Adjuvant potential of low dose all-trans retinoic acid during oral typhoid vaccination in Zambian men.

There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of α4ß7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10 nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3 h after 10 mg ATRA. We then evaluated the effect of 10 mg ATRA given 1 h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] C(max) was 26·2 (11·7-39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P = 0·02) and protein (P = 0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant.

Screening for hepatocellular carcinoma among adults with HIV/HBV co-infection in Zambia: a pilot study.

BACKGROUND AND AIMS: Chronic hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) in sub-Saharan Africa (SSA). An HCC screening initiative was piloted in an established cohort of individuals co-infected with human immunodeficiency virus (HIV) and HBV on antiretroviral therapy (ART) at two outpatient clinics in Lusaka, Zambia. METHODS: All patients underwent abdominal ultrasound (AUS) and transient elastography. RESULTS: Among 279 patients co-infected with HIV/HBV, 165 (59.1%) were men, median age was 34 years [interquartile range (IQR) 28-39 years] and median CD4 count was 246 cells/µL (IQR 112-355 cells/µL) at ART initiation. While 102 (55.7%) individuals had elevated transaminases, 114 (59.7%) had HBV levels >2000 IU/mL and 59 (24.6%) had significant fibrosis. At their first AUS measurement, 75 (26.9%) participants had hepatomegaly and 69 (24.7%) had periportal fibrosis. Five patients had a liver lesion >1 cm, an indication for confirmatory imaging. CONCLUSIONS: In one of the first HCC screening initiatives in SSA, 2% of patients co-infected with HIV/HBV had significant liver lesions, and one-quarter had findings suggestive of schistosomiasis-induced liver damage.

In a trial of the use of miltefosine to treat HIV-related cryptosporidiosis in Zambian adults, extreme metabolic disturbances contribute to high mortality.

There is still no effective treatment for cryptosporidiosis even though the disease has a significant impact on HIV-infected adults and children. Following evidence of the drug's promising efficacy in vitro, a phase-1-phase-2 study of miltefosine (given at 2.5 mg/kg for 14 days, with the dose capped at 100 mg/day) was recently initiated among Zambian adults with HIV-related cryptosporidiosis. Seven patients were recruited before the trial was terminated prematurely because of lack of efficacy and the development of severe adverse events. The latter may have been entirely drug-related or the result of extreme metabolic abnormalities already present in the patients enrolled in the trial. In future trials of miltefosine, attention will have to be paid to the possibility of metabolic abnormalities in the subjects investigated.

Insulin Resistance is Associated with Higher Plasma Viral Load Among HIV-Positive Adults Receiving Longer-Term (1 Year) Combination Antiretroviral Therapy (ART).

Background: As HIV-positive persons survive longer due to the success of combination antiretroviral therapy (ART) in decreasing mortality, the burden of non-communicable diseases including diabetes mellitus (DM) is anticipated to rise. HIV is characterized by systemic inflammations, markers of which decrease quickly following ART initiation, but typically do not completely normalize. Inflammation may be accompanied by insulin resistance (IR), and both are implicated in the pathogenesis of DM in HIV-positive individuals. Sub-Saharan Africa accounts for almost two-thirds of the global HIV burden but there are few reports of IR, DM and HIV in this region. We assessed the relationship between IR and viral suppression among HIV-positive adults in the Zambian national ART program. Methods: We conducted a cross-sectional survey evaluating HIV-positive adults that had received first line ART (usually TDF/FTC/EFV) for 12 months (± 3 months). Twenty clinics were sampled systematically based on the random starting-point, sampling interval and cumulative population size. Eligible patients had plasma viral load (VL), fasting insulin, and glucose performed. Insulin resistance was determined using Homeostatic model assessment (HOMA). We determined proportions for each outcome using linearized standard error 95% confidence intervals and summary estimates. Viral suppression was defined according to the detection threshold of<20 copies/mL and treatment failure was defined as VL>1,000 copies/mL. Results: Of 473 patients enrolled, 46.8% were male and 53.2% were female. 142 (30%) [95% CI: 0.26-0.34] had IR. Among those with IR, 55 (38.7%) were male whereas 87 (61.3%) were female (p value=0.104). 19% of individuals with IR had treatment failure compared to 5.7% without IR (p value<0.0001). 427 (90.3%) participants had treatment success (VL<1,000 copies/mL), and this was associated with a lower likelihood of IR (odds ratio (OR)=0.26 [0.14, 0.48], p value<0.0001). In addition, a significantly lower proportion of patients with IR were virologically suppressed at one-year compared to individuals without IR, 58% [0.54-0.70] versus 70% [0.65-0.75], respectively (p value=0.042). Conclusion: In Zambian adults on ART for a year, the development of insulin resistance was strongly associated with suboptimal HIV outcomes, specifically non-viral suppression and treatment failure. Further investigations are warranted to determine if this positive association between IR and VL is causally related, and if so in which direction.

Gastric Malignancy Survival in Zambia, Southern Africa: A Two Year Follow up Study.

Background: Gastric cancer poses a significant global health burden. It is the second most common cause of cancer death worldwide and the ninth leading cause of cancer mortality in Zambia, at a rate of 3.8/100,000; comparable to USA (2/100,000) and UK (3.4/100,000). Survival data on gastric malignancy in Zambia is not known. Objectives: To provide preliminary survival rates of patients with histologically proven gastric adenocarcinoma in Zambia. Study Design: Using our prospective gastric cancer research database, we conducted a retrospective audit of patients diagnosed with gastric cancer at the University Teaching Hospital, Zambia, from June 2010 until January 2012. We contacted patients or their relatives using phone numbers provided at time of enrollment. Main Outcomes: We reviewed age, sex, demographic data (income, education), body mass index, symptoms, duration of symptoms, treatment (surgery, chemotherapy, radiotherapy or combination) and survival outcome. Analysis was performed using Kaplan-Meier models and log rank test. Results: Fifty one patients were diagnosed with gastric adenocarcinoma during the study period, but follow-up data were available for 50. Median survival was 142 days. Age, sex, income, education, BMI, tumor location, and treatment modality were not significantly associated with overall survival. In Cox regression models, covariates associated with survival were a history of regular alcohol intake (HR 0.49, 95%CI 0.26,0.92; P=0.025) and intestinal type cancer histology (HR 0.40, 95%CI 0.19,0.83; P=0.01). Conclusion: Prognosis of newly diagnosed gastric cancer in Zambia is poor with significant mortality within 1 year of diagnosis, particularly among patients with weight loss and dysphagia.

Gastric adenocarcinoma in Zambia: a case-control study of HIV, lifestyle risk factors, and biomarkers of pathogenesis.

BACKGROUND: Gastric cancer is a leading cause of cancer deaths worldwide but there are few data from Africa. We recently observed a trend towards diagnosis in younger patients. OBJECTIVE: To test the hypothesis that HIV might have altered risk factors for acquisition of gastric cancer, in a case-control study in the University Teaching Hospital, Lusaka, Zambia. METHODS: Patients (n=52) with confirmed gastric adenocarcinoma and controls (n=94) undergoing endoscopy but with no macroscopic gastric pathology. Established risk factors and HIV status were compared. RESULTS: HIV status did not differ significantly between cases and controls (odds ratio 1.03; 95% CI 0.2 - 4.3; p=1.00) and seroprevalence in cases was similar to that of the Zambian population. Smoking, regular alcohol intake, and gastric atrophy were all associated with cancer in univariate and multivariate analysis. Helicobacter pylori serology was positive in 84% of patients studied and cagA serology in 66%; neither serological marker was associated with cancer. Atrophy was common in cases (57%) and controls (30%) and associated with both smoking and alcohol use. Intestinal metaplasia was present in 17% of the controls, but was not associated with atrophy. CONCLUSIONS: HIV was not associated with gastric cancer and does not explain the apparent younger age distribution. Atrophy was common and was not essential for the development of intestinal metaplasia, suggesting that gastric carcinogenesis in Africa does not always follow the pathway from atrophy to intestinal metaplasia to gastric carcinoma (the so-called Correa pathway).