Patrick MacPhail

Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene

The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C-->T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 microg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 microg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

Background:In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. Design and methods:Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. Results:A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1–26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0–21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/μl (IQR 77–265) in programmes with viral load monitoring and 102 cells/μl (44–181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7–18 after starting ART (aHR 1.38; 95% CI 0.97–1.98), similar during months 19–30 (aHR 0.97; 95% CI 0.58–1.60) and less common during months 31–42 (aHR 0.29; 95% CI 0.11–0.79). Conclusion:In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs.

Using vital registration data to update mortality among patients lost to follow-up from ART programmes: evidence from the Themba Lethu Clinic, South Africa

Objective  To estimate the rates of mortality in patients lost to follow‐up (LTFU) from a large urban public sector HIV clinic in South Africa.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy

Objectives  To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment.

The prevalence of hepatitis B co-infection in a South African urban government HIV clinic

OBJECTIVE There are an estimated 350 million hepatitis B carriers worldwide. In South Africa the prevalence of mono-infection with hepatitis B has been estimated to range from 1% in urban areas to approximately 10% in rural areas. The exact prevalence of hepatitis B in the HIV-infected population has not been well established. Hepatitis B screening is not standard practice in government HIV clinics. Co-infection with hepatitis B and HIV can influence antiretroviral treatment and prognosis of both diseases. The purpose of this study was to evaluate the prevalence of hepatitis B/HIV coinfection. DESIGN This is believed to be the first prospective observational report on the prevalence of hepatitis B/HIV co-infection in South Africa. Patients on whom hepatitis B serological tests could not have been done previously were recruited from an HIV clinic in a regional hospital in Johannesburg. Standard hepatitis B serological tests were performed. RESULTS Five hundred and two participants were screened. The cohorts average age was 37 +/- 9 years and the average CD4 count was 128 cells/pi. Twenty-four (4.80%) were hepatitis B surface antigen positive. Nearly half (47%) of the participants showed some evidence of hepatitis B exposure. The risk of hepatitis B co-infection was not significantly different when analysed in terms of sex, race, CD4 count or age. Liver function tests were not a good predictor of hepatitis B infection. CONCLUSION The rate of hepatitis B infection, as defined by hepatitis B surface antigen positivity in HIV-infected individuals in urban South Africa was 5 times the rate in people who were not HIV-infected. A 5% rate of hepatitis B/HIV co-infection is a reason to increase the accessibility of tenofovir/emtricitabine (Truvada) for first-line treatment for this population.

Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment.

Objective:To compare clinical, immunologic and virologic outcomes among stable HIV-positive patients down-referred to a nurse-managed primary healthcare clinic (PHC) for treatment maintenance to those who remained at a doctor-managed treatment-initiation site. Design:We conducted a matched cohort analysis among stable HIV patients at the Themba Lethu Clinic in Johannesburg, South Africa. Eligible patients met the criteria for down-referral [undetectable viral load <10 months, antiretroviral therapy (ART) >11 months, CD4 cell count ≥200 cells/&mgr;l, stable weight and no opportunistic infections], regardless of whether they were down-referred to a PHC for treatment maintenance between February 2008 and January 2009. Patients were matched 1 : 3 (down-referred : treatment-initiation) using propensity scores. Methods:We calculated rates and hazard ratios (HRs) for the effect of down-referral on loss to follow-up (LTFU) and mortality and the relative risk of down-referral on viral rebound by 12 months of follow-up. Results:Six hundred and ninety-three down-referred patients were matched to 2079 treatment-initiation patients. Two (0.3%) down-referred and 32 (1.5%) treatment-initiation patients died, 10 (1.4%) down-referred and 87 (4.2%) treatment-initiation patients were lost, and 22 (3.3%) down-referred and 100 (5.6%) treatment-initiation patients experienced viral rebound by 12 months of follow-up. After adjustment, patients down-referred were less likely to die [hazard ratio (HR) 0.2, 95% confidence interval (CI) 0.04–0.8], become LTFU (HR 0.3, 95% CI 0.2–0.6) or experience viral rebound (relative risk 0.6, 95% CI 0.4–0.9) than treatment-initiation patients during follow-up. Conclusion:The utilization of nurse-managed PHCs for treatment maintenance of stable patients could decrease the burden on specialized doctor-managed ART clinics. Patient outcomes for down-referred patients at PHCs appear equal, if not better, than those achieved at ART clinics among stable patients.

Mortality after failure of antiretroviral therapy in sub-Saharan Africa

Objective  To assess the outcome of patients who experienced treatment failure with antiretrovirals in sub‐Saharan Africa.

Transmission of Kaposi sarcoma-associated herpesvirus between mothers and children in a South African population.

Background:To assess whether Kaposi sarcoma-associated herpesvirus (KSHV) with or without HIV coinfection in South African mothers is associated with higher KSHV seropositivity in their children. Methods:We tested sera from 1287 South African children and 1179 mothers using assays for KSHV lytic K8.1 and latent ORF73 antigens. We computed odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between KSHV serostatus and risk factors. Results:KSHV seroprevalence was 15.9% (204 of 1287 subjects) in children and 29.7% (350 of 1179 subjects) in mothers. The risk of KSHV seropositivity was significantly higher in children of KSHV-seropositive mothers compared with those of KSHV-seronegative mothers. The HIV status of mothers was marginally associated with an increased risk of KSHV seropositivity in their children (OR = 1.6, 95% CI: 1.0 to 2.6; P = 0.07). KSHV seroprevalence was significantly higher in HIV-infected subjects (P = 0.0005), and HIV-infected subjects had significantly higher lytic and latent KSHV antibody levels than HIV-negative subjects. Conclusions:The risk of acquisition of KSHV was higher among children of KSHV-seropositive mothers. Although KSHV seroprevalence was significantly higher in children and mothers who were infected with HIV, the HIV status of the mother was only marginally associated with an increased risk of KSHV seropositivity in the child.

Occult hepatitis B virus infection in patients with isolated core antibody and HIV co-infection in an urban clinic in Johannesburg, South Africa.

BACKGROUND The prevalence of HIV/hepatitis B virus (HBV) co-infection in South Africa ranges from 4.8% to 17% using the standard marker surface antigen (hepatitis B surface antigen, HBsAg) for chronic active HBV infection. However, sensitive molecular techniques for detecting HBV DNA in serum can detect occult HBV infection. We report the first observational prospective study of occult HBV infection in HIV-positive people in South Africa. METHODS Five hundred and two patients attending an urban hospital were screened for HBV using serological testing for HBsAg, core antibody (anti-HBc), and surface antibody (anti-HBs). DNA was analyzed using real-time quantitative PCR to determine the HBV viral load. RESULTS Of the 502 participants, 24 (4.8%) were HBsAg-positive and 53 (10.6%) were positive for anti-HBc alone. Of these 53, screening for occult disease was carried out in 43, of whom 38 (88.4%) were positive. The mean HBV viral load was 2.8 x 10(4) copies/ml (range 1 x 10(2) to 1 x 10(6) copies/ml). CONCLUSIONS Combining the participants with positive HBsAg and occult HBV DNA results, the prevalence of HBV increases from 4.8% (HBsAg alone) to 12.4%. While the clinical impact of occult HBV infection is unclear, consideration should be given to changing the guidelines to recommend dual HBV therapy for the treatment of co-infected patients in the developing world.