Evolution of Anemia Types During Antiretroviral Therapy-Implications for Treatment Outcomes and Quality of Life Among HIV-Infected Adults.

This study examined whether the type of anemia in persons living with HIV/AIDS (PLWHA) changed from the beginning of highly antiretroviral therapy (HAART) and had implications for treatment outcomes and quality of life (QOL). If present, the anemia-type was defined as microcytic, macrocytic or anemia of chronic disease (ACD) at study months 0, 6, 12, and 18. Multinomial logistic regression quantified sociodemographic and HIV-treatment factors associated with incident microcytic anemia or ACD over 18 months. Repeated measures linear regression models estimated the anemia-type associated change in the CD4 cell-count, QOL, body mass index (BMI) and frailty over 18 months. Cox proportional hazard models estimated associations between anemia-type and time to (a) gain at least 100 CD4 cells/L and (b) hospitalization/death. Analyses were implemented in Statistical Analysis Software (v.9.4) from which odds ratios (ORs) mean differences (ß) and corresponding 95% confidence intervals (CI) were estimated. At enrollment, ACD, macrocytic and microcytic anemia was present in 36.8% (n = 147), 11.3% (n = 45) and 9.5% (n = 38), respectively with 42% (n = 170) anemia-free. By the study end, only 23% (n = 115) were without anemia. Among the 251 with anemia at the study end, 53.3% (n = 195) had macrocytic anemia, 12.8% (n = 47) had ACD and 2.5% (n = 9) had microcytic anemia. Incident macrocytic anemia was positively associated with baseline hyperferritinemia (OR = 1.85, 95%CI: 1.03⁻3.32), inversely associated with wealth (OR = 0.87, 95%CI: 0.67⁻1.03) and inversely associated with efavirenz-containing HAART (OR = 0.42, 95%CI: 0.21⁻0.85). ACD incidence decreased by 53% (95%CI: 0.27⁻0.79) per 100 cells/L increase in baseline CD4-cell count and decreased by 90% (95%CI: 0.01,0.87) among adults treated with nevirapine-containing HAART. ACD was associated with a lower BMI at months 6 (ß = -0.33, 95% CI: -0.64, -0.01) and 12 (ß = -0.41, 95%CI: -0.73, -0.09), with lower QOL (ß = -3.2, 95%CI: -5.94, -0.53) at month 12 and with elevated frailty (ß = 1.2; 95%CI: 0.46, 1.86) at month 12. Macrocytic anemia did not predict a post-enrollment change in CD4, BMI or QOL during follow-up. However, the time to gain 100 CD4 cells/L was 43% slower (p < 0.05) and the frailty was higher at month 12 for PLWHA with the baseline or sustained macrocytic vs. no anemia. A substantial decline in ACD and microcytic anemia occurred in tandem with large increase in the macrocytic anemia over 18 months on HAART. Interventions to mitigate all anemia-particularly ACD, is expected to improve the immune recovery rate, lower frailty, and enhanced QOL.

Vitamin-D deficiency impairs CD4+T-cell count recovery rate in HIV-positive adults on highly active antiretroviral therapy: A longitudinal study.

BACKGROUND & AIMS: We implemented a prospective study among human immunodeficiency virus (HIV)-positive adults to examine the association between vitamin-D deficiency (VDD) and insufficiency (VDI) vs sufficiency (VDS) and CD4+T-cell improvement over 18 months of highly active antiretroviral therapy (HAART). METHODS: We used data from a randomized placebo-controlled micronutrient trial with 25-hydroxy vitamin-D (25(OH)D) measured at enrollment in 398 adults. CD4+T-cell count was measured repeatedly at months 0, 3, 6, 12 and 18. Linear mixed models quantified the vitamin-D-related differences in CD4+T-cell count and associated 99% confidence intervals at baseline and respective follow-up intervals. RESULTS: At baseline 23%, 60% and 17% of participants were VDS, VDI and VDD, respectively. Absolute CD4+T- cell counts recovered during follow-up were persistently lower for baseline VDD and VDI relative to VDS participants. The greatest deficit in absolute CD4+T-cells recovered occurred in VDD vs VDS participants with estimates ranging from a minimum deficit of 26 cells/µl (99% CI: -77, 26) to a maximum deficit of 65 cells/µl (99% CI: -125, -5.5) during follow-up. This VDD-associated lower absolute CD4+T-cell gain was strongest among patients 35 years old or younger and among participants with a baseline body mass index of less than 25 kg/m(2). CONCLUSIONS: VDD is associated with lower absolute CD4+T-cell count recovery in HIV-positive patients on HAART. Vitamin-D supplementation may improve CD4+T-cell recovery during HAART. However, future intervention studies are needed to definitively evaluate the effectiveness of this vitamin as an adjunct therapy during HAART.

The effect of standard dose multivitamin supplementation on disease progression in HIV-infected adults initiating HAART: a randomized double blind placebo-controlled trial in Uganda.

BACKGROUND: Efficacy trials investigating the effect of multivitamin (MV) supplementations among patients on Highly Active Antiretroviral Therapy (HAART) have so far been inconclusive. We conducted a randomized, double blind, placebo controlled trial to determine the effect of one recommended daily allowance (RDA) of MV supplementation on disease progression in patients initiating HAART. METHODS: Eligible subjects were randomized to receive placebo or MV supplementation including vitamins B-complex, C and E. Participants were followed for up to 18 months. Primary endpoints were: change in CD4 cell count, weight and quality of life (QoL). Secondary endpoints were: i) development of a new or recurrent HIV disease progression event, including all-cause mortality; ii) switching from first- to second-line antiretroviral therapy (ART); and iii) occurrence of an adverse event. Intent-to-treat analysis, using linear regression mixed effects models were used to compare changes over time in the primary endpoints between the study arms. Kaplan-Meier time-to-event analysis and the log-rank test was used to compare HIV disease progression events and all-cause mortality. RESULTS: Four hundred participants were randomized, 200 onto MV and 200 onto placebo. By month 18, the average change in CD4 cell count in the MV arm was 141 cells/uL compared to 147 cells/uL in the placebo arm, a mean difference of -6 · 17 [95 % CI -29 · 3, 16 · 9]. The average change in weight in the MV arm was 3 · 9 kg compared to 3 · 3 kg in the placebo arm, a mean difference of 0 · 54 [95 % CI -0 · 40, 1 · 48]; whereas average change in QoL scores in the MV arm was 6 · 8 compared to 8 · 8 in the placebo arm, a mean difference of -2.16 [95 % CI -4 · 59,0 · 27]. No significant differences were observed in these primary endpoints, or in occurrence of adverse events between the trial arms. CONCLUSIONS: One RDA of MV supplementation was safe but did not have an effect on indicators of disease progression among HIV infected adults initiating HAART. TRIAL REGISTRATION: Clinical trials NCT01228578 , registered on 15th October 2010.

Prevalence and correlates of cytopenias in HIV-infected adults initiating highly active antiretroviral therapy in Uganda.

BACKGROUND: Cytopenias are the most common HIV-associated hematological abnormality. Cytopenias have been associated with several factors including sex, race/ethnicity, geographical location and comorbidities such as tuberculosis, hepatitis B infection, fever and oral candidiasis. Cytopenias become more prevalent as HIV progresses and are often fatal. Data from resource-limited settings about the prevalence and correlates of cytopenia are limited. Therefore we conducted this cross-sectional study to assess the prevalence and correlates of cytopenia among adult AIDS patients at initiation of HAART in Uganda. METHODS: 400 HIV-infected subjects who were HAART-naïve or on HAART for ≤ 6 months were enrolled into the Multivitamins, HAART and HIV/AIDS Trial. Anemia was defined according to WHO guidelines as any hemoglobin concentration < 12 g/dl for non-pregnant females and < 13 g/dl for males. Leucopenia and thrombocytopenia were defined using study site laboratory reference ranges for lack of generally accepted definitions for these 2 cell lines as leucopenia if white blood cell count < 2.75 × 109 cells/litre and thrombocytopenia if platelets < 125 × 109 cells/litre for females and < 156 × 109 cells/litre for males. Univariate and bivariate analyses were done to describe the patient population and log-binomial regression was used to quantify the correlates of cytopenia. RESULTS: Sixty five percent of the 400 subjects had at least one form of cytopenia. Anemia occurred in 47.8%, leucopenia in 24.3%, thrombocytopenia in 8.3%, bicytopenia in 21.9% and only 2 had a pancytopenia. Cytopenia was more prevalent in females (prevalence ratio [PR]:1.33, 95% confidence interval [CI]:1.12-1.59); CD4 count category 50 to <200 (PR: 0.75, 95% CI: 0.64 -0.88) and CD4 count category 200 to <350 (PR: 0.74, 95% CI: 0.59 - 0.92) compared to CD4 count category <50; normal BMI (PR: 0.82, 95% CI:0.68-1.00) and overweight BMI (PR: 0.64, 95% CI:0.50- 0.82) compared to underweight BMI and those with a history or presence of oral candidiasis. CONCLUSIONS: Cytopenias are a frequent complication in HIV-infected adults at initiation of HAART in Uganda. The presence of any cytopenia was associated with female sex, decreasing CD4 count and decreasing body mass index. Prospective studies in resource-limited settings on the trend in HIV-related cytopenias are needed.

Multivitamin supplementation in HIV infected adults initiating antiretroviral therapy in Uganda: the protocol for a randomized double blinded placebo controlled efficacy trial.

BACKGROUND: Use of multivitamin supplements during the pre-HAART era has been found to reduce viral load, enhance immune response, and generally improve clinical outcomes among HIV-infected adults. However, immune reconstitution is incomplete and significant mortality and opportunistic infections occur in spite of HAART. There is insufficient research information on whether multivitamin supplementation may be beneficial as adjunct therapy for HIV-infected individuals taking HAART. We propose to evaluate the efficacy of a single recommended daily allowance (RDA) of micronutrients (including vitamins B-complex, C, and E) in slowing disease progression among HIV-infected adults receiving HAART in Uganda. METHODS/DESIGN: We are using a randomized, double-blind, placebo-controlled trial study design. Eligible patients are HIV-positive adults aged at least 18 years, and are randomized to receive either a placebo; or multivitamins that include a single RDA of the following vitamins: 1.4 mg B1, 1.4 mg B2, 1.9 mg B6, 2.6 mcg B12, 18 mg niacin, 70 mg C, 10 mg E, and 0.4 mg folic acid. Participants are followed for up to 18 months with evaluations at baseline, 6, 12 and 18 months. The study is primarily powered to examine the effects on immune reconstitution, weight gain, and quality of life. In addition, we will examine the effects on other secondary outcomes including the risks of development of new or recurrent disease progression event, including all-cause mortality; ARV regimen change from first- to second-line therapy; and other adverse events as indicated by incident peripheral neuropathy, severe anemia, or diarrhea. DISCUSSIONS: The conduct of this trial provides an opportunity to evaluate the potential benefits of this affordable adjunct therapy (multivitamin supplementation) among HIV-infected adults receiving HAART in a developing country setting. TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01228578.

Causes of early mortality in HIV-infected TB suspects in an East African referral hospital.

BACKGROUND: Respiratory infections are a leading cause of death in Africa, especially among HIV-infected patients. Data on the etiology of fatal respiratory diseases are largely based on autopsy studies. We evaluated causes of pneumonia associated with early mortality among hospitalized HIV-infected patients in Kampala, Uganda. METHODS: Prospective cohort study of HIV-infected patients admitted to Mulago Hospital, Kampala, with at least 2 weeks of cough. Consecutively enrolled patients with negative Ziehl Neelsen sputum smears for acid-fast bacilli underwent bronchoscopy with bronchoalveolar lavage and examination for mycobacteria (smear, solid culture), Pneumocystis jirovecii (Giemsa stain), and fungi (KOH mount, India ink stain, Sabouraud culture). Early mortality was defined as death before the 2-month follow-up visit. RESULTS: Follow-up data were available for 353 (87%) of 407 patients enrolled. Of participants with follow-up data, 112 (32%) died within 2 months. Among patients with early mortality, a diagnosis was confirmed in 74 (66%), including tuberculosis (TB) (56%), cryptococcal pneumonia (1%), Pneumocystis pneumonia (3%), pulmonary Kaposi sarcoma (4%), and pneumonia caused by 2 or more disease processes (3%). CONCLUSIONS: Mortality in HIV-infected TB suspects is high, with TB associated with the largest proportion of deaths. A significant proportion of patients die without a confirmed diagnosis.

Clinical and radiographic factors do not accurately diagnose smear-negative tuberculosis in HIV-infected inpatients in Uganda: a cross-sectional study.

BACKGROUND: Although World Health Organization guidelines recommend clinical judgment and chest radiography for diagnosing tuberculosis in HIV-infected adults with unexplained cough and negative sputum smears for acid-fast bacilli, the diagnostic performance of this approach is unknown. Therefore, we sought to assess the accuracy of symptoms, physical signs, and radiographic findings for diagnosing tuberculosis in this population in a low-income country with a high incidence of tuberculosis. METHODOLOGY: We performed a cross-sectional study enrolling consecutive HIV-infected inpatients with unexplained cough and negative sputum smears for acid-fast bacilli at Mulago Hospital in Kampala, Uganda. Trained medical officers prospectively collected data on standard symptoms and signs of systemic respiratory illness, and two radiologists interpreted chest radiographs in a standardized fashion. We calculated positive- and negative-likelihood ratios of these factors for diagnosing pulmonary tuberculosis (defined when mycobacterial cultures of sputum or bronchoalveolar lavage fluid were positive). We used both conventional and novel regression techniques to develop multivariable prediction models for pulmonary tuberculosis. PRINCIPAL FINDINGS: Among 202 enrolled HIV-infected adults with negative sputum smears for acid-fast bacilli, 72 (36%) had culture-positive pulmonary tuberculosis. No single factor, including respiratory symptoms, physical findings, CD4+ T-cell count, or chest radiographic abnormalities, substantially increased or decreased the likelihood of pulmonary tuberculosis. After exhaustive testing, we were also unable to identify any combination of factors which reliably predicted bacteriologically confirmed tuberculosis. CONCLUSIONS AND SIGNIFICANCE: Clinical and radiographic criteria did not help diagnose smear-negative pulmonary tuberculosis among HIV-infected patients with unexplained cough in a low-income setting. Enhanced diagnostic methods for smear-negative tuberculosis are urgently needed.

The prevalence and clinical course of HIV-associated pulmonary cryptococcosis in Uganda.

BACKGROUND: The prevalence and clinical course of pulmonary cryptococcosis in Sub-Saharan Africa are not well described. METHODS: Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between September 2007 and July 2008 with cough >or=2 weeks were enrolled. Patients with negative sputum smears for acid-fast bacilli were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii, and fungi. Patients were followed 2 and 6 months after hospital discharge. RESULTS: Of 407 patients enrolled, 132 (32%) underwent bronchoscopy. Of 132 BAL fungal cultures, 15 (11%) grew Cryptococcus neoformans. None of the patients were suspected to have pulmonary cryptococcosis on admission. The median CD4 count among those with pulmonary cryptococcosis was 23 cells per microliter (interquartile range = 7-51). Of 13 patients who completed 6-month follow-up, 4 died and 9 were improved, including 5 who had started antiretroviral therapy but had not received antifungal medication. CONCLUSIONS: Pulmonary cryptococcosis is common in HIV-infected tuberculosis suspects in Uganda. Early initiation of antiretroviral therapy in those with isolated pulmonary infection may improve outcomes, even without antifungal therapy. This finding suggests that some HIV-infected patients with C. neoformans isolated from respiratory samples may have colonization or localized infection.

Poor performance of universal sample processing method for diagnosis of pulmonary tuberculosis by smear microscopy and culture in Uganda.

Laboratory methods to improve smear microscopy are an urgent priority for global tuberculosis control. The novel universal sample processing (USP) method has been reported to improve conventional diagnostic testing for tuberculosis while also providing inhibitor-free specimens for molecular assays. However, no studies evaluating the method in the field have been conducted. In this study, we compared the performance of the USP method to that of the standard N-acetyl-L-cysteine-NaOH (NALC) method for conventional diagnosis of tuberculosis in 252 adults admitted to Mulago Hospital in Kampala, Uganda, with a clinical suspicion of pneumonia. A single early-morning sputum specimen collected from each patient was divided into two aliquots, each of which was assigned a random identification number. One randomly numbered specimen was processed by the USP method and the other by the NALC method. Mycobacterial cultures were more frequently negative in USP compared to NALC specimen aliquots (58% versus 43%; P < 0.001). There was no difference in the proportion of contaminated mycobacterial cultures (12% versus 11%; P = 0.87). The sensitivity and specificity of smear microscopy for the USP method were 52% and 86%, respectively, and were not significantly different from those for the NALC method (56% and 86%, respectively) using mycobacterial culture results as a reference standard. These results suggest that the USP method did not provide any significant advantage over the standard NALC method for conventional diagnosis of tuberculosis in our setting and illustrate the importance of well-designed, field-level evaluations of novel diagnostic techniques.