-
1.
Clinical outcomes and risk factors for death from disseminated histoplasmosis in patients with AIDS who visited a high-complexity hospital in Campo Grande, MS, Brazil.
Boigues, BCS, Paniago, AMM, Lima, GME, Nunes, MO, Uehara, SNO
Revista da Sociedade Brasileira de Medicina Tropical. 2018;(2):155-161
Abstract
INTRODUCTION Disseminated histoplasmosis (DH) is a systemic mycosis caused by Histoplasma capsulatum (H. capsulatum) and is characterized by progressive and fatal evolution in immunocompromised patients. Moreover, it is considered an AIDS-defining disease. METHODS We performed an observational, analytical, retrospective study to identify the clinical outcomes and risk factors for death from DH in patients with AIDS at an infectious diseases service facility in Brazil between September 2011 and July 2016. Patients with a positive serology for HIV and DH were diagnosed via direct examination and/or positive cultures for H. capsulatum. RESULTS Twenty-three patients were included in this study. Approximately, 82.6% were men, with a mean age of 41.0±11.5 years, and 52.2% had a concomitant diagnosis of AIDS and DH. The median CD4+ T cell count was 19 cells/mm3, and 56.5% of the patients died. The most frequently observed symptoms were fever, dyspnea, and skin lesions. On the basis of a comparative analysis of those who died and survived, the absence of splenomegaly and hepatomegaly and the presence of H. capsulatum in the peripheral blood were considered as risk factors for death. Those who died had a higher leukocyte count; CRP, urea, and lactate dehydrogenase levels; AST index; and international normalized ratio prothrombin time. The serum total protein and albumin levels of the patients were lower. CONCLUSIONS The mortality rate for DH is high among severely immunocompromised patients with AIDS. The risk factors for death were those traditionally associated with blood dyscrasia, inflammatory activity, as well as increased renal and nutritional impairment.
-
2.
As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial.
Hosseinipour, MC, Kang, M, Krown, SE, Bukuru, A, Umbleja, T, Martin, JN, Orem, J, Godfrey, C, Hoagland, B, Mwelase, N, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018;(2):251-260
-
-
Free full text
-
Abstract
BACKGROUND Mild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART. METHODS Chemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response. RESULTS Of 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks. CONCLUSIONS Among HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low. CLINICAL TRIALS REGISTRATION NCT01352117.
-
3.
Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa.
Hakim, J, Musiime, V, Szubert, AJ, Mallewa, J, Siika, A, Agutu, C, Walker, S, Pett, SL, Bwakura-Dangarembizi, M, Lugemwa, A, et al
The New England journal of medicine. 2017;(3):233-245
-
-
Free full text
-
Abstract
BACKGROUND In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. METHODS In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality. RESULTS A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. CONCLUSIONS Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .).
-
4.
Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients.
Sada-Ovalle, I, Ocaña-Guzman, R, Pérez-Patrigeón, S, Chávez-Galán, L, Sierra-Madero, J, Torre-Bouscoulet, L, Addo, MM
Journal of the International AIDS Society. 2015;(1):20078
-
-
Free full text
-
Abstract
INTRODUCTION T cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis. MATERIALS AND METHODS HIV+ patients naïve to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis-infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units. RESULTS We showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim-3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production. CONCLUSIONS In this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis. The use of ART and the in vitro manipulation of the Tim-3 and PD-1 molecules restored the functionality of T cells and macrophages to restrict bacterial growth. Our results provide a novel immune strategy that may be implemented in the near future in order to improve the immune responses in HIV+ patients.
-
5.
Treatment of pulmonary tuberculosis.
Nunn, A, Phillips, PP, Abubakar, I
Current opinion in pulmonary medicine. 2013;(3):273-9
Abstract
PURPOSE OF REVIEW Despite reduction in incidence in several regions, tuberculosis (TB) remains a pandemic of world-wide significance. There is an urgent need to develop better regimens, to shorten treatment and to effectively manage both drug-sensitive and drug-resistant disease. RECENT FINDINGS There has been a substantial increase in numbers of drugs in the development pipeline and two of the candidates are expected to receive widespread accelerated approval for the treatment of multidrug-resistant TB (MDR-TB). An important determining factor in the choice of regimens for phase III is the speed with which patients become culture negative during treatment, measured as either time to culture conversion or culture negativity at a given time point. It is impossible to consider the treatment of TB in sub-Saharan Africa without considering the patients who are coinfected with HIV, and the decision of when to commence treatment with antiretrovirals is critical. What, if any, is the role of adjunctive treatments such as vitamin D? SUMMARY In this review, we describe the encouraging data on a number of drugs which are about to enter phase II or phase III trials, results from trials of standard regimens in close to programme conditions and a series of trials highlighting the importance of an early commencement of antiretroviral treatment.
-
6.
Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection.
Rodger, AJ, Fox, Z, Lundgren, JD, Kuller, LH, Boesecke, C, Gey, D, Skoutelis, A, Goetz, MB, Phillips, AN, ,
The Journal of infectious diseases. 2009;(6):973-83
-
-
Free full text
-
Abstract
BACKGROUND Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. METHODS Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD. RESULTS The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level > or =5 microg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level <1 microg/mL (P=.003, by test for trend) and patients with an IL-6 level > or =3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level <1.5 pg/mL (P=.02, by test for trend). No other baseline biomarkers predicted development of an OD. Latest follow-up hsCRP level for those with an hsCRP level > or =5 microg/mL (compared with a level <1 microg/mL; odds ratio [OR], 7.6; 95% CI, 2.0-28.5; [P=.002, by test for trend), latest amyloid-A level for those with an amyloid-A level > or =6 mg/L (compared with a level <2 mg/L; OR, 3.8; 95% CI, 1.1-13.4; P=.03, by test for trend), and latest IL-6 level for those with an IL-6 level > or =3 pg/mL (compared with a level <1.5 pg/mL; OR 2.4; 95% CI, 0.7-8.8; P=.04, by test for trend) were also associated with development of an OD. CONCLUSIONS Higher IL-6 and hsCRP levels independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting the risk of OD.
-
7.
Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens.
Cello, JP, Day, LW
Gastroenterology. 2009;(6):1952-65
-
-
Free full text
-
Abstract
Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients.
-
8.
Evaluation and treatment of oral candidiasis in HIV/AIDS patients in Enugu, Nigeria.
Oji, C, Chukwuneke, F
Oral and maxillofacial surgery. 2008;(2):67-71
Abstract
INTRODUCTION Oral candidiasis is one of the common diseases seen in HIV/AIDS patients. It is rare if CD4+ cell counts are above 500 microl. Outbreaks are more common as the count drops to 100 microl. It may be more difficult to treat when CD4+ cell counts fall below 50 microl. MATERIALS AND METHODS A retrospective review of 112 HIV/AIDS patients with lesions in the mouth, head, and neck seen at the oral and maxillofacial surgery units of two public hospitals in eastern Nigeria was carried out between 2000 and 2003. The focus was on oral candidiasis patients. Twenty-nine of these patients, made up of 11 males and 18 females, had oral candidiasis. To compare the action of two drugs, namely, nystatin (a topical antifungal drug) and ketoconazole (a systemic antifungal drug), we treated 15 of the patients with nystatin in the first 2 years and the remaining 14 with ketoconazole in the following 2 years. RESULTS AND DISCUSSION Amongst the 15 patients treated with topical drugs, 7 (46.7%) had complete remission, 2 (13.3%) had partial response, 4 (26.7%) remained stationary, and 2 (13.3%) died. Out of the 14 cases treated with systemic drugs, 11 (78.6%) had complete remission, 2 (14.3%) had partial response, and 1 (7.1%) died.
-
9.
Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.
, , El-Sadr, WM, Grund, B, Neuhaus, J, Babiker, A, Cohen, CJ, Darbyshire, J, Emery, S, Lundgren, JD, Phillips, A, et al
Annals of internal medicine. 2008;(5):289-99
Abstract
BACKGROUND Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN Randomized, controlled trial. SETTING Sites in 33 countries. PATIENTS 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS Opportunistic disease or death was the primary outcome. RESULTS Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. CONCLUSION Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.
-
10.
Dermatologic adverse effects of antiretroviral therapy: recognition and management.
Luther, J, Glesby, MJ
American journal of clinical dermatology. 2007;(4):221-33
Abstract
Despite the decrease in opportunistic infections associated with HIV in the highly active antiretroviral treatment (HAART) era, a significant number of patients still present with skin pathology, some of which can be attributed directly or indirectly to antiretroviral therapy. The non-nucleoside reverse transcriptase inhibitors exhibit a class effect with regard to skin adverse manifestations, and the spectrum of disease can vary from a mild morbilliform rash to Stevens-Johnson syndrome. Certain protease inhibitors are associated with rash, and indinavir causes retinoid-like manifestations such as paronychia, alopecia, ingrown toe-nails, and curling of straight hair. Abacavir, a nucleoside reverse transcriptase inhibitor, is notorious for causing a hypersensitivity reaction in select patients. The fusion inhibitor enfuvirtide causes injection-site reactions in the overwhelming majority of patients, although a new method of delivery has decreased the rate and severity of these reactions. A syndrome of lipoatrophy with or without lipohypertrophy, often termed lipodystrophy, has been described in patients receiving HAART. Potential management of lipoatrophy includes switching antiretrovirals and surgical treatment with facial fillers. Lastly, skin manifestations of the immune reconstitution inflammatory syndrome, including herpes zoster and warts, must be recognized and treated accordingly. In the evaluation of the individual HIV-infected patient receiving antiretroviral therapy who presents with a skin disorder, clinicians should consider the CD4 cell count as a marker of the degree of immunodeficiency, the specific antiretrovirals used, and the timing of the initiation of antiretroviral therapy in order to formulate a rational differential diagnosis. Management should be individualized based on the specific drug that is implicated and the severity of the reaction.