Early immunologic and virologic responses to highly active antiretroviral therapy and subsequent disease progression among HIV-infected injection drug users.

We examined the prevalence and prognostic value of early responses to highly active antiretroviral therapy (HAART) among community-based injection drug users (IDUs) in Baltimore. Virologic (HIV RNA <1000 copies/ml) and immunologic (CD4 >500 cells/ul or increase of 50 cells/ul from the pre-HAART level) responses were examined in the 1st year of HAART initiation. Cox regression was used to examine the effect of early response on progression to new AIDS diagnosis or AIDS-related death. Among 258 HAART initiators, 75(29%) had no response, 53(21%) had a virologic response only, 38(15%) had an immunologic response only and 92(36%) had a combined immunologic and virologic response in the first year of therapy. Poorer responses were observed in those who were older, had been recently incarcerated, reported injecting drugs, had not had a recent outpatient visit and had some treatment interruption within the 1st year of HAART. In multiple Cox regression analysis, the risk of progression was lower in those with combined virologic and immunologic response than in non-responders, (relative hazard [RH], 0.32; 95% confidence interval [CI], 0.17-0.60). Those with discordant responses had reduced risk of progression compared to non-responders but experienced faster progression than those with a combined response, although none of these differences was statistically significant. Early discordant and non response to HAART was common, often occurred in the setting of injection drug use and treatment interruption and was associated with poorer survival. Interventions to reduce treatment interruptions and to provide continuity of HIV care during incarceration among IDUs are needed to improve responses and subsequent survival.

An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection.

The cytokine tumor necrosis factor alpha (TNF-alpha) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene, TNF. We hypothesized that SNPs in TNF may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine TNF SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1.91, 95% CI 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of TNF-alpha in determining outcomes of HCV infection.

Dynamics of SEN virus infection among injection drug users.

SEN virus (SENV) is a recently discovered group of DNA viruses whose members (SENV-D and SENV-H) are linked to posttransfusion hepatitis. Of 397 injection drug users (IDUs) in Baltimore, Maryland, SENV-D infection was detected by polymerase chain reaction in serum samples from 130 (32.7%) and SENV-H infection in 149 (37.5%). Of 41 IDUs in whom SENV-D DNA was initially detected, retesting for viral persistence a median of 9.3 years later detected SENV-D in 25 (61.0%), whereas SENV-H was detected on retesting in only 14 (26.9%) of 52 IDUs in whom the virus was originally found. Reinfection was apparent (>5% nucleotide difference) in 77.8% of IDUs who repeatedly tested positive for SENV-D DNA and in 55.6% of those who repeatedly tested positive for SENV-H DNA. Among Baltimore IDUs, SENV-D and SENV-H infections are common and dynamic, including both viral clearance and reinfection. The clinical significance of SENV infection in this setting remains unknown.

Isoniazid preventive therapy, hepatitis C virus infection, and hepatotoxicity among injection drug users infected with Mycobacterium tuberculosis.

Treatment of latent Mycobacterium tuberculosis infection with isoniazid can cause hepatotoxicity, but the risk of isoniazid-associated hepatotoxicity among persons coinfected with hepatitis C virus (HCV) is unknown. We conducted a prospective study among 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminase values who were treated with isoniazid. Of 146 participants, 138 (95%) were HCV-seropositive. Thirty-seven participants (25%) were human immunodeficiency virus (HIV)-seropositive. Thirty-two (22%; 95% confidence interval [CI], 16%-30%) of 146 participants developed transaminase value elevations to >3 times the upper limit of normal. Transaminase value elevation was associated with concurrent alcohol use but not with race, age, presence of hepatitis B surface antigen, HIV-1 infection, or current injection drug use. Isoniazid was withdrawn from 11 participants (8%; 95% CI, 4%-13%). Of 8 deaths during follow-up, none were attributed to isoniazid-associated hepatotoxicity. The risk of transaminase value elevation and drug discontinuation for HCV-infected persons receiving isoniazid was within the range reported for populations with lower HCV prevalence.

Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women.

Human immunodeficiency virus (HIV) infection and related immunosuppression are associated with excess risk for cervical neoplasia and human papillomavirus (HPV) persistence. Type-specific HPV infection was assessed at 6-month intervals for HIV-positive and HIV-negative women (median follow-up, 2.5 and 2.9 years, respectively). The type-specific incidence of HPV infection was determined, and risk factors for HPV persistence were investigated by statistical methods that accounted for repeated measurements. HIV-positive women were 1.8, 2.1, and 2.7 times more likely to have high-, intermediate-, and low-risk HPV infections, respectively, compared with HIV-negative women. In multivariate analysis, high viral signal, but not viral risk category, was independently associated with persistence among HIV-positive subjects (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-2.9). Furthermore, persistence was 1.9 (95% CI, 1.5-2.3) times greater if the subject had a CD4 cell count <200 cells/microL (vs. >500 cells/microL). Thus, HIV infection and immunosuppression play an important role in modulating the natural history of HPV infection.

Racial differences in HLA class II associations with hepatitis C virus outcomes.

A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53-0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17-0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23-4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort.

Initial plasma HIV-1 RNA levels and progression to AIDS in women and men.

BACKGROUND: It is unclear whether there are differences between men and women with human immunodeficiency virus type 1 (HIV-1) infection in the plasma level of viral RNA (the viral load). In men, the initial viral load after seroconversion predicts the likelihood of progression to the acquired immunodeficiency syndrome (AIDS), but the relation between the two has not been assessed in women. Currently, the guidelines for initiating antiretroviral therapy are applied uniformly to women and men. METHODS: From 1988 through 1998, the viral load and the CD4+ lymphocyte count were measured approximately every six months in 156 male and 46 female injection-drug users who were followed prospectively after HIV-1 seroconversion. RESULTS: The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter in the men but only 15,103 copies per milliliter in the women (P<0.001). The median initial CD4+ count did not differ significantly according to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1 infection progressed to AIDS in 29 men and 15 women, and the risk of progression did not differ significantly according to sex. For each increase of 1 log in the viral load (on a base 10 scale), the hazard ratio for progression to AIDS was 1.55 (95 percent confidence interval, 0.97 to 2.47) among the men and 1.43 (95 percent confidence interval, 0.76 to 2.69) among the women. The median initial viral load was 77,822 HIV-1 RNA copies per milliliter in the men in whom AIDS developed and 40,634 copies per milliliter in the men in whom it did not; the corresponding values in the women were 17,149 and 12,043 copies per milliliter. Given the recommendation that treatment should be initiated when the viral load reaches 20,000 copies per milliliter, 74 percent of the men but only 37 percent of the women in our study would have been eligible for therapy at the first visit after seroconversion (P<0.001). CONCLUSIONS: Although the initial level of HIV-1 RNA was lower in women than in men, the rates of progression to AIDS were similar. Treatment guidelines that are based on the viral load, rather than the CD4+ lymphocyte count, will lead to differences in eligibility for antiretroviral treatment according to sex.

Multicenter evaluation of hepatitis C RNA levels among female injection drug users.

The purpose of this investigation was to identify factors that determine the blood level of hepatitis C virus (HCV) RNA. By use of a quantitative polymerase chain reaction assay, the level of HCV RNA was ascertained in stored serum samples from 676 women enrolled in a multicenter prospective investigation who were seropositive for anti-HCV antibodies. HCV RNA levels ranged from undetectable to 22.4x106 copies/mL in these women. Among the 520 women with detectable HCV RNA, levels were higher among those who were >41 years old and those who had human immunodeficiency virus (HIV) infection. After adjusting for age in a multivariate linear regression model, HCV RNA levels were more strongly associated with HIV RNA levels than with CD4(+) lymphocyte counts. However, <6% of person-to-person variance was explained by the factors evaluated. Additional research is needed to ascertain what determines the level of HCV RNA in blood.

The natural history of hepatitis C virus infection: host, viral, and environmental factors.

CONTEXT: Hepatitis C virus (HCV) infection may resolve (viral clearance), persist without complications, or cause end-stage liver disease (ESLD). The frequency and determinants of these outcomes are poorly understood. OBJECTIVE: To assess the incidence and determinants of viral clearance and ESLD among persons who acquired HCV infection from injection drug use. DESIGN AND SETTING: Community-based prospective cohort study with enrollment in 1988-1989 and a median follow-up of 8.8 years. SUBJECTS: A total of 1667 persons aged 17 years or older with a history of injection drug use and an HCV antibody-positive test result during follow-up. MAIN OUTCOME MEASURES: Viral clearance was assessed in a subset of 919 patients and defined as failure to detect HCV RNA in at least 2 consecutive samples collected 5 or more months apart. End-stage liver disease was assessed at semiannual visits and by review of medical records and death certificates and defined by the presence of ascites, esophageal varices, or hepatic encephalopathy, or when ESLD was stated as a cause of death. RESULTS: Viral clearance was observed in 90 persons who were compared with 722 with persistent viremia, while the viremia of 107 was not resolved. Viral clearance occurred more often in nonblacks (adjusted odds ratio [OR], 5.15; 95% confidence interval [CI], 2.60-10.17) and those not infected with human immunodeficiency virus (HIV) (adjusted OR, 2.19; 95% CI, 1.26-3.47). Forty cases of ESLD were observed throughout follow-up (incidence, 3.1 per 1000 person-years). In a multivariate model, risk of ESLD was higher for persons aged 38 years or older at enrollment (adjusted relative incidence, 3.67; 95% CI, 1.96-6.88) and who reported ingestion of more than 260 g of alcohol per week (adjusted relative incidence, 3.60; 95% CI, 1.73-7.52). Of 210 patients without ESLD randomly selected for biopsy, only 2 had cirrhosis. CONCLUSIONS: Our results indicate that although HCV infection can be self-limited or associated with ESLD, the majority of adults have persistent viremia without clinically demonstrable liver disease. Further research is needed to explain the less frequent clearance of HCV infection among black persons and to improve utilization of treatment for those infected in the context of injection drug use. JAMA. 2000;284:450-456

Determinants of the quantity of hepatitis C virus RNA.

To test the hypothesis that person-to-person variability in blood levels of hepatitis C virus (HCV) RNA can be explained, the quantity of HCV RNA was assessed in 969 persons who acquired HCV infection in the context of injection drug use. Serum HCV RNA levels ranged from 200,000 to >120 million equivalents/mL (the linear range of the assay). The median log10 HCV RNA level was 0.46 higher in 468 human immunodeficiency virus (HIV)-positive persons than in 501 HIV-negative persons (P<.001). In addition, among HIV-negative persons, lower HCV RNA levels were independently associated with younger age (P<.001), ongoing hepatitis B infection (P=.005), and the absence of needle sharing (P=.02). However, >90% of the person-to-person HCV RNA level variability was not explained by these sociodemographic, environmental, and virologic factors. Additional research is necessary to ascertain what determines the level of HCV RNA in blood.

Screening for hepatitis C virus in human immunodeficiency virus-infected individuals.

Immunosuppression from human immunodeficiency virus (HIV) may impair antibody formation, and false-negative hepatitis C virus antibody (anti-HCV) tests have been reported in individuals coinfected with HIV and HCV. It is unknown if the frequency of false-negative tests is sufficiently high to change screening recommendations in this setting. Thus, the prevalence of false-negative results for anti-HCV by third-generation tests was determined with samples from HIV-infected individuals. Sera from 559 HIV-infected and 944 HIV-negative prospectively followed injection drug users were tested for anti-HCV by a third-generation enzyme immunoassay and for HCV RNA by using a branched DNA assay and the HCV COBAS AMPLICOR system. Of 559 HIV-infected participants, 547 (97.8%) were anti-HCV positive. One of the remaining 12 anti-HCV-negative participants was HCV RNA positive, and she later developed detectable anti-HCV. Of the 944 HIV-negative participants, 825 (87.4%) were anti-HCV positive. One of the remaining 119 anti-HCV-negative participants was HCV RNA positive, and she also developed detectable anti-HCV at a later visit. These data indicate that HIV infection does not alter the approach to hepatitis C virus screening, which should be performed with third-generation assays for anti-HCV unless acute infection is suspected.

Evaluating supervised HAART in late-stage HIV among drug users: a preliminary report.

OBJECTIVE: To examine response to highly active antiretroviral therapy (HAART) among a sample of treatment-experienced patients in the late stage of human immunodeficiency virus (HIV) infection in residential health care facilities (RHCFs) in New York City facilities designated for HIV/AIDS (acquired immunodeficiency syndrome) when access and adherence are maximized. METHODS: Medical record review of 111 patients. RESULTS: Demographics were mean age 42 years; 58% male; 60% African-American; 31% Hispanic; 57% injection drug users (IDUs); 23% with history of dementia; 52% hepatitis C virus (HCV) antibody seropositive; 80% on HAART, of whom 18% had lipodystrophy. Of 88 patients on HAART, 52% had a decreased viral load (>1/2 log) versus 13% of 23 not on HAART (P<.05); a >1/2 log viral load increase was seen in 8% and 35%, respectively (P<.05). Those with viral load increase were more likely than those with stable/decreased viral load to be IDUs (71% vs. 64%) and to have HCV seropositivity (86% vs. 53%), even with similar initial CD4+ cell count, viral load, and follow-up time. CONCLUSION: In a predominantly minority IDU population who are treatment experienced, 50% of the patients successfully responded to treatment with supervised therapy. The RHCFs in New York City provide a unique opportunity to examine further factors associated with response to HAART in an environment in which medication administration and adherence are maximized and monitored carefully.

Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters.

Cross-sectional studies have demonstrated lower plasma human immunodeficiency virus type 1 (HIV-1) RNA virus levels (VLs) in women than in men, but it is unknown whether this sex difference is present at the time of seroconversion and throughout the course of infection. A nested case-control study was performed among HIV-1 seroconverters within a cohort of injection drug users. Plasma VL was determined longitudinally among both rapid progressors to AIDS (24 patients) and nonprogressors (47 controls). The initial median VL among female patients (n=10) was 14,918 copies/mL, compared with 148,354 copies/mL among male patients (n=14; P=.001); median plasma VL also tended to be lower among female (n=10) than among male controls (n=37; 11,917 vs. 61,311 copies/mL; P=.08). VL increased more rapidly over time in women than in men and subsequently converged in patients and controls, respectively. Understanding the mechanisms responsible for the sex difference in VL may provide insight into HIV-1 pathogenesis.

Comparison of clinical manifestations of HIV infection among women by risk group, CD4+ cell count, and HIV-1 plasma viral load. HER Study Group. HIV Epidemiology Research.

OBJECTIVES: To compare the prevalence of HIV-related symptoms, physical examination findings, and hematologic variables among women whose risk for HIV is injection drug use since 1985 as opposed to sexual contact and to evaluate the influence of HIV plasma viral load and CD4+ cell count on clinical manifestations according to risk. METHODS: Participants of the HIV Epidemiology Research Study (HERS; a multicenter, prospective, controlled study of HIV infection in women) were administered a risk behavior and symptom interview, underwent a physical examination, and received hematologic testing, including CD4+ cell counts done on study entry. Plasma HIV-1 viral loads were performed on stored frozen plasma using an ultrasensitive branched-DNA (b-DNA) signal amplification assay. CD4+ counts were categorized as <200 cells/microl, 200 to 499 cells/microl, or > or =500 cells/microl, and HIV viral loads were characterized in tertiles. RESULTS: Cross-sectional analysis was conducted on data available for 724 HIV-infected women: 387 had a history of intravenous drug use and 337 were infected through heterosexual contact. The median CD4+ count was 376 cells/microl; the median HIV-1 viral load was 1135 copies/ml; and 281 of 724 HIV-infected women (38.8%) had an undetectable HIV-1 viral load. In analyses adjusting for CD4+ cell level alone and for plasma viral load combined with CD4+ cell level, injection drug users (IDUs) were more likely than those infected through heterosexual contact to report a recent episode of memory loss and weight loss, but less likely to have recent episodes of genital herpes; to have enlarged livers and a body mass index (BMI) <24, and to have hematocrit levels <34% and platelet counts <150,000 cells/ml. After adjustment for CD4+ cell level and risk group, high and medium HIV-1 plasma viral load levels were associated with the presence of oral hairy leukoplakia on examination, and only the highest level of plasma viral load was associated with recent histories of fever and thrush, oral hairy leukoplakia, pseudomembranous candidiasis, and BMI <24 on examination, and hematocrit <34%. CONCLUSIONS: In this cohort of women, the distribution of HIV-1 plasma viral load was lower than that previously reported in populations of HIV-infected men. This study also shows some differences in frequency of signs, symptoms, and laboratory values between risk groups of HIV-infected women, but these results may be due to effects of injection drug use rather than HIV infection. Signs and symptoms identified as associated with increasing levels of viral load that were not different across risk groups suggest more direct association of these findings with HIV infection.

Comparison between a whole blood interferon-gamma release assay and tuberculin skin testing for the detection of tuberculosis infection among patients at risk for tuberculosis exposure.

A new test that measures interferon-gamma (IFN-gamma) release in whole blood following stimulation with tuberculin has the potential to detect tuberculosis infection using a single blood draw. The IFN-gamma release assay was compared with the standard tuberculin skin test (TST) among 467 intravenous drug users at risk for tuberculosis in urban Baltimore. Among 300 human immunodeficiency virus (HIV)-seronegative patients, the IFN-gamma release assay was positive in 177 (59%), whereas the TST was positive in 71 (24%), for a percent agreement of 59% (kappa=26%). Among 167 HIV-seropositive subjects, the IFN-gamma release assay identified 32 reactors (19%); the TST identified 16 reactors (9.6%), for a percent agreement of 82% (kappa=28%). The IFN-gamma release assay detected more reactors than did the TST, but its agreement with TST was weak. As the TST is an imperfect standard, further evaluation of the IFN-gamma release assay among uninfected persons and persons with culture-confirmed tuberculosis will be useful.

Cell-associated infectious HIV-1 viral load as a predictor of clinical progression and survival among HIV-1 infected injection drug users and homosexual men.

Cell-associated infectious HIV-1 viral load was measured using semi-quantitative microculture techniques to determine its predictive capability for progression to AIDS or survival among HIV-1 infected injecting drug users (IDU) and homosexual men (HM). The authors followed 296 IDU and 240 HM from February 1992 through September 1995 for: (i) death, (ii) AIDS, and (iii) AIDS or bacterial infection. At baseline, viral load was quantified using microculture techniques to determine infectious units per million peripheral blood mononuclear cells (IUPM). Data were analyzed using standard statistical methods for survival analysis. Of the 536 total participants, 106 died (20%), and 98 of the 481 AIDS-free participants developed AIDS (20%). The relative hazard of AIDS for a viral load of > or = 100 IUPM, relative to a negative culture (0 IUPM), was 6.73 (95% CI: 2.23-20.3) after adjusting for risk group, initial CD4+ count, and other covariates. The adjusted relative hazard of death for a viral load of > or = 100 IUPM vs. 0 IUPM was 2.57 (95% CI: 0.97 6.80). Viral load predicted time to death within the < 200 cells/ul CD4+ stratum. The predictive value of viral load on HIV-1 progression did not vary by risk group. These data show that cell associated infectious HIV-1 viral load was significantly predictive of progression across risk groups for AIDS and death among those severely immune compromised.

Class II HLA alleles and hepatitis B virus persistence in African Americans.

Persistence of hepatitis B virus (HBV) infection is likely due to the interplay of the virus and host immune response. Given its critical role in antigen presentation, allelic differences in the HLA complex may affect HBV persistence. In a prospectively followed African American cohort, molecular class I and class II HLA typing was done on 31 subjects with persistent HBV infection and 60 controls who cleared the infection. HBV persistence was significantly associated with two class II alleles, DQA1 *0501 (odds ratio [OR], 2.6; P=.05) and DQB1 *0301 (OR, 3.9; P=.01), the two-locus haplotype consisting of these same two alleles (OR, 3; P=. 005) and the three-locus haplotype, DQA1 *0501, DQB1 *0301, and DRB1 *1102 (OR, 10.7; P=.01). In addition, HBV persistence was associated with class II allelic homozygosity. Several class I associations with persistence were also noted but were not statistically significant after correction for multiple comparisons. These results underscore the importance of the class II-mediated immune response in recovery from HBV infection.

Direct comparison of time to AIDS and infectious disease death between HIV seroconverter injection drug users in Italy and the United States: results from the ALIVE and ISS studies. AIDS Link to Intravenous Experiences. Italian Seroconversion Study.

OBJECTIVE: To compare the rate of HIV disease progression in a sample of polydrug injectors (AIDS Link to Intravenous Experiences [ALIVE] study) with that in a sample of predominantly opiate injectors (Italian Seroconversion Study [ISS]). DESIGN: Prospective cohort studies of HIV-positive individuals whose date of seroconversion (SC) is known with a good degree of precision. The ALIVE study involves a community-based cohort of injection drug users (IDU) in the United States and the ISS reports on a clinic-based cohort of seroconverters in Italy with different exposure modalities to HIV. METHODS: Data from the two cohorts were combined. The date of SC was estimated as the midpoint in time between the last negative and the first positive HIV test. Time-to-event (i.e., AIDS or death from an infectious disease) statistical methods were used. Relative hazards (RH) of progression to event were adjusted by age at SC, gender, and year of SC. RESULTS: Of the 1003 IDUs (251 from ALIVE and 752 from ISS), 226 progressed to AIDS, and 146 died after AIDS or from an infectious disease; of these, 10 were without an AIDS diagnosis. The two groups of IDUs differed in terms of age at SC (median, 35 years for ALIVE and 25 years for ISS), proportion of women (24% versus 31%), race (7.6% versus 100% white), and year of seroconversion (i.e., ISS participants seroconverted, on average, earlier than ALIVE participants). Although the univariate analysis suggested possible differences for progression to AIDS, or to death from infectious disease between cohorts, multivariate analyses that adjusted for age showed no significant differences by cohort, gender, race, or time of seroconversion. The median time to AIDS for 25-year-old persons was 12.3 years for ALIVE and 11.8 years for ISS; for 35-year-old persons, it was 8.5 and 8.2 years, respectively. These estimates were similar to those for non-IDUs observed in the ISS and to those from large cohort of homosexual men. CONCLUSION: Our results confirm the importance of accounting for age when considering the incubation period for HIV infection. Despite differences in drug use characteristics, the similar median times to AIDS, for each age, between the two cohorts of IDUs and between the IDUs and the non-IDUs suggest a negligible effect of injection drug use on HIV progression.

A prospective, community-based evaluation of liver enzymes in individuals with hepatitis C after drug use.

Serum alanine transaminase (ALT) levels are used to select hepatitis C virus (HCV)-infected patients for treatment and liver biopsy. However, the natural history of these measurements is poorly understood. To examine the hypothesis that ALT levels vary over time in HCV-infected patients, serial serum ALT levels were prospectively measured in a cohort of 1,235 persons with a history of prior illicit drug use. Over 25 months of follow-up, there was a median of four evaluations per patient. ALT values were higher in 1,164 (94%) HCV-infected individuals than in 71 (6%) HCV-uninfected individuals. The remainder of the analysis focused on these HCV-infected individuals, 647 (62%) of whom had normal ALT values at their initial visit. However, 323 (49%) of these had at least one elevated ALT over the next 25 months. Of the 395 patients whose ALT was initially abnormal, 332 (84%) had at least one normal value over the next 25 months. Overall, among individuals with four or more visits, ALT values were persistently normal in 42%, persistently elevated in 15%, and intermittently elevated in 43%. Because serum ALT levels have high visit-to-visit variability, single assessments should not be used to manage HCV-infected individuals. Further investigation is needed to ascertain the correlation of serial ALT trends with important disease outcomes.

Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy.

CONTEXT: Recent studies suggest that one third of tuberculosis cases in urban areas result from recent transmission. Improved tuberculosis control measures such as uniform implementation of directly observed therapy might reduce the proportion of cases resulting from recent transmission. OBJECTIVE: To determine patterns of tuberculosis transmission in Baltimore, Md, after 15 years of community-based directly observed therapy. DESIGN: A 30-month (January 1994-June 1996), prospective, city-wide study of all cases of tuberculosis using traditional contact investigations, geographic information systems data, and molecular epidemiologic comparison of Mycobacterium tuberculosis isolates with 2 DNA probes. PATIENTS: One hundred eighty-two patients with culture-positive tuberculosis. MAIN OUTCOME MEASURES: Proportion of disease defined as recently transmitted based on epidemiologic linkage by traditional contact tracing and molecular linkage by DNA fingerprint analysis of isolates; geographic foci of transmission based on linkage of residences by geographic information systems data. RESULTS: Of the 182 patients who had isolates of M tuberculosis available, 84 (46%) showed molecular clustering with 58 (32%) defined as being recently transmitted. Only 20 (24%) of 84 cases with clustered DNA fingerprints had epidemiologic evidence of recent contact. Geographic analysis showed significant spatial aggregation of the 20 clustered cases with epidemiologic links (P<.001), occurring in areas of low socioeconomic status and high drug use. The 64 cases with clustered DNA fingerprints but without epidemiologic links shared common risk factors and demographic features with the 20 clustered patients who did have epidemiologic links. CONCLUSIONS: Recently transmitted tuberculosis accounts for a high proportion of tuberculosis cases in Baltimore. Recently transmitted cases occur in geographically distinct areas of Baltimore, and location-based control efforts may be more effective than contact tracing for the early identification of cases.