Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa

Objective: To determine the effectiveness of twice-weekly directly observed therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients, irrespective of their previous treatment history. Also to determine the predictive value of 2-3 month smears on treatment outcome. Methods: Four hundred and sixteen new and 113 previously treated adults with culture positive pulmonary TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa. Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice a week to 6 months in the community. Results: Outcomes at 6 months among the 416 new patients were: transferred out 2%; interrupted treatment 17%; completed treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%; 95% CI 92-99%) new patients. Outcomes were similar among previously treated and new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2 months did not predict the final outcome. Conclusion: A twice-weekly rifampicin-containing drug regimen given under DOT cures most adherent patients irrespective of HIV status and previous treatment history. The 2 month smear may be safely omitted. Relapse rates need to be determined, and an improved system of keeping treatment interrupters on therapy is needed. Simplified TB treatment may aid implementation of the DOTS strategy in settings with high TB caseloads secondary to the HIV epidemic. (C) 1999 Lippincott Williams & Wilkins.

Potential strategies utilised by papillomavirus to evade host immunity

The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced mechanisms by which PV might avoid specific and non-specific host immune responses. Low level expression of PV proteins in infected basal epithelial cells, together with an absence of inflammation and of virus-induced cell lysis, restricts the opportunity for effective PV protein presentation to immunocytes by dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may restrict the efficacy of antigen presentation by these cells. Should an immune response be induced to PV antigens, resting keratinocytes (KC) appear resistant to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL. Thus, KC, in the absence of inflammation, may represent an immunologically privileged site for PV infection. Together, these mechanisms play a parr in allowing persistence of PV-induced proliferative skin lesions for months to years, even in immunocompetent hosts.

Relapse and mortality among HIV-infected and uninfected patients with tuberculosis successfully treated with twice weekly directly observed therapy in rural South Africa

Objective: To determine post-treatment relapse and mortality rates among HIV-infected and uninfected patients with tuberculosis treated with a twice-weekly drug regimen under direct observation (DOT). Setting: Hlabisa, South Africa. Patients: A group of 403 patients with tuberculosis (53% HIV infected) cured following treatment with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice weekly to 2 months and HR twice weekly to 6 months in the community under DOT. Methods: Relapses were identified through hospital readmission and 6-monthly home visits. Relapse (culture for Mycobacterium tuberculosis) and mortality given as rates per 100 person-years observation (PYO) stratified by HIV status and history of previous tuberculosis treatment. Results: Mean (SD) post-treatment follow-up was 1.2 (0.4) years (total PYO = 499); 78 patients (19%) left the area, 58 (14%) died, 248 (62%) remained well and 19 (5%) relapsed. Relapse rates in HIV-infected and uninfected patients were 3.9 [95% confidence interval (CI) 1.5-6.3] and 3.6 (95% CI 1.1-6.1) per 100 PYO (P = 0.7). Probability of relapse at 18 months was estimated as 5% in each group. Mortality was four-fold higher among HIV-infected patients (17.8 and 4.4 deaths per 100 PYO for HIV-infected and uninfected patients, respectively; P < 0.0001). Probability of survival at 24 months was estimated as 59% and 81%, respectively. We observed no increase in relapse or mortality among previously treated patients compared with new patients. A positive smear at 2 months did not predict relapse or mortality. Conclusion: Relapse rates are acceptably low following successful DOT with a twice weekly rifampifin-containing regimen, irrespective of HIV status and previous treatment history. Mortality is substantially increased among HIV-infected patients even following successful DOT and this requires further attention. (C) 1999 Lippincott Williams & Wilkins.

Emergence of multidrug-resistant tuberculosis in a community-based directly observed treatment programme in rural South Africa

OBJECTIVE: Although little studied in developing countries, multidrug-resistant tuberculosis (MDR-TB) is considered a major threat. We report the molecular epidemiology, clinical features and outcome of an emerging MDR-TB epidemic. METHODS: In 1996 all tuberculosis suspects in the rural Hlabisa district, South Africa, had sputum cultured, and drug susceptibility patterns of mycobacterial isolates were determined. Isolates with MDR-TB (resistant to both isoniazid and rifampicin) were DNA fingerprinted by restriction fragment length polymorphism (RFLP) using IS6110 and polymorphic guanine-cytosine-rich sequence-based (PGRS) probes. Patients with MDR-TB were traced to determine outcome. Data were compared with results from a survey of drug susceptibility done in 1994. RESULTS: The rate of MDR-TB among smear-positive patients increased six-fold from 0.36% (1/275) in 1994 to 2.3% (13/561) in 1996 (P = 0.04). A further eight smear-negative cases were identified in 1996 from culture, six of whom had not been diagnosed with tuberculosis. MDR disease was clinically suspected in only five of the 21 cases (24%). Prevalence of primary and acquired MDR-TB was 1.8% and 4.1%, respectively. Twelve MDR-TB cases (67%) were in five RFLP-defined clusters. Among 20 traced patients, 10 (50%) had died, five had active disease (25%) and five (25%) were apparently cured. CONCLUSIONS: The rate of MDR-TB has risen rapidly in Hlabisa, apparently due to both reactivation disease and recent transmission. Many patients were not diagnosed with tuberculosis and many were not suspected of drug-resistant disease, and outcome was poor.

Traditional healers as tuberculosis treatment supervisors: precedent and potential

SETTING: Hlabisa, South Africa. OBJECTIVE: To determine precedent and potential for traditional healers to act as tuberculosis (TB) treatment supervisors. METHODS: Literature review to describe precedent for the involvement of traditional healers in TB treatment supervision. Interviews with 100 TB patients to determine use of healers and their acceptability as supervisors. Interviews with 24 healers in the project sub-district to determine willingness to act as supervisors. RESULTS: Despite extensive literature on the interaction between traditional healers and conventional health services, including descriptions of traditional understandings of TB, no published work was identified that reported supervision of TB patients by traditional healers. Of 100 patients interviewed, only 10% had used a healer as the first health provider for their illness, but 40% had attended a healer at some time prior to diagnosis. Although only 4% believe healers can cure TB, 84% would consider choosing a healer as a treatment supervisor. Of the 24 healers, 15 (63%) distinguished between two types of diagnosis made among patients with. symptoms suggestive of TB: TB and idliso. Idliso is poisoning or bewitching, and is said to be best cured by healers, while TB is infectious and cannot be cured by healers. Most healers (88%) reported having referred patients with possible TB to hospital in the past; all were keen to negotiate collaboration with health services, and 92% were willing to act as treatment supervisors. CONCLUSIONS: While there is little reported precedent for traditional healers to interact formally with tuberculosis treatment services, the potential for collaboration seems to be high, at least in our setting.

Tuberculosis and health sector reform: experience of integrating tuberculosis services into the district health system in rural South Africa

SETTING: Hlabisa health district, South Africa. OBJECTIVE: To describe the integration of a vertical tuberculosis control programme into an emerging 'horizontal' district health system, within the context of health sector reform. DESIGN: Descriptive account of the process of integration of the programme into the health system. RESULTS: A highly 'vertical' system of delivering tuberculosis treatment (with poor programme outcomes) was converted into a (horizontal' team, integrated within the district health system, that used available resources such as village clinics and community health workers, with improved programme outcomes. CONCLUSIONS: In some settings at least, integration of tuberculosis 'programmes' into the district health system as tuberculosis 'teams' is feasible, and may produce highly cost-effective outcomes.

HIV infection among women admitted to the gynaecology service of a district hospital in South Africa

Our objective was to determine the prevalence of HIV infection and disease-specific HIV prevalence among women admitted to the gynaecology service of a district hospital in South Africa over a 3-month period in 1997. This was done with the goal of developing HIV education and counselling services in this setting. HIV status was determined among 196 (96%) of 205 consecutive admissions; 82 (42%) tested HIV positive. The HIV-infected women were younger than the HIV uninfected women (mean age 27 vs 33 years, P=0.001). The disease-specific HIV prevalence was greater than or equal to 40% among women who had had abortions, pelvic inflammatory disease, or ectopic pregnancy. The length of hospital stay (mean 5.4 days) and mortality (1%) were similar in the 2 groups. Inpatient gynaecology services may be act important setting in Africa, within which to provide HIV education, counselling and care.

Who fails to complete tuberculosis treatment? Temporal trends and risk factors for treatment interruption in a community-based directly observed therapy programme in a rural district of South Africa

SETTING: Hlabisa Tuberculosis Programme, Hlabisa, South Africa. OBJECTIVE: To determine trends in and risk factors for interruption of tuberculosis treatment. METHODS: Data were extracted from the control programme database starting in 1991. Temporal trends in treatment interruption are described; independent risk factors for treatment interruption were determined with a multiple logistic regression model, and Kaplan-Meier survival curves for treatment interruption were constructed for patients treated in 1994-1995. RESULTS: Overall 629 of 3610 surviving patients (17%) failed to complete treatment; this proportion increased from 11% (n = 79) in 1991/1992 to 22% (n = 201) in 1996. Independent risk factors for treatment interruption were diagnosis between 1994-1996 compared with 1991-1393 (odds ratio [OR] 1.9, 95% confidence interval [CT] 1.6-2.4); human immunodeficiency virus (HIV) positivity compared with HIV negativity (OR 1.8, 95% CI 1.4-2.4); supervised by village clinic compared with community health worker (OR 1.9, 95% CI 1.4-2.6); and male versus female sex (OR 1.3, 95% CI 1.1-1.6). Few patients interrupted treatment during the first 2 weeks, and the treatment interruption rate thereafter was constant at 1% per 14 days. CONCLUSIONS: Frequency of treatment interruption from this programme has increased recently. The strongest risk factor was year of diagnosis, perhaps reflecting the impact of an increased caseload on programme performance. Ensuring adherence to therapy in communities with a high level of migration remains a challenge even within community-based directly observed therapy programmes.

Effect of coinfection with STDs and of STD treatment on HIV shedding in genital-tract secretions - Systematic review and data synthesis

Objective: To determine whether coinfection with sexually transmitted diseases (STD) increases HIV shedding in genital-tract secretions, and whether STD treatment reduces this shedding. Design: Systematic review and data synthesis of cross-sectional and cohort studies meeting. predefined quality criteria. Main Outcome Measures: Proportion of patients with and without a STD who had detectable HIV in genital secretions, HIV toad in genital secretions, or change following STD treatment. Results: Of 48 identified studies, three cross-sectional and three cohort studies were included. HIV was detected significantly more frequently in participants infected with Neisseria gonorrhoeae (125 of 309 participants, 41%) than in those without N gonorrhoeae infection (311 of 988 participants, 32%; P = 0.004). HIV was not significantly more frequently detected in persons infected with Chlamydia trachomatis (28 of 67 participants, 42%) than in those without C trachomatis infection (375 of 1149 participants, 33%; P = 0.13). Median HIV load reported in only one study was greater in men with urethritis (12.4 x 10(4) versus 1.51 x 10(4) copies/ml; P = 0.04). In the only cohort study in which this could be fully assessed, treatment of women with any STD reduced the proportion of those with detectable HIV from 39% to 29% (P = 0.05), whereas this proportion remained stable among controls (15-17%), A second cohort study reported fully on HIV load; among men with urethritis, viral load fell from 12.4 to 4.12 x 10(4) copies/ml 2 weeks posttreatment, whereas viral load remained stable in those without urethritis. Conclusion: Few high-quality studies were found. HIV is detected moderately more frequently in genital secretions of men and women with a STD, and HIV load is substantially increased among men with urethritis, Successful STD treatment reduces both of these parameters, but not to control levels. More high-quality studies are needed to explore this important relationship further.

Immune responses induced by BCG recombinant for human papillomavirus L1 and E7 proteins

Recombinant bacille Calmette-Guerin (BCG) based vaccine delivery systems could potentially share the safety and effectiveness of BCG. We therefore prepared recombinant BCG vaccines which expressed the L1 late protein of the human papillomavirus (HPV) 6b or the E7 early protein of the HPV 16. The two recombinants were evaluated as immunogens in C57BL/6J and BALB/c mice, and compared with a conventional protein/adjuvant system using E7 or L1 mixed with Quil-A adjuvant. rBCG6bL1 and rBCG16E7 primed specific immune responses, represented by DTH, T-proliferation and antibody, and rBCG16E7 induced cytotoxic immune response to E7 protein. The magnitude of the observed responses were less than those elicited by protein/adjuvant vaccine. As recombinant BCG vaccines expressing HPV6bL1 or HPV16E7 persist at low levels in the immunised host, they may be beneficial to prime or retain memory responses to antigens, but are unlikely to be useful as a single component vaccine strategy. (C) 2000 Elsevier science Ltd. All rights reserved.

Trial-of-antibiotic algorithm for the diagnosis of tuberculosis in a district hospital in a developing country with high HIV prevalence

OBJECTIVE: To evaluate a diagnostic algorithm for pulmonary tuberculosis based on smear microscopy and objective response to trial of antibiotics. SETTING: Adult medical wards, Hlabisa Hospital, South Africa, 1996-1997. METHODS: Adults with chronic chest symptoms and abnormal chest X-ray had sputum examined for Ziehl-Neelsen stained acid-fast bacilli by light microscopy. Those with negative smears were treated with amoxycillin for 5 days and assessed. Those who had not improved were treated with erythromycin for 5 days and reassessed. Response was compared with mycobacterial culture. RESULTS: Of 280 suspects who completed the diagnostic pathway, 160 (57%) had a positive smear, 46 (17%) responded to amoxycillin, 34 (12%) responded to erythromycin and 40 (14%) were treated as smear-negative tuberculosis. The sensitivity (89%) and specificity (84%) of the full algorithm for culture-positive tuberculosis were high. However, 11 patients (positive predictive value [PPV] 95%) were incorrectly diagnosed with tuberculosis, and 24 cases of tuberculosis (negative predictive value [NPV] 70%) were not identified. NPV improved to 75% when anaemia was included as a predictor. Algorithm performance was independent of human immunodeficiency virus status. CONCLUSION: Sputum smear microscopy plus trial of antibiotic algorithm among a selected group of tuberculosis suspects may increase diagnostic accuracy in district hospitals in developing countries.

High HIV incidence and prevalence among young women in rural South Africa: Developing a cohort for intervention trials

Objective: To measure prevalence and model incidence of HIV infection. Setting: 2013 consecutive pregnant women attending public sector antenatal clinics in 1997 in Hlabisa health district, South Africa. Historical seroprevalence data, 1992-1995. Methods: Serum remaining from syphilis testing was tested anonymously for antibodies to HIV to determine seroprevalence. Two models, allowing for differential mortality between HIV-positive and HIV-negative people, were used. The first used serial seroprevalence data to estimate trends in annual incidence. The second, a maximum likelihood model, took account of changing force of infection and age-dependent risk of infection, to estimate age-specific HIV incidence in 1997. Multiple logistic regression provided adjusted odds ratios (OR) for risk factors for prevalent HIV infection. Results: Estimated annual HIV incidence increased from 4% in 1992/1993 to 10% in 1996/1997. In 1997, highest age-specific incidence was 16% among women aged between 20 and 24 years. in 1997, overall prevalence was 26% (95% confidence interval [CI], 24%-28%) and at 34% was highest among women aged between 20 and 24 years. Young age (<30 years; odds ratio [OR], 2.1; p = .001), unmarried status (OR 2.2; p = .001) and living in less remote parts of the district (OR 1.5; p = .002) were associated with HIV prevalence in univariate analysis. Associations were less strong in multivariate analysis. Partner's migration status was not associated with HIV infection. Substantial heterogeneity of HIV prevalence by clinic was observed (range 17%-31%; test for trend, p = .001). Conclusions: This community is experiencing an explosive HIV epidemic. Young, single women in the more developed parts of the district would form an appropriate cohort to test, and benefit from, interventions such as vaginal microbicides and HIV vaccines.

Papillomavirus virus-like particles for the delivery of multiple cytotoxic T cell epitopes

Chimeric papillomavirus (PV) virus-like particles (VLPs) based on the bovine papillomavirus type 1 (BPV-1) L1 protein were constructed by replacing the 23-carboxyl-terminal amino acids of the BPV1 major protein L1 with an artificial polytope minigene, containing known CTL epitopes of human PV16 E7 protein, HIV IIIB gp120 P18, Nef, and reverse transcriptase (RT) proteins, and an HPV16 E7 linear B epitope. The CTL epitopes were restricted by three different MHC class 1 alleles (H-2(b), H-2(d), HLA-A*0201). The chimeric L1 protein assembled into VLPs when expressed in SF-9 cells by recombinant baculovirus. After immunization of mice with polytope VLPs in the absence of adjuvant, serum antibodies were detected which reacted with both polytope VLPs and wild-type BPV1L1 VLPs, in addition to the HPV16E7 linear B cell epitope. CTL precursors specific for the HPV16 E7, HIV P18, and RT CTL epitopes were also detected in the spleen of immunized mice. Polytope VLPs can thus deliver multiple B and T epitopes as immunogens to the MHC class I and class II pathways, extending the utility of VLPs as self-adjuvanting immunogen delivery systems. (C) 2000 Academic Press.