Efficacy of vitamin D3 supplementation in reducing incidence of pulmonary tuberculosis and mortality among HIV-infected Tanzanian adults initiating antiretroviral therapy: study protocol for a randomized controlled trial.

BACKGROUND: HIV-infected adults initiating antiretroviral therapy (ART) in sub-Saharan Africa continue to experience high rates of morbidity and mortality during the initial months of treatment. Observational studies in high-income and resource-limited settings indicate that HIV-infected adults with low vitamin D levels may be at increased risk of mortality, HIV disease progression, and incidence of pulmonary tuberculosis (TB). As a result, vitamin D3 supplementation may improve survival and treatment outcomes for HIV-infected adults initiating ART. METHODS/DESIGN: The Trial of Vitamins-4 (ToV4) is an individually randomized, double-blind, placebo-controlled trial of vitamin D3 (cholecalciferol) supplementation conducted among 4000 HIV-infected adults with low vitamin D levels [25-hydroxyvitamin D (25(OH)D) <30 ng/mL] initiating ART in Dar es Salaam, Tanzania. The two primary aims of the trial are to determine the effect of a vitamin D3 supplementation regimen on incidence of (1) mortality and (2) pulmonary TB as compared to a matching placebo regimen. The primary safety outcome of the study is incident hypercalcemia. The investigational vitamin D3 regimen consists of oral supplements containing 50,000 IU vitamin D3 taken under direct observation at randomization and once a week for 3 weeks (four doses) followed by daily oral supplements containing 2000 IU vitamin D3 taken at home from the fourth week until trial discharge at 1 year post ART initiation. Trial participants are followed up at weekly clinic visits during the first month of ART and at monthly clinic visits thereafter until trial discharge at 1 year post ART initiation. Secondary aims of the trial are to examine the effect of the vitamin D3 regimen on CD4 T cell reconstitution, incidence of non-TB comorbidities, body mass index (BMI), depression and anxiety, physical activity, bone health, and immunologic biomarkers. DISCUSSION: The ToV4 will provide causal evidence on the effect of vitamin D3 supplementation on incidence of pulmonary TB and mortality among HIV-infected Tanzanian adults initiating ART. The trial will also give insight to whether vitamin D3 supplementation trials for the prevention of pulmonary TB should be pursued in HIV-uninfected populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01798680 . Registered on 21 February 2013.

Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research.

Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity.

Challenges of malnutrition care among HIV-infected children on antiretroviral treatment in Africa.

More than 90% of the estimated 3.2 million children with HIV worldwide, at the end of 2013, were living in sub-Saharan Africa. The management of these children was still difficult in 2014 despite the progress in access to antiretroviral drugs. A great number of HIV-infected children are not diagnosed at 6 weeks and start antiretroviral treatment late, at an advanced stage of HIV disease complicated by other comorbidities such as malnutrition. Malnutrition is a major problem in the sub-Saharan Africa global population; it is an additional burden for HIV-infected children because they do not respond as well as non-infected children to the usual nutritional care. HIV infection and malnutrition interact, creating a vicious circle. It is important to understand the relationship between these 2 conditions and the effect of antiretroviral treatment on this circle to taking them into account for an optimal management of pediatric HIV. An improved monitoring of growth during follow-up and the introduction of a nutritional support among HIV-infected children, especially at antiretroviral treatment initiation, are important factors that could improve response to antiretroviral treatment and optimize the management of pediatric HIV in resource-limited countries.

Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.

BACKGROUND: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART). METHODS: Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients. RESULTS: Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART. CONCLUSION: Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.

Role of selenium in HIV infection.

HIV infection is a global disease that disproportionately burdens populations with nutritional vulnerabilities. Laboratory experiments have shown that selenium has an inhibitory effect on HIV in vitro through antioxidant effects of glutathione peroxidase and other selenoproteins. Numerous studies have reported low selenium status in HIV-infected individuals, and serum selenium concentration declines with disease progression. Some cohort studies have shown an association between selenium deficiency and progression to AIDS or mortality. In several randomized controlled trials, selenium supplementation has reduced hospitalizations and diarrheal morbidity, and improved CD4(+) cell counts, but the evidence remains mixed. Additional trials are recommended to study the effect of selenium supplementation on opportunistic infections, and other HIV disease-related comorbidities in the context of highly active antiretroviral therapy in both developing and developed countries.

The TCM remedies for treatment of AIDS--a clinical report of 60 cases.

OBJECTIVE: To evaluate the clinical effects of TCM remedies in treatment of acquired immune deficiency syndrome (AIDS). METHOD: 60 cases of AIDS or AIDS-related complex (ARC) were divided into four different TCM patterns and treated accordingly. RESULTS: Of the 60 cases, 52 patients (86.7%) experienced remarkable improvement in general symptoms and lab findings, including virus loading and CD4 T lymphocyte count. CONCLUSION: The TCM remedies could definitely improve the symptoms and signs of AIDS or ARC, enhance the immune function, decrease the possibility of contracting opportunistic infection, improve the life quality, and prolong the survival period, with no apparent toxic and side effects.

Immunosuppression and GB virus C-RNA detection among HIV-infected patients in Cambodia.

In this survey, 213 patients in an antiretroviral treatment programme in Phnom Penh, Cambodia, were tested for GB virus C (GBV-C) RNA before treatment initiation. Most had advanced HIV infection, only 34 having CD4 cell counts > 200 cells/microl. GBV-C-RNA was detected in 35 patients. The proportion with positive GBV-C-RNA decreased dramatically with CD4 cell counts < 100 cells/microl. In multivariate analysis, low CD4 cell counts, tuberculosis, anaemia, and traditional medicine were independently and negatively associated with GBV-C-RNA detection.

Role of Mycobacterium xenopi disease in patients with HIV infection at the time of highly active antiretroviral therapy (HAART). Comparison with the pre-Haart period.

BACKGROUND AND SETTING: A reliable and timely clinical, radiological, and bacteriological diagnosis, and an optimal treatment of non-tubercular mycobacteriosis (including Mycobacterium xenopi disease), remain an unanswered challenge for clinicians facing immunocompromised patients, including those with HIV infection. OBJECTIVE: The aim of our survey is to report the frequency, and the epidemiological, immunological, microbiological, clinical, and therapeutic features of all confirmed HIV-associated M. xenopi disease observed from 1993-2002, with special attention paid to eventual differences that emerged after the introduction of potent antiretroviral therapy (highly active antiretroviral therapy, HAART), on the basis of an international literature update. DESIGN AND RESULTS: Our series of 17 consecutive confirmed M. xenopi infections retrieved in 14 out of 3000 patients followed for HIV disease complications raises a broad series of clinical, diagnostic, therapeutic, and prophylactic concerns. The great majority of M. xenopi disease involved the lower respiratory tract, but atypical features including cavitation and prominent exudative features became apparent in patients successfully treated with HAART, pointing out the possible role of the so-called immune reconstitution syndrome in these episodes. CONCLUSIONS: Diagnostic problems represented by late or missed identification due to slow culture and frequently concomitant opportunistic disorders, join therapeutic difficulties due to the unpredictable in vitro antimicrobial susceptibility profile of these organisms, selection of treatment and chemoprophylaxis according with clinical-radiological and microbiological suspicion, and concomitantly administered medications.

Impact of selenium status on the pathogenesis of mycobacterial disease in HIV-1-infected drug users during the era of highly active antiretroviral therapy.

The risk of mycobacterial disease is significantly increased in drug abusers as well as in immunocompromised HIV-1-infected individuals. The essential trace element selenium has an important function in maintaining immune processes and may, thus, have a critical role in clearance of mycobacteria. The impact of selenium status on the development of mycobacterial diseases in HIV-1-seropositive drug users was investigated over a 2-year period (1999-2001). Twelve cases of mycobacterial disease (tuberculosis, 9; infection due to atypical Mycobacterium species, 3) occurred; these 12 cases were compared with 32 controls with no history of respiratory infections who were matched on age, sex, and HIV status. Significant risk for development of mycobacterial disease was associated with a CD4 cell count of <200/mm 3, malnutrition, and selenium levels of

Oropharyngeal candidiasis in patients with human immunodeficiency virus: correlation of clinical outcome with in vitro resistance, serum azole levels, and immunosuppression.

Azole-resistant thrush has emerged as a problem in people who are infected with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), especially those who have low CD4 cell counts who have had a previous relapse of oral candidiasis, and in those who require long-term suppressive antifungal therapy. Because of the development of a standardized methodology for antifungal susceptibility testing and interpretive criteria for resistance testing, studies of the clinical predictive value of in vitro results are possible. In this study, 61% of organisms isolated from patients who were receiving azole therapy and who had clinically resistant thrush had minimal inhibitory concentration values that would classify the isolate as "resistant" or "susceptible dose dependent." In contrast, 86% of isolates from patients with thrush that was clinically responsive to an azole were classified in vitro as "susceptible" or "susceptible dose dependent." No resistant isolates were detected in samples obtained from asymptomatic control patients who were not exposed to azole drugs. Serum levels of azole and CD4 cell counts were also important parameters with regard to prediction of response. We conclude that in vivo and in vitro correlations compare favorably to studies of susceptibility testing in bacteria.

Dynamics of plasma cytokine levels in patients with advanced HIV infection and active tuberculosis: implications for early recognition of patients with poor response to anti-tuberculosis treatment.

OBJECTIVE: To examine whether the serial measurement of plasma cytokine levels can assist in the early recognition of AIDS/tuberculosis patients with poor response to anti-tuberculosis treatment. DESIGN: Longitudinal, prospective cohort study. SETTING: A university hospital, the largest centre for HIV/AIDS patients in Taiwan. METHODS: Between January 1997 and September 1998, 25 consecutive patients with advanced HIV infection and suspected tuberculosis were enrolled in the study. Plasma samples were obtained on day 1 (baseline), 3, 7 and 14 of anti-tuberculosis treatment and the levels of tumour necrosis factor-alpha (TNF-alpha) were measured. Patients were classified as either responders or non-responders according to the results of assessment of symptoms and follow-up cultures during the sixth and eighth week of anti-tuberculosis treatment. Thirty consecutive HIV-negative tuberculosis patients were also enrolled in the study. RESULTS: The data of a total of 16 AIDS patients (median CD4 cell count 16 x 10(6)/l; 12 responders and four non-responders) and 21 HIV-negative patients (16 responders and five non-responders), whose tuberculosis was culture-proven, were included for analysis. In responders, TNF-alpha levels declined remarkably within the first week of anti-tuberculosis treatment; however, the decline of TNF-alpha levels in non-responders was significantly less [the median ratio of TNF-alpha level on day 7 to that at baseline was 0.32 versus 0.85 (P < 0.001) in AIDS patients; 0.34 versus 0.80 (P = 0.001) in HIV-negative patients). The lack of a > or = 50% reduction in pre-treatment TNF-alpha levels during the first week of treatment was strongly associated with a poor response to anti-tuberculosis treatment (P = 0.001 in AIDS patients; P < 0.001 in HIV-negative patients). CONCLUSION: Serial measurement of plasma TNF-alpha levels may help to assess the response to anti-tuberculosis treatment in AIDS patients, in spite of very low CD4 cell counts. Failure of TNF-alpha levels to decline by > or = 50 % of pre-treatment levels in the first week of treatment may be an early surrogate marker of a poor response.

Stressful events, pessimism, natural killer cell cytotoxicity, and cytotoxic/suppressor T cells in HIV+ black women at risk for cervical cancer.

OBJECTIVE: This study examines whether stressful negative life events and pessimism were associated with lower natural killer cell cytotoxicity (NKCC) and T cytotoxic/suppressor cell (CD8+CD3+) percentage in black women co-infected with human immunodeficiency virus Type 1 (HIV-1) and human papillomavirus (HPV), a viral initiator of cervical cancer. METHOD: Psychosocial interviews, immunological evaluations, and cervical swabs for HPV detection and subtyping were conducted on 36 HIV+ African-American, Haitian, and Caribbean women. RESULTS: Greater pessimism was related to lower NKCC and cytotoxic/suppressor cells after controlling for presence/absence of HPV Types 16 or 18, behavioral/lifestyle factors, and subjective impact of negative life events. CONCLUSIONS: A pessimistic attitude may be associated with immune decrements, and possibly poorer control over HPV infection and increased risk for future promotion of cervical dysplasia to invasive cervical cancer in HIV+ minority women co-infected with HPV.

Transfer factor.

AIDS: Transfer factor, a natural substance of the immune system, was discovered in 1949. More than 3,000 scientific articles have established it as an effective treatment for many diseases, usually those related to the immune system. In China, more than six million people have used transfer factor as a prophylaxis for hepatitis. Information on ordering articles on transfer factor, olive leaf extract, and coconut oil is included.^ieng

Jarrow formulas: "colostrum specific" for cryptospordium.

AIDS: Colostrum Specific is effective in treating Cryptosporidium, but has received little press attention. It has been used successfully in regimens that include treatment 4 times daily for 21 consecutive days. Pharmaceutical companies have not gotten involved in making transfer factor for hard-to-reach infections; but it is hoped that the dietary supplement industry will.^ieng

Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS.

Zinc is perhaps the most important trace element for immune function. Congenital or acquired zinc deficiencies are associated with immune abnormalities and increased susceptibility to infectious diseases. AIDS subjects suffer from reduced zinc bioavailability, more severe in stage IV than in stage III. Such zinc deficiency causes, among other effects, a profound reduction in the biological activity of one of the thymic hormones, thymulin (zinc-facteur-timique-serique, ZnFTS). With these premises, zinc sulphate was administered orally at a daily dose of 200 mg for 30 days to AZT-treated stage III subjects with generalized lymphadenopathy (17 subjects) and stage IV subgroup C1 (12 subjects) AIDS patients. 18 stage III subjects with generalized lymphoadenopathy and 10 stage IV subgroup C1 subjects treated only with AZT served as controls. Zinc sulphate supplementation of stage III and in stage IV C1 patients was followed by an increase or a stabilization in the body weight and an increase of the number of CD4+ cells and the plasma level of active zinc-bound thymulin. The frequency of opportunistic infectious episodes in the 24 months following entry into the study was reduced after zinc supplementation in stage IV C1 subjects (11 infections vs 25 in controls) and delayed in stage III zinc-treated subjects (1 infection/24 months vs 13 infections/24 months in controls). The effect of zinc on opportunistic infections is restricted to infections due to Pneumocystis carinii and Candida, whereas no variations have been observed in the frequencies of cytomegalovirus and toxoplasma infections. These data may support the benefit of zinc as an adjunct to AZT therapy in AIDS pathology.

Augmentation of CD8 and CD4 lymphocytes subsets in AIDS infected children after treatment with a non-toxic chelating agents compound--Rodilemid.

Twelve children were included into the protocol, 5 in March 1989 and 7 in April 1993. All of them were HIV 1 positive and had diarrhoea, important adenopathy and opportunistic infections. Seven out of 12 patients had an immunological monitoring. One out of 12 children with B hepatitis died with liver cirrhosis. Eleven children had a clear improvement in their clinical course, during the treatment. Five out of 7 patients had a significant increase of the CD4 lymphocytes at 4 and 7 months follow-up. Four patients had an important and significant increase of the CD8 count at 4 months and 6 out of 7 patients at 7 months. Interestingly, in 4 out of 7 patients after 7 months treatment we observed higher than normal value of the CD8 count. Variations observed for CD8 population compared to CD4 were more important.

A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group.

BACKGROUND: Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. METHODS: We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. RESULTS: After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the clotrimazole group; adjusted relative hazard, 8.5; 95 percent confidence interval, 1.9 to 37.6). The benefit of fluconazole was greater for the patients with 50 or fewer CD4+ cells per cubic millimeter than for the patients with higher counts. Fluconazole was also effective in preventing esophageal candidiasis (adjusted relative hazard, 5.8; 95 percent confidence interval, 1.7 to 20.0; P = 0.004) and confirmed and presumed oropharyngeal candidiasis (5.7 and 38.1 cases per 100 years of follow-up in the fluconazole and clotrimazole groups, respectively; P < 0.001). Survival was similar in the two groups. CONCLUSIONS: Fluconazole taken prophylactically reduces the frequency of cryptococcosis, esophageal candidiasis, and superficial fungal infections in HIV-infected patients, especially those with 50 or fewer CD4+ lymphocytes per cubic millimeter, but the drug does not reduce overall mortality.

Effects of psoralen plus UVA radiation (PUVA) on HIV-1 in human beings: a pilot study.

BACKGROUND: Laboratory data document the activation of the HIV-1 genome on exposure to UV radiation, including PUVA. The overall effects of UV radiation exposure on HIV-1 infection in human beings are unknown. OBJECTIVE: Our purpose was to observe CD4 cell counts and quantitative markers of HIV-1 load in late-stage HIV-1-infected human beings receiving PUVA for various cutaneous diseases. METHODS: Samples of peripheral blood were obtained on days 0, 14, 30, and 60 of PUVA administered in therapeutic doses. Number of CD4+ T lymphocytes was determined by flow cytometry, and HIV-1 load was measured by semiquantitative polymerase chain reaction for viral genome in peripheral blood mononuclear cells, semiquantitative RNA-polymerase chain reaction for HIV-1 RNA in serum, and determination of p24 in serum. RESULTS: No significant changes in the measurements were observed. CONCLUSION: This study did not detect a deleterious effect on CD4 cell count or HIV-1 load during 2 months of PUVA treatment for patients in late stages of infection, with low CD4 cell counts and high HIV-1 loads.

Resistance to intestinal parasites during murine AIDS: role of alcohol and nutrition in immune dysfunction.

A murine AIDS model with many similarities to human AIDS, LP-BM5 Murine Leukaemia, suppresses T and B cell numbers and functions in the intestine. This permits chronic colonization by Giardia and Cryptosporidium. Cocaine and the nutrient alcohol, which are immunosuppressive, further reduce resistance to intestinal parasites and intestinal lymphocyte numbers. Protein undernutrition, vitamin E supplementation, and alcohol use further modify immune dysfunction induced by the murine retrovirus infection. This suggests that both undernutrition and nutrient supplementation could affect parasite resistance during AIDS. Thus this murine model of human AIDS has great potential to accelerate studies of the role of nutrients in immune dysfunction and resistance to intestinal parasites.