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Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study).

Objective:This study evaluated maintenance with lopinavir/ritonavir monotherapy vs. continuing lopinavir/ritonavir and 2 nucleosides in HIV-infected patients with suppressed HIV replication. Design:Randomized, controlled, open-label, multicenter, pilot clinical trial. Methods:Adult patients were eligible if they had no history of virologic failure while receiving a protease inhibitor, were receiving 2 nucleosides + lopinavir/ritonavir (400/100 mg b.i.d.) for >1 month and had maintained serum HIV RNA <50 copies/mL for >6 months prior to enrollment. Results:Forty-two patients were randomly assigned 1:1 to continue or stop the nucleosides. At baseline there were no significant differences between groups in median CD4 cells/μL (baseline or nadir), pre-HAART (highly active antiretroviral therapy) HIV log10 viremia, or time with HIV RNA <50 copies/mL prior to enrollment. After 48 weeks of follow-up, percentage of patients remaining at <50 HIV RNA copies/mL (intention to treat, M = F) was 81% for the monotherapy group (95% CI: 64% to 98%) vs. 95% for the triple-therapy group (95% CI: 86% to 100%); P = 0.34. Patients in whom monotherapy failed had significantly worse adherence than patients who remained virally suppressed on monotherapy. Monotherapy failures did not show primary resistance mutations in the protease gene and were successfully reinduced with prerandomization nucleosides. Mean change in CD4 cells/μL: +70 (monotherapy) and +8 (triple) (P = 0.27). Mean serum fasting lipids remained stable in both groups. No serious adverse events were observed. Conclusion:Most of the patients maintained with lopinavir/ritonavir monotherapy remain with undetectable viral load after 48 weeks. Failures of lopinavir/ritonavir monotherapy were not associated with the development of primary resistance mutations in the protease gene and could be successfully reinduced adding back prior nucleosides.

Rheumatic manifestations in 556 patients with human immunodeficiency virus infection

We studied in retrospect the rheumatic manifestations of 556 patients with human immunodeficiency virus (HIV) infection. Eighty percent were men. Eighty-six percent were intravenous drug abusers (IVDAs), 9% homosexual, 3% partners of high-risk persons having the infection, 0.4% hemophiliacs, and 2% had no known risk factors. We found rheumatic disorders in 63 (11%) patients. The most frequent findings were myalgias and/or arthralgias (4.5%; one patient had an inflammatory myopathy), skeletal infections (3.6%), and arthralgias (1.6%). Reiters syndrome and seronegative arthritis were present only in 0.5%, and HIV-associated arthritis and vasculitis in 0.4%, respectively. Skeletal infections were caused predominantly by Staphylococcus aureus (60%) and Candida albicans (20%). All these patients were IV drug abusers whose clinical features were similar to those previously described in skeletal infections of non-HIV-infected IVDAs. Comparing these data with other studies composed primarily of homosexual men where Reiters syndrome is the predominant rheumatic disorder, we conclude that the type of rheumatic complaint is more related to the risk factors than to HIV itself.

Tuberculous Radiculomyelitis Complicating Tuberculous Meningitis: Case Report and Review

Tuberculous radiculomyelitis (TBRM) is a complication of tuberculous meningitis (TBM), which has been reported rarely in the modern medical literature. We describe a case of TBRM that developed in an human immunodeficiency virus (HIV)-infected patient, despite prompt antituberculous treatment. To our knowledge, this is the second case of TBRM reported in an HIV-infected patient. We also review 74 previously reported cases of TBRM. TBRM develops at various periods after TBM, even in adequately treated patients after sterilization of the cerebrospinal fluid (CSF). The most common symptoms are subacute paraparesis, radicular pain, bladder disturbance, and subsequent paralysis. CSF evaluation usually shows an active inflammatory response with a very high protein level. MRI and CT scan are critical for diagnosis, revealing loculation and obliteration of the subarachnoid space along with linear intradural enhancement. As in other forms of paradoxical reactions to antituberculous treatment, there is evidence that steroid treatment might have a beneficial effect.

Clinical, virologic, and immunologic response to efavirenz-or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 study).

Objective:To compare the clinical, immunologic, and virologic outcomes of efavirenz (EFV)-based versus protease inhibitor (PI)–based highly active antiretroviral therapy (HAART) in severely immunosuppressed HIV-1–infected patients. Design:Retrospective observational cohort study. Methods:Responses were analyzed according to the intent-to-treat principle among antiretroviral-naive patients with <100 CD4 cells/μL who started EFV (n = 92) or a PI (n = 218) plus 2 nucleoside reverse transcriptase inhibitors. The primary end point was time to treatment failure. Secondary end points were percentage of patients with a viral load <400 copies/mL, time to virologic failure, time to CD4 lymphocyte count >200 cells/μL, and incidence of opportunistic events or death. Results:The median baseline CD4 cell count and viral load were 34 cells/μL and 5.54 log10 copies/mL (EFV group) and 38 cells/μL and 5.40 log10 copies/mL (PI group). Time to treatment failure was shorter with a PI-based regimen than with an EFV-based regimen (adjusted relative hazard [RH] = 2.19, 95% confidence interval [CI]: 1.23–3.89). After 12 months of therapy, a significantly higher proportion of patients receiving EFV reached a viral load <400 copies/mL (69.4 vs. 45.1%; P < 0.05). The probability of virologic failure was higher with a PI than with EFV (adjusted HR = 2.52, 95% CI: 1.14–5.61; P = 0.024). There was no difference in time to CD4 cell count >200 cells/μL or in incidence of opportunistic events or death. Conclusion:In severely immunosuppressed, antiretroviral-naive, HIV-1–infected patients, treatment with an EFV-based regimen compared with a nonboosted PI-based regimen resulted in a superior virologic response with no difference in immunologic or clinical effectiveness.

Osteoarticular infection in intravenous drug abusers: influence of HIV infection and differences with non drug abusers.

OBJECTIVES--To determine (a) the influence of HIV in developing osteoarticular infections in intravenous drug abusers (IVDAs) and (b) the differences between the clinical features of osteoarticular infections in IVDAs and a control group of non-IVDAs. METHODS--A comparative study of the clinical features of osteoarticular infections in all HIV positive and HIV negative IVDAs admitted to the departments of rheumatology and internal medicine during a 10 year period was carried out. The joint infections of all IVDAs, irrespective of HIV status, were compared with those of a control group of non-IVDAs lacking risk factors for HIV infection. RESULTS--A total of 482 HIV positive and 85 HIV negative IVDAs was studied, in whom 25 (5%) and six (7%) osteoarticular infections were found respectively. There were no differences in age, sex, joints affected, and causative agents between these two groups. A comparison of the 31 (5.5%) osteoarticular infections in all IVDAs with 21 infections in 616 (3.4%) non-IVDAs showed significant differences in the mean age (27.5 v 54), the frequency of affection of the axial joints (hip, sacroiliac, and sternocostal joints) (64.5% v 16.6%), and in the incidence of Candida albicans (19% v 0%). CONCLUSIONS--(1) HIV may not predispose to osteoarticular infections in IVDAs. (2) The hip, sacroiliac, and sternocostal joints (axial joints) were most commonly affected in IVDAs. (3) In Spain, unlike other countries, Gram positive bacteria and C albicans seem to be predominant agents in osteoarticular infections in IVDAs, with a low incidence of Gram negative bacteria.

Abnormalities in the bone mineral metabolism in HIV-infected patients

ObjectiveTo evaluate bone mineral metabolism in HIV infected and asymptomatic patients receiving highly active antiretroviral therapy (HAART) containing protease inhibitors (PI) and naïve patients.MethodsWe studied 30 asymptomatic HIV infected male patients, 13 in the naive group and 17 in the IP group, both without differences in demographics characteristics. We excluded women and patients with any known factor associated to osteopenia. We did a nutritional questionnaire, a DEXA scan in lumbar spine and femur, a study of CD4 lymphocytes, viral load and an analysis of bone formation and resorption markers in all patients. We compared vitamin D and PTH levels with a control group of healthy male volunteers age-pareated. For the statistical analysis we used the SPSS program.ResultsOsteopenia was present in 17/30 (57%), 8/13 (61.5%) in the naïve group and 9/17 (53%) in the PI group (not significant differences). We found a vitamin D deficiency in 86% of patients, with mean serum levels that was found to be significantly lower than those from a healthy control group (p=0.04). Testosterone level was significantly related to bone mineral density in lumbar spine (p≤0.05).ConclusionsHIV may be an individual risk factor in bone disorders, requiring calcium and vitamin D supplementation.

Drug interactions with new hepatitis C oral drugs

Introduction: Chronic hepatitis C virus (HCV) infection has recently become a curable disease with antiviral therapy. The knowledge of drug interactions using direct-acting antivirals (DAA) may permit maximizing antiviral efficacy and avoiding drug-related toxicities. Ageing in the chronic hepatitis C population, along with added co-morbidities that require other medications, has increased the attention on drug interactions using DAA. Areas covered: This review provides an update of the most clinically significant pharmacokinetic and pharmacodynamic drug interactions occurring between currently available DAA and other medications. The review also revisits how drug interactions with DAA can be prevented and managed. Expert opinion: Interactions between DAA and other drugs are frequent in clinical practice. The most frequent drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposures. Through this mechanism HCV protease inhibitors, especially when co-formulated with ritonavir as pharmacoenhancer, and non-nucleoside HCV polymerase inhibitors interact with other medications. In contrast, NS5B nucleos(t)ide analog inhibitors (i.e., sofosbuvir) and some HCV NS5A inhibitors (i.e., ledipasvir), which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions. However, exposure to HCV nucleos(t)ide analogs may be influenced by induction/inhibition of drug transporters (i.e., P-glycoprotein) as well as by pharmacodynamic interference with other nucleos(t)ide analogs used as antivirals or cancer drugs. Drug interactions for some NS5A inhibitors (i.e., daclatasvir) are generally moderate and can be managed with dose adjustments.

Discontinuation of Primary and Secondary Toxoplasma gondii Prophylaxis Is Safe in HIV-Infected Patients after Immunological Restoration with Highly Active Antiretroviral Therapy: Results of an Open, Randomized, Multicenter Clinical Trial

BACKGROUND To our knowledge, no randomized trials have evaluated whether prophylaxis against toxoplasmic encephalitis can be safely discontinued after the CD4+ T cell count increases in response to highly active antiretroviral therapy. METHODS We conducted a randomized, nonblinded, multicenter clinical trial of the discontinuation of primary or secondary prophylaxis against toxoplasmic encephalitis in human immunodeficiency virus (HIV)-infected patients with a sustained response to antiretroviral therapy (defined as a CD4+ T cell count of > or =200 cells/mm3 and a plasma HIV type 1 [HIV-1] RNA level of <5000 copies/mL for at least 3 months). Prophylaxis was restarted if the CD4+ T cell count decreased to <200 cells/mm3. RESULTS The 381 patients receiving primary prophylaxis had a median CD4+ T cell count on study entry of 343 cells/mm3, and 318 (83%) of 381 patients had undetectable HIV-1 RNA in plasma. After a median follow-up period of 25 months (409 person-years), there were no episodes of toxoplasmic encephalitis among the 196 patients who discontinued prophylaxis (at 1 year, the upper limit of the 95% confidence interval for relapse rate was 2.40%). For the 57 patients receiving secondary prophylaxis, the median CD4+ T cell count on entry was 407 cells/mm3, and 49 (86%) of 57 patients had undetectable HIV-1 RNA in plasma. After a median follow-up period of 30.5 months (69 person-years), there were no episodes of toxoplasmic encephalitis among the 28 patients who discontinued prophylaxis (at 1 year, the upper limit of the 95% confidence interval for relapse rate was 16%). CONCLUSIONS In HIV-infected adult patients receiving effective highly active antiretroviral therapy, primary and secondary prophylaxis against toxoplasmic encephalitis can be safely discontinued after the CD4+ T cell count has increased to > or =200 cells/mm3 for >3 months.