High levels of T lymphocyte activation in Leishmania-HIV-1 co-infected individuals despite low HIV viral load

Background: Concomitant infections may influence HIV progression by causing chronic activation leading to decline in T-cell function. In the Americas, visceral (AVL) and tegumentary leishmaniasis (ATL) have emerged as important opportunistic infections in HIV-AIDS patients and both of those diseases have been implicated as potentially important co-factors in disease progression. We investigated whether leishmaniasis increases lymphocyte activation in HIV-1 co-infected patients. This might contribute to impaired cellular immune function. Methods: To address this issue we analyzed CD4(+) T absolute counts and the proportion of CD8(+) T cells expressing CD38 in Leishmania/HIV co-infected patients that recovered after anti-leishmanial therapy. Results: We found that, despite clinical remission of leishmaniasis, AVL co-infected patients presented a more severe immunossupression as suggested by CD4(+) T cell counts under 200 cells/mm(3), differing from ATL/HIV-AIDS cases that tends to show higher lymphocytes levels (over 350 cells/mm(3)). Furthermore, five out of nine, AVL/HIV-AIDS presented low CD4(+) T cell counts in spite of low or undetectable viral load. Expression of CD38 on CD8(+) T lymphocytes was significantly higher in AVL or ATL/HIV-AIDS cases compared to HIV/AIDS patients without leishmaniasis or healthy subjects. Conclusions: Leishmania infection can increase the degree of immune system activation in individuals concomitantly infected with HIV. In addition, AVL/HIV-AIDS patients can present low CD4(+) T cell counts and higher proportion of activated T lymphocytes even when HIV viral load is suppressed under HAART. This fact can cause a misinterpretation of these laboratorial markers in co-infected patients.

Incidence and predictors of severe liver fibrosis in HIV-infected patients with chronic hepatitis C in Brazil

The aim of this study was to examine the incidence and factors associated with the severity of liver fibrosis in 234 coinfected patients in Brazil. Patients were cared for in our clinic, from 1996 to 2004. Eligible patients were defined as patients with documented HIV and hepatitis C virus (HCV) infections and had previously undergone a liver biopsy. Patients with persistently normal alanine aminotransferase (ALT) were also included. The variables selected for study were age, gender, risk category, history of high alcohol consumption, CD4(+) T cell count, antiretroviral therapy usage, HCV genotype and duration of HCV infection. Stage of fibrosis was scored as follows: F0, no fibrosis; F1, portal fibrosis with no septa; F2, portal fibrosis with few septa; F3, bridging fibrosis with many septa; and F4, cirrhosis. The liver fibrosis stage was F3 in 39 (16.6%) and F4 in 20(8.5%) patients. Among patients with normal ALT, the liver fibrosis stage was F3-F4 in three patients (5.6%). Predictors of severe liver fibrosis (17344) by multivariate analysis were age (older patients) and genotype 3 (genotype I odds ratio [OR], 0.28; 95% confidence interval [0], 0.12 0.65). In summary, in the present study severe liver fibrosis was found in 25% of our patients and was associated with an age of more than 38 years at the time of liver biopsy as well as, HCV genotype 3. No differences were found with respect to CD4(+) T cell counts although patients with a CD4(+) T cell count greater than 50 were excluded.

HIV testing and care of the patient co-infected with tuberculosis and HIV

Human immunodeficiency virus (HIV) infection poses one of the greatest challenges to tuberculosis (TB) control, with TB killing more people with HIV infection than any other condition. The standards in this chapter cover provider-initiated HIV counselling and testing and the care of HIV-infected patients with TB. All TB patients who have not previously been diagnosed with HIV infection should be encouraged to have an HIV test. Failing to do so is to deny people access to the care and treatment they might need, especially in the context of the wider availability of treatments that prevent infections associated with HIV A clearly defined plan of care for those found to be co-infected with TB and HIV should be in place., with procedures to ensure that the patient has access to this care before offering routine testing for HIV in persons with TB. It is acknowledged that people caring for TB patients should ensure that those who are HIV positive are transferred for the appropriate ongoing care once their TB treatment has been completed. In some cases, referral for specialised HIV-related treatment and care may be necessary during treatment for TB. The aim of these standards is to enable patients to remain as healthy as possible, whatever their HIV status.

Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa

Objective: To determine the effectiveness of twice-weekly directly observed therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients, irrespective of their previous treatment history. Also to determine the predictive value of 2-3 month smears on treatment outcome. Methods: Four hundred and sixteen new and 113 previously treated adults with culture positive pulmonary TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa. Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice a week to 6 months in the community. Results: Outcomes at 6 months among the 416 new patients were: transferred out 2%; interrupted treatment 17%; completed treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%; 95% CI 92-99%) new patients. Outcomes were similar among previously treated and new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2 months did not predict the final outcome. Conclusion: A twice-weekly rifampicin-containing drug regimen given under DOT cures most adherent patients irrespective of HIV status and previous treatment history. The 2 month smear may be safely omitted. Relapse rates need to be determined, and an improved system of keeping treatment interrupters on therapy is needed. Simplified TB treatment may aid implementation of the DOTS strategy in settings with high TB caseloads secondary to the HIV epidemic. (C) 1999 Lippincott Williams & Wilkins.

Who fails to complete tuberculosis treatment? Temporal trends and risk factors for treatment interruption in a community-based directly observed therapy programme in a rural district of South Africa

SETTING: Hlabisa Tuberculosis Programme, Hlabisa, South Africa. OBJECTIVE: To determine trends in and risk factors for interruption of tuberculosis treatment. METHODS: Data were extracted from the control programme database starting in 1991. Temporal trends in treatment interruption are described; independent risk factors for treatment interruption were determined with a multiple logistic regression model, and Kaplan-Meier survival curves for treatment interruption were constructed for patients treated in 1994-1995. RESULTS: Overall 629 of 3610 surviving patients (17%) failed to complete treatment; this proportion increased from 11% (n = 79) in 1991/1992 to 22% (n = 201) in 1996. Independent risk factors for treatment interruption were diagnosis between 1994-1996 compared with 1991-1393 (odds ratio [OR] 1.9, 95% confidence interval [CT] 1.6-2.4); human immunodeficiency virus (HIV) positivity compared with HIV negativity (OR 1.8, 95% CI 1.4-2.4); supervised by village clinic compared with community health worker (OR 1.9, 95% CI 1.4-2.6); and male versus female sex (OR 1.3, 95% CI 1.1-1.6). Few patients interrupted treatment during the first 2 weeks, and the treatment interruption rate thereafter was constant at 1% per 14 days. CONCLUSIONS: Frequency of treatment interruption from this programme has increased recently. The strongest risk factor was year of diagnosis, perhaps reflecting the impact of an increased caseload on programme performance. Ensuring adherence to therapy in communities with a high level of migration remains a challenge even within community-based directly observed therapy programmes.

Evolutionary conservation of the membrane fusion machine

Recent structural studies of proteins mediating membrane fusion reveal intriguing similarities between diverse viral and mammalian systems. Particularly striking is the close similarity between the transmembrane envelope glycoproteins from the retrovirus HTLV-1 and the filovirus Ebola. These similarities suggest similar mechanisms of membrane fusion. The model that fits most currently available data suggests fusion activation in viral systems is driven by a symmetrical conformational change triggered by an activation event such as receptor binding or a pH change. The mammalian vesicle fusion mediated by the SNARE protein complex most likely occurs by a similar mechanism but without symmetry constraints.

Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions - Systematic review and data synthesis

Objective: To determine whether coinfection with sexually transmitted diseases (STD) increases HIV shedding in genital-tract secretions, and whether STD treatment reduces this shedding. Design: Systematic review and data synthesis of cross-sectional and cohort studies meeting. predefined quality criteria. Main Outcome Measures: Proportion of patients with and without a STD who had detectable HIV in genital secretions, HIV toad in genital secretions, or change following STD treatment. Results: Of 48 identified studies, three cross-sectional and three cohort studies were included. HIV was detected significantly more frequently in participants infected with Neisseria gonorrhoeae (125 of 309 participants, 41%) than in those without N gonorrhoeae infection (311 of 988 participants, 32%; P = 0.004). HIV was not significantly more frequently detected in persons infected with Chlamydia trachomatis (28 of 67 participants, 42%) than in those without C trachomatis infection (375 of 1149 participants, 33%; P = 0.13). Median HIV load reported in only one study was greater in men with urethritis (12.4 x 10(4) versus 1.51 x 10(4) copies/ml; P = 0.04). In the only cohort study in which this could be fully assessed, treatment of women with any STD reduced the proportion of those with detectable HIV from 39% to 29% (P = 0.05), whereas this proportion remained stable among controls (15-17%), A second cohort study reported fully on HIV load; among men with urethritis, viral load fell from 12.4 to 4.12 x 10(4) copies/ml 2 weeks posttreatment, whereas viral load remained stable in those without urethritis. Conclusion: Few high-quality studies were found. HIV is detected moderately more frequently in genital secretions of men and women with a STD, and HIV load is substantially increased among men with urethritis, Successful STD treatment reduces both of these parameters, but not to control levels. More high-quality studies are needed to explore this important relationship further.

A multi-sectorial committee in directing HIV/AIDS-specific interventions in the occupational setting: An example from South Africa

We present a descriptive analysis of a mechanism to coordinate and implement human immunodeficiency virus (HIV) prevention and care in the occupational setting. The mechanism we describe is a multidisciplinary committee composed of stakeholders in the occupational health environment including unions, management, medical researchers, and medical personnel. The site chosen for the analysis was a South African sugar mill in rural KwaZulu-Natal. The factory is situated in an area of high HIV seroprevalence and has a workforce of 400 employees. The committee was initiated to coordinate a combined prevention-care initiative. The issues that were important in the formation of the committee included confidentiality, trust, and the traditional roles of the stakeholder relationships. When these points were addressed through the focus on a common goal, the committee was able to function in its role as a coordinating body. Central to this success was the inclusion of all stakeholders in the process, including those with traditionally opposing, interests and legitimacy conferred by the stakeholders. This committee was functionally effective and demonstrated the benefit of a freestanding committee dedicated to addressing HIV/acquired immune deficiency syndrome (AIDS) issues. We describe the implementation and feasibility of a multisectoral committee in directing HIV/AIDS initiatives in the occupational setting in rural South Africa.

Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World

Comorbidity from tegumentary leishmaniasis and AIDS is poorly characterized. To describe a series of patients coinfected with Leishmania and human immunodeficiency virus (HIV). Clinical records from patients were analysed by demographic data, clinical manifestations, diagnoses, treatments and outcomes. Fifteen cases of AIDS/tegumentary leishmaniasis were found. The diagnosis of leishmaniasis was confirmed by the detection of Leishmania amastigotes or antigens from the cutaneous or mucosal lesions. The mean CD4+ T-cell count was 84 cells mm(-3) (range 8-258) and all patients were classified as having AIDS according to the Centers for Disease Control and Prevention. A wide range of manifestations was found, varying from a single ulcer to multiple and polymorphic lesions. Mucosal lesions were present in 80% and cutaneous lesions in 73% of patients (53% with mucocutaneous form), disseminated lesions in 60% and genital lesions in 27% of patients. All patients received anti-Leishmania therapy and 53% showed relapses. Sixty-seven per cent received highly active antiretroviral therapy but showed no difference in outcomes and relapses compared with those not using medication. Forty per cent died during the study period. In these patients, the anti-Leishmania antibody and Montenegro skin test were useful in the diagnosis of leishmaniasis, probably because leishmaniasis preceded immunosuppression due to HIV infection. Clinical manifestations of tegumentary leishmaniasis in HIV-infected patients are diverse. Our data emphasize possible unusual manifestations of this disease in HIV-infected patients, particularly in severely immunosuppressed cases (< 200 CD4+ cells mm(-3)).

Viral Load Predicts New World Health Organization Stage 3 and 4 Events in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy, Independent of CD4 T Lymphocyte Value

Background. Many resource-limited countries rely on clinical and immunological monitoring without routine virological monitoring for human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy (HAART). We assessed whether HIV load had independent predictive value in the presence of immunological and clinical data for the occurrence of new World Health Organization (WHO) stage 3 or 4 events (hereafter, WHO events) among HIV-infected children receiving HAART in Latin America. Methods. The NISDI (Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative) Pediatric Protocol is an observational cohort study designed to describe HIV-related outcomes among infected children. Eligibility criteria for this analysis included perinatal infection, age ! 15 years, and continuous HAART for >= 6 months. Cox proportional hazards modeling was used to assess time to new WHO events as a function of immunological status, viral load, hemoglobin level, and potential confounding variables; laboratory tests repeated during the study were treated as time-varying predictors. Results. The mean duration of follow-up was 2.5 years; new WHO events occurred in 92 (15.8%) of 584 children. In proportional hazards modeling, most recent viral load 15000 copies/mL was associated with a nearly doubled risk of developing a WHO event (adjusted hazard ratio, 1.81; 95% confidence interval, 1.05-3.11; P = 033), even after adjustment for immunological status defined on the basis of CD4 T lymphocyte value, hemoglobin level, age, and body mass index. Conclusions. Routine virological monitoring using the WHO virological failure threshold of 5000 copies/mL adds independent predictive value to immunological and clinical assessments for identification of children receiving HAART who are at risk for significant HIV-related illness. To provide optimal care, periodic virological monitoring should be considered for all settings that provide HAART to children.

Protein crystallography and examples of its applications in medicinal chemistry

The field of protein crystallography inspires and enthrals, whether it be for the beauty and symmetry of a perfectly formed protein crystal, the unlocked secrets of a novel protein fold, or the precise atomic-level detail yielded from a protein-ligand complex. Since 1958, when the first protein structure was solved, there have been tremendous advances in all aspects of protein crystallography, from protein preparation and crystallisation through to diffraction data measurement and structure refinement. These advances have significantly reduced the time required to solve protein crystal structures, while at the same time substantially improving the quality and resolution of the resulting structures. Moreover, the technological developments have induced researchers to tackle ever more complex systems, including ribosomes and intact membrane-bound proteins, with a reasonable expectation of success. In this review, the steps involved in determining a protein crystal structure are described and the impact of recent methodological advances identified. Protein crystal structures have proved to be extraordinarily useful in medicinal chemistry research, particularly with respect to inhibitor design. The precise interaction between a drug and its receptor can be visualised at the molecular level using protein crystal structures, and this information then used to improve the complementarity and thus increase the potency and selectivity of an inhibitor. The use of protein crystal structures in receptor-based drug design is highlighted by (i) HIV protease, (ii) influenza virus neuraminidase and (iii) prostaglandin H-2-synthetase. These represent, respectively, examples of protein crystal structures that (i) influenced the design of drugs currently approved for use in the treatment of HIV infection, (ii) led to the design of compounds currently in clinical trials for the treatment of influenza infection and (iii) could enable the design of highly specific non-steroidal anti-inflammatory drugs that lack the common side-effects of this drug class.

Evaluation of the poly-L-lactic acid implant for treatment of the nasolabial fold: 3-year follow-up evaluation

The search for an ideal filler for soft tissue augmentation still continues. Because aging changes are continuous, temporary fillers should be preferred against permanent ones. Since 1999, the poly-L-lactic acid filler (PLA) has been marketed in Europe as Newfill. As a synthetic biocompatible polymer, PLA originally was used in suture materials and screws. In 2004, the U.S. Food and Drug Administration approved PLA under the name of Sculptra for the treatment of human immunodeficiency virus-related facial lipoatrophy. This study aimed to evaluate a 3-year follow-up investigation into the effect of PLA implant injection for the treatment of sunken nasolabial folds. Between October 2003 and February 2004, 10 women with a median age of 54 years (range, 43-60 years) were injected with polylactic acid hydrogel (Newfill) in the nasolabial fold area for aesthetic reasons. All the patients underwent three injections: one injection per month for 3 months. Evaluation of the results based on clinical examination and photography was performed at each session, at 6 months, and then 36 months after the third session. Injectable PLA was able to correct nasolabial folds successfully with a more lasting result than absorbable fillers commonly used in clinical practice, such as hyaluronic acid and collagen. Careful and standardized photographic documentation is indispensable.

Tuberculosis-Associated Collapsing Glomerulopathy: Remission after Treatment

Collapsing glomerulopathy (CG) is a severe form of nephrotic syndrome and has been mostly associated with human immunodeficiency virus (HIV) infection. Treatment response is poor, and the disease frequently leads to end-stage renal disease. More recently, CG has been described in association with other conditions, such as drug exposure and other infections, but renal prognosis remains unfavorable. This paper reports an interesting case of an HIV-negative patient with tuberculosis-related CG who needed dialysis for five months but presented full renal recovery after tuberculosis (TB) treatment and corticotherapy.

Genotypic distribution of hepatitis C among hepatitis C and HIV co-infected patients in Brazil

Information on hepatitis C virus (HCV) genotypic distribution among HIV-HCV co-infected patients is lacking in Brazil as well as other Latin American countries. The objective of this study was to evaluate the level of exposure to different risk factors associated with HCV transmission among a group of co-infected patients and to characterize the genotypic distribution of HCV in this cluster. A series of 100 HIV-HCV co-infected patients was analysed. The data to be analysed were collected from specific laboratory tests. Information was collected through a questionnaire. HCV genotyping was carried out by sequencing the 5 ` non-coding region of HCV. Chi-square and Fischer association tests or Kruskal-Wallis test were used to study the association between HCV transmission-related variables and the established genotypes. In conclusion, exposure to multiple risk factors associated with HCV transmission was common among HIV co-infected patients and an association between HCV genotype 3 and intravenous drug user was observed.

Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients

The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 mu g/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 +/- 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline < 1.19 log for genotype-1 and < 0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second-phase viral decline slope (i.e., measured from day 2 to 29) < 0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (< 0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.