate the extent to which syphilis reinfections were contributing to the syphilis epidemic in Antwerp. We then characterised the features of the syphilis infections in individuals with five or more episodes of syphilis. A total of 729 syphilis episodes were diagnosed in 454 persons. The majority of syphilis episodes occurred in people who had more than one episode of syphilis (445/729; 61%). A total of 10 individuals had five or more episodes of syphilis diagnosed over this period. All were men who have sex with men, HIV positive and on antiretroviral therapy. They had a total of 52 episodes of syphilis diagnosed and treated. In 38/42 of the episodes of repeat syphilis in these 10 individuals, they presented without any signs or symptoms of syphilis. Given that the majority of cases of incident syphilis in our clinic were persons with reinfections and that they frequently presented without signs of symptoms of syphilis, there is a strong case for frequent and repeated screening in all persons with a diagnosis of syphilis.

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.

Prevalence of chronic renal failure stage 3 or more in HIV-infected patients in Antwerp: an observational study.

The introduction of Highly Active Antiretroviral Therapy has transformed HIV-infection from an inevitably lethal disease to a chronic condition with a life expectancy comparable to that of people with diabetes mellitus. In recent years it has become evident that people living with HIV/AIDS have an increased risk of developing cardiovascular disease and it is expected that the prevalence of chronic kidney disease will rise accordingly. To investigate the prevalence of chronic kidney disease in patients with HIV, we conducted a retrospective observational analysis using the clinical database of a large centre (Institute of Tropical Medicine) in the urban area of Antwerp, Belgium. The prevalence of chronic kidney disease among HIV infected subjects was found to be 3.0%. The development of chronic kidney disease was associated with age above 50 years, lower CD4 cell counts and Caucasian origin. Screening for chronic renal disorders and prevention of evolution toward chronic renal failure is a crucial challenge in the management of people living with HIV/AIDS.

Immune reconstitution inflammatory syndrome in an HIV/TB co-infected patient four years after starting antiretroviral therapy.

The Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy for HIV is well known. We describe an HIV seropositive woman, presenting 2 IRIS episodes associated with Mycobacterium tuberculosis. Exceptional was that the last episode occurred 4 years after initiating antiretroviral treatment, when her CD4+ lymphocyte count had been around 300 cells/mm3 for one year.

Opportunistic infections and HIV clinical disease stage among patients presenting for care in Phnom Penh, Cambodia.

This prospective, cross-sectional study sought to assess the spectrum of HIV-associated complications and disease stage among individuals presenting for first-time care in Phnom Penh, Cambodia between November 2001 and September 2002. One hundred patients participated in this study. All study participants presented with advanced stages of HIV disease. Seventy-four percent of the subjects had CD4 cell counts <50 cells/mm3. Tuberculosis was the most common AIDS-defining illness among participants, with a prevalence of 43%. A spectrum of other opportunistic infections, including cryptosporidiosis (13%), severe bacterial infections (12%), cryptococcosis (12%), and Pneumocystis jiroveci pneumonia (10%), was identified. These findings underscore the need for widespread HIV treatment and prevention in this setting. Increased screening for HIV and routine health maintenance for those infected are urgently needed in order to facilitate management of both opportunistic infections and the secondary prevention of HIV infection.

Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources.

Mycobacterium tuberculosis infection accounts for probably one third of human immunodeficiency virus (HIV) related immune reconstitution inflammatory syndrome (IRIS) events, particularly in developing countries where HIV and tuberculosis (TB) co-infection is very common. Small cohort studies of HIV-positive patients with active TB treated with antiretroviral therapy (ART) suggest an incidence of TB IRIS varying between 11% and 45%. Risk factors for TB IRIS that have been suggested in certain studies but not in others include: starting ART within 6 weeks of starting TB treatment; extra-pulmonary or disseminated disease; a low CD4+ lymphocyte count and a high viral load at the start of ART; and a good immunological and virological response during highly active antiretroviral therapy (HAART). It is important to agree on a clinical case definition of TB IRIS that could be used in resource-limited settings. Such a case definition could be used to determine the exact incidence and consequences of TB IRIS and would be valuable worldwide in clinical trials that are needed to answer questions on how this phenomenon could be prevented and treated.

The first reported cases of disseminated histoplasmosis in Cambodia, complicated by multiple opportunistic infections.

Although disseminated histoplasmosis is recognized as a common opportunistic infection in HIV-infected persons living in endemic areas, it is not widely reported in Southeast Asia, and has not been reported in Cambodia. It remains unanswered whether this is secondary to a low disease prevalence, or whether the disease, which is associated with a nonspecific clinical presentation, is under diagnosed. In addition to a review of the literature regarding histoplasmosis in Southeast Asia, we provide a description of two HIV-1 infected patients with documented disseminated histoplasmosis complicating other opportunistic infections in Phnom Penh, Cambodia. These two cases highlight the need for both a high clinical suspicion, and reliable laboratory testing, in a setting where there is likely to be more than one infection complicating the patient's clinical course.

Patients with HIV infection and fever: a diagnostic approach.

Fever is a common sign among patients with HIV infection and frequently leads to a medical consultation. It is generally caused by infections. The type of infection depends on the stage of the disease. Opportunistic infections occur only in the presence of severe immunodeficiency. A systematic approach will identify most causes of fever. Since the incidence of opportunistic infections has dramatically decreased with the use of highly active antiretroviral treatments, other causes of fever including immune restoration disease, neoplasm and drug-fever should be considered.

Changing epidemiological and clinical aspects of imported malaria in Belgium.

BACKGROUND: In the early nineties the increase of imported malaria in some European countries was temporarily halted, but it resumed in 1994. More Africans, more European travelers, and fewer long-term residents were counted amongst patients. A shift towards more subacute disease has been noted. This study intends to assess whether the same trends were observed in Belgium. METHODS: Clinical and epidemiological data of 128 patients treated for malaria in 1997 at the Institute of Tropical Medicine and the University Hospital of Antwerp were compared with 209 malaria patients treated in 1988/1989. Risk factors for clinical presentation and parasitemia were analysed. RESULTS: In Belgium the number of reported imported malaria cases remained almost stable between 1988 and 1997. In 1997, there were more African patients, less infections from Central Africa, and 50% less residents. Less patients reported prophylaxis use. The causative agent shifted from Plasmodium falciparum to other species. Subacute and atypical malaria became less frequent. In both years, there were no deaths, and severe malaria did not increase significantly. Mefloquine disappeared almost as a curative treatment, and was replaced by quinine, with or without a long acting agent, or by halofantrine. The ethnic origin, nor the use of chemoprophylaxis, influenced disease characteristics. In 1988, malaria attacks in the previous months predisposed to subacute disease; longer residence, and attacks in the previous months, protected against high parasitemia; longer symptom duration correlated with absence of fever, and with splenomegaly. None of these risk factors was correlated with severe malaria. CONCLUSION: The incidence of subacute malaria dropped significantly in the last decade. Although this presentation is almost limited to residents, the decline in malaria can not be explained by an overall shorter duration of stay, since the decline in this particular clinical presentation of malaria was also spectacular in residents. Apparently, insufficient treatment of malaria attacks in the previous months is the only independent risk factor.