Clinical Case Definition For AIDS Research Articles

Evaluation of the status of tuberculosis as part of the clinical case definition of AIDS in India

Aim: To assess HIV associated tuberculosis in a high tuberculosis prevalence setting and its status in the clinical case definition of AIDS. Methods: All HIV patients attending the infectious disease...

Unexpectedly high prevalence of sexually transmitted diseases in married women attending family planning clinics in Yaounde, Cameroon

The increased number of sexually transmitted diseases (STD) and HIV screening and counselling centres in major cities in sub-Saharan Africa facilitates epidemic investigations elucidating the extent method of transmission and clinical consequences of STD. The aim of the present study was to evaluate the prevalence of STD and HIV/ AIDS among women attending family planning clinics in Yaounde Cameroon and presenting with clinical signs and symptoms related to these infections. From December 1997 to December 1998 783 women of reproductive age attending the three main family planning clinics in Yaounde were prospectively enrolled. These centres offered multipurpose reproductive health services including provision of STD services as well as operating as voluntary HIV testing and counselling centres in Yaounde. Written informed consent was obtained from all women. Reasons for attendance sociodemographic and behavioural data obstetric and STD histories were elicited in a structured interview. Women underwent general genital and pelvic examination during which serum vaginal and cervical samples were collected. Clinical immunosuppression or AIDS-related symptoms were assessed using the World Health Organization Bangui clinical case definition for AIDS in Africa. A seven-day follow-up appointment was arranged for all women and appropriate treatment was provided for any treatable STD syndrome or genital pathogen diagnosed. (excerpt)

Causes of death in a rural, population-based human immunodeficiency virus type 1 (HIV-1) natural history cohort in Uganda.

While human immunodeficiency virus (HIV)-related causes of death have been well documented in developed countries, in Africa data are scanty and mainly based on autopsy studies from city hospitals which are highly selective and may not represent causes of HIV-associated deaths in the general population. This study, from a rural population, describes the causes of death in HIV-positive people and their HIV-negative controls. A natural history cohort comprising HIV-1 infected participants and HIV-negative controls was established in rural Uganda in 1990. Causes of death were determined by reviewing the premorbid clinical and laboratory findings and from information obtained from relatives. Blindness to the deceased's HIV serostatus was maintained throughout. In all, 78 deaths occurred over a 6-year period: 63 deaths occurred in the HIV-positive cases (53 prevalent and 10 incident cases) and 15 deaths in the HIV-negative controls. Of the prevalent cases, 56%, and 9% the incident cases enrolled died, compared with 7% of the HIV-negative controls. Of the 55 HIV-positive cases with sufficient data to establish cause of death, 52 (95%) were assessed as having HIV-associated deaths and 48 (87%) died in WHO stage 4 (AIDS). The main causes of death were wasting syndrome (31%), chronic diarrhoea (22%), cryptococcal meningitis (13%) and chest infection (11%). Our results represent an unbiased selection of deaths in a rural area. The HIV-positive cases have high death rates and die of HIV-related pathologies. The main causes of death reflect the WHO clinical case definition of AIDS. Cryptococcal meningitis is also a common cause of death in this population.

Impact of the 1994 expanded World Health Organization AIDS case definition on AIDS surveillance in university hospitals and tuberculosis centers in Côte d'Ivoire.

To assess the impact of the 1994 expanded World Health Organization (WHO) AIDS case definition on AIDS surveillance in Côte d'Ivoire. Prospective AIDS case surveillance. From March 1994 through December 1996, passive AIDS case surveillance was conducted at the three university hospitals in Abidjan, and active AIDS case surveillance was conducted at the eight tuberculosis (TB) centers in Côte d'Ivoire. Standardized questionnaires were administered and blood samples for HIV serologic testing were collected from the patients evaluated. The numbers of persons who met the modified 1985 WHO clinical AIDS case definition (Bangui definition) and the 1994 expanded WHO AIDS case definition were determined, and the clinical characteristics of these patients were assessed. Of 8648 university hospital patients, 3658 (42.3%) met the clinical and/or the expanded case definition: 744 (20.3%) HIV-seropositive persons met only the expanded definition, 44 (1.2%) HIV-seropositive persons met only the clinical definition, 2334 (63.8%) HIV-seropositive persons met both definitions, and 536 (14.7%) HIV-seronegative persons met only the clinical definition. Of 18,661 TB center patients, 9664 (51.8%) met the clinical and/or the expanded definition: 5685 (58.8%) HIV-seropositive persons met only the expanded definition, none of the HIV-seropositive persons met only the clinical definition (by definition), 2625 (27.2%) HIV-seropositive persons met both definitions, and 1354 (14.0%) HIV-seronegative persons met only the clinical definition. Because of the inclusion of multiple severe HIV-related illnesses into the expanded definition, the number of reportable AIDS cases in HIV-seropositive patients increased 31.3% in the university hospitals, and 217% in the TB centers. The inclusion of HIV seropositivity as a criterion for the expanded definition also enhanced the specificity of AIDS case reporting, eliminating 536 cases in the university hospitals and 1354 cases in the TB centers in HIV-seronegative patients who had clinical signs of AIDS. The use of the 1994 expanded definition for surveillance purposes should be encouraged in areas of the developing world where HIV serologic testing is available.

Redefining AIDS: towards a modification of the current AIDS case definition.

AIDS is defined by the occurrence of an opportunistic infection or tumor considered indicative of advanced infection with human immunodeficiency virus (HIV). Even though recent modifications have improved the widely used AIDS case definition issued by the World Health Organization and the Centers for Disease Control and Prevention, the modified version has fallen short of generating a globally functional instrument for the surveillance of HIV-related infections. The clinical AIDS case definition should be as comprehensive as possible. In many countries, only the diagnosis of an AIDS-defining illness will grant the affected patient social benefits or access to medical care. An expanded AIDS case definition is also likely to improve surveillance of HIV-associated morbidity and mortality; increase the awareness of emerging infections; increase the number of clinical endpoints in clinical trials; and facilitate the introduction of diagnostic tests, screening programs, and preventive measures. Examples of opportunistic infections and tumors that could be considered in future modifications of the AIDS case definition are discussed in detail.

Limitations of the WHO/CDC clinical case definition for AIDS in Africa.

The authors screened 268 patients over the period July-September 1990 selected by systematic sample from those attending the sexually transmitted diseases section of the adult filter clinic at the University Teaching Hospital in Lusaka Zambia. Clinical findings were recorded to establish whether each patient fulfilled the World Health Organization (WHO) clinical case definition for AIDS. For pragmatic reasons the presence of oral candida any episode of herpes simplex and any episode of herpes zoster were considered positive criteria. Participants were also examined for the presence of palpable epitrochlear lymph nodes enlarged to one centimeter or more. Blood was drawn for analysis for HIV-1 antibody using HIVCHEK and for syphilis using Syfacard-R. 158 participants were found to be HIV-1 seropositive. It was also determined that current WHO criteria for the clinical case definition of AIDS offers only low positive predictive value and sensitivity. The authors therefore urge that caution be taken in interpreting that case definition and that serological testing for HIV be used in conjunction with the clinical case definition whenever possible. HIVCHEK can be routinely used in areas where there is no serological evidence of HIV-2. Furthermore epitrochlear adenopathy is a simple clinical finding which has in this study a positive predictive value for HIV infection of 77%; a similar study in Zambia showed a positive predictive value of 89%. Further studies are needed to validate this finding in other settings but the presence of the nodes may provide an additional clinical criterion for predicting HIV seropositivity in the absence of other known causes of epitrochlear lymphadenopathy.

General and HIV-1-associated morbidity in a rural Ugandan community.

The AIDS epidemic in sub-Saharan Africa affects whole communities, adding to the already high burden of morbidity. Reports of AIDS cases are usually from hospital attenders, often diagnosed using the World Health Organization (WHO) clinical case definition. Little is known about the extent of HIV-associated morbidity in the general population. The objectives of this study were to describe the prevalence of (1) markers of general morbidity and (2) the criteria of the WHO clinical case definition for AIDS and (3) to determine the association between these markers and HIV-1 serostatus in a rural Ugandan community. A survey was conducted among the adult population (aged > or = 13 years) of 15 neighbouring villages in Masaka District, south-west Uganda. The survey included medical history, physical examination and testing for HIV-1 antibodies. The HIV-1 seroprevalence among 4175 out of 5278 (79%) eligible adults was 8.2%. Current health problems were reported by 57.6% of adults, with increased rates in HIV-1-positive subjects, women and older people. Five of the 10 most common complaints showed significant associations with HIV-1 status, as did reported genital ulcer and vaginal discharge. The crude HIV-1 attributable disease burden in the population was 1.2% for current illness, 4.3% for previous serious illness and 9.9% for illness leading to hospital admission. Overall, 11 (3.3%) of the HIV-1-positive and nine (0.2%) of the HIV-1-negative subjects had AIDS as defined by the clinical case definition. The positive and negative predictive values and specificity were 55.0, 92.0%, and 99.8%, respectively. Against a background of high general morbidity, we observed a relatively small population attribution of HIV-1-associated morbidity. The results indicate that the clinical AIDS case definition may provide a useful tool for population surveys.

A SIMPLIFIED SURVEILLANCE CASE DEFINITION OF AIDS DERIVED FROM EMPIRICAL CLINICAL DATA

A clinical AIDS case definition is needed for surveillance in countries where the CDC case definition is not practical. To derive such a definition, we compared 110 HIV-seropositive and 135 randomly selected HIV-seronegative adult medical-ward inpatients in Brazil. Multivariate analysis of clinical signs and symptoms and simple diagnoses resulted in a discriminant function with sensitivity of 89% and specificity of 96% in predicting for AIDS. These data were the empirical basis for a clinical definition of AIDS in adults drafted in a Caracas, Venezuela, workshop sponsored by the Pan American Health Organization. The revised "Caracas" definition presented here requires a positive HIV serology, the absence of cancer or other cause of immunosuppression, plus > or = 10 cumulative points, as follows: Kaposi's sarcoma (10 points); extrapulmonary/noncavitary pulmonary tuberculosis (10); oral candidiasis or hairy leukoplakia (5); cavitary pulmonary/unspecified tuberculosis (5); herpes zoster < 60 years of age (5); CNS dysfunction (5); diarrhea > or = 1 month (2); fever > or = 1 month (2); cachexia or > 10% weight loss (2); asthenia > or = 1 month (2); persistent dermatitis (2); anemia, lymphopenia, or thrombocytopenia (2); persistent cough or any pneumonia except TB (2); and lymphadenopathy > or = 1 cm at > or = 2 noninguinal sites for > or = 1 month (2). This definition has a sensitivity of 95% and a specificity of 100% (91% without HIV serology) when applied to the Brazilian patients in this study. The Caracas definition has been adopted by Brazil, Honduras, and Surinam, and is in validation elsewhere. The use of a reasonably sensitive and specific case definition commensurate with available diagnostic resources should facilitate AIDS surveillance in developing countries.

High HIV seroprevalence and increased HIV-associated mortality among hospitalized patients with deep bacterial infections in Dar es Salaam, Tanzania

To correlate deep bacterial infections with HIV infection and evaluate the influence of HIV on clinical picture and outcome in patients with meningitis, pneumonia or pyomyositis. Case-control comparison of HIV seroprevalence between patients and an age- and sex-matched control group in a prospective cross-sectional study of hospitalized patients. One hundred and sixty-five patients admitted to hospital with either purulent meningitis, pneumonia or pyomyositis and 165 age- and sex-matched controls from orthopaedic/trauma wards. University Hospital, Dar es Salaam, Tanzania. Differences in HIV seroprevalence and mortality. Of 78 patients with purulent meningitis, 19 (24%) were HIV-seropositive, compared with 13 (17%) in the control group (P = 0.345). Of 36 patients with meningitis seen before a meningococcal epidemic affected Dar es Salaam, there was a statistically significant association with HIV infection (P = 0.013). Ten out of 19 (53%) HIV-seropositives died, compared with nine out of 59 (15%) seronegatives (P = 0.028). Of patients with pneumococcal meningitis, five out of six (83%) seropositives died, compared with two out of 12 (17%) seronegatives (P = 0.013). Fifteen out of 45 (33%) patients with pneumonia were HIV-seropositive, compared with four (9%) in the control group (P = 0.001). There was no difference in mortality between seropositive and seronegative patients with pneumonia. HIV seroprevalence was 62% among 42 patients with pyomyositis and 12% among 42 controls (P less than 0.0001). Eighteen out of 25 (72%) seropositive patients with pyomyositis fulfilled the World Health Organization (WHO) clinical case definition for AIDS. Response to recommended antibiotic treatment was satisfactory among patients with pneumonia and pyomyositis. These results show a strong association between pyomyositis, pneumonia and HIV infection. They also indicate an increased mortality associated with HIV infection in patients with pyogenic meningitis, especially pneumococcal meningitis. Pyomyositis should be considered an indicator of stage III HIV disease in the proposed WHO clinical staging system.

Predictors of Mortality among HIV-infected Women in Kigali, Rwanda

To better characterize the natural history of disease due to human immunodeficiency virus (HIV) infection in African women. Prospective cohort study over a 2-year follow-up period. A total of 460 HIV-seropositive women and a comparison cohort of HIV-seronegative women recruited from prenatal and pediatric clinics in Kigali, Rwanda in 1988. Clinical signs and symptoms of HIV disease, AIDS, and mortality. Follow-up data at 2 years were available for 93% of women who were still alive. At enrollment, many seropositive women reported symptoms listed in the World Health Organization (WHO) clinical case definition of AIDS, but these were nonspecific and often improved over time. The 2-year mortality among HIV-infected women by Kaplan-Meier survival analysis was 7% (95% CI, 5% to 10%) overall, and 21% (CI, 8% to 34%) for the 40 women who fulfilled the WHO case definition of AIDS at entry. In comparison, the 2-year mortality in women not infected with HIV was only 0.3% (CI, 0% to 7%). Independent baseline predictors of mortality in seropositive women by Cox proportional hazards modeling were, in order of descending risk factor prevalence: a body mass index of 21 kg/m2 or less (relative hazard, 2.3; CI, 1.1 to 4.8), low income (relative hazard, 2.3; CI, 1.1 to 4.5), an erythrocyte sedimentation rate exceeding 60 mm/h (relative hazard, 4.9; CI, 2.2 to 10.9), chronic diarrhea (relative hazard, 2.6; CI, 1.1 to 5.7), a history of herpes zoster (relative hazard 5.3; CI, 2.5 to 11.4), and oral candida (relative hazard, 7.3; CI, 1.6 to 33.3). Human immunodeficiency virus disease was the cause of death in 38 of the 39 HIV-positive women who died, but only 25 met the WHO definition of AIDS before death. Human immunodeficiency virus disease now accounts for 90% of all deaths among child-bearing urban Rwandan women. Many symptomatic seropositive patients may show some clinical improvement and should not be denied routine medical care. Easily diagnosed signs and symptoms and inexpensive laboratory tests can be used in Africa to identify those patients with a particularly good or bad prognosis.

What use is a clinical case definition for AIDS in Africa?

The article proposes that the clinical case definition for Acquired Immunodeficiency Syndrome in Africa is an unworkable concept, with the wrong definition, incorrect validation, improper use, and consequently is a poor surveillance tool. The definition was proposed by the World Health Organization in 1986 to satisfy the use in countries with limited diagnostic resources, and resources for serological testing. Critical review until now of this procedure was lacking. Currently serological testing is available and of high quality. It does not seem justifiable to continue using a provisional surveillance definition. Abandoning this classification procedure may also lead to the focus on problems other than opportunistic infections and AIDs. Clinical surveillance is important, but as well morbidity and mortality need monitoring. It is argued that the definition is an unworkable concept because patients with underlying immunosuppression disorders such as AIDs can not be easily distinguished from chronic disease patients; i.e., pulmonary tuberculosis, renal failure, uncontrolled diabetes, or diarrhea with weight loss. Clinical accuracy is insufficient. It is the wrong definition because pulmonary tuberculosis with a persistent cough cannot be distinguished for those HIV positive and those not. There is inconsistency in the WHO clinical definition and the Centers for Disease Control definitions of AIDs. The incidence of tuberculosis in countries with unmodified clinical case definitions may contribute to an inflated number of AIDs cases. The wrong standards were used to validate the WHO definition in evaluative studies. The reference sensitivity ranges indicate that the definition is insensitive to identifying seropositive patients. Also, the HIV status of patients does not equate with AIDs. Although designed for surveillance, the clinical case definition is used by doctors for individual patient management. Labeling a patient as having AIDs, when he is HIV negative, leads to negative consequences. Researchers compare African AIDs data with North American data with imprecise and noncomparable definitions. As a surveillance tool in countries with a fragmentary or without a vital registration system, it is an inaccurate tool. Alternatives to obtaining data about the spread and impact of HIV are cluster sampling, hospital surveillance of selected populations, anonymous testing of pregnant women or patients in sexually transmitted disease clinics. In Nairobi, a necropsy survey found that 16% had AIDs but 38% were HIV positive.

Prevalence of HIV-1 Infection and Symptomatology of AIDS in Severely Malnourished Children in Dar Es Salaam, Tanzania

In Dar es Salaam, Tanzania, 200 children with severe malnutrition and controls matched for age, sex, and area of residence were screened for serological evidence of infection with the human immunodeficiency virus type 1 (HIV-1) over 5 months in 1988. The prevalence of HIV-1 antibodies in the malnourished group was 25.5% (51 of 200) compared with 1.5% (three of 200) in the controls. The seroprevalence rate was equally high in malnourished children above the age of 18 months (26 of 102; 25.5%), as in those below this age (25 of 98; 25.5%). The prevalence rate was higher in children with marasmus (38.2%) as compared to children with marasmic-kwashiorkor (12.3%) or kwashiorkor (12.2%). The prevalence of clinical features known to be associated with AIDS was higher in the HIV seropositive malnourished children as compared to the seronegative children. The modified World Health Organization clinical case definition of AIDS in children was also evaluated and found to have a low sensitivity and positive predictive value (62.8 and 57.1%, respectively) but a fairly high specificity (83.9%). It is recommended to routinely rule out HIV infection in malnourished children, especially those with marasmus.

HIV-2 infection in hospitalized patients in Bissau, Guinea-Bissau

During 11 months in 1989-1990, 1009 consecutive hospitalized adult patients admitted to the medical wards of the National Hospital in Bissau were interviewed, examined clinically, and tested for antibodies to HIV-1 and HIV-2. The prevalence of HIV-2 infection was 20.4% (206 out of 1009) and of HIV-2-associated AIDS 4.4% (44 out of 1009). HIV-2 infection was more frequent in women (25%, 110 out of 440) than in men (16.9%, 96 out of 569). HIV-1 infection was diagnosed in one patient only, and one patient (with AIDS) had reactivity to both HIV-1 and HIV-2. Among HIV-2-seropositive patients, AIDS was demonstrated in 21.3% and AIDS-related symptoms (not fulfilling the AIDS criteria) in 19.4%. The frequency of AIDS-associated symptoms was significantly higher in HIV-2-seropositive patients than in seronegative patients. The clinical profile of the HIV-2-associated AIDS cases was very similar to that described in HIV-1-associated AIDS cases in Africa. Seven out of 51 patients fulfilling the clinical criteria for AIDS were HIV-seronegative. The World Health Organization (WHO) clinical case definition for AIDS in Africa had a specificity of 99% and a positive predictive value of 86%. Tuberculosis was more common in HIV-2-seropositive patients (6.3%) than in HIV-2-seronegative patients (2.2%). A history of blood transfusion was a significant risk factor for HIV-2 infection. HIV-2 infection and AIDS are public health problems in Guinea-Bissau.

HIV-1 Infection in HIV-1 Enzyme-Linked Immunoassay Seronegative Patients in Kinshasa, Zaire

Serum samples of 62 African patients who had clinical manifestations of HIV-1 infection but were seronegative for HIV-1 by ELISA (Organon) were subsequently further tested by another HIV-1 ELISA test (Wellcozyme), HIV-1 IgG Western blot, HIV-1 antigen detection and HIV-2 ELISA. Patients' lymphocytes were cultured for HIV-1 and 2. Because of limited quantities of serum available all tests were not performed on all samples. Seven (26%) of 27 sera of patients meeting the WHO clinical case definition of AIDS were Western-blot-positive. In contrast, of 35 patients' sera with possible HIV related disease, only one (3%) was Western blot positive (P = 0.02) and none of 75 sera from HIV-1 ELISA (Organon) seronegative blood donors (P less than 0.01) were Western blot positive. Of 30 HIV-1 ELISA (Organon) seronegative patients tested with the HIV-1 ELISA Wellcozyme assay only one was seropositive (this patient's serum was also Western blot positive). Of 17 HIV-1 ELISA (Organon) seronegative patients tested, HIV-1 antigen was found in 1 case (6%) (this patient's serum was Western blot negative). None of the 34 patients tested by HIV-2 serology was HIV-2 seropositive. HIV-1 was isolated by culture in 3 (21%) of 14 HIV-1 ELISA seronegative patients (sera of the 3 patients were Western blot negative). In total, 12 (19%) of 62 HIV-1 ELISA (Organon) seronegative patients were found to be positive for HIV, either by Western blot HIV antigen testing or viral culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Surveillance for AIDS in Uganda

In the developed world, surveillance for AIDS has provided up-to-date information for researchers, clinicians, public health workers and policy makers. In Africa, however, there is no standardized format or methodology for AIDS surveillance. In August 1987, Uganda developed a clinical case definition for AIDS reporting, based upon the World Health Organization (WHO) clinical case definition for AIDS in Africa and began formal surveillance. Surveillance is passive and primarily hospital-based. At the end of July 1988, 5142 cases of AIDS had been reported to the Ministry of Health; 4583 (89%) had confirmatory HIV-antibody testing. Of the 4938 (96%) cases that had their sex recorded, 2358 (48%) were male and 2580 (52%) were female. The mean age of 28.4 years for male patients is higher than that of 24.4 years for female patients (P less than 0.0001). Only 18 (less than 1%) cases have been reported in children between 5 and 12 years of age. Case reports are returned via the District Medical Officers to the Ministry of Health where they are entered into a microcomputer from which a monthly report is generated for feedback to the reporting stations. Here we describe a simple national reporting system to follow the progression of the AIDS epidemic which could be established in Africa using limited resources.

Evaluation of the WHO clinical case definition for AIDS in Uganda

Evaluation of the WHO clinical case definition for AIDS in Uganda

Evaluation of the WHO Clinical Case Definition for AIDS in Uganda

Infections with human immunodeficiency virus are common in areas of the world where laboratory testing and sophisticated diagnostic facilities are unavailable. A World Health Organization clinical case definition for acquired immunodeficiency syndrome was developed in 1985 for use in such areas. In 1987, we tested this definition on 1328 inpatients and outpatients in 15 hospitals throughout Uganda. Five hundred sixty-two patients (42%) were positive by enzyme-linked immunosorbent assay for human immunodeficiency virus antibody. The World Health Organization definition had a sensitivity of 55%, a specificity of 85%, and a positive predictive value of 73%. Modification of the case definition by excluding a known cough from tuberculosis as a minor criteria decreased sensitivity slightly to 52%, but specificity and positive predictive value increased to 92% and 83%, respectively. Amenorrhea, although not specifically asked about, was a symptom noted by many female patients (26% of females who were positive by enzyme-linked immunosorbent assay); as a symptom indicative of human immunodeficiency virus infection, amenorrhea had a specificity of 99%, with a positive predictive value of 89%. These findings support the generalizability of the World Health Organization clinical acquired immunodeficiency syndrome definition and its use (especially the modified version) in areas of Uganda without sophisticated facilities.

Clinical aspects of HIV infection in developing countries.

The HIV epidemic probably arose in Africa at about the same time as in the West, and there is a significant seroprevalence of HIV in the central African region. However, the epidemiology and clinical course of AIDS are different in Africa and in the West. In Africa males are infected as often as females, and the commonest means of transmission is heterosexual intercourse. Many HIV-infected people are symptomless, but many others present with or progress to generalized lymphadenopathy, pruritus, herpes zoster, herpes simplex, cellulitis, and oral candidiasis. The World Health Organization developed a clinical case-definition of AIDS in Africa, which was found to have a specificity of 90% and a sensitivity of 59% when tested in Zaire. The Kaposi's sarcoma seen in African AIDS patients is more aggressive than that seen in the West and is often visceral. Gastrointestinal AIDS (the "slim" disease) with weight loss and diarrhea is common in Africa, as are oral and esophageal candidiasis. In Africa Pneumocystis carinii pneumonia is rare, but pulmonary tuberculosis is common. Neurological manifestations include cerebral toxoplasmosis, cytomegalovirus infection, headache, and terminal encephalopathy. About 60% of infants born to seropositive women are infected and die within the 1st year of life. Lack of drugs and diagnostic facilities make both diagnosis and treatment of opportunistic infections difficult.