In sub-Saharan Africa, the transmission of Human Immunodeficiency Virus (HIV-1) occurs mostly through heterosexual contact and the progression to Acquired Immunodeficiency Syndrome (AIDS) and premature death is the reality for people in most poor areas with limited access to Antiretroviral Therapy (ART) [1-3]. HIV disease progresses from an asymptomatic period of variable duration, through mild symptoms, to severe disease characteristic of cellular immunodeficiency [1].

Human Immunodeficiency Virus clinical presentation is known to be complex since AIDS was described in 1981[2, 3]. HIV can manifest in a variety of ways depending on the organs affected and concurrent infections prevalent in the area. The initial clinical presentation may mimic symptoms of common endemic diseases in that particular region [4, 5] However, the severity of manifestation depends on the infected individual’s baseline health status. The most significant early manifestation of HIV infection in Africa was marked by slim disease (diarrhoea and wasting); tuberculosis; variety of Opportunistic Infections (OI); weight loss, fever; and dermatological symptoms [2,5,6]. With the exception of tuberculosis which continues to increase, other AIDS related diseases are declining gradually due to the widespread use of OI drugs.

World Health Organization (WHO) has established a four stage clinical classification system determined by the presence of Opportunistic Infections and other HIV related conditions [7]. This classification tried to incorporate most of the AIDS-defining illnesses occurring in all regions of the world making a global tool for HIV/AIDS patients care and treatment. It has been a very useful tool in Sub Saharan Africa at the introduction of antiretroviral drugs and establishment of HIV/AIDS treatment cohorts [8]. It helped to capture rapid deteriorating patients and initiation of ART in settings with limited diagnostic resources and less trained clinicians.

Antiretroviral drugs are widely available nowadays and continue to be scaled up in remote rural areas of sub Saharan Africa [9, 10]. The aim of rapid scale up is to reach more people living with HIV and AIDS who cannot easily access ART services in urban hospitals. The main challenges to this plausible strategy include availability of qualified health workers and laboratory services to ensure quality care and the monitoring of drug use [11-13]. In addition, most patients including HIV-infected patients in Sub Saharan Africa present late for hospital care and treatment when the disease has advanced [13-15]. By then initial AIDS signs and symptoms might have been treated empirically through self medication or use of herbal medicines. Such remedial actions usually obscure important AIDS clinical features and make it difficult for the attending clinician to solicit signs and symptoms to properly stage the patient.

It is evident that HIV/AIDS patients’ management in Sub Saharan Africa continues to be guided primarily by clinical staging [8, 16, 17] owing to the insufficient availability and/or frequent breakdowns of CD4 cells count machines, shortage of qualified medical personnel and laboratory reagents and other logistic issues impair [18]. On the other hand WHO clinical staging depends on a patient presenting signs and symptoms; knowledge and skills of the health care worker to make a definitive staging [8,17,19]. Furthermore, WHO clinical staging is less sensitive in identifying patients with CD4 cell counts between 200 -350 cells per µL [4, 20]. Therefore, it fails to identify some patients in need of ART.

Taking into considerations the complexities of HIV clinical manifestation in our setting which often does not match WHO clinical staging. Clinicians in lower health facilities, who are expected to attend to HIV patients in their local settings, need simplified and easy to use clinical staging guidelines developed by utilizing site specific data and clinical experiences. This approach could effectively support management of HIV/AIDS patients in ART cohorts based on site specific experiences. Moreover, the broader availability of ART as well as new approaches to deal with opportunistic infections call for a review of the clinical presentations seen within care and treatment programs in different settings. To date, no studies have proposed simplified HIV/AIDS clinical staging based on local experience. With the inspiration of WHO validated HIV/AIDS clinical definition, our study aimed at developing simplified HIV/AIDS clinical staging system based on data generated locally from peri-urban and rural health facilities to allow more effective patient management and ART cohorts at peripheral level in the absence of CD4 counts.

During the study period 421 HIV-infected patients aged 15 to 80 years were recruited to participate in the study, 341(81.0%) and 80(19.0%) were from Tumbi hospital and Chalinze health centre, respectively. Sixty one (14.5%) patients declined to participate due to various reasons (Fig. 1). In total 360(85.5%) patients were consented, complete data for analysis was recorded from 331 (78.6%) patients. Twenty nine patients were excluded from the final analysis due to incomplete data, i.e. doubtful CD4 counts results or names, age and sex not corresponding to clinical information. Patients rejected to participate in the study and those excluded from analysis had similar social and demographic characteristics to those finally analyzed.

This study attempted to develop and validate HIV clinical staging tailored to a particular geographical and endemic area in comparison to the well established WHO-staging. The clinical profiles of about 34% of patients were unique and obscured which in turn resulted in WHO staging that was inconsistent with the CD4 cell counts. The majority of the patients presented with clinical features of weight loss (and wasting); chronic cough; and persistent fever for more than 2 weeks. These are common symptoms and signs which were described as early HIV manifestation and significantly were associated with sero-conversion in the first decades of HIV epidemic [23, 24]. We also observed a marked shift in AIDS clinical manifestation from the classical AIDS clinical manifestations [23] which previously was marked by profound weight loss of more than 10% body weight; chronic diarrhoea and prolonged fever for more than one month to a mixed picture of signs and symptoms [23-25]. Although, our patients had reported weight loss, the weight loss was limited to more than 5 kg and less than 5% (data not shown) of their initial body weight. The clinical spectrum seen among the patients in both study sites are quite representative to the overall clinical pictures of the HIV/AIDS patients in the area. The two sites are the only care and treatment centres in the whole area.

Interestingly, only 10.6% of the patients presented with chronic diarrhoea. This is a marked reduction in occurrence of diarrhoea among HIV/AIDS patients attending care and treatment clinics. Diarrhoea is well known to affect 40%-80% HIV infected persons and was also associated with high mortality rates in Sub-Saharan Africa [24, 26, 27]. The reduction in prevalence of diarrhoea in HIV infected people can be explained by the now broader availability of OIs drugs and co-trimoxazole without prescription.

Working at care and treatment centres, we recruited newly diagnosed HIV patients that were all included in the ART cohorts according to the Tanzania National HIV/AIDS control programme guidelines. We expected to record more pre-AIDS signs and symptoms such as generalized lymphadenopathy, Herpes zoster and mucocutaneous lesions. Instead, one third of our patients presented with minor non specific and often no symptoms. Most of these patients had CD4 cell counts less than 200 cells per µL. Herpes zoster was diagnosed in 5% of patients, most of them had CD4 cell counts below 200 cells per µL which is contrary to the common believe that Herpes zoster is a stage II disease. It is a reality in most rural, poor communities to accept a HIV test after suffering for a long time and tried on all kinds of remedies without success. During this time their CD4 cell counts progressively declined.

Most of the known common HIV related opportunistic infections were less frequent than expected in this population despite many patients having CD4 cell counts less than 200 cells per µL. It is well established that patients at this level of CD4 cell counts have high risk of AIDS opportunistic infections and AIDS related cancers [28]. Tuberculosis was diagnosed in only 15% of the patients despite the high frequency of chronic cough and difficulty in breathing. Patients with extra pulmonary tuberculosis and Pneumocystis carinii pneumonia could be missed due to limited respective diagnostic facilities. The diagnosis of these diseases was based on sputum and chest x-ray findings. In routine practice, tuberculosis in HIV-infected patients requires regular screening at every visit because single screening does not exclude latent infection that can flare up in the course of HIV disease progression.

Cryptococcus meningitis and Kaposi’s sarcoma were diagnosed in only 3% of the patients. However, the lower rate of HIV related cancers can be justified by the small sample size of this study. Overall, the different clinical patterns and frequencies of opportunistic infections may largely be due to changed approaches in the clinical management brought forward by (i) the broader availability of ART in combination with the establishment of care and treatment centres as part of the Tanzania National HIV/AIDS control program and (ii) the new approaches to handle prophylactically and therapeutically opportunistic infections also outside the Tanzania National HIV/AIDS control program.

The level of incorrect WHO clinical staging found in this study is almost similar to Ugandan experiences where about 50% of patients were inappropriately staged [20]. In routine clinical practice WHO clinical stages determine the direction of HIV/AIDS case management. Patients in clinical stages I and II usually receive long time appointments accompanied by minimum laboratory investigations. While, patients in clinical stages III and IV usually receive clinical and laboratory assessment to determine their eligibility to start ART. Therefore, when a sizable proportion of patients cannot be staged correctly at first contact in ART clinics, the initiation of ART is delayed and higher mortality rates can be expected in the first three months of ART [13].

More than half of our patients were in WHO clinical stages III and IV which was consistent to the number of patients with CD4 cell counts of less than 200 cells per µL. This is the reality of late presentation and a challenge to ART programs. Using the cut off point for severe immunosuppression of CD4 cell counts ≤200 cells per µL; comparison is more conservative based on the Tanzania Care and Treatment Guidelines [16]. However, if a CD4 cell count of ≤350 cells per µL is taken as cut off for advanced immune depression, then the proportion of patients with severe immune depression reaches about 70% of all cases seen in this study. Taking into consideration the high proportion of patients presenting late with obscured clinical features to care and treatment for the first time, it appears advantageous to classify patients into severe and moderate immune-suppression. Such an approach simplifies the process of clinical staging and reduces the chances of missed appropriate staging and hence delays in starting ART can be avoided.

In our study, skin diseases and fungal infections of the skin and mucous membranes indicated severe immuno-suppression when used clinically to stage patients. However, these symptoms do not strongly predict severe immunodeficiency based on CD4 decline (odds ratio 1.2, 95%CI, 0.52-2.92). In addition about 75% of patients with herpes zoster were severely immunosuppressed. Most of the symptoms showed high sensitivity in predicting severe immunosuppression which is also an indication of clinicians’ adherence to treatment guidelines. When compared to CD4 count levels, there was no consistency. If the combination of three clinical features is used, the probability of predicting severe disease reaches 100% and is consistent with the decline of CD4 cell counts. High sensitivity with lower specificity further supports this patients’ classification because of the vulnerability of HIV patients to opportunistic infections if missed and delayed to receive ART.

Based on these study findings, we then recommend for the local application of the new classification of HIV infected patients into severe and moderate immuno-suppression based on duration of clinical manifestations. This classification guided by local clinical experience - requires further validation. We recognize the small sample size used in this study as a limitation. However the composition of patients from rural and urban settings implies that the guidelines established can be used at a regional level. Therefore and besides our current own efforts, more studies should be conducted to validate the proposed approach of staging, not only for patients’ classification but also for monitoring drug side effects and treatment failure in other geographical and endemic settings.

The broader availability of HIV/AIDS treatment as well as new approaches to deal with opportunistic infections, we call for a review of the clinical presentations seen within care and treatment programs in different settings. Besides applying the WHO clinical staging care and treatment centres that look after large cohorts of HIV and AIDS patients information should also be collected to develop and validate site specific guidelines based on local experiences as shown in this study of which the results are currently being validated in other settings.