Developing WHO guidelines with pragmatic, structured, evidence-based processes: A case study.

Many guidelines, including those produced by the World Health Organisation (WHO), have failed to adhere to rigorous methodological standards. Operational examples of guideline development processes may provide important lessons learned to improve the rigour and quality of future guidelines. To this end, this paper describes the process of developing WHO guidelines on prevention and care interventions for adults and adolescents living with HIV. Using a pragmatic, structured, evidence-based approach, we created an organising committee, identified topics, conducted systematic reviews, identified experts and distributed evidence summaries. Subsequently, 55 global HIV experts drafted and anonymously submitted guideline statements at the beginning of a conference. During the conference, participants voted on statements using scales evaluating appropriateness of the statements, strength of recommendation and level of evidence. After review of voting results, open discussion, re-voting and refinement of statements, a draft version of the guidelines was completed. A post-conference writing team refined the guidelines based on pre-determined guideline writing principles and incorporated external comments into a final document. Successes and challenges of the guideline development process were identified and are used to highlight current issues and debates in developing guidelines with a focus on implications for future guideline development at WHO.

Viral load as an independent risk factor for opportunistic infections in HIV-infected adults and adolescents.

OBJECTIVE: We investigated whether HIV plasma RNA (viral load; VL) predicts risk for opportunistic infections (OI) in HIV-infected persons, independent of CD4 lymphocyte count and other factors that might affect disease outcome. METHODS: Among persons who had initiated antiretroviral therapy (ART), we studied the risk for OI following a VL measurement in the Centers for Disease Control and Prevention Adult and Adolescent Spectrum of HIV Disease (ASD) Project, a medical record review study of HIV-infected persons in 11 US cities. Analysis was limited to persons who had initiated ART and who had VL data, primarily from the period 1996-1999. Persons were considered at risk for OI for 1 to 6 months after a given VL; risk for OI was assessed using a Poisson multiple regression model controlling for CD4 lymphocyte count, ART, and other variables potentially associated with development of OI: history of AIDS OI, age, sex, race, HIV risk category, OI prophylaxis, and calendar year. RESULTS: Although decreasing CD4 count was the strongest predictor of risk for OI [relative risk (RR), 13.3 for persons with CD4 lymphocyte count < 50 x 10(6)/l compared with persons with CD4 lymphocyte count > or = 500 x 10(6)/l], increasing VL was independently associated with increased risk [RR, 1.6, 1.9, 2.7, and 3.5 for VL of 7000-19 999, 20 000-54 999, 55 000-149 999, and > or = 150 000 copies/ml (by reverse transcription-PCR), respectively, compared with VL < 400]. Similar results were obtained when the risk period was reduced to 5, 4, 3, and 2 months after VL measurement. CONCLUSIONS: VL is an independent risk factor for OI and should be considered in special situations, such as in decisions to discontinue primary or secondary OI prophylaxis after CD4 lymphocyte counts have increased in response to ART.

Prophylaxis with trimethoprim-sulfamethoxazole for human immunodeficiency virus-infected patients: impact on risk for infectious diseases.

Trimethoprim-sulfamethoxazole (TMP-SMZ) is widely prescribed as prophylaxis for Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)-infected persons. Its efficacy against other infections has not been thoroughly evaluated. To compare the risk for infectious diseases for persons who were prescribed TMP-SMZ with that for patients who were not prescribed TMP-SMZ, we examined data collected from the medical records of HIV-infected patients (January 1990 through September 1999) who were enrolled in the Adult and Adolescent Spectrum of HIV Disease Project. During intervals when patients had CD4(+) T lymphocyte counts of <200 cells/microL (19,081 persons; 22,801 person-years), prescription of TMP-SMZ was associated with significant protection from toxoplasmosis, salmonellosis, infection with Haemophilus species, invasive or any staphylococcal infection, and PCP, but not from Shigella, pneumococcal or nonpneumococcal Streptococcus, Klebsiella, or Pseudomonas species. We demonstrate that prescription of TMP-SMZ for PCP prophylaxis in persons with HIV infection is associated with significantly decreased risk for several infectious diseases. These findings may be of interest to HIV prevention programs in resource-poor countries.

Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination.

To determine the factors associated with pneumococcal disease (pneumococcal pneumonia or invasive disease) and the impact of pneumococcal vaccine in HIV-infected persons, we analyzed patient data collected by the Adult and Adolescent Spectrum of HIV Disease Project for person-time between January 1990 and December 1998. Among 39,086 persons with 71,116 person-years (py) of observation, 585 episodes of pneumococcal disease were diagnosed (incidence, 8.2 episodes per 1000 py). Factors associated with an increased risk for pneumococcal disease (P < .05) included injection drug use (adjusted relative risk [RR], 1.5) and blood transfusion (RR, 2.0) as the mode of HIV transmission (referent, male-male sex); black race/ethnicity (RR, 1.5; referent, white race); history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness (RR, 2.1); a CD4(+) cell count of 200-499 cells/microL (RR, 2.5) or < 200 cells/microL (RR, 3.7; referent, CD4(+) cell count of > or = 500 cells/microL); and alcoholism (RR, 2.0). Factors associated with a decreased risk included prescription of antiretroviral therapy (RR for monotherapy, 0.6; for dual therapy, 0.7; for triple therapy, 0.5) and pneumococcal vaccination (RR for persons vaccinated at a CD4(+) cell count of > or = 500 cells/microL, 0.5). We recommend that pneumococcal vaccine be given to HIV-infected persons before profound immunosuppression has occurred.

Preventing opportunistic infections among human immunodeficiency virus-infected adults in African countries.

The burden of human immunodeficiency virus (HIV)-related disease in sub-Saharan Africa continues to increase; providing adequate care for the huge number of people affected is a daunting task, especially given the limited resources available. Recent studies have shown that low-cost regimens can prevent some of the most important causes of HIV-related disease in African countries. Isoniazid preventive therapy can reduce the incidence of tuberculosis; priorities are to seek opportunities for implementation, to assess effectiveness under operational conditions, and to monitor its effect on resistance patterns. Cotrimoxazole was shown to be highly effective in reducing morbidity and mortality among individuals with symptomatic HIV disease in Côte d'Ivoire, and should be implemented where it is likely to be of benefit. Pneumococcal polysaccharide vaccine was disappointingly ineffective among HIV-infected Ugandan adults, but newer conjugate vaccines are becoming available that should be investigated. The benefit of these preventive regimens to the individual may be modest when compared with the effect of antiretroviral therapy. However, simple preventive therapies could reach a much wider population than is immediately feasible for expensive and complex antiretroviral regimens, and thus have the potential for substantial benefit at the population level. The availability of effective and affordable regimens to prevent HIV-related disease may also encourage people to seek HIV testing, combat denial, and help overcome the sense of powerlessness in countries where the HIV epidemic has hit hardest.

Effect of clinical events on plasma HIV-1 RNA levels in persons with CD4+ T-lymphocyte counts of more than 500 x 10(6) cells/l.

OBJECTIVE: Immune stimulation of CD4 lymphocytes is thought to enhance HIV-1 replication in vivo. Therefore, we sought to define the impact of clinical events identified as putative immune activators on the variability of plasma HIV-1 RNA levels in persons with CD4 cell counts greater than 500 x 10(6) cells/l. DESIGN: We prospectively recorded clinical events and measured plasma HIV-1 RNA levels weekly for 24 weeks in 16 HIV-1-infected adults who were not receiving antiretroviral therapy and who had CD4 cell counts greater than 500 x 10(6) cells/l. METHODS: Standard weekly interviews were conducted to capture potential immune activators (e.g., infections, immunizations, and allergic reactions). All plasma HIV-1 RNA levels were measured using the Amplicor HIV-1 Monitor assay (Roche Diagnostics, Branchburg, New Jersey, USA) according to the manufacturer's instructions. RESULTS: Participants had remarkably stable viral loads during the 6 month study period. Infections were significantly more frequent during the 7 days prior to individual HIV-1 RNA measurements that exceeded the assay variation thresholds determined for this study (+/- 0.324 log) than during the comparable time periods preceding stable measurements (P = 0.023). As a group, the eight participants who had one to four HIV-1 RNA measurements that exceeded the thresholds experienced more infections and declining CD4 cell counts over the study course compared to the eight participants whose measurements all fell within the thresholds (P = 0.058 and 0.053 respectively). CONCLUSIONS: Our study suggests that in untreated HIV-1-infected persons with CD4 cell count greater than 500 x 10(6) cells/l, viral load is generally quite stable, although acute minor infections are associated with transient fluctuations generally lasting no more than 1 week.

Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds.

To determine incidence and risk for preventable opportunistic infections (Pneumocystis carinii pneumonia [PCP] and disseminated Mycobacterium avium-complex [MAC] infection) in persons whose CD4(+) T lymphocyte counts had increased by >/=100 cells/microL to exceed the threshold of risk and in persons whose CD4(+) counts had never dropped below the threshold of risk, we analyzed data collected during the period 1990-1998 in the Adult/Adolescent Spectrum of HIV (Human Immunodeficiency Virus) Disease Project. Using a counting-process formulation of the Cox model, we analyzed observation time in these 2 groups for persons who were prescribed antiretroviral therapy but not prophylaxis. The incidences of the infections were low for patients whose CD4(+) count rose above the threshold of risk (PCP, 0.6 cases per 100 person-years [PY]; MAC, 1. 0 cases per 100 PY) and not higher than in persons whose CD4(+) counts had not decreased below these thresholds, which suggests that discontinuation of primary prophylaxis for opportunistic infections may be considered for some patients.

Introduction to the 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.

Opportunistic infections (OIs) are well recognized to produce substantial morbidity and mortality among patients with HIV infection. Since measures are available for reducing the incidence and the impact of these processes for patients, the United States Public Health Service and the Infectious Diseases Society of America, with endorsing professional societies, have developed guidelines for implementing a comprehensive strategy to prevent these OIs. These guidelines have been developed by a diverse working group of expert health care providers and patient representatives in order to synthesize available data and to provide practical advice for health care practitioners and patients.

Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy.

The incidence of nearly all AIDS-defining opportunistic infections (OIs) decreased significantly in the United States during 1992-1998; decreases in the most common OIs (Pneumocystis carinii pneumonia ¿PCP, esophageal candidiasis, and disseminated Mycobacterium avium complex ¿MAC disease) were more pronounced in 1996-1998, during which time highly active antiretroviral therapy (HAART) was introduced into medical care. Those OIs that continue to occur do so at low CD4+ T lymphocyte counts, and persons whose CD4+ counts have increased in response to HAART are at low risk for OIs, a circumstance that suggests a high degree of immune reconstitution associated with HAART. PCP, the most common serious OI, continues to occur primarily in persons not previously receiving medical care. The most profound effect on survival of patients with AIDS is conferred by HAART, but specific OI prevention measures (prophylaxis against PCP and MAC and vaccination against Streptococcus pneumoniae) are associated with a survival benefit, even when they coincide with the administration of HAART. Continued monitoring of incidence trends and detection of new syndromes associated with HAART are important priorities in the HAART era.

Protists as opportunistic pathogens: public health impact in the 1990s and beyond.

Protist organisms (protozoa and fungi) have become increasingly prominent as opportunistic pathogens among persons infected with human immunodeficiency virus (HIV) and among organ transplant recipients--two immunocompromised populations that have increased dramatically in the past two decades. Pneumocystis carinii pneumonia continues to be the most common serious opportunistic infection (OI) among HIV-infected persons in the United States, occurring frequently among persons not previously receiving medical care. Toxoplasmosis, cryptococcosis, cryptosporidiosis, and isosporiasis occur frequently in HIV-infected persons in the developing world. Candidiasis and aspergillosis are common OIs in organ transplant recipients. As these populations of immunosuppressed patients continue to expand worldwide new OIs caused by protist pathogens are likely to emerge.

Risk factors for community-acquired pneumonia among persons infected with human immunodeficiency virus.

Two hundred eleven adults with human immunodeficiency virus (HIV) infection hospitalized for community-acquired pneumonia, including Pneumocystis carinii pneumonia (PCP; patients), and 192 matched HIV-infected hospitalized patients without pneumonia (controls) were interviewed to determine risk factors for pneumonia. Multivariate logistic regression showed that patients were less likely than controls to have used trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.12-0.41) and more likely to have been hospitalized previously with pneumonia (OR, 6.25; CI, 3.40-11.5). Patients were also more likely than controls to have gardened (OR, 2.24; CI, 1.00-5.02) and to have camped or hiked (OR, 4.95; CI, 1.31-18.7), but stratified analysis by etiologic agent showed this association only for PCP. These findings reconfirm the efficacy of TMP-SMZ in preventing community-acquired pneumonia. In addition, hospitalization for pneumonia might represent a missed opportunity to encourage HIV-infected patients to enter into regular medical care and to adhere to prescribed antiretroviral and prophylaxis medications.

Risk factors for human T cell lymphotropic virus type II infection among the Guaymi Indians of Panama.

To examine risk factors for human T cell lymphotropic virus type II (HTLV-II) infection, a case-control study was conducted among the Guaymi Indians of Panama. In females, HTLV-II seropositivity was associated with early sexual intercourse (15 years; odds ratio [OR], 2.50; 95% confidence interval [CI], 1.11-6.14) and number of lifetime sex partners. One partner increased risk of seropositivity by 30% (OR, 1.30; CI, 1.05-1.64), and risk increased with number of partners. Similar risk was associated with number of long-term sexual relationships. Among males, intercourse with prostitutes was associated with HTLV-II seropositivity (OR, 1.68; CI, 1.04-2.72). These data support a role for sexual transmission in HTLV-II infection. Association of seropositivity with primary residence in a traditional village (OR, 3.75; CI, 1.02-15.38) and lack of formal education (0 vs. >6 years [OR, 3.89; CI, 1.67-9.82]) observed in males may reflect differences in sexual practices associated with acculturation.

Adherence to guidelines for antiretroviral therapy and for preventing opportunistic infections in HIV-infected adults and adolescents in Ryan White-funded facilities in the United States.

To determine adherence by health care providers to guidelines for antiretroviral therapy and for prevention of opportunistic infections (OIs) in adults with HIV infection in federally funded facilities in the United States, we reviewed records of HIV-infected adults (>13 years) in 11 Ryan White Title III facilities in four states for information on eight standard-of-care recommendations during November 1996 through September 1997. Eligibility required a visit to the facility within 6 months before record abstraction and a lowest CD4+ lymphocyte count <500 cells/microl. Reviews were completed for 148 patients in Maryland, 355 in New York, 370 in Georgia, and 538 in Illinois. Adherence to prevention measures by health care providers was >85% for HIV plasma RNA testing, prescription of antiretroviral therapy, Pneumocystis carinii pneumonia (PCP) prophylaxis, anti-Toxoplasma antibody testing, and obtaining Papanicolaou (Pap) smears but lower (69%-80%) for Mycobacterium avium complex (MAC) prophylaxis, tuberculin skin testing (TST), and pneumococcal vaccination. Adherence was similar by patient age, gender, racial/ethnic group, urban versus rural, and hospital versus clinic setting but was generally lower for injecting drug users (IDUs) than for patients with other HIV exposures (p < .05 by multivariate analysis for TST, anti-Toxoplasma antibody testing, Pap smear, and measurement of HIV plasma RNA). Adherence by health care providers to guidelines for preventing OIs in these federally funded facilities is generally high but could be improved for some prevention measures, for instance, MAC prophylaxis, TST, and pneumococcal vaccination, especially for IDUs.

Surveillance for AIDS-defining opportunistic illnesses, 1992-1997.

PROBLEM/CONDITION: Acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (OIs) are the major cause of morbidity and mortality among persons infected with human immunodeficiency virus (HIV). As a result of new treatments that reduce mortality for persons with AIDS, the number of persons living with AIDS is increasing, and the incidence of AIDS is decreasing. In 1997, an estimated 271,245 persons were living with AIDS in the United States and thus were at high risk for OIs. In 1997, an estimated 21,909 HIV-infected persons died with AIDS, nearly all as a result of OIs. REPORTING PERIOD COVERED: Aggregate data and trends for 1992-1997 were examined to determine a) the frequencies at which OIs occurred first; b) the incidence of OIs; c) the percentage of persons among those who have died who had had a given OI during their course of AIDS, and d) the frequency of prescriptions for antiretroviral therapy and prophylaxis for Pneumocystis carinii pneumonia (PCP) and for Mycobacterium avium complex disease (MAC). DESCRIPTION OF SYSTEM: Data were analyzed from the Adult/Adolescent Spectrum of HIV Disease (ASD) sentinel surveillance project, a prospective medical record review of HIV-infected persons aged > or = 13 years conducted in 11 U.S. cities. ASD data were standardized to national AIDS surveillance data for 1992-1997 by age; race; sex; country of birth; year of AIDS diagnosis; HIV exposure mode; and for incidence calculations, by CD4+ T-lymphocyte distribution. RESULTS: The incidence declined significantly for each of 15 of the 26 specific AIDS-defining OIs (p<0.05). PCP was the most common AIDS-defining OI to occur first (PCP was the first OI to occur for 36% of HIV-infected persons), the most common incident AIDS-defining OI (274 cases per 1000 person-years), and the most common AIDS-defining OI to have occurred during the course of AIDS (53% of persons who died with AIDS had PCP diagnosed at some time during their course of AIDS). Of persons with CD4+ T-lymphocyte counts <500 cells/microL, the number with prescriptions for triple combination therapy increased from zero in 1992 to 40% in 1997, and 80% of persons had a prescription for any antiretroviral therapy in 1997. Of persons with CD4+ T-lymphocyte counts <200 cells/microL, the percentage with prescriptions for PCP prophylaxis remained stable from 1992 through 1997 (range: 75% to 80%). Of persons with CD4+ T-lymphocyte counts <50 cells/microL, the percentage with prescriptions for MAC prophylaxis increased from 9% in 1992 to 44% in 1997. INTERPRETATIONS: The incidences of many OIs are decreasing primarily because of advances in HIV-related therapy. However, OIs are still occurring, especially when patients access care late during the course of disease. Even after accessing care, persons may develop OIs because of lack of prescription for prophylaxis, antiretroviral drug resistance, or poor adherence to therapy. During 1992-1997, most patients in need of PCP prophylaxis received a prescription for it; however, even in 1997, most patients in need of MAC prophylaxis did not receive a prescription for it. ACTIONS TAKEN: These surveillance data are used by persons involved with developing guidelines for preventing OIs to determine the importance of and trends in OIs and preventive therapy. CDC is developing population-based approaches for surveillance of HIV disease progression, OIs, and therapies with the goal of making these data available in more geographic areas to help assess public health and health-care programs.

Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis.

Risk factors for the development of a first episode of Pneumocystis carinii pneumonia (PCP) were investigated in the Adult and Adolescent Spectrum of Disease Project, a medical record review study involving longitudinal follow-up of human immunodeficiency virus-infected adults in 9 US cities. Risk factors included decreasing CD4 lymphocyte count and history of AIDS-defining illness, non-P. carinii pneumonia, oral thrush, or unexplained fever for > or = 2 days; PCP prophylaxis was protective. PCP incidence/100 person-years of observation among persons not prescribed PCP prophylaxis was higher in those with CD4 lymphocyte counts < 250 cells/microL or CD4 cell percent < 14% (8.3; 95% confidence interval [CI], 7.7-9.0) than in persons with CD4 cell counts < 200 or history of thrush or fever, which constitute current criteria for prophylaxis against PCP (5.9; 95% CI, 5.5-6.4). Because of increased efficiency in capturing persons at highest risk, CD4 cell count < 250 or CD4 cell percent < 14% should be considered as criteria for prophylaxis against first episodes of PCP.

A 70-kDa amino-terminal fibronectin fragment supports gelatin binding to macrophages and decreases gelatinase activity.

We previously reported that a macrophage response that increased binding to 125I-radiolabeled soluble denatured collagen (gelatin) was induced by preincubation of macrophage with a 70-kDa amino-terminal fibronectin fragment and soluble nonlabeled gelatin [S. F. Penc, F. A. Blumenstock, J. E. Kaplan (1995) J. Leukoc. Biol. 58, 501-509]. We now report that neither protein synthesis nor recycling of receptors between the cell surface and interior were required for this response. However, removal of cell surface components with trypsin demonstrated that induced gelatin binding required native cell surface constituents. It was found that in the presence of the 70-kDa fibronectin fragment and gelatin, matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9) activity in the cell layers was significantly decreased or undetectable, respectively. Similar levels of increased gelatin binding could be reproduced after inhibition of matrix-degrading metalloprotease activity with 1'10-phenanthroline. These results demonstrate that a macrophage specific response that decreased gelatinase activity and increased gelatin binding was initiated by interaction with a 70-kDa fibronectin fragment and gelatin.