David L. Hom

A Trial of Three Regimens to Prevent Tuberculosis in Ugandan Adults Infected with the Human Immunodeficiency Virus

BACKGROUND Infection with the human immunodeficiency virus (HIV) greatly increases the risk of reactivation tuberculosis. We evaluated the safety and efficacy of three preventive-therapy regimens in a setting where exposure to tuberculosis is common. METHODS We performed a randomized, placebo-controlled trial in 2736 HIV-infected adults recruited in Kampala, Uganda. Subjects with positive tuberculin skin tests (induration, > or =5 mm) with purified protein derivative (PPD) were randomly assigned to one of four regimens: placebo (464 subjects), isoniazid daily for six months (536), isoniazid and rifampin daily for three months (556), or isoniazid, rifampin, and pyrazinamide daily for three months (462). Subjects with anergy (0 mm induration in reaction to PPD and candida antigens) were randomly assigned to receive either placebo (323 subjects) or six months of isoniazid (395). The medications were dispensed monthly and were self-administered. RESULTS Among the PPD-positive subjects, the incidence of tuberculosis in the three groups that received preventive therapy was lower than the rate in the placebo group (P=0.002 by the log-rank test). The relative risk of tuberculosis with isoniazid alone, as compared with placebo, was 0.33 (95 percent confidence interval, 0.14 to 0.77); with isoniazid and rifampin, 0.40 (0.18 to 0.86); and with isoniazid, rifampin, and pyrazinamide, 0.51 (0.24 to 1.08). Among the subjects with anergy, the relative risk of tuberculosis was 0.83 (95 percent confidence interval, 0.34 to 2.04) with isoniazid as compared with placebo. Side effects were more common with the multidrug regimens, and particularly with the regimen containing pyrazinamide. Survival did not differ among the groups, but the subjects with anergy had a higher mortality rate than the PPD-positive subjects. CONCLUSIONS A six-month course of isoniazid confers short-term protection against tuberculosis among PPD-positive, HIV-infected adults. Multidrug regimens with isoniazid and rifampin taken for three months also reduce the risk of tuberculosis.

A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006)

OBJECTIVE To determine the safety, pharmacokinetics, tolerance, antiretroviral activity, and infant HIV infection status after giving a single dose of nevirapine to HIV-1-infected pregnant women during labor and their newborns during the first week of life. DESIGN An open label phase I/II study. SETTING Tertiary care hospital, Kampala, Uganda. PATIENTS AND INTERVENTIONS Nevirapine, 200 mg, was given as a single dose during labor to 21 HIV-1-infected pregnant Ugandan women. In cohort 1, eight infants did not receive nevirapine whereas in cohort 2, 13 infants received a single dose of nevirapine, 2 mg/kg, at 72 h of age. OUTCOMES The number and type of adverse events; nevirapine concentrations in the plasma and breast milk; maternal plasma HIV-1 RNA copy number before and up to 6 weeks after delivery; and HIV-1 infection status of the infants were monitored. RESULTS Nevirapine was well tolerated by women and infants; no serious adverse events that were related to nevirapine were observed. Median nevirapine concentration in the women at delivery was 1623 ng/ml (range 238-2356 ng/ml); median cord/maternal blood ratio of 0.75 (0.37-0.93). The median half-life in women was 61.3 h (27-90 h) and the transplacental nevirapine half-life in infants who did not receive a neonatal dose was 54 h. The median half-life after a single dose at 72 h in infants was 46.5 h. During the first week of life, the median colostrum/breast milk to maternal plasma nevirapine concentration was 60.5% (25-122%). The median nevirapine concentration in breast milk 1 week after delivery was 103 ng/ml (25-309 ng/ml). Plasma nevirapine concentrations were above 100 ng/ml in all infants from both cohorts tested at age 7 days. Maternal HIV-1 RNA levels decreased by a median of 1.3 logs at 1 week postpartum, and returned to baseline by 6 weeks postpartum. Detectable plasma HIV-1 RNA was observed in one out of 22 (4.5%) infants at birth; three out of 21 (14%) at 6 weeks; and four out of 21 (19%) at 6 months of age. CONCLUSION The administration of a single dose of nevirapine to women during labor and to their newborns at 72 h was well tolerated and showed potent antiretroviral activity in the women at 1 week after dosing without rebound above baseline 6 weeks after a single dose. The nevirapine concentration was maintained above the target of 100 ng/ml in infants at age 7 days, even in those infants not receiving a neonatal dose. This regimen has promise as prophylaxis against intrapartum and early breast milk transmission in a breastfeeding population.

Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda.

BackgroundRetrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis. MethodsIn a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status. ResultsDuring the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07–1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 × 106 cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 × 106 /l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27–3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 × 106/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91;P  < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 × 106 cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P  = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24–2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62–5.63) for subjects with CD4 lymphocyte counts > 200 × 106/l and 1.5 (95% CI, 0.99–2.40) for subjects with a CD4 lymphocyte count of 200 × 106/l or fewer. ConclusionThe findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.

Clinical Management of Keratoconus: A Multicenter Analysis

The clinical management of 746 eyes in 417 patients referred for keratoconus from January 1984 through January 1988 was retrospectively analyzed. In 357 patients, 554 eyes (74%) did not require surgery and were managed with contact lenses or spectacles, 156 eyes (21%) in 137 patients either underwent penetrating keratoplasty (PK) (140 eyes) or surgery was recommended (16 eyes), and 36 eyes (4%) in 34 patients underwent epikeratoplasty. Comparing baseline and final examination findings, the nonsurgical group showed a significant improvement in average best-corrected visual acuity from 20/30 to 20/25, the PK group from 20/70 to 20/25, and the epikeratoplasty group from 20/40 to 20/30. Average keratometry was unchanged in the nonsurgical group, but decreased by 10.7 diopters (D) for the PK group and 6.5 D for the epikeratoplasty group. Corneal cylinder was unchanged in the nonsurgical group, whereas there was a reduction of the percentage of eyes with indeterminant cylinder from 55 to 2% in the PK group and from 36 to 0% in the epikeratoplasty group. Previous contact lens history, best-corrected visual acuity of 20/50 or worse, and average keratometry of 55 D or greater at baseline were associated with a significant risk for PK. No baseline variables were associated with significant risk for epikeratoplasty, suggesting that this group was similar to the nonsurgical group, except for contact lens intolerance. The nonsurgical management of keratoconus continues to play a predominant role in the management of this disorder in a referral population.

Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults

BackgroundTreatment of latent infection is needed to protect HIV-infected individuals against tuberculosis. A previous report addressed short-term efficacy of three regimens in HIV-infected adults. We now report on long-term efficacy of the study regimens. MethodsThree daily self-administered regimens were compared in a randomized placebo-controlled trial in 2736 purified protein derivative (PPD)-positive and anergic HIV-infected adults. PPD-positive subjects were treated with isoniazid (INH) for 6 months (6H), INH plus rifampicin for 3 months (3HR), INH plus rifampicin and pyrazinamide for 3 months (3HRZ), or placebo for 6 months. Anergic subjects were randomized to 6H or placebo. Results6H initially protected against tuberculosis in PPD-positive individuals; however, benefit was lost within the first year of treatment. Sustained benefit was observed in persons receiving 3HR and 3HRZ. In a Cox regression analysis, the adjusted relative risk for tuberculosis compared with placebo was 0.67 [95% confidence interval (CI), 0.42–1.07] for 6H, 0.49 (95% CI, 0.29–0.82) for 3HR, and 0.41 (95% CI, 0.22-0.76) for 3HRZ. When the rifampicin-containing regimens were combined, the adjusted relative risk for tuberculosis compared with placebo was 0.46 (95% CI, 0.29–0.71). Among anergic subjects, a modest degree of protection with 6H was present (adjusted relative risk, 0.61; 95% CI, 0.32–1.16). Treatment of latent tuberculosis infection had no effect on mortality. ConclusionSix months of INH provided short-term protection against tuberculosis in PPD-positive HIV-infected adults. Three month regimens including INH plus rifampicin or INH, rifampicin and pyrazinamide provided sustained protection for up to 3 years.

Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients

Active TB in HIV‐1‐infected subjects is associated with increased HIV‐1‐related immunodeficiency and mortality. We assessed plasma viral load in HIV‐1‐infected patients with pulmonary TB (HIV/TB) and non‐TB symptomatic HIV‐1‐infected patients (HIV). HIV‐1 load was higher in HIV/TB compared with HIV at higher CD4 counts (> 500/μl) (P < 0·01), but not at lower CD4 counts (< 500/μl). We also evaluated the status of HIV‐1 gene expression in peripheral blood mononuclear cells (PBMC) and serum from HIV/TB and CD4‐matched healthy HIV‐infected patients (HIV/C) by reverse transcriptase‐polymerase chain reaction over a range of CD4 (> 900/μl to < 200/μl). HIV‐1 RNA in serum and PBMC correlated to one another, and both were markedly higher in HIV/TB compared with HIV/C with higher CD4 counts. Also, during a longitudinal study of anti‐tuberculous chemoprophylaxis in HIV‐1‐infected patients, 10 subjects who developed TB had serologies before, at the time, and after the diagnosis of TB. These HIV/TB patients had an increase in viral load (average 2·5‐fold) at the time of diagnosis of TB (P < 0·05). Overall, these data indicate that the transcriptional activity of HIV‐1 is enhanced in HIV‐1‐infected patients with active TB, especially during early HIV‐1 disease. As TB often is an early HIV‐1 opportunistic infection, it may particularly favour early viral replication and dissemination, and therefore contribute to progression of HIV‐1 disease.

The bleeding severity index: Validation and comparison to other methods for classifying bleeding complications of medical therapy

Reports of bleeding complications of medical therapy should be based on valid methods of classification, but the reproducibility of existing methods has not been tested. Therefore, we prospectively studied three methods to classify the severity of bleeding: a purely subjective implicit method, a previously published explicit method using brief criteria, and the bleeding severity index, which is a new explicit method using detailed criteria about the amount, rate, and consequences of bleeding. Three physicians independently reviewed abstracts of 168 patients treated with anticoagulants. The proportion of cases classified as major bleeding varied widely when the implicit method was used (2, 14 and 39%), less when the old explicit method was used (28, 40 and 47%), and not at all when the new bleeding severity index was used (20, 20 and 20%). Intraobserver agreement was excellent for both explicit methods (kappa greater than or equal to 0.95). However, interobserver agreement was better for the bleeding severity index (kappa = 0.87) than for the old explicit method (kappa = 0.69) or the implicit method (kappa = 0.39). We conclude that the classification of bleeding complications of medical therapy depends on the method used. In comparison to older methods, the bleeding severity index is highly reproducible and should be tested more widely to determine whether it can be applied to the burgeoning clinical research in anticoagulation and thrombolysis.

Immunogenicity of a Recombinant Human Immunodeficiency Virus (HIV)–Canarypox Vaccine in HIV-Seronegative Ugandan Volunteers: Results of the HIV Network for Prevention Trials 007 Vaccine Study

In the first preventative human immunodeficiency virus (HIV) vaccine study to be carried out in Africa, 40 HIV-seronegative Ugandan volunteers were randomly assigned to receive a canarypox vector containing HIV-1 clade B (env and gag-pro) antigens (ALVAC-HIV; n = 20), control vector containing the rabies virus glycoprotein G gene (n = 10), or saline placebo (n = 10). Cytotoxic T lymphocyte activity against target cells expressing clade A, B, and D antigens was assessed using standard chromium-release and confirmatory interferon-gamma enzyme-linked immunospot (ELISPOT) assays. Neutralizing antibody responses to cell line-adapted strains and primary isolates in all 3 clades were also tested. Twenty percent of vaccine recipients generated detectable cytolytic responses to either Gag or Env, and 45% had vaccine-induced HIV-specific CD8(+) T cell responses, as measured by the ELISPOT assay. In contrast, only 5% of the control group had vaccine-specific responses. Neutralizing antibodies against primary and laboratory-adapted HIV-1 clade B strains were seen in 10% and 15% of vaccine recipients, respectively, but responses against clades A and D were not detected. Although the immunogenicity of this clade B-based vaccine was low, ALVAC-HIV elicited CD8(+) T cell responses with detectable cross-activity against clade A and D antigens in a significant proportion of vaccine recipients.

Randomized Controlled Trial of Mycobacterium vaccae Immunotherapy in Non-Human Immunodeficiency Virus-Infected Ugandan Adults with Newly Diagnosed Pulmonary Tuberculosis

Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, placebo-controlled trial of 120 non-human immunodeficiency virus-infected adults with newly diagnosed pulmonary tuberculosis. Patients were randomized to a single dose of M. vaccae or placebo 1 week after beginning chemotherapy and were followed up for 1 year. M. vaccae was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group and only 14% in the placebo group (P = .01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P = .04) and 12 months (94% vs. 80%; P = .04) after initiation of tuberculosis treatment. These data provide evidence of an early increase in sputum culture conversion and greater radiographic improvement among patients who received M. vaccae. Further studies are warranted.

Site of disease and opportunistic infection predict survival in Hiv-associated tuberculosis

Objective:Infection with HIV adversely affects survival in patients with tuberculosis (TB), even when TB is effectively treated. The aim of this study was to identify the determinants of survival in HIV-associated TB. Design:Retrospective cohort study. Setting:Four US academic medical centers. Patients:An inception cohort of 112 HIV-infected patients (mean age 41 years, 96% men, 46% African American) with their first episode of culture-proven TB. Outcome measures:Observed survival from the date of diagnosis of TB to the date of death or censoring. Independent variables included demographics, HIV-related conditions, risk behavior for HIV, absolute CD4+ counts, and site of disease with Mycobacterium tuberculosis. Results:Of the 112 patients, 54 (48%) had pulmonary TB alone, 36 (32%) had both pulmonary and extra-pulmonary TB and 22 (20%) had extrapulmonary TB alone. Median CD4+ count was 95 × 106/l (range, 2–767 × 106/l). During follow-up, 45 patients (40%) died. Median survival was shortest in patients with both pulmonary and extrapulmonary disease (8.4 months), followed by extrapulmonary disease alone (15.6 months), then pulmonary disease (30.4 months; P < 0.001, log-rank test). Median survival was also reduced in patients with previous opportunistic infection and in those with CD4+ < 200 × 106/l. In a proportional hazards regression analysis, which adjusted for CD4+ count, extrapulmonary disease and previous opportunistic infection were the only factors independently associated with shorter survival. Of the extrapulmonary sites of disease, TB meningitis was associated with the greatest risk of death. Conclusion:The site of culture-proven TB at presentation and the history of previous opportunistic infection are important predictors of survival in HIV-infected patients with TB.