K.P.W.J. McAdam

Tuberculosis and Chronic Hepatitis B Virus Infection in Africans and Variation in the Vitamin D Receptor Gene

The active metabolite of vitamin D, 1,25 dihydroxyvitamin D3, is an important immunoregulatory hormone [1]. Its effects are exerted by interaction with the vitamin D receptor, which is present on human monocytes and activated T and B lymphocytes. Variation in the vitamin D receptor gene was typed in 2015 subjects from large case-control studies of three major infectious diseases: tuberculosis, malaria, and hepatitis B virus. Homozygotes for a polymorphism at codon 352 (genotype tt) were significantly underrepresented among those with tuberculosis (chi2=6.22, 1 df, P=. 01) and persistent hepatitis B infection (chi2=6.25, 1 df, P=.01) but not in subjects with clinical malaria compared with the other genotypes. Therefore, this genetic variant, which predisposes to low bone mineral density in many populations, may confer resistance to certain infectious diseases.

The ethics of research related to healthcare in developing countries

In April 2002 the Nuffield Council on Bioethics published the Report The Ethics of Research Related to . It provides an ethical framework for those designing or conducting healthcarerelated Healthcare in Developing Countries research in developing countries. This paper will draw on the conclusions made in the Report, and present some of the recommendations. It will cover the importance of genuine consent, standards of care and ethical review of research. The focus will be on what happens when research is over and benefits to the community. The Report concludes that rigorous safeguards must be in place to prevent the exploitation of those who take part in externally-sponsored research.

Twice weekly tuberculosis preventive therapy in HIV infection in Zambia.

Background:A randomized double-blind placebo-controlled trial was conducted to estimate the efficacy of preventive therapy for tuberculosis (TB) in HIV-infected adults in Lusaka, Zambia. The main outcome measures were the incidence of TB, mortality and adverse drug reactions. Methods:During a 2 year period, 1053 HIV-positive individuals without evidence of clinical TB were randomly assigned to receive 6 months of isoniazid twice a week (H), or 3 months of rifampicin twice a week (R) plus pyrazinamide (Z), or a placebo. Therapy was taken twice a week and was self administered. Subjects presenting with symptoms during the follow-up period were investigated for TB. Results:The 1053 subjects in the study were followed up for a total of 1631 person-years (median = 1.8 years). Twenty-nine subjects were taken off treatment as a result of adverse drug reactions. A total of 96 cases of TB/probable TB (59 TB and 37 probable TB) were diagnosed during the study period and 185 deaths were reported. One hundred and fifteen subjects (11%) did not return to the study clinic at any time after enrolment. The incidence of TB was lower in those subjects on preventive therapy (H and RZ groups combined) compared with those on placebo (rate ratio = 0.60, 95% CI: 0.36–1.01, P = 0.057), as was the incidence of TB/probable TB (rate ratio = 0.60, 95% CI: 0.40–0.89, P = 0.013). The effect of preventive therapy was greater in those with a tuberculin skin test (TST) of 5 mm or greater, in those with a lymphocyte count of 2 × 109/l or higher, and in those with haemoglobin of 10 g/dl or higher. There was no difference in mortality rates between the preventive therapy and placebo groups. The effect of preventive therapy declined after the first year of the study so that by 18 months the rates of TB in the treated groups were similar to that in the placebo group. Conclusion:This study has demonstrated that preventive therapy with either twice weekly isoniazid for 6 months or a combination of rifampicin and pyrazinamide for 3 months reduced the incidence of TB in HIV-infected persons in Zambia. No effect was observed on mortality. The effect was greatest in persons who had a positive TST or a lymphocyte count of 2 × 109/l or greater, indicating that preventive therapy may be more effective in people with less advanced immunosuppression. The limited duration of the protective effect reported in this study raises the question of the need for lifelong preventive therapy or re-prophylaxis.

Impact of HIV on tuberculosis in Zambia: a cross sectional study.

OBJECTIVE--To examine the contribution of HIV infection to the apparently increasing incidence of tuberculosis in central Africa. DESIGN--Cross sectional study. SETTING--Outpatient clinic in teaching hospital, Lusaka, Zambia. PATIENTS--346 Adult patients with tuberculosis. RESULTS--Overall, 206 patients (60%; 95% confidence interval 54% to 65%) were positive for HIV--in one or both assays used. The peaks for both tuberculosis and HIV infection were among men aged 25-34 years and women aged 14-24 years. Of patients with confirmed pulmonary tuberculosis, 73/149 (49%; 41% to 57%) were positive for HIV; 67/83 (81%; 70% to 89%) patients with pleural disease and 16/19 (84%; 60% to 97%) patients with pericardial disease were positive. HIV positive patients with positive sputum culture were less likely to have had a positive sputum smear, and their chest x ray films less often showed classic upper zone disease or cavitation. Of 72 patients who fulfilled clinical criteria for AIDS, 17 were negative for HIV. CONCLUSIONS--The high prevalence of HIV in patients with tuberculosis suggests that an epidemic of reactivating tuberculosis is arising in those who are infected with HIV. The redirection of public health priorities towards tuberculosis would focus on a major treatable and preventable complication of the AIDS epidemic.

Negative sputum smear results in HIV-positive patients with pulmonary tuberculosis in Lusaka, Zambia

During recruitment to a prospective study of tuberculosis patients in Lusaka, Zambia, 109 had pulmonary disease proven by sputum culture for Mycobacterium tuberculosis, of whom 72 were HIV-1 antibody-positive and 37 were HIV-negative. Among these culture-proven cases, 43% of the HIV-positive patients had a negative sputum smear, compared with 24% of the HIV-negative cases. There was a strong trend towards lower grade or negative sputum smear in the HIV-positive group (P = 0.003). HIV-positive cases also had lower colony counts on culture and colonies took longer to appear. The findings imply that cases of HIV-associated pulmonary tuberculosis may frequently be missed and emphasise the need for new diagnostic methods.

Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study

Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.

Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: Results of a randomized controlled trial

Objectives: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV‐1‐infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV‐1‐infected adults. Design and setting: Randomized, double‐blind, placebo‐controlled trial in Nairobi, Kenya. Subjects: Six hundred and eighty‐four HIV‐1‐infected adults. Main outcome measures: Development of tuberculosis and death. Results: Three hundred and forty‐two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 × 106/l in the isoniazid and placebo groups, respectively. The overall median follow‐up from enrolment was 1.83 years (range, 0–3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person‐years (PY) of observation [95% confidence interval (CI) 2.78–6.33] and 3.86 per 100 PY of observation (95% CI, 2.45–5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49–1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)‐positive subjects was 0.60 (95% CI, 0.23–1.60) and for the TST‐negative subjects, 1.23 (95% CI, 0.55–2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79–1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST‐positive of 0.33 (95% CI, 0.09–1.23) and for TST‐negative subjects, 1.39 (95% CI, 0.90–2.12). Conclusions: Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST‐positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

Increased recurrence of tuberculosis in HIV-1-infected patients in Kenya

There is evidence that in human immunodeficiency virus 1 (HIV-1) infected patients with tuberculosis the rate of recurrence of tuberculosis is increased in those patients treated with a standard thiacetazone-containing regimen. To assess the impact of HIV-1 on tuberculosis in Kenya, patients with tuberculosis were studied prospectively. After treatment with either a standard thiacetazone plus isoniazid regimen or a short-course thiacetazone-containing regimen, overall recurrence rate of tuberculosis was 34 times greater in 58 HIV-1-positive patients than in 138 HIV-1-negative patients (adjusted rate ratio 33.8, 95% CI 4.3-264). Recurrence in the HIV-1-positive group was strongly associated with a cutaneous hypersensitivity reaction due to thiacetazone during initial treatment (rate ratio 13.2, 95% CI 3.1-56.2). In all patients with a cutaneous hypersensitivity reaction ethambutol was substituted for thiacetazone. No significant association was found between recurrence among HIV-1-positive patients and initial resistance, initial treatment regimen, a diagnosis of AIDS (WHO definition), or poor compliance. DNA fingerprinting suggested that both relapse and new infection may have produced recurrence of tuberculosis. In patients who had a cutaneous hypersensitivity reaction, increased recurrence rate may have been related to interruption of treatment, subsequent poor compliance, or more advanced immunosuppression. Alternatively, a change to the combination of ethambutol and isoniazid in the continuation phase for 11 months only may not be adequate.

Acute-phase protein synthesis in human hepatoma cells: differential regulation of serum amyloid A (SAA) and haptoglobin by interleukin-1 and interleukin-6.

Interlcukin‐6 (IL‐6, BSF‐2 or IFN‐β2) is thought to be the major regulator of the acute‐phase protein response that follows tissue injury and inflammation, with interleukin‐1 (IL‐1), tumour necrosis factor and more recently, LIF or HSF III, slightly stimulatory on only certain acute phase proteins. The synthesis of the major acute‐phase protein SAA, originally described as being synthesized in response to IL‐1, has been claimed recently to be mainly under IL‐6 regulation. Our results show that in the human hepatoma cell line HuH‐7, IL‐1 is the major stimulating cytokine increasing SAA synthesis by a factor in excess of 100‐fold. We also show that under most conditions interleukin‐6 and tumour necrosis factor stimulate additively in combination with IL‐1. Isoelectric focusing has demonstrated that SAA1 and SAA2α are expressed but not SAA2β. The HuH‐7 cell line is IL‐6 responsive since haptoglobin is stimulated mainly by IL‐6.

The impact of HIV on infectiousness of pulmonary tuberculosis : a community study in Zambia

OBJECTIVE To examine the impact of HIV on infectiousness of pulmonary tuberculosis (TB). DESIGN A cross-sectional tuberculin survey carried out among household contacts of HIV-1-positive and negative patients with bacteriologically confirmed pulmonary TB. Contacts were also examined for active TB. SETTING Index cases were recruited from patients attending the University Teaching Hospital in Lusaka, Zambia and household contacts were examined during visits to their homes within Lusaka. PATIENTS, PARTICIPANTS A total of 207 contacts of 43 HIV-positive patients, and 141 contacts of 28 HIV-negative patients with pulmonary TB were examined. MAIN OUTCOME MEASURES Proportion of contacts of HIV-positive and negative index cases with a positive tuberculin response (diameter of induration > or = 5 mm to a dose of 2 tuberculin units). RESULTS Fifty-two per cent of contacts of HIV-positive pulmonary TB patients had a positive tuberculin response compared with 71% of contacts of HIV-negative patients (odds ratio, 0.43; 95% CI, 0.26-0.72; P < 0.001). This difference persisted after allowing for between-household variations in the tuberculin response. Tuberculin response in the contact was related to age of contact, intimacy with the index case and crowding in the household. However, the effect of HIV status of the index case was not confounded by these variables. Tuberculin response in the contact was also related to the number of bacilli seen in the sputum smear of the index case which partially explained the effect of HIV status of the index case. Active TB was diagnosed in 4% of contacts of HIV-positive and 3% of contacts of HIV-negative cases, respectively (P = 0.8). CONCLUSIONS HIV-positive patients with pulmonary TB may be less infectious than their HIV-negative counterparts and this may partly be explained by lower bacillary load in the sputum.