Jean W. Pape

Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection

Tuberculosis occurring with human immunodeficiency virus (HIV) infection is a serious and growing public health problem. We have carried out a randomised clinical trial of a 12-month course of isoniazid plus vitamin B6 versus vitamin B6 alone in Port-au-Prince, Haiti, to assess the efficacy of isoniazid in preventing active tuberculosis in symptom-free HIV-infected individuals. The effect of prophylaxis on the development of HIV disease, AIDS, and death was also investigated. 118 subjects were assigned treatment with isoniazid plus B6 (n = 58) or B6 alone (n = 60) between 1986 and 1989. The treatment groups were similar at study entry in demographic, clinical, and immunological characteristics. Interim analysis in 1990 revealed no significant difference in tuberculosis outcome measures. Follow-up was continued until 1992, at which time significant protection by isoniazid against the development of tuberculosis was apparent, both for the whole study population and for subjects positive for purified protein derivative of tuberculin (PPD). The incidence of tuberculosis was lower in isoniazid recipients than in patients who received B6 alone (2.2 vs 7.5 per 100 person-years). The relative risk of tuberculosis was 3.4 (95% CI 1.1-10.6) for B6 alone versus isoniazid plus B6 (p < 0.05). Isoniazid also delayed progression to HIV disease and AIDS and death. Thus isoniazid effectively decreases the incidence of tuberculosis and delays the onset of HIV-related disease in symptom-free HIV-seropositive individuals. Isoniazid prophylaxis should be considered for HIV-seropositive, PPD-positive subjects, and may also be appropriate for PPD-negative patients in areas where tuberculosis is highly endemic.

Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

BACKGROUND Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. METHODS We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. RESULTS A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38). CONCLUSIONS Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.).

Early Versus Standard Antiretroviral Therapy for HIV Infected Adults in Haiti

BACKGROUND For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. METHODS We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. RESULTS Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). CONCLUSIONS Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)

Snapshot of Moving and Expanding Clones of Mycobacterium tuberculosis and Their Global Distribution Assessed by Spoligotyping in an International Study

ABSTRACT The present update on the global distribution of Mycobacterium tuberculosis complex spoligotypes provides both the octal and binary descriptions of the spoligotypes for M. tuberculosis complex, including Mycobacterium bovis, from >90 countries (13,008 patterns grouped into 813 shared types containing 11,708 isolates and 1,300 orphan patterns). A number of potential indices were developed to summarize the information on the biogeographical specificity of a given shared type, as well as its geographical spreading (matching code and spreading index, respectively). To facilitate the analysis of hundreds of spoligotypes each made up of a binary succession of 43 bits of information, a number of major and minor visual rules were also defined. A total of six major rules (A to F) with the precise description of the extra missing spacers (minor rules) were used to define 36 major clades (or families) of M. tuberculosis. Some major clades identified were the East African-Indian (EAI) clade, the Beijing clade, the Haarlem clade, the Latin American and Mediterranean (LAM) clade, the Central Asian (CAS) clade, a European clade of IS6110 low banders (X; highly prevalent in the United States and United Kingdom), and a widespread yet poorly defined clade (T). When the visual rules defined above were used for an automated labeling of the 813 shared types to define nine superfamilies of strains (Mycobacterium africanum, Beijing, M. bovis, EAI, CAS, T, Haarlem, X, and LAM), 96.9% of the shared types received a label, showing the potential for automated labeling of M. tuberculosis families in well-defined phylogeographical families. Intercontinental matches of shared types among eight continents and subcontinents (Africa, North America, Central America, South America, Europe, the Middle East and Central Asia, and the Far East) are analyzed and discussed.

Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome

Isospora belli has recently been recognized as an opportunistic protozoan pathogen in patients with the acquired immunodeficiency syndrome (AIDS). Although I. belli rarely causes diarrhea in patients with AIDS in the United States, we have documented isosporiasis in 15 percent (20 of 131) of such patients in Haiti. The infection was associated with chronic watery diarrhea and weight loss that was clinically indistinguishable from disease caused by the related coccidia cryptosporidium. No demographic or laboratory data distinguished the patients with AIDS and isosporiasis from those with either cryptosporidiosis or other opportunistic infections. Neither I. belli nor cryptosporidium was detected in stool samples from 170 healthy siblings, friends, and spouses of the patients with AIDS. In all patients with isosporiasis, diarrhea stopped within two days of the beginning of treatment with oral trimethoprim-sulfamethoxazole. Recurrent symptomatic isosporiasis developed in 47 percent of the patients, but it also responded promptly to therapy with trimethoprim-sulfamethoxazole. We conclude that isosporiasis is common in Haitian patients with AIDS, and that it responds to therapy with trimethoprim-sulfamethoxazole but is associated with a high rate of recurrence.

Characteristics of the acquired immunodeficiency syndrome (AIDS) in Haiti.

To identify the characteristics of the acquired immunodeficiency syndrome (AIDS) as it occurs in Haiti, we studied 61 previously healthy Haitians who had diagnoses of either Kaposis sarcoma (15), opportunistic infections (45), or both (1) established in Haiti between June 1979 and October 1982. The first cases of Kaposis sarcoma and opportunistic infections in Haiti were recognized in 1978-1979, a period that coincides with the earliest reports of AIDS in the United States. We do not believe that AIDS existed in Haiti before this period. The types of opportunistic infections and the clinical course in Haitians with Kaposis sarcoma and opportunistic infections were similar in most aspects to those in patients with AIDS in the United States. The median age of Haitians with Kaposis sarcoma and opportunistic infections was 32 years, and 85 per cent were men. The interval between diagnosis and death was six months in 80 per cent of the patients. Diarrhea was the most common reason for seeking medical attention in patients with opportunistic infections. Lymphopenia and skin-test anergy were observed in 86 and 100 per cent of patients, respectively. Potential risk factors (bisexual activity or blood transfusions) were identified in 17 per cent of male and 22 per cent of female patients. Demographic information suggests that patients belonged to all socioeconomic strata of Haitian society.

Global Distribution of Mycobacterium tuberculosis Spoligotypes

We present a short summary of recent observations on the global distribution of the major clades of the Mycobacterium tuberculosis complex, the causative agent of tuberculosis. This global distribution was defined by data-mining of an international spoligotyping database, SpolDB3. This database contains 11,708 patterns from as many clinical isolates originating from more than 90 countries. The 11,708 spoligotypes were clustered into 813 shared types. A total of 1,300 orphan patterns (clinical isolates showing a unique spoligotype) were also detected.

Cyclospora infection in adults infected with HIV. Clinical manifestations, treatment, and prophylaxis.

Coccidial infection of the gastrointestinal tract causes an acute self-limited diarrheal illness in the immunocompetent host [1, 2]. Cryptosporidium and Isospora belli are well recognized causes of chronic enteric infection in patients with the acquired immunodeficiency syndrome (AIDS) and other immunodeficiency states [1-4]. Recently, another coccidial parasite was identified in feces of immunocompetent and immunocompromised patients with diarrhea [5-12]. This new pathogen belongs to the genus Cyclospora based on results from electron microscopy, in vitro sporulation, and excystation studies [13]. In 1983, Haitian patients with AIDS who had diarrhea were noted to have an acid-fast Cryptosporidium-like organism in their stool samples. The organism was intermediate in size between Cryptosporidium and I. belli, was morphologically similar to Cryptosporidium, and responded to therapy with trimethoprim-sulfamethoxazole. In 1985, a medical student from Cornell University Medical College (in New York City) working in Haiti developed severe intermittent diarrhea. Extensive studies in New York City showed an organism in feces from this student identical to the Big Crypto we had observed in Haitian patients with AIDS [5]. The diarrhea resolved without therapy, and the patient has remained well. Subsequent studies have shown prolonged but self-limited diarrheal illness in travelers to Mexico, Nepal, Morocco, Pakistan, and India; in U.S. medical personnel; and in infants and children from Peru [5, 7-10, 12, 13]. Our report describes the clinical manifestations, diagnosis, treatment, and secondary prophylaxis of Cyclospora infection in Haitian patients infected with human immunodeficiency virus (HIV). Methods Between June 1990 and February 1993, 4850 patients were referred to the Institut National de Laboratoire et de Recherches in Port-au-Prince, Haiti, for HIV testing. This unit is the national referral center for AIDS and provides free HIV testing. A total of 2400 adults had positive test results for HIV by enzyme immunoassay (Abbott Diagnostic, North Chicago, Illinois). Among 2400 adults who were seropositive for HIV, 840 had a history of chronic or intermittent diarrhea during the preceding 2 years and 502 currently had diarrhea. Diarrhea was defined as the passage of at least one liquid stool daily for 3 or more weeks. A total of 450 patients provided stool specimens on two different occasions within a 10-day period before the initiation of therapy. Stool specimens were processed as previously described [3, 4]. Cultures for enteric bacterial pathogens were not routinely done because fewer than 1% of Haitian patients with AIDS who were previously studied had cultures that yielded Salmonella or Shigella species [4, 14]. Stool specimens were not examined for the presence of toxic Escherichia coli, Campylobacter species, or enteric viral pathogens. For examination, stool specimens were not concentrated and saline wet mounts were used. After formalin ethyl acetate concentration, coccidial oocysts were identified on slides stained by a variation of the modified Kinyoun acid-fast method. Specimens containing coccidia identified by wet mount or acid-fast staining were also stained with safranin, methylene blue, Giemsa, Gram, Grocott-Gomori silver stain, and auramine rhodamine [15]. The auramine rhodamine smears were examined by fluorescent microscopy. The criteria used for identification of Cyclospora species were presence of round acid-fast oocysts that were intermediate in size (8 to 9 microns) between Cryptosporidium (5 microns) and Isospora (25 15 microns) species. Forty-three of 51 patients with chronic Cyclospora infection were enrolled in a prospective study of treatment and prophylaxis. Cyclospora was identified in two separate stool specimens from each patient. Patients were excluded if they were terminally ill, pregnant, or unable to be followed for a minimum of 1 month. Patients were treated with trimethoprim sulfamethoxazole (160 mg and 800 mg, respectively), given orally four times a day for 10 days. Stool examinations were repeated on the fifth day of treatment, on the tenth and final day of therapy, and weekly after therapy. Laboratory personnel were blinded as to which patients were receiving antibiotics. Patients with recurrent diarrhea and Cyclospora organisms in their stool were retreated with the same regimen and then placed on prophylaxis with trimethoprim-sulfamethoxazole (160 mg and 800 mg, respectively) orally, three times a week. Results During the period between June 1990 and February 1993, 51 of 450 patients seropositive for HIV who had chronic diarrhea for more than 3 weeks had Cyclospora species identified in their fecal specimens. Other protozoa identified included Cryptosporidium in 135 patients (30%); I. belli in 54 patients (12%); Giardia lamblia in 14 patients (3%); and Entamoeba histolytica in 4 patients (1%). Six patients had Cyclospora species identified in association with I. belli (2 patients), Cryptosporidium (2 patients), and G. lamblia (2 patients). A second stool examination was done only on patients with enteric pathogens noted on the initial test; 43 of 45 patients with Cyclospora as their sole pathogen had confirmation of the organism on the second stool examination. Cyclospora was not identified in a single stool examination of 50 adults with diarrhea who were seronegative for HIV and who were randomly selected from patients referred to the same facility for HIV testing. One of 50 persons without diarrhea who were seronegative for HIV had Cyclospora on a routine stool examination. The sensitivity of other diagnostic methods for Cyclospora was evaluated using fecal specimens that gave positive results with the modified acid-fast stain. The diagnostic methods gave sensitivities of 75% for wet mount, of 30% for safranin stain, and of 23% for auramine rhodamine. Cyclospora was not identified by any of the other six staining techniques used, including Gram, Giemsa, methylene blue, Grocott-Gomori silver, Lugol iodine, and hematoxylin-eosin. Acid-fast stained organisms appeared red or pink with variable staining intensity and had 10- to 20-dot granular inclusions that tended to coalesce and to clump as crescent shape structures (Figure 1). Cyclospora organisms were nonrefractile and measured 8 to 9min diameter in wet mount preparations. Safranin staining more clearly outlined the membrane, but internal structure definition was poor. Fluorescence with auramine rhodamine staining was weak and irregular, but the internal structure with granules and network was more readily visualized. Figure 1. Concentrated fresh stool sample from a patient with AIDS, stained with modified Kinyoun stain and showing oocysts indicative of Cyclospora species. The mean age of patients was 24 years (range, 25 to 28 years); there were 30 men and 13 women. The patients had a history of chronic or intermittent diarrhea for a mean of 4 months (range, 1 to 24 months). Therefore, all patients fulfilled the current World Health Organization (WHO) definition of chronic diarrhea (duration 1 month). At the time of their entry into the study, all patients had had a weight loss of 10% or more during the previous 2 months. Diffuse, crampy abdominal pain was reported in 56% of patients, and a temperature of 38.5 C or more was documented in 35% of patients. No patients had vomiting that interfered with administration of oral medications or rehydration. Severe dehydration required using intravenous fluid in 3 patients (7%). All 43 patients completed the 10-day course of treatment with trimethoprim-sulfamethoxazole; no adverse drug reactions were observed during primary therapy. One patient developed pruritus while receiving trimethoprim-sulfamethoxazole and isoniazid as prophylaxis. The trimethoprim-sulfamethoxazole was withdrawn and then restarted without incident. Diarrhea and abdominal pain stopped in all patients after a mean of 2.5 days (range, 1 to 5 days). Stool samples were examined for the presence of parasites on the fifth day of treatment in 23 patients and on the last day of treatment in all 43 patients. All test results for Cyclospora species were negative, including repeat examinations done on all patients 1 week after discontinuation of therapy. No other protozoa or helminths were found either during or immediately after therapy. Twenty-eight patients provided weekly stool specimens for a minimum period of 1 month after completing therapy (mean, 9 months; range, 1 to 28 months). Twelve of 28 patients (44%) had recurrent diarrhea associated with the presence of Cyclospora in stool at a mean time of 2.5 months after therapy (range, 1 to 3 months). The recurrent episodes of cyclosporiasis were clinically indistinguishable from the initial episode and also responded after 2 days of trimethoprim-sulfamethoxazole therapy. After retreatment, these 12 patients were placed on trimethoprim-sulfamethoxazole prophylaxis orally three times a week. After a mean follow-up period of 7 months (range, 2 to 27 months), 1 of 12 patients had a third episode of cyclosporiasis that again responded promptly to trimethoprim-sulfamethoxazole therapy. Sixteen of 43 patients (37%) seropositive for HIV who had cyclosporiasis had previously met criteria from the Centers for Disease Control and Prevention (CDC) for a diagnosis of AIDS (wasting syndrome, 10 patients; pulmonary tuberculosis, 5 patients; and cryptosporidiosis, 1 patient). Seven patients had diagnoses concurrently established that fulfilled criteria for AIDS (Candida esophagitis, 3 patients; isosporiasis, 3 patients; and cryptosporidiosis, 1 patient). Sixteen of the remaining 20 patients fulfilled CDC criteria for AIDS within a mean period of 4 months of their diagnosis of cyclosporiasis. The opportunistic infections identified included Candida esophagitis (3 patients); cryptosporidiosis (2 patients); tuberculosis (2 patients); anogenital herpes infection of 3 months or more (

Treatment and Prophylaxis of Isospora belli Infection in Patients with the Acquired Immunodeficiency Syndrome

Enteric infection with the protozoan Isospora belli is common in patients with the acquired immunodeficiency syndrome (AIDS) and causes severe diarrhea. I. belli responds well to treatment with trimethoprim-sulfamethoxazole, but there is a high rate of recurrence. To investigate the effect of long-term prophylaxis, we studied 32 Haitian patients with AIDS complicated by I. belli infection and chronic diarrhea. All were treated with trimethoprim (160 mg) and sulfamethoxazole (800 mg), given orally four times a day for 10 days; the patients were then randomly assigned to receive 500 mg of sulfadoxine and 25 mg of pyrimethamine weekly, 160 mg of trimethoprim and 800 mg of sulfamethoxazole three times a week, or placebo. Half of the patients (5 of 10) who received placebo had recurrent, symptomatic isosporiasis a mean of 1.6 months after the initial treatment. All 22 patients who received either trimethoprim-sulfamethoxazole or sulfadoxine-pyrimethamine remained asymptomatic. I. belli was identified in the stools of only one of these patients, who was receiving trimethoprim-sulfamethoxazole. The study medications were generally well tolerated but had to be discontinued in the cases of two patients because of severe pruritus. In 10 patients, the prophylactic regimen has been continued for a mean of 16 months without recurrent isosporiasis. We conclude that isosporiasis in patients with AIDS can be treated effectively with a 10-day course of trimethoprim-sulfamethoxazole and that recurrent disease can subsequently be prevented by ongoing prophylaxis with either trimethoprim-sulfamethoxazole or sulfadoxine-pyrimethamine.

Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial

BACKGROUND Patients with HIV-1 infection respond well to treatment for active tuberculosis, but whether such patients are at increased risk of disease recurrence after complete cure is uncertain. We did a randomised trial in Port au Prince, Haiti, to determine whether recurrent tuberculosis after curative tuberculosis treatment is more common in HIV-1-infected individuals than HIV-1-uninfected individuals, and to determine whether post-treatment isoniazid prophylaxis decreases the risk of recurrent tuberculosis. METHODS Patients older than 18 years who were diagnosed with a first episode of tuberculosis at the national HIV testing centre in Haiti, and who successfully completed a 6-month rifampicin-containing regimen for active pulmonary tuberculosis, were randomly assigned 1 year of post-treatment isoniazid prophylaxis or placebo. The primary outcome measure was rate of recurrent tuberculosis after at least 24 months. An intention-to-treat analysis was used. FINDINGS Of 354 patients with active pulmonary tuberculosis, 274 successfully completed treatment, and 233 were randomised. Of 142 HIV-1-positive patients, 68 were assigned isoniazid and 74 placebo. Of 91 HIV-1-negative individuals, 51 were assigned isoniazid and 40 placebo. The rate of recurrent tuberculosis was 4.8 per 100 person-years in HIV-1-infected individuals and 0.4 per 100 person-years in uninfected individuals (relative risk 10.7 [95% CI 1.4-81.6]). Among HIV-1-positive patients receiving isoniazid, the tuberculosis recurrence rate was 1.4 per 100 person-years, and among HIV-1-positive patients receiving placebo, it was 7.8 per 100 person-years (0.18 [0.04-0.83]). Among HIV-1-positive individuals, all cases of recurrent tuberculosis occurred in individuals with a history of HIV-1-related symptoms before initial tuberculosis diagnosis. INTERPRETATION The rate of recurrent tuberculosis is higher in HIV-1-positive individuals than in HIV-1-negative individuals, and is strongly associated with a history of symptomatic HIV-1 disease before initial tuberculosis diagnosis. Post-treatment isoniazid prophylaxis decreases the risk of recurrence in HIV-1-positive individuals, and should be considered for HIV-1-positive individuals with a history of HIV-1-related symptoms at the time of tuberculosis diagnosis.