PROCEDIMIENTOS Y SANCIONES
COMPONENTE URBANO DEL ESQUEMA DE ORDENAMIENTO TERRITORIAL DEL MUNICIPIO DE LA PAZ CESAR
In the majority of countries in sub-‐Saharan Africa, CD4 count measurement using laboratory-‐based platforms is not feasible and point of care CD4 count measurement has not yet been introduced233. Therefore, ART eligibility cannot be determined by
identifying whether HIV-‐infected individuals have a CD4 count of less than the WHO-‐ or nationally-‐recommended CD4 count threshold. Instead, clinical staging assessments are used where assessment of physical signs and symptoms and diagnosis of opportunistic infections and cancers are used to categorise individuals to a stage that can be used to monitor disease progression and identify when ART should be initiated according to risk of illness and death. The WHO Clinical Staging and Disease Classification System (“WHO clinical staging system”) can be used in resource-‐limited settings and is currently widely used in most HIV programmes in sub-‐Saharan Africa.
The WHO clinical staging system arose out of a need for highly specific means of diagnosing AIDS in resource-‐limited settings in the early days of the epidemic, when rapid testing for HIV was not available. A provisional case definition was developed in Zaire in 1986239 before being approved by WHO at a meeting in Bangui, Central African
Republic in the same year240, 241. The case definition was evaluated in hospitalised in-‐
patients and rural community members in Zaire and in-‐patients and in outpatients in Uganda, showing of sensitivity of between 50-‐59% and a specificity of 78-‐90%239, 242, 243
In 1990, WHO published a proposal for a staging system for HIV that could be used to “improve clinical management of patients; establish reliable prognoses; help in designing and evaluating drug and vaccine trials and perform studies on pathogenesis and natural history of HIV infection”244. Four stages were included in the system, comprising of: 1. Asymptomatic/persistent generalised lymphadenopathy; 2. Early disease; 3. Moderate disease; and 4. Severe disease (AIDS). Although WHO stated in the description of the staging system that a major advantage was that classification of stage could be made using by clinical assessment facilitating use in resource-‐limited settings, a number of stage-‐defining conditions (particularly in stage 4) require laboratory diagnosis of an organism (for example: cryptosporidiosis or cytomegalovirus)245. The WHO clinical
staging system was revised in 2005246 and again in 2007247. Table 2.3 shows current
stages and stage-‐defining conditions included in the 2007 WHO clinical staging system.
Table 2.3: WHO Clinical Staging System (2007) for adults with confirmed HIV infection
Stage WHO clinical stage-‐defining conditions
1. Asymptomatic
Persistent generalized lymphadenopathy
2. Moderate unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections
(sinusitis, tonsillitis, otitis media and pharyngitis) Herpes zoster
Angular cheilitis
Recurrent oral ulceration Papular pruritic eruption Seborrhoeic dermatitis Fungal nail infections
3. Unexplained severe weight loss
(>10% of presumed or measured body weight)
Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever
(above 37.6°C intermittent or constant, for longer than one month) Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (current) Severe bacterial infections
(such as pneumonia, empyema, pyomyositis, bone or joint infection, meningitis or bacteraemia)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre) or chronic thrombocytopaenia (<50 × 109 per litre)
4. HIV wasting syndrome Pneumocystis pneumonia
Recurrent severe bacterial pneumonia Chronic herpes simplex infection
(orolabial, genital or anorectal of more than one month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
Extrapulmonary tuberculosis Kaposi’s sarcoma
Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis
HIV encephalopathy
Extrapulmonary cryptococcosis including meningitis Disseminated non-‐tuberculous mycobacterial infection Progressive multifocal leukoencephalopathy
Chronic cryptosporidiosis (with diarrhoea) Chronic isosporiasis
Disseminated mycosis (coccidiomycosis or histoplasmosis) Recurrent non-‐typhoidal Salmonella bacteraemia
Lymphoma (cerebral or B-‐cell non-‐Hodgkin) or other solid HIV-‐associated tumours Invasive cervical carcinoma
Atypical disseminated leishmaniasis
Symptomatic HIV-‐associated nephropathy or symptomatic HIV-‐associated cardiomyopathy
In a number of prospective studies both in developed countries and in sub-‐Saharan Africa, the prognostic value of the WHO clinical staging system has been clearly
demonstrated. In pre-‐ART era studies from Uganda248, 249, there was a clear relationship
between advanced WHO clinical stage and risk of death, with 73% of individuals in stage 1 alive at 6-‐years compared to 6% of individuals in stage 4. WHO clinical stage is also a good predictor of prognosis following initiation of ART, with higher rates of mortality and lost and loss-‐to-‐follow-‐up in individuals in more advanced stages250, 251.
Because of the limited capacity for assessment of immune status by measurement of CD4 count in much of sub-‐Saharan Africa, most national programmes recommend that WHO clinical stage be used for screening for eligibility for ART. For example, in Malawi, HIV-‐infected patients in WHO stage 3 or 4 are eligible for ART initiation174. WHO also
recommends that, where CD4 count measurement is not possible, HIV-‐positive individuals in WHO stage 3 or 4 should be initiated on to ART229.
However there are concerns that WHO clinical staging has low sensitivity compared to CD4 count when used as an eligibility assessment tool, potentially resulting in delayed initiation of ART until immunosuppression is advanced252. Tables 2.4 and 2.5 summarise
studies identified in a systematic literature review (conducted by Chigomezgo Munthali, MPH student at LSTM, and myself) that have reported on the diagnostic performance of WHO clinical stage 3 or 4 disease in identifying ART eligibility thresholds of CD4 count ≤200 cells/mm3, ≤350 cells/mm3 and ≤500 cells/mm3. Weighted summary estimates
were obtained by fitting a two-‐level mixed logistic regression model, with independent binomial distributions for the true positives and true negatives conditional on the sensitivity and specificity in each study, and a bivariate normal model for the logit transforms of sensitivity and specificity between studies using a method described by
Harbord et al253. Hierarchical summary receiver operator characteristic (HSROC) curves
were plotted (Figures 2.11 and 2.12).
Table 2.4: Summary estimates and meta-‐analysis of studies comparing WHO clinical stage 3/4 with CD4 ≤200 cells/mm3
Cochran’s Q statistic for heterogeneity – sensitivity: Q=914.26, p<0.001; specificity Q=1439.43, p<0.001
NR: not reported
Clinician may mean either a doctor, a nurse or clinical officer. Where subcategory not specified, healthworkers from more than one cadre performed staging
Study Country HIV-‐positive population
Cadre of healthworker
performing WHO staging
N Sensitivity (95% CI) Specificity (95% CI)
Boniphace 2011254 Tanzania Hospital outpatients NR 331 72% (65%-‐78%) 57% (49%-‐67%) Carter 2010255 Cameroon, Cote d’Ivoire, Kenya, Mozambique, Rwanda, South Africa, Uganda, Zambia, and Thailand Antenatal clinic attendees Clinicians 6036 27% (24%-‐29%) 93% (92%-‐94%)
Fox 2010256 South Africa outpatients Hospital NR 802 (52%-‐61%) 56% (56%-‐67%) 62% French
1999257 Uganda outpatients Hospital NR 210 (59%-‐80%) 71% (58%-‐76%) 67% Ilovi 2011258 Kenya Inpatients and outpatients NR 152 89% (81%-‐95%) (41%-‐66%) 54% Jaffar 2008259 Uganda Primary clinic attendees Clinicians (Doctors) 4302 (50%-‐54%) 52% (66%-‐70%) 68% Kagaayi
2007260 Uganda Community members Clinicians 1221 (46-‐56%) 51% (85%-‐90%) 88% McGrath
2007261 Malawi Community members
Clinicians (Clinical Officer) 120 (7%-‐41%) 20% (87%-‐98%) 94% Morpeth 2007262 Tanzania Hospital outpatients NR 202 75% (66%-‐83%) 35% (26%-‐46%) Tassie 2004263 Malawi Pre-‐ART clinic attendees NR 206 (74%-‐90%) 83% (42%-‐62%) 52% Torpey 2009264 Ghana Pre-‐ART clinic attendees Clinicians 5784 70% (69-‐72%) 59% (57%-‐61%) Weighted Summary 20,197 (48%-‐74%) 62% (56%-‐81%) 70%
Table 2.5: Summary estimates and meta-‐analysis of studies comparing WHO clinical stage 3/4 with CD4≤350 cells/mm3
Cochran’s Q statistic for heterogeneity – sensitivity: Q=1607.31, p<0.001; specificity Q=896.70, p<0.001
NR: not reported
Clinician may mean either a doctor, a nurse or clinical officer. Where subcategory not specified, healthworkers from more than one cadre in this cadre performed staging
Study Country HIV-‐positive population Cadre of healthworker performing WHO staging N Sensitivity (95% CI) Specificity (95% CI) Baveewo
2011265 Uganda Pre-‐ART clinic attendees Clinicians 395 (43%-‐55%) 49% (79%-‐92%) 87%
Carter 2010255 Cameroon, Cote d’Ivoire, Kenya, Mozambique, Rwanda, South Africa, Uganda, Zambia, and Thailand Ante-‐natal clinic attendees Clinicians 6036 18% (17%-‐20%) (94%-‐95%) 95%
Ilovi 2011258 Kenya Inpatients and outpatients
NR 152 (73%-‐88%) 82% (46%-‐78%) 63% Jaffar 2008259 Uganda Pre-‐ART clinic
attendees Clinicians (Doctors) 4302 48% (46%-‐50%) 74% (72%-‐77%) McGrath 2007261 Malawi Community members Clinical Officers 120 22% (11%-‐35%) 100% (95%-‐ 100%) Torpey
2009264 Ghana Pre-‐ART clinic attendees Clinicians 5784 (64%-‐67%) 65% (68%-‐74%) 71% Weighted Summary 16,789 45% (26%-‐66%) 85% (69-‐93%)
Figure 2.10: Hierarchical summary receiver operator characteristic (HSROC) plot for accuracy of WHO stage 3/4 disease in identifying CD4≤200 cells/mm3
Figure 2.11: Hierarchical summary receiver operator characteristic (HSROC) plots for accuracy of WHO clinical stage 3/4 in identifying CD4≤350 cells/mm3
A considerable degree of heterogeneity was found between studies and so summary estimates should be treated with caution. At the ART eligibility threshold of CD4 ≤200 cells/mm3, the sensitivity and specificity of WHO clinical 3 or 4 disease were 60% (95%
CI: 45%-‐73%) and 73% (95% CI: 60%-‐83%) respectively. Analysis at the higher ART eligibility threshold of CD4 ≤350 cells/mm3 the sensitivity and specificity were 45% (95%
CI: 26%-‐66%) and 85% (95% CI: 69%-‐93%) respectively. Only one study was identified that examined the ART eligibility threshold of CD4 ≤500cells/mm3, which found a
sensitivity and specificity of 14% (95% CI: 13%-‐15%) and 95% (95% CI: 94%-‐96%) respectively.
These analyses show that a substantial number of patients in need of ART are likely to be missed when WHO clinical staging alone is used as an ART eligibility assessment tool, with worsening performance as CD4 count thresholds are increased. Until point of care CD4 count measurement is readily available in remote and rural sites, and at primary health care centres and antenatal clinics, alternative, simplified and accurate ART eligibility assessment tools are required.