|Year : 2016 | Volume
| Issue : 3 | Page : 158-164
Clinicopathological characterization of cancer patients with human immunodeficiency virus infection in Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
Adeyemi S Adewuyi1, Olanrewaju A Oguntayo2, Adegbemisola M. O. Samaila3, Roseline K Adewuyi4, Omolara A Kolawole2, Festus Igbinoba5
1 Department of Radiotherapy and Oncology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Obstetrics and Gynaecology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
3 Department of Pathology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
4 Department of Nursing Services, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
5 Department of Radiotherapy, National Hospital, Abuja, Nigeria
|Date of Web Publication||17-Mar-2017|
Adeyemi S Adewuyi
Department of Radiotherapy and Oncology, Ahmadu Bello University Teaching Hospital, Zaria
Source of Support: None, Conflict of Interest: None
Background: Cancer and human immunodeficiency virus (HIV) infections are commonly associated diseases, particularly in subsaharan Africa. The objective of this study was to evaluate the clinical and pathological characteristics of cancer patients with background HIV infection.
Patients and Methods: This study was a retrospective study carried out between July 2006 and June 2013, at the radiotherapy and oncology department of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria. One hundred and two (102) histologically confirmed cancer patients were diagnosed to be HIV seropositive, of which 88 patients' folders were retrieved for retrospective analysis. Patients' clinical and laboratory information was documented during each visit and were analyzed using Epi Info software version 3.4.1; 2007 edition.
Results: Out of the 88 patients studied, the male-to-female ratio was 1:2; median age was 40 years and age range was 23–65 years. Only 27 patients were housewives and 7 were students. Primary education and above was attained by 71 patients, and there was no formal education in 15 patients. Cancer-related symptoms were the indication for HIV screening in 45 patients and ill-health in another 43 patients. Source of HIV infection was attributed to heterosexuality and blood transfusion in 76 and 4 patients, respectively. Using enzyme-linked immunosorbent assay, HIV-1 was seen in 37 patients, 1 patient had HIV-2, and 10 patients had HIV-1 and 2 seropositivity. Type of HIV was unspecified in 40 patients. Cervical cancer was the most common cancer (29) followed by Kaposi's sarcoma (23). Ocular cancer accounted for 12 out of 16 head and neck cancers. Most patients (70) presented with locally advanced disease and 16 patients with metastatic disease. The mean CD4 count was 323 and 402 cells/μl at presentation and 6 weeks after treatment, respectively. Only 44 patients were on highly active antiretroviral therapy at presentation. Only 24 patients had surgery; combination of chemotherapy and radiotherapy were given to 33 patients. No definitive treatment was given to 21 patients.
Conclusion: Cervical cancer and Kaposi's sarcoma were the most common malignancies seen with an underlying HIV infection.
Keywords: Cancer and HIV seropositive patients, chemotherapy, clinicopathologic characterization, radiotherapy
|How to cite this article:|
Adewuyi AS, Oguntayo OA, Samaila AM, Adewuyi RK, Kolawole OA, Igbinoba F. Clinicopathological characterization of cancer patients with human immunodeficiency virus infection in Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Arch Int Surg 2016;6:158-64
|How to cite this URL:|
Adewuyi AS, Oguntayo OA, Samaila AM, Adewuyi RK, Kolawole OA, Igbinoba F. Clinicopathological characterization of cancer patients with human immunodeficiency virus infection in Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Arch Int Surg [serial online] 2016 [cited 2017 Dec 11];6:158-64. Available from: http://www.archintsurg.org/text.asp?2016/6/3/158/202370
| Introduction|| |
Cancer and human immunodeficiency virus (HIV) infections are chronic diseases prevalent in the study environment., Although the management of this group of patients is still evolving, the presence of both in a patient not only stresses the patient but has management challenges. Does the presence of HIV change the natural history of disease, response to standard treatment, prognosis, and types of cancers seen? The authors hope this study will contribute in elucidating the pattern of cancers in HIV-positive patients.
In 1983, HIV-1 was cultured from the lymph node of a homosexual patient. Homosexuality is still a very high risk for HIV infection, although globally, most patients with HIV infection are heterosexual. As of 2006, the impact of the epidemic was staggering, with 40 million people worldwide being infected with HIV and an annual death rate of 3 million, making HIV the fourth leading cause of death worldwide and the first in South Africa. The HIV epidemic continues to grow internationally with the majority of the world's current HIV-positive individuals found in Africa. Access to highly active antiretroviral therapy (HAART) has changed the landscape of HIV-related care in the world with marked reduction in morbidity and mortality. The resultant effect is long-term survival of HIV-positive patients, with HIV infection becoming a chronic disease and a high possibility of patients developing HIV-related malignancies., The common HIV-related malignancies include Kaposi sarcoma, cervical cancer, anal cancer and non-Hodgkin's lymphoma, and HIV is a confounding factor in the management of these cancers due to drug toxicities, poor performance status, advanced disease, immunosuppression, and resultant opportunistic infections.,,
The World Health Organization (WHO) reports that cancer cases are on the rise and new cancer cases will double by 2020 with an annual death toll of 12 million. This calls for concern, especially in developing countries where HIV is a pandemic and there is a small number of facilities to manage cancers. Despite the deficient cancer registry in the country, the incidence of cancer is increasing in Nigeria. In the study environment, breast and cervical cancers are the leading malignancies in females whereas it is head and neck and prostate cancers in the males. The increase may be due to improvement in diagnostic facilities and life expectancy and an increase in awareness. The confounding issues of late presentation, advanced disease, and prevailing poverty have made optimal care a big challenge to the oncologist in this environment.,,
With HAART, the spectrum of malignancies in HIV-positive patients has been changing. Non-AIDS-defining cancers have been reported with increased incidence, including those most common in the general population. Some evidence, however, suggests that HIV-positive patients with cervical cancer are more likely than HIV-negative patients to have advanced disease at presentation, shorter duration of symptoms, undifferentiated histology, higher recurrence rate, and metastasis to unusual sites.,,
The approach to treatment does not differ from that of the HIV-negative patients, although cognizance of the special risks associated with chemotherapy is important, and as such facility to measure the CD4 count and viral load is a mandatory requirement for the safe and optimal management of this group of patients as it is a marker of immunologic status. In parallel with the treatment of chemotherapy-responsive malignancies, combination antiretroviral therapy with two or more agents appears to be the most effective way to suppress viral replication and to reduce the emergence of resistant virus.
The limitations in this study include social stigma, which prevents HIV-positive persons seeking hospital care and the high loss to follow-up among the populace. Other limitations include the small study population, the retrospective-descriptive study design, and missing folders.
There is need for concerted effort and collaboration among oncologists and clinicians involved in managing HIV patients for the best treatment options with resulting improved survival and less toxicities to therapy. This study is aimed at determining the sociodemographic and clinicopathological characteristics of cancer patients with background HIV infection.
| Patients and Methods|| |
This study was conducted retrospectively at the Radiotherapy and Oncology Department, Ahmadu Bello University Teaching Hospital, Nigeria. The institution is a tertiary referral center for cancer patients and HIV-related ailments, and one of the designated centers for the Federal Government of Nigeria assisted antiretroviral therapy PEPFAR (President's Emergency Plan For AIDS Relief) program located in the North-west geopolitical zone.
Between July 2006 and June 2013, consecutive patients seen with HIV infection, irrespective of diagnosis, comorbidity, histology report, stage of disease, and performance status were analyzed. The study involved only patients with histologically confirmed malignancies with associated HIV infection referred to the unit for further management. The biodata and all relevant clinical information were obtained from the patients' folder retrospectively. A total of 1402 cancer patients were seen, of which 102 patients were found to be HIV seropositive; however, only 88 patients' folder were retrieved and analyzed. Clinical staging was based on general examination, results of investigations at presentation, and findings at examination using the TNM classification of UICC 1997. Stage of disease was considered to be early stage if there was no extension into adjacent structures or regional lymph node involvement; locally advanced if there was involvement of adjacent structures, regional lymph node involvement, inoperable, bilateral or widespread in the absence of distant metastasis; and metastatic stage if there was distant metastasis. Metastatic sites were confirmed using relevant investigations [computed tomography (CT) scan, Chest X-rays, ultrasound of abdomen, bone scan, skeletal X-rays]. No metastatic site nor bone marrow was biopsied for histologic confirmation. The patients in this study included those referred from other clinical departments within the hospital and those referred from other hospitals within and outside the geopolitical zone. The histology reports from referring physicians were used for the study. Patients' folders were reviewed retrospectively with a structured proforma, and information retrieved included age, sex, histology, duration of symptoms, HIV type, CD4 count, blood transfusion history, sexual activity, employment and educational status, social habits, site of cancer, stage of disease, comorbidity, treatment received, and treatment-induced morbidity and mortality. Data were analyzed using Epi Info software version 3.4.1; 2007 edition, and the results presented in tables.
| Results|| |
[Table 1] shows the sociodemographic and clinicopathological characteristics of the patients. Analysis of the 88 seropositive patients revealed M:F = 1:2, median age of 40 years, and age range of 23–65 years. Only 27 patients were unemployed housewives, 23 had white collar jobs, 17 were petty traders, 14 were artisans, and 7 were students. Most patients (73) were married; 71 patients had at least primary school education, Arabic education in 2, patients and no formal education in 15 patients.
|Table 1: The sociodemographic and clinicopathologic characteristics of cancer patients with HIV|
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Cancer-related symptoms were the indication for HIV screening in 45 patients and ill-health in another 43 patients. Source of HIV infection was attributed to heterosexuality and blood transfusion in 76 and 4 patients, respectively, and unknown in 8 patients. HIV-1 was seen in 37 patients, 1 patient had HIV-2, and 10 patients had HIV-1 and 2 seropositivity. Type of HIV was unspecified in 40 patients.
Cervical cancer was the most common cancer (29 patients) followed by Kaposi's sarcoma, head and neck, and breast cancers with 23, 16, and 7, patients respectively. Ocular cancer (squamous cell carcinoma) accounted for 12 out of 16 head and neck cancers. The disease was locally advanced in 70 patients and 16 patients had metastatic disease. Metastases were to skin and ribs in addition to lungs, liver, and vertebral bones.
On diagnosis of cancer, the CD4 count range was 44–707 cells/µl of blood, with a of mean 323 cells, and 6 weeks after treatment, the range improved to 292–746 cells, with a mean of 402 cells/µl of blood. Only 44 patients were on HAART at presentation. All patients were sent to PEPFAR for further evaluation and commencement of HAART.
Combination of chemotherapy and radiotherapy were given to 33 patients, whereas 20 patients had chemotherapy only and 11 patients had radiotherapy only. Only 24 patients had surgery and no definitive treatment was given to 21 patients.
Of the 23 patients with Kaposi's sarcoma, both lower limbs were involved in 9 patients, only one lower limb in 4 patients, upper and lower limbs in 2 patients, and generalized involvement in 7 patients. Thirty-nine patients are alive, 40 were lost to follow up, and 9 confirmed dead. Six of the 9 dead patients died of AIDS. Clinical improvement was noted in 66 patients after treatment.
| Discussion|| |
The results of this study revealed that the number of female patients doubled that of male patients. This is related to the sociocultural practices in the study environment that favor early age of marriage/coitus and multiple sexual partners through polygamy as well as a high rate of divorce and remarriages, resulting in a risk of cervical cancer. The median age at presentation was 40 years, which is lower than the median age of 50 years for HIV-negative cancer patients, as seen in publications from the study environment which also agrees with the literature.,, The implication is that patients with background HIV infection are likely to develop cancer earlier than their counterparts without HIV infection by approximately 10 years. In a previous study on patients with cervical cancer with background HIV infection, the patients were also found to be younger.
The proportion of the patients seen with cancer and background HIV infection is 6.3%, which is similar to the HIV prevalence in some states, especially in northern Nigeria., With an improved prognosis for patients with HIV infection as a result of advances in supportive care and antiretroviral therapy, the neoplastic complications of HIV infection will grow in importance., This is the situation at present in HIV endemic regions in East and Southern Africa., There is a need for collaborative and multidisciplinary efforts on the part of subspecialty providers, and the extreme form of skepticism should be replaced by a cautious optimism as durable remissions will translate into long-term survival in patients whose HIV load can be suppressed.
The patients seen cut across different socioeconomic strata as both working class and unemployed were seen [Table 1]. Students were the least seen, which implies that the concerted effort on campaign against unprotected sex among students in higher institutions is yielding positive results. The alarming aspect is the high number of married people having cancer with background HIV. There is a need to include married people as a target of campaign against unprotected sex. However, high level of education alone may not prevent HIV infection.
Source of HIV infection was attributed to heterosexuality in a majority of cases. Homosexuality and use of drugs is illegal in Nigeria and patients are not likely to admit to the practice openly. Blood transfusion and blood related contacts were considered to be the source of infection in patients with a history of blood transfusion and no history of sexual activity. The virus is transmitted sexually, parenterally, and vertically. Worldwide, heterosexual transmission is most common although in the United States, and homosexual men are the largest HIV risk group. Other risk groups include injection drug users and health care workers.,, These results support the findings worldwide as well as in Africa that the HIV-1 is the predominant type., HIV-positive patients referred from other sister institutions rarely specify the HIV type in the result of HIV screening done.
Globally, the most common HIV-related malignancy is Kaposi sarcoma followed by non-Hodgkin's lymphoma. In this study, cervical cancer was the most common HIV-related cancer followed by Kaposi sarcoma. Some evidence, however, suggests that HIV-positive patients with cervical cancer are more likely than HIV-negative patients to have an advanced disease at presentation, shorter duration of symptoms, undifferentiated histology, poor response to conventional treatments, higher recurrence rate, and metastasis to unusual sites.,, In this study, another observation was that, among the head and neck cancers, ocular cancers arising from the conjunctiva (squamous cell carcinoma) accounted for three-quarter of the cases. This may be a new finding because conjunctival cancers have not been documented in the literature as an HIV-related cancer. The pattern of distribution in patients with Kaposi sarcoma is such that involvement of both lower limbs is the most common followed by generalized involvement of the lower and upper limbs and the trunk. In some KS cases, there is involvement of the oral cavity and the throat. The pattern of KS seen is similar to that seen in other HIV endemic regions.,,, The risk of development of KS for an HIV-positive patient in the pre-HAART era was estimated to be greater than 1000 times the risk in the HIV-negative population; with antiretroviral therapy, the incidence has reduced substantially., Aggressive B-cell non-Hodgkin's lymphomas including primary brain lymphoma have been formally recognized as AIDS-defining cancer.,, In this study, no patient presented with primary brain lymphoma despite radiation therapy being the choice of treatment. Patients with breast cancers were having bilateral breast cancer and metastatic disease at presentation.
Although previous study from this environment documented that approximately 70–80% of the HIV-negative patients present with locally advanced and metastatic disease; in HIV-positive patients, 98% of the patients presented with locally advanced and metastatic disease.,, The background immunosuppression accounted for the advanced stage and relative aggression of the disease in the studied patients. This is consistent with the literature.,,, The duration of symptoms is relatively shorter than HIV-negative patients and the disease progressed rapidly within the short duration. It was also found that the sites of distant metastases were different from usual sites documented in the literature according to the natural history of the disease and the tumor biology., In this study, cervical cancer was found to metastasize to bones (humerus and ribs) with pathologic fracture. Metastases to skin as nodules on the back, trunk, and neck were also seen. All the patients with non-Hodgkin's lymphona had extranodal involvement with symptoms of intestinal obstruction in addition to widespread lymphadenopathy, B symptoms, and bulky disease in the abdomen, liver, and spleen with a risk of tumor lysis syndrome. According to the literature, advanced stage with disease above and below the diaphragm, extranodal disease, and constitutional symptoms are frequently seen in patients with HIV-associated lymphoma., According to this study, advanced and metastatic stage necessitates combination chemotherapy as the mainstay of therapy. The challenge that remains is to integrate the growing armamentarium of antiretroviral therapies with efforts to balance efficacy and chemotherapy-related toxicities.
Following significant improvement in the quality of life of most patients with HAART and treatment of opportunistic infections, many oncologists became quite comfortable with treating HIV-positive cancer patients. A confounding factor is the level of CD4 count that is optimal for therapeutic intervention in this class of patients., In this study, a minimum level of CD4 count of 200 cells per microlitre of blood was used for therapeutic intervention, which at times difficult to achieve. Patients were generally optimized with HAART, antibiotics, antifungal, supplements, blood transfusion, and antimalarials depending on the need, especially in patients with CD4 count of less than 200 cells/µl. No patients received chemotherapy or radiotherapy with a CD4 count of less than 200 cells/µl. There was evidence of improvement clinically and in the quality of life of the patients treated, as in many cases symptoms were well-palliated and CD4 count improved significantly. Despite the administration of conventional treatment, the response was suboptimal, especially in those with metastatic disease. The best outcomes were seen in patients with Kaposi sarcoma with limited disease, followed by non-Hodgkin's lymphoma. The response was poor in patients with head and neck, cervical, and breast cancers. Persistent disease and disease progression was the situation with cervical cancer as most patients are weak for brachytherapy procedures. Those who had brachytherapy relapsed within a very short period with distant metastasis.
With adequate optimization, three-quarter patients were optimally palliated using chemotherapy, radiotherapy, or both. A quarter of the patients were referred back to parent clinicians. We found a uniformly high rate of disease progression and mortality clustered among patients with initial low CD4 count (below 200 cells/µl) and those who failed to improve despite commencement of HAART. This is consistent with the literature., In this study, patients with good CD4 count tolerated the treatment better with improvement in quality of life and survival.
In those confirmed dead, AIDS was the main culprit. Follow-up in cancer patients is a major problem in the study environment. Once patients have some improvement clinically, most fail to come for follow-up until there is a relapse, distant metastases, or medical problems, which may not be related to the primary cancer. The use of GSM telephoning was introduced but only useful in few patients due to nonexistent network in the villages and the patients' inability to purchase phones. Despite the poor prognosis of cancer in HIV-positive patients, approximately half of the patients are alive with significantly improved quality of life and survival. There is a need for further study to evaluate the best chemotherapy regimen as well as measures to be taken to reduce mortality. The authors believe that a more aggressive supportive care will reduce mortality and routine screening for cancer in the HIV clinics will reduce late presentation and advanced disease.
| Conclusion|| |
Females and housewives are twice at risk of HIV-related cancer compared to males. Cervical cancer is the most common cancer followed by Kaposi sarcoma in HIV seropositive patients. Ocular cancer (squamous cell carcinoma) accounted for the majority of head and neck cancers. HIV type 1 is the most common type of HIV infection occurring in cancer patients. There is a need for routine screening for cancer in the HIV clinics to reduce late presentation and advanced disease. A collaborative study is needed to further elucidate the measures required to reduce mortality and improve the overall survival of this class of patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Adewuyi SA. Cervical Cancer in HIV Seropositive patients. Ann Afr Med 2007;6:41-2.
] [Full text]
Adewuyi SA, Shittu SO, Rafindadi AH. Sociodemographic and Clinicopathologic Characterization of Cervical Cancer in Northern Nigeria. Eur J Gynaec Oncol 2008;29:61-4.
Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al
. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868-71.
UNAIDS/WHO: AIDS epidemic update; 2006.
Leblanc PA. Impact of HIV/AIDS on trends in major causes of death at a rural mission hospital in Kenya: Review of 4858 records. Ann Afr Med 2006;5:142-8.
Erhabor O, Ejele OA, Uko EK. HAART-Dependent CD4+ lymphocyte response based on pre-therapeutic CD4 lymphocyte count in HIV-infected Nigerians. Ann Afr Med 2006;5:153-7.
Cameron DW, Heath-Chiozzi M, Danner S. Prolongation of life and prevention of AIDS complications in a randomized controlled clinical trial of ritonavir in patients with advanced HIV disease. Lancet. 1998;351:543-9.
Oguntayo OA, Zayyan M, Kolawole AOD, Adewuyi SA, Samaila MOA. Epidemiology of Gynaecologic cancers in Zaria, Northern Nigeria. Ital J Gynaecol Obstet 2012;24:168-73.
Adewuyi SA, Campbell OB, Ketiku KK, Duronsinmi-Etti FA, Kofi-Duncan JT, Okere PC. Current Status of Radiation Oncology Facilities in Nigeria. West Afr J Radiol 2013;20:30-6. [Full text]
Dawotola DA, Olasinde TA. Radiotherapy in Cancer management at Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. Niger Med Pract 2004;45:45-8.
Grulich AE, Li Y, McDonald A, Correll PK, Law MG, Kaldor JM. Rates of non–AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS 2002;16:1155-61.
Gates AE, Kaplan LD. AIDS malignancies in the era of highly active antiretroviral therapy. Oncology 2002;16:441-59.
Ambinder RF. HIV-Associated malignancies. In: Abeloff MD, Armitage OJ, Niederhuber JE, Kastan BM, McKenna GW, Editors. Abeloff's Clinical Oncology. Clinical Oncology. 3rd
ed. Philadelphia: Elsevier Churchill Livingstone Publishers; 2004. p. 2647-59.
Xicoy B, Ribera JM, Miralles P, Berenguer J, Rubio R, Mahillo B, et al
. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral therapy in advanced stage, human immunodeficiency virus–related Hodgkin's lymphoma. Haematologica 2007;92:191-8.
Nasidi A, Harry TO. The Epidemiology of HIV/AIDS in Nigeria. In: Adeyi O, Kanki PJ, Odutolu O, Idoko JA, editors. AIDS in Nigeria: A nation on the threshold. Cambridge (Massachusetts): Harvard Center for population; 2006. p. 17-36.
In a New Survey, Nigeria's HIV/AIDS Prevalence drops to 3.4%. www.thisdaylive.com. December 6, 2013.
Batter V, Matela B, Nsuami M, Manzila T, Kamenga M, Behets F, et al
. High HIV-1 incidence in young women masked by stable overall seroprevalence among child bearing women in Kinshasa, Zaire: Estimating incidence from serial seroprevalence data. AIDS 1994;8:811-7.
Zwi K, Pettifor J, Soderlund N, Meyers T. HIV infection and in-hospital mortality at an academic hospital in South Africa. Arch Dis Child 2000;83:227-30.
Gerberding JL. Clinical practice: Occupational exposure to HIV in health care settings. N Engl J Med 2003;348:826-33.
Dal Maso L, Serraino D, Franceschi S. Epidemiology of AIDS-related tumours in developed and developing countries. Eur J Cancer 2001;37:1188-201.
Moore PS. The emergence of Kaposi's sarcoma–associated herpesvirus (human herpesvirus 8). N Engl J Med 2000;343:1411-3.
Kirk O, Cozzi-Lepri A, Antunes F, Miller V, Gatell JM, Katlama C, et al
. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001;98:3406-12.
Besson C, Goubar A, Gabarre J, Rozenbaum W, Pialoux G, Châtelet FP, et al
. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001;98:2339-44.
Hoffmann C, Wolf E, Fätkenheuer G, Buhk T, Stoehr A, Plettenberg A, et al
. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 2003;17:1521-9.
Levine AM, Scadden DT, Zaia JA, Krishnan A. Hematologic aspects of HIV/AIDS. Haematology 2001;2001:463-78.
Sparano JA. Clinical aspects and management of AIDS-related lymphoma. Eur J Cancer 2001;37:1296-305.
Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137:381-433.
Thorner A, Rosenberg E. Early versus delayed antiretroviral therapy in patients with HIV infection: A review of the current guidelines from an immunological perspective. Drugs 2003;63:1325-37.