Tuberculosis took center stage at the 9th CROI, but there was little good news to report. In a special symposium, four speakers addressed important new scientific developments in the area of TB and its control. Dr. Nulda Beyers of the University of Stellenbosch, S. Africa, reported on the innovative epidemiologic research her group has been carrying out, largely in HIV-negative patients [Abstract S5]. Using DNA fingerprints, she and her colleagues have determined transmission dynamics of TB in a developing country setting, noting a few surprises. While conventional dogma has it that TB is transmitted in the home, Beyers has found that much transmission occurs outside the home. Over 60% of TB in her study is recently transmitted, but within households experiencing more than one case of TB, two-thirds of patients have unrelated strains of TB, implying that infection was acquired outside the home. Community studies reveal that much TB is spread in the setting of alcohol use, often in bars and other social settings. Beyers also reported that a large proportion of recurrent TB in her community was from re-infection, not relapse (even among HIV-negative patients). She also pointed out that rates of transmission in the community are so high (>3.5% per year), that virtually all adults are infected. This means that the introduction of a highly effective new TB vaccine will have no impact on TB incidence for an entire generation. As HIV enters this community, the situation will get even worse.

Dr. Chris Whalen of Case Western University discussed interactions of TB and HIV, based largely on the studies carried out with his colleagues at the Makkerre University in Kampala, Uganda [Abstract S6]. He noted that a bi-directional interaction exists with TB and HIV, each pathogen increasing the pathogenicity of the other. HIV decreases immune control of latent TB infection, greatly increasing the risk of reactivation to active disease. Conversely, TB upregulates HIV expression through several mechanisms, including release of pro-inflammatory cytokines such as TNF and IL-6. As a result, the natural history of each infection is exacerbated by the other. Whalen showed that patients with HIV who develop TB have higher rates of subsequent disease progression, measured both by decline in CD4 count and rates of opportunistic infections and death. In discussing management options, Whalen presented the results of a recent controlled trial of prednisone in patients with HIV-related TB receiving anti-TB but not antiretroviral therapy. The hypothesis of the study was that treatment with prednisone would reduce the production of pro-inflammatory cytokines and lessen the impact of TB on HIV disease. Paradoxically, patients receiving prednisone had significantly greater increases in both CD4 count and viral load, but the differences disappeared after the drug was discontinued. Whalen concluded that the most effective means for managing TB during HIV was to treat with antiretrovirals.

Joanne Flynn of the University of Pittsburgh next presented an overview of TB vaccine development [Abstract S7]. She described the complex host responses to TB infection, and the importance of both CD4 and CD8 cells in controlling infection. She noted that a successful vaccine would need to provide as good or better protection against disease as natural infection. Ironically, natural infection is contained by more than 90% of infected people (except in HIV-infection), and efforts to improve on this have proved difficult. The current TB vaccine, BCG, is not thought to provide protection against pulmonary TB in adults in most settings. In animal models, however, BCG reduces TB in tissues by 1-2 logs. Most new vaccine candidates in recent years have been less effective than BCG, however. There are a number of new TB vaccines in the pipeline, including a few that have been more effective than BCG in animals. Flynn was cautiously optimistic about prospects for producing an efficacious new vaccine, and predicted that clinical trials of several candidates would begin in the coming several years.

Dr. Gary Maartens of the University of Cape Town, South Africa gave the closing talk of the symposium, in which he addressed the impact of the TB and HIV epidemics in sub-Saharan Africa [Abstract S8]. He noted that Africa has 8% of the world’s population but 18% of its TB cases and 71% of its HIV-infections. The collision of these epidemics has been catastrophic, with escalating case rates leading to an overburdening of clinical services and high mortality. Maartens discussed some of the clinical dilemmas in HIV-related TB, especially the problem of smear-negative disease. Patients with negative sputum smears may have TB or another infection that requires different therapy. Mortality in these patients is very high when they are treated for TB, either as a result of advanced AIDS with a failure to respond to treatment, or because they actually have another disease that is fatal when left untreated. Maartens reviewed clinical algorithms for managing these patients, including empiric therapy for bacterial pneumonia before a trial of anti-TB treatment. He also discussed management of HIV disease in TB patients in a high burden setting, emphasizing the importance of trimethoprim-sulfa treatment to reduce mortality. Data from South Africa confirm findings of a clinical trial in the Ivory Coast which showed that TMP-SMX reduces mortality in HIV/TB patients significantly. Another important approach to controlling the dual epidemics is to increase diagnosis of TB in HIV-infected populations. Among HIV seropositive patients in Voluntary Counseling and Testing (VCT) centers in Cape Town, 8% were found to have active TB and another 29% were either on TB therapy or had recently been treated for TB. Maartens was not enthusiastic about preventive therapy for TB in African patients with HIV, citing an analysis that showed that 19 tuberculin-positive patients with HIV would need to be treated to prevent one case of active TB. He concluded with data demonstrating the impact of antiretroviral therapy on TB incidence. Patients receiving HAART in Cape Town had an 84% reduction in TB incidence compared to patients treated with one nucleoside analogue or no antiretrovirals, similar to the data from the U.S. and Europe. He concluded that massive efforts were required to bring the necessary clinical services to the millions of people with HIV and TB in Africa.

Several other TB presentations were included in the poster sessions. Girardi and colleagues from GISTA-SISMIP study group in Italy reported that 5% of 129 initially tuberculin negative patients who had responded to HAART converted their skin tests after a mean of 31 months on treatment [Abstract 624-W]. Conversions were not associated with anergy at baseline, but were strongly related to CD4 count at the time the second test was applied: 6/7 convertors had a current CD4 count of >200/mm³. They recommended retesting tuberculin negative patients who have responded to HAART when the CD4 count rises to above 200/mm³. Girardi and associates also presented data on HIV-infected patients who developed TB in the era of HAART [Abstract 623-W]. Of 272 TB/HIV-infected patients identified between May 1999 and September 2000, one-third were immigrants to Italy, half were injection drug users, and 16% had a previous TB diagnosis. HIV was diagnosed at the time of TB diagnosis in 30%, and 40% were not receiving antiretrovirals at the time of TB diagnosis. Failure to treat known latent TB was responsible for only 5% of cases.

Rivero and colleagues presented data from a controlled trial of TB prophylaxis in HIV-infected, anergic patients [Abstract 625-W]. Three hundred-nineteen patients were randomized to receive INH for 6 months, INH-rifampin for 3 months, rifampin-PZA for 2 months or no treatment. Rates of TB per 100 person-years were, respectively, 3.4, 3.1, 1.2 and 3.1. The authors concluded that preventive therapy was not effective and was not necessary in this population. The rates of reported TB, however, are for the most part fairly high, so the conclusion that preventive therapy is not needed is unwarranted, in my view. A number of studies have shown a lack of benefit from preventive treatments in anergic patients, but several, like this trial, show that the risk remains high. One possible explanation is that the patients are acquiring new TB infections after they finish their prophylaxis, in which case infection control measures may be more important than preventive treatment.

A final study of TB and HIV was reported by Hung and colleagues from Taiwan [Abstract 636-W]. They compared the clinical course of 116 HIV-infected patients who developed TB with 525 HIV patients without TB. Patients with TB had lower initial CD4 counts (median 32 vs. 71), higher viral loads (310,000 vs. 76,000), and were more likely to be immigrants to Taiwan and to have acquired HIV heterosexually. Prior to the introduction of HAART, TB patients had slightly greater mortality rates than non-TB patients, but these differences disappeared after the advent of HAART. Among patients treated with HAART, TB patients had similarly good responses compared to non-TB patients, with the majority achieving an undetectable viral load. The authors concluded that TB has no adverse effect on HIV course and that response to HAART is not impaired by TB or TB drugs. They recommended that HAART be initiated early in patients with HIV-related TB.

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