Search

Redefinition of the disease AIDS because the range of biologic agents capable of infecting persons with the disease is now known to be much broader than the original 12 included in the initial definition of AIDS. New definition of AIDS by the Centers for Disease Control; review of the principal pathogens associated with the end-stage HIV (human immunodeficiency virus) immunosuppressions (AIDS) as well as milder forms.

In 2018, the Bill and Melinda Gates Foundation convened over thirty subject matter experts in clinical development, manufacturing, and regulatory assessment to determine how the development and approval of medical countermeasures could be accelerated in the event of Disease X. Disease X is the result of a presently unknown pathogen with epidemic or pandemic potential. A key opportunity to accelerate the scientific assessment and regulatory approval of medical countermeasures exists within efficient navigation of facilitated regulatory pathways. It was identified that not all stakeholders will be able to skillfully navigate the facilitated pathways offered by the various regulatory agencies during a public health emergency. To democratize this knowledge, we have written an overview of the facilitated approaches which have been developed and refined by Stringent Regulatory Authorities and the World Health Organization for the primary assessment of medical products. We discuss the conditions necessary for use of these approaches, scenarios in which certain pathways may be applicable, and the pros and cons of these approaches. We also address opportunities available to developers in, or developers who wish to access, low-income countries that may have nascent regulatory frameworks., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

The pharmacokinetics of pyrazinamide (PZA) in patients with human immunodeficiency virus (HIV)-related tuberculosis are incompletely characterized. Serum PZA concentrations were determined at 2, 6, and 10 h after dosing in 48 subjects with HIV-related tuberculosis. Estimates of drug exposure using 2-h concentrations and 2- and 3-time point estimates of area under time-concentration curves (AUCs) were compared. For daily dosing, 2-h concentrations less than low and very low literature-defined cut points (i.e., 20 and 10 mg/L) were noted for 2 subjects (4%) and 1 subject (2%), respectively. For intermittent PZA dosing, 1 subject (4%) had a 2-h concentration that was less than the low cut point (25 mg/L). Correlations between 2-h concentration and AUC estimates based on 2- or 3-time point concentration determinations were strong. In HIV-infected persons receiving antituberculosis regimens containing PZA, lower-than-expected 2-h concentrations are uncommon. For therapeutic monitoring of PZA drug exposure, determination of a 2-h postdose concentration appears as reliable as 2- or 3-time point estimates of the AUC for PZA.

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

Objectives: To determine differences in rates of reactivity to purified protein derivative (PPD) tuberculin and of skin test anergy in relationship to serostatus, immune status, demographic characteristics, and other risk factors in women infected with or at high risk for infection with HIV-1; and to compare the usefulness of three different antigens in assessing delayed type hypersensitivity., Design/methods: Cross-sectional analysis of baseline data in a multicenter prospective cohort study of 1343 HIV-1-seropositive and 390 seronegative but at-risk women recruited from sites of HIV primary care and through community-based outreach for a longitudinal cohort study., Results: 4.7% of the 1343 HIV-1-seropositive women and 15.4% of the 390 HIV-seronegative women were tuberculin-positive (p < .001). A lower threshold in millimeters of induration for tuberculin reactivity among HIV-seropositive women resulted in a smaller difference between the seropositive and the seronegative groups. Even when a 2-mm threshold was used in HIV-seropositive respondents, with a 10-mm threshold among seronegative participants, the difference between the seropositive (6.9% reactive) and the seronegative (15.4% reactive) groups remained statistically significant (p < .001). Limiting analysis to women who responded to the non-PPD antigens did not eliminate the differences in PPD reactivity between the HIV-seropositive and HIV-seronegative women. In multivariate analysis, tuberculin reactivity was associated with HIV-negative serostatus, a history of tuberculosis infection or disease, geographic site, and CD4 count >200 cells/mm3 in the HIV-seropositive women. In all, 41% of HIV-seropositive women and 12% of seronegative women were anergic (p < .001). Candida antigen had the lowest response rates. In multivariate analyses, only HIV-serostatus and CD4 cell counts in HIV-seropositive women were significantly associated with anergy., Conclusions: In this community-based cohort of HIV-seropositive and HIV-seronegative women, we found significant differences between the seronegative and seropositive women even with a lower threshold of induration defining PPD reactivity among seropositive women and among women not anergic to the non-PPD antigens. Prevalence of PPD reactivity was higher than in previously described in cohorts of homosexual men, but lower than in cohorts of predominantly male injection drug users. Rates of anergy were similar to those in most previously described cohorts.

Setting: Mortality associated with human immunodeficiency virus (HIV) related multidrug-resistant tuberculosis (MDR-TB) is reduced with effective early therapy. Identifying predictors of, and effective regimens for, MDR-TB is critical., Objective: A multicenter prospective study was initiated to 1) determine the demographic, behavioral, clinical and geographic risk factors associated with the occurrence of MDR-TB among HIV-infected patients, and 2) to evaluate the overall survival and clinical response of MDR-TB patients treated with specific drug regimens., Methods: Patients were prospectively evaluated for MDR-TB. Information included history of prior treatment for tuberculosis, close contact with a known case of MDR-TB, and residence in a facility with known or suspected MDR-TB transmission. Patients with known MDR-TB, or those suspected to be at high risk, were offered enrollment in a treatment pilot study. Study drugs included levofloxacin and at least two additional drugs to which the patient's isolate was known, or most likely, to be susceptible. Survival was the primary endpoint., Results: Complete data are available for 156 HIV-infected patients with confirmed tuberculosis. Sixteen (10%) had MDR-TB. Only a history of prior tuberculosis treatment was associated with MDR-TB in multivariate analysis (OR = 4.4, P < 0.02). Twelve patients with MDR-TB enrolled in the treatment pilot had a median CD4 cell count of 51/mm3. The cumulative probability of survival at one year was 75% (95% CI 50.5-99.5) and at 18 months, 65.6% (95% CI 38.1-93.1). Toxicity requiring discontinuation of medications occurred in two patients., Conclusions: A history of treatment for tuberculosis was the only predictor for MDR-TB in a cohort of HIV-infected patients with tuberculosis. In addition, this prospective study supports the results of prior retrospective studies that effective treatment impacts on mortality. Current second-line treatment, including high dose levofloxacin, appears to be reasonably well tolerated.

Background: A growing proportion of AIDS cases in the United States are due to heterosexual transmission of HIV, particularly in women. The risk of heterosexually acquired HIV was prospectively studied in a cohort of inner-city women with no history of parenteral drug use., Methods: Study participants were evaluated at 6-month intervals for the presence of HIV antibody, sexually transmitted diseases, self-reported sexual behavior, and drug use by self-report and urine screening., Results: Of 449 initially HIV-negative women who were seen at least once in follow-up, 4 seroconverted to HIV, with a cumulative incidence of 2.4% at 30 months. Risk factors for HIV seroconversion included nonparenteral drug use (p < .02) and anal intercourse (p < .01). Sexually transmitted diseases were not associated with HIV, although the power to detect such an association was limited. In addition, 3 of 4 seroconverters became pregnant, yielding a rate of 55.5 pregnancies/100 person-years of follow-up compared with a rate of 11.1 pregnancies/100 person-years of follow-up in nonseroconverters (p < .03)., Conclusion: The incident rate of heterosexually acquired HIV in this inner-city U.S. cohort of women who were not using parenteral drugs is comparable with that reported in some developing countries where heterosexually acquired HIV is endemic. Most seroconversions appeared related to risk behavior seen in association with nonparenteral drug use. The previously unreported association of incident HIV infection with pregnancy in this cohort may be related to either behavioral or biologic factors.

This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates.

Objective: To characterize the susceptibility to levofloxacin of clinical isolates of Mycobacterium tuberculosis (MTB) obtained from patients with HIV-related tuberculosis and to characterize the molecular genetics of levofloxacin resistance., Design and Methods: Isolates from culture-positive patients in a United States multicenter trial of HIV-related TB were tested for susceptibility to levofloxacin by minimum inhibitory concentration (MIC) determinations in Bactec 7H12 broth. Automated sequencing of the resistance determining region of gyrA was performed., Results: Of the 135 baseline MTB isolates tested, 134 (99%; 95% exact binomial confidence interval, 95.9-99.9%) were susceptible to levofloxacin with an MIC < or = 1.0 microg/ml. We identified a previously unrecognized mis-sense mutation occurring at codon 88 of gyrA in a levofloxacin mono-resistant MTB isolate obtained from a patient with AIDS who had received ofloxacin for 8 months prior to the diagnosis of tuberculosis., Conclusions: Clinical MTB isolates from HIV-infected patients were generally susceptible to levofloxacin. However, the identification of a clinical isolate with mono-resistance to levofloxacin highlights the need for circumspection in the use of fluoroquinolones in the setting of potential HIV-related tuberculosis and for monitoring of rates of resistance of MTB isolates to fluoroquinolones.

Our aim was to evaluate the effect of human immunodeficiency virus (HIV) disease stage on chest radiographic (CXR) findings among patients with HIV-related pulmonary tuberculosis (TB). Data are from a prospective multicenter treatment trial for HIV-related TB. Baseline CXR findings and CD4+ lymphocyte counts were compared among patients with HIV-related TB. Data from published studies describing CXR findings in HIV-infected patients were reviewed and a pooled-data analysis was conducted. Of 135 patients with culture-confirmed HIV-related TB, 128 had both CXR and CD4+ lymphocyte data. CD4+ lymphocyte counts of < 200/mm3 (n = 98) were significantly associated with hilar/mediastinal adenopathy on CXR (30%, vs. 7% with counts > or = 200/mm3; P = .01); counts of > or = 200/mm3 (n = 30) more frequently were associated with cavitation (20% vs. 7%; P = .08). Analyses of these results, pooled with other published data, confirmed these findings. This study demonstrates associations of certain CXR findings with HIV disease stage. Knowledge of the degree of immunosuppression is important when evaluating CXR findings in HIV-infected patients.

Setting: Incident patients with active tuberculosis (TB) resistant to two or more drugs in New York City hospitals in 1992., Objective: To examine the New York-wide distribution of Public Health Research Institute (PHRI) strain W of Mycobacterium tuberculosis, an extremely drug-resistant strain identified by a 17-band Southern hybridization pattern using IS6110, during the peak tuberculosis year of 1992. We also compared strain W with other strains frequently observed in New York., Design: Blinded retrospective study of stored M. tuberculosis cultures by restriction fragment length polymorphism (RFLP) DNA fingerprinting, and chart review., Results: We found 112 cultures with the strain W fingerprint and 8 variants in 21 hospitals among incident patients hospitalized in 1992. Almost all isolates were resistant to four first-line drugs and kanamycin. This single strain made up at least 22% of New York City multiple-drug-resistant (MDR) TB in 1992, far more than any other strain. Almost all W-strain cases were acquired immune deficiency syndrome (AIDS) patients. The cluster is the most drug-resistant cluster identified in New York and the largest IS6110 fingerprint cluster identified anywhere to date., Conclusion: Because recommended four-drug therapy will not sterilise this very resistant strain, there was a city-wide nosocomial outbreak of W-strain TB in the early 1990s among New York AIDS patients. Other frequently seen strains were either also very resistant, or, surprisingly, pansusceptible. Individual MDR strains can be spread widely in situations where AIDS and TB are both common.

To assess whether HIV infection is associated with menstrual abnormalities in HIV-infected women without AIDS, we evaluated 248 premenopausal HIV-infected women without AIDS and 82 HIV-negative women. Detailed medical, drug use, and menstrual histories (using menstrual calendars) were obtained. Complete physical and pelvic examinations and CD4 counts were performed. HIV-infected women were more likely to experience intervals > 6 weeks without menstrual bleeding [8 vs. 0%, odds ratio (OR) = 10.8, 95% confidence interval (CI) 1.8-1,000) and amenorrhea > 3 months (5 vs. 0%, OR = 7.1, 95% CI 1.1-1,000) (after adjustment for drug use, age, and race). Premenstrual breast swelling (p = 0.01), tenderness (p = 0.01), and dysmenorrhea (p = 0.04) were less common in HIV-infected women. There were no differences in intermenstrual bleeding or irregular menstrual cycles. Among HIV-infected women, only a past history of substance abuse was significantly associated with menstrual irregularities in a logistic regression model adjusting for age, current and past drug use, alcohol use, cigarette smoking, CD4 count, and category B conditions [1993 Centers for Disease Control (CDC) classification system]. The increase in amenorrhea (> 3 months) and in menstrual cycle intervals > 6 weeks and the lower rates of premenstrual breast symptoms in HIV-positive women suggest the possibility of disturbances in menstrual function that do not appear to be attributable to clinically apparent secondary complications of HIV. Changes in menstrual function were also significantly associated with a past history of, but not current, substance abuse, suggesting the possibility that socioeconomic factors rather than biologic effects of drugs may be responsible.

Objective: To compare the prevalence of genital herpes simplex virus type 2 (HSV-2) shedding in human immunodeficiency virus (HIV)-seropositive women and HIV-seronegative women., Design: Cross-sectional study., Setting: A major inner-city medical center., Patients: 106 women who were HIV-seropositive and HSV-2-seropositive and 70 women who were HIV-seronegative and HSV-2-seropositive were enrolled from various primary care settings., Measurements: Herpes simplex virus type 2 antibody determinations were done for all patients. Regardless of symptoms, vulvar and cervical HSV cultures were obtained from all HIV-seropositive women and from a randomly selected subgroup of HIV-seronegative women., Results: The prevalence of HSV-2 shedding was nearly four times greater in HIV-seropositive than in HIV-seronegative women (13.2% compared with 3.6%; P = 0.04; odds ratio, 4.1 [95% CI, 1.0 to 27.4]) when the serum antibody for HSV-2 was present. Seventy-nine percent of viral shedding among HIV-seropositive women was asymptomatic. Overall viral shedding increased significantly as the CD4 cell count decreased., Conclusions: Women with HIV infection, particularly those with low CD4 cell counts, shed HSV-2 from the vulva and cervix more commonly than women not infected with HIV. Most of this shedding is asymptomatic.

Voided urine samples from persons with and without human immunodeficiency virus (HIV) infection were examined for mycoplasmas. Mycoplasma hominis organisms were identified in cultures of urine from 32 (18%) of 180 HIV-positive individuals and from 8 (21%) of 38 HIV-negative individuals. In contrast, glucose-utilizing mycoplasmas were identified in the urine of 30 (17%) of the HIV-positive individuals and in none of those who were HIV-negative. Assays of growth inhibition around disks containing specific antisera identified 14 of the 30 glucose-utilizing mycoplasmas as Mycoplasma fermentans. Four isolates were presumptively identified as Mycoplasma pirum. Growth on solid media was insufficient to permit the identification of the species of the other 12 isolates by growth inhibition.

From October 1987 to June 1988, we attempted to determine the prevalence of HIV infection among patients hospitalized with tuberculosis and the extent of immunosuppression among those tuberculosis patients infected with HIV. Of 178 consecutive patients, 18-65 years of age, who were hospitalized with newly diagnosed, previously untreated tuberculosis, 46% (82 out of 178) had clinical or serological evidence of HIV infection, 30% (54 out of 178) were HIV-seronegative, and 24% (42 out of 178) could not be assessed for the presence of HIV infection. Among the HIV-seropositive patients without an AIDS-defining diagnosis by non-tuberculous criteria, the median CD4 lymphocyte (CD4) count was 133 x 10(6) cells/l (range: 11-677 x 10(6]; among the HIV-seronegative patients, the median CD4 count was 613 x 10(6) cells/l (range: 238-1614 x 10(6); P less than 0.001). Among the HIV-seropositive patients, those with disseminated tuberculosis (median CD4 = 79 x 10(6) cells/l) and those with pulmonary tuberculosis who had radiographic evidence of mediastinal or hilar adenopathy (median CD4 = 45 x 10(6) cells/l) had the most severe CD4 depletion, whereas those with localized extrapulmonary tuberculosis (median CD4 = 242 x 10(6) cells/l) and those with pulmonary tuberculosis without adenopathy (median CD4 = 299 x 10(6) cells/l) were less severely immunosuppressed. Of the 178 patients, 6% (11 out of 178) were infected with strains of Mycobacterium tuberculosis resistant to both isoniazid and rifampin.

Children with sickle cell disease and acute chest syndrome were investigated for infection with Chlamydia pneumoniae and Mycoplasma pneumoniae. Of 30 patients who had 32 episodes of acute chest syndrome, four (13%) had C. pneumoniae isolated from the nasopharynx; two of these also had serologic evidence of acute infection, and one had positive nasopharyngeal isolates on two subsequent occasions during the course of 1 year with stable, elevated titers of anti-C. pneumoniae IgG, suggesting chronic infection. Two patients with negative cultures had serologic evidence of infection with C. pneumoniae. None of 32 cultures for M. pneumoniae were positive, and although anti-M. pneumoniae IgM developed in two patients, one of these patients had evidence of C. pneumoniae infection (positive culture and seroconversion). We conclude that C. pneumoniae infection is prevalent in our sickle cell population with acute chest syndrome. Until further studies clarify the pathophysiologic significance of C. pneumoniae infection, we believe that early inclusion of erythromycin as antimicrobial therapy for acute chest syndrome seems reasonable.

Pneumocystis carinii has taken on new importance with the emergence of the human immunodeficiency virus. It is the most common life-threatening opportunistic infection in the acquired immunodeficiency syndrome and eventually develops in 80% or more of those not receiving primary prophylaxis. This review focuses on the clinical presentation, diagnosis, treatment, and prophylaxis of P carinii pneumonia in patients with human immunodeficiency virus infection.

The number of intravenous drugs users (IVDUs) developing end-stage renal disease at our institution increased 400% between 1981 and 1987. During this period the total number of IVDUs in our catchment area remained stable and referral patterns to our hospital were unchanged. A serologic, clinical and risk-factor survey for HIV infection was conducted in our maintenance hemodialysis unit with the objective of evaluating the interrelationship between HIV infection and the increasing incidence of renal failure in IVDUs. The risk of nosocomial transmission of HIV in a hemodialysis unit with an expected high prevalence of infection was also investigated. The effect of HIV seropositivity on the clinical course of patients receiving maintenance hemodialysis was evaluated prospectively. Twenty-seven (39%) out of 70 maintenance hemodialysis patients tested were seropositive for HIV. Twenty-three (88%) out of 26 IVDUs receiving dialysis were seropositive for HIV. Despite marked CD4 cell depletion (mean CD4 cell count 225), none of the seropositive patients had AIDS when first evaluated and only one developed AIDS during 12 months of follow-up. None of the dialysis staff members or dialysis patients without HIV risk factors was seropositive for HIV. IVDUs who develop end-stage renal disease appear to have a high rate of infection with HIV. We can expect that the number of HIV-infected dialysis patients will continue to increase. Fortunately, even in a high prevalence hemodialysis unit, the risk of nosocomial transmission of HIV appears to be low.

A preliminary study of 86 patients undergoing maintenance hemodialysis in an urban unit serving a large number of intravenous drug addicts revealed that the HIV seroprevalence rate was 27% (27 of 70 screened). Twenty-three of 26 (89%) positive patients were intravenous addicts, and the remaining four included Haitian immigrants and gay men. There were no false positive ELISA reactions against HIV. No patient without a risk factor for HIV was seropositive, indicating an absence of nosocomial spread within a dialysis unit.