Clinical Characteristics and The Selection of Initial ARV Regimen Therapy for HIV-Infected Patients in VCT-CST RSUP Sanglah, Denpasar

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1 Clinical Characteristics and The Selection of Initial ARV Regimen Therapy for HIV-Infected Patients in VCT-CST RSUP Sanglah, Denpasar I G. A. Putu Candradewi, I Ketut Agus Somia Departement of Internal Medicine, Medical Faculty of Udayana University/RSUP Sanglah ABSTRACT Number of new cases of HIV infections in Bali is still high and ARV becomes the one and only therapy. There are many ARV drugs used globally. The selection of ARV regimens are closely related to the patients clinical characteristics. So that, in this study, the author investigates the clinical characteristics of initial ARV regimen therapy in VCT-CST RSUP Sanglah so does the factors related to the selection of initial ARV regimen. This study is retrospective study, using descriptive methods. Data of the patients are distributed based on initial ARV regimen and other variables related to therapy and patients clinical characteristics. The significance of differences of patients clinical characteristics among the initial ARV regimens are also tested using ANOVA and chi-square test to find out the factors related to the selection of inital ARV regimen for the patients. Based on the study of 127 patient s medical records, 69.3% (n=88) of patients receive NVP based regimen (AZT/3TC/NVP), 21.3% (n=27) of patients receive EFV based regimen (AZT/3TC/EFV), and 9.4% (n=12) of patients receive TDF based regimen (TDF/3TC/NVP or TDF/3TC/EFV). Characteristics that are significantly different among the three regimens are patients opportunistic infections (p=0.000), initial hemoglobin (p=0.009), side effect appearance (p=0.022) and change of regimen during 6 months of therapy (p=0.048). Initial ARV regimens commonly used for HIVinfected patients at VCT-CST RSUP Sanglah are NVP based regimen (AZT/3TC/NVP), EFV based regimen (AZT/3TC/EFV), and TDF based regimen (TDF/3TC/NVP or TDF/3TC/EFV). Selection of initial ARV regimens is related to the opportunistic infections, initial hemoglobin of the patients, the appearance of side effect, and tendency to change ARV regimen. Keywords. HIV infection, initation of ARV regimen therapy, ARV regimens, characteristics of ART, treatment onset, change of regimen. INTRODUCTION Human Immunodeficiency Virus (HIV) infection has been an endemic worldwide. An estimation of 35.3 ( ) million people were living with HIV all over the world in New HIV infection cases in 2012 was 2.3 ( ) million. However, it declines if compared to the number of new infections in 2001 which is 3.4 ( ) million. The number of death cases because of AIDS (Acquired Immunodeficiency Syndrome) is also declining, from 2.3 ( ) million in 2005 to 1.6 ( ) million AIDS deaths in

2 Bali as one of popular tourists destination has been very open to global world. So does the infection, which can be easily spread from people who are travelling in Bali to local people and vice versa. It causes Bali places the top five provinces with the highest HIV cases in Indonesia. Many ways have been done to prevent HIV transmission among people in Bali, either by the government, health care providers, or community organization. However, the number of new HIV infection cases is still high eventhough it is decreasing year by year. There haven t been any treatment that can eradicate HIV virus from human body. In order to survive with the virus inside their body, HIV infected person needs to be treated with drugs that can suppress the viral repication and progression which called antiretroviral (ARV). Suppression of HIV replication is important in prolonging life and improving the quality of life in patients with HIV infection. Patients undergoing treatment for HIV infection have to take a daily regimen of at least three antiretroviral drugs. 2 Antiretroviral (ARV) therapy has been used widely around the world to treat people who are already infected by HIV. The number of ART receiver all over the world is increasing year by year. 1 However, there are still many issues about starting antiretroviral therapy such as the timing and regimen for initiation of therapy. Based on a study, early initiation of ARV therapy, especially within the first 6 months after HIV infection can give better outcome compared to the therapy initiated during chronic HIV infection. 3 HHS Panel on Antiretroviral Guidelines for Adults and Adolescents has classified many kinds of ARV regimens into 3 groups: preferred regimens, alternative regimens, and other regimens. 4 Among many kinds of initial ARV regimen, patients clinical characteristics are important to determine which initial ARV regimens will be given to patients. As the effectiveness of therapy and outcome are very closely related to the factors mentioned before, the author would like to discuss about the clinical characteristics of ARV therapy and selection of initial ARV regimen for HIV-infected patients in VCT-CST clinic of RSUP Sanglah, Denpasar. METHODS This study is a retrospective study using descriptive method to presents the clinical characteristics of patients among the initial ARV regimens used in VCT-CST RSUP Sanglah, Denpasar in The study was done at VCT-CST clinic of RSUP Sanglah, Denpasar. The data was collected on November 21 st 25 th, Population of this study is HIV-infected patients who receive their initial ARV regimen therapy in VCT- CST RSUP Sanglah in Sample is taken from the population after excluding some patients whose medical records cannot be found. This study begins with collecting data that is taken from the patients medical records, then processed, analyzed and presented in form of frequency and descriptive tables. Data processing and analyzing are done by distributing the independent variables toward the dependent variable. Dependent variable is the type of ARV regimens received by HIV patients in VCT-CST RSUP Sanglah in Independent variables are age, sex, pregnancy status, body weight, clinical manifestation, x-ray finding, opportunistic infection, initial laboratory result (hemoglobin, SGOT/SGPT, BUN/SC, and initial CD4+ count), treatment onset, CD4+ 2

3 after 6 months of therapy, side effect of initial ARV regimen, change of regimen during 6 months of therapy, CD4+ change after 6 months of therapy, and mortality. RESULTS Distribution of Data Based on the Initial ARV Regimen Based on the study of 127 patient s medical records, there are 3 different regimens of antiretroviral (ARV) used in VCT-CST RSUP Sanglah to initiate the treatment of HIV-infected patients in All of the regimens contain lamivudine (3TC), but the other two drugs are different based on the patient s characteristic and doctor s consideration. Other ARV drugs used as initial treatment are zidovudine (AZT), nevirapine (NVP), efavirenz (EFV), tenofovir disoproxil fumarate (TDF). Data of 127 patients medical record is distributed based on 3 ARV regimens, which are nevirapine based (AZT/3TC/NVP), efavirenz based (AZT/3TC/EFV), and tenofovir disoproxil fumarate based (TDF/3TC/NVP and TDF/3TC/EFV). Frequency of the 3 kinds of regimen used is shown in Figure % 21.3% 9.4% Figure 1. Frequency of initial ARV regimen used in VCT-CST RSUP Sanglah in 2012 (n=127) Patients Clinical Characteristics among the Three Initial ARV Regimens Therapy Based on Table 1, the mean age of patients using NVP based therapy is years, while the EFV based is years and TDF based is years. Most of the patients are male. There are 5 patients among females who are pregnant. Means of body weight of the patients are kg in NVP based regimen, kg in EFV based regimen, and kg in TDF based regimen. Most of the patients initiate therapy before 6 months after the date of firstly diagnosed as positive HIVinfected. Almost all of the patients show some clinical manifestations when initiating therapy. Patients with 3

4 opportunistic infections mostly receive NVP based therapy. Opportunistic infections are related to the selection of initial ARV regimen (p<0.05). Table 1. Sociodemographic Characteristic of patients of Each Initial ARV Regimen Therapy Variables NVP based Missing EFV based Missing TDF based Missing p (n=88) Data (n=27) Data (n=12) Data value Age, mean±sd, years 32.66± ± ± Male, frequency (%) 53 (65.4) 0 20 (24.7) 0 8 (9.9) Pregnant, frequency 3 (60) 0 1 (20) 0 1 (20) (%) Body weight, 52.78± ± ± mean±sd, kg Treatment onset, 3.98± ± ± mean±sd, months With clinical 64 (66.7) 2 20 (20.8) 1 12 (12.5) manifestation, freq. (%) With oppurtunistic infection, freq. (%) 37 (51.4) 1 25 (34.7) 0 10(13.9) Table 2. Characteristics of Initial Laboratory Results of patients of Each Initial ARV Regimen Therapy Variables With abnormal x-ray finding, freq. (%) Initial Hb, mean±sd, g/dl Initial SGOT, mean±sd, U/L Initial SGPT, mean±sd, U/L Initial BUN, mean±sd, mg/dl Initial SC, mean±sd, mg/dl Initial CD4+, mean±sd, cells/ul NVP based (n=88) Missing Data EFV based (n=27) Missing Data TDF based (n=12) Missing Data p value 11 (57.9) 2 6 (31.6) 1 2 (10.5) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Abbreviation: SD, standard deviasion; Hb, hemoglobin; SGOT, Serum Glutamic Oxaloacetic Transaminase; SGPT, Serum Glutamic Pyruvic Transaminase; BUN, Blood Urea Nitrogen; SC, Serum Creatinine. In Table 2, 57.9% of patients who have abnormalities on their x-ray examination receive NVP based regimen, 31.6% receive EFV based regimen, and 10.5% receive EFV based regimen. Means of initial hemoglobin of the patients receiving the three initial regimens are g/dl (NVP based), g/dl (EFV based), and g/dl (TDF based). Variable initial Hb has p<0.05, means that this variable is significantly different among the three initial ARV regimens. It also means that initial hemoglobin count is related to the selection of initial ARV regimen. Mean of initial CD4+ count of the patients receiving NVP based regimen is cells/µl, while in EFV based regimen is cells/µl and in TDF based regimen is cells/µl. 4

5 Table 3. Characteristics of Patients Outcome after 6 Months of Therapy Variables CD4+ after 6 months of therapy, mean±sd, cells/ul Side effect appears, freq. (%) Toxicity appears, freq. (%) Change of regimen, freq. (%) After 6 months CD4+ change, freq. (%) NVP based Missing EFV based Missing TDF based Missing p (n=88) Data (n=27) Data (n=12) Data value ± ± ± (84.1) 0 6 (13.6) 0 1 (2.3) (100) 0 0 (0) 0 0(0) (84.2) 0 5 (13.2) 0 1 (2.6) (69.6) (21.5) 10 7 (8.9) Mortality, freq. (%) 4 (57.1) 0 1 (14.3) 0 2 (28.6) After 6 months of therapy, the means of patients CD4+ count are cells/µl in patients receiving NVP based regimen, cells/µl in patients receiving EFV based regimen, and 137 cells/µl in patients receiving TDF based regimen. Side effects are common in patients using NVP based regimen. The appearance of side effects is significantly different among the three regimens (p<0.05) means that it is related to the selection of initial ARV regimen. Toxicity is very rarely happen. One case of toxicity in the table above is mild toxicity caused by nevirapine (NVP). Some patients change the component or drug of their initial ARV regimen during the first 6 months of therapy. The difference is significant among the three regiems, means that the tendency to change ARV regimen are related to the selection of initial ARV regimen. 57.1% of patients who died during the first 6 months of therapy are from NVP based receivers, 14.3% are from EFV based receivers, and 28.6% are from TDF based receivers. Table 4. Distribution of Data of Each Initial ARV Regimen Based on Treatment Onset from Firstly Diagnosed until Initiation of Therapy Treatment Onset NVP based (n=88) EFV based (n=27) TDF based (n=12) Frequency (%) Frequency (%) Frequency (%) <6 months months 2 years >2 years Not known Based on the table above, most of the patients initiate ARV regimen therapy in the first 6 months after they are firstly diagnosed as positive for HIVinfection. Among them, 70.5% receive NVP based regimen, 21% receive EFV based regimen, and 8.6% receive TDF based regimen. Only 5 patients initiate therapy after 2 years since the date of diagnosis and they receive NVP based regimen. 5

6 Table 5. Distribution of Data of Each Initial ARV Regimen Based on Patients Clinical Manifestation Clinical manifestation NVP based (n=64) EFV based (n=20) TDF based (n=12) Frequency (%) Frequency (%) Frequency (%) Weight loss Cough Oral thrust Dysphagia Fever Diarrhea Skin abnormalities Lymph node enlargement Gonorrhea Herpes zooster Miscellaneous The most common clinical manifestation of patients receiving ARV regimen therapy is weight loss, which is 64.5% patients receive NVP based regimen, 24.2% patients receive EFV based regimen, and 11.3% patients receive TDF based regimen. Skin abnormalities includes some abnormal skin effloresence such as hyperpigmented macule, prurigo nodularis, erythema, and skuama. There is one case of gonorrhea infection and the patient receive NVP based regimen. Miscellaneous clinical manifestations includes headache, stomachache, blurred vision, and running nose. Table 6. Distribution of Data of Each Initial ARV Regimen Based on Opportunistic Infection Opportunistic Infection NVP based (n=37) EFV based (n=25) TDF based (n=10) Frequency (%) Frequency (%) Frequency (%) Lung tuberculosis PCP URTI Bronchitis Pneumonia Oral candidiasis Toxoplasmosis Lymphatic system infection Hepatitis B Miscellaneous The most common opportunistic infection occurs in patients receiving ARV regimen therapy is lung tuberculosis. 45.7% of patients with lung tuberculosis receive NVP based regimen, 45.7% others receive EFV based regimen, and the other 8.7% receive TDF based regimen. PCP reffers to Pneumocystis Carinii Pneumonia and URTI reffers to upper respiratory tract infection. Lymphatic system infection 6

7 includes lymphadenitis tuberculosis and lymphangitis tuberculosis. Miscellaneous finding includes herpes zooster, retinitis CMV, diarrhea, condiloma accuminata, herpes simplex genital, recurrent varicella, and blepharoconjunctivitis. The difference of lung tuberculosis, hepatitis B, and miscellaneous infections percentage among the three regimens is significant (p<0.05). It indicates that the appearance of those opportunistic infections are related to the selection of initial ARV regimen and vice versa. Table 7. Distribution of Data of Each Initial ARV Regimen Based on X-ray Abnormalities X-ray finding NVP based (n=11) EFV based (n=6) TDF based (n=2) Frequency (%) Frequency (%) Frequency (%) Pneumonia Bronchitis Pleural efusion Suspect BE Infiltrate Lung tuberculosis PCP Miscellaneous The most common abnormality found on patients x-ray result is pneumonia. 60% of patients with pneumonia receive NVP based regimen and 40% of them receive EFV based regimen. All patients with bronchitis, pleural effusion, and PCP findings receive NVP based regimens. Suspect BE reffers to suspect bronchiectasis and PCP reffers to Pneumocystis Carinii Pneumonia. Miscellaneous finding includes cardiomegaly and toxoplasmosis. In the table, of lung tuberculosis is less than It indicates that x-ray finding of lung tuberculosis is related to the selection of initial ARV regimen for the patient. Table 8. Distribution of Data of Each Initial ARV Regimen Based on Side Effects Side Effects NVP based (n=37) EFV based (n=6) TDF based (n=1) Frequency (%) Frequency (%) Frequency (%) Anemia Skin abnormalities Itching Stevens-Johnson Syndrome Allergy Nausea Miscellaneous Anemia is the most common side effect occurs on patients receiving initial ARV regimen therapy. 88.9% cases of anemia occurs on patients receiving NVP based regimen and 11.1% occurs on patients receiving EFV based regimen. Skin abnormalities in NVP based regimen reffers to erythema multiforme (30%), urticaria (30%), reddish papules (20%), and skin redness (20%). While, skin 7

8 abnormality in TDF based regimen reffers to erythema multiforme. Miscellaneous side effect includes vomiting, tinitus, dizziness, and dyspepsia. Table 9. Distribution of Data of Each Initial ARV Regimen Based on After 6 Months CD4+ Change After 6 Months CD4+ NVP based (n=88) EFV based (n=27) TDF based (n=12) p Change Frequency (%) Frequency (%) Frequency (%) value Increase Decrease Not known Table 10. Pattern of Average Increase in CD4+ count after 6 Months of Therapy NVP based (51) Average increase, mean±sd, cells/µl EFV based (15) Average increase, mean±sd, cells/µl NVP based (7) Average increase, mean±sd, cells/µl ± ± ± Most of the patients develop an incerase in their CD4+ count after 6 months of therapy. 69.9% of patients whose CD4+ count increases are patients receiving NVP based therapy, 20.5% are from EFV based and 9.6% others are from TDF based one. Decrease in CD4+ count also occurs in NVP based regimen (66.7%) and EFV based regimen (33.3%). None of the classification of after 6 months CD4+ change has p<0.05 indicates that those changes are not significantly different among the three initial ARV regimens. The average of increase of CD4+ count after 6 months of therapy among the three regimens are not significantly different as shown in the Table 10. DISCUSSION Based on 127 patients who initiate their ARV regimen therapy at VCT-CST RSUP Sanglah in 2012, 69.3% of them receiving NVP based regimen (AZT/3TC/NVP) for initial therapy. Only 21.3% of patiens receive EFV based regimen and 9.4% receive TDF based. Compared to the guidelines from HHS Panel on Antiretroviral Guidelines for Adults and Adolescents, 4 none of those three regimens are included in the preferred or alternative regimens. They all belong to the other regimens for initial therapy. The initial regimens used in VCT-CST RSUP Sanglah are same as the initial regimens used in resourcelimited settings. 5 Other related study conducted in Kenya, Uganda, and Tanzania stated that the most common NRTI component used in the initial ARV combination is stavudine (d4t). Higher WHO stage of the patients is associated with a higher chance of d4t use in the first regimen in these countries. 6 Based on the Table 1, most of the characteristics of the three regimens have no significance differences. The differences are caled significant if p < But, there are some variables that are significantly different among the three regimens. These variables are opportunistic infection, initial hemoglobin, side effects, and change of regimen. It means that opportunistic infection and initial hemoglobin count 8

9 are related to the selection of initial ARV regimens and the selection of initial ARV regimens is related to the side effects appearance and tendency to change ARV regimen, based on chisquare analysis. Lung tuberculosis and hepatitis B are also related to initial ARV regimen selection, so are some other miscellaneous opportunistic infections (Table 4 and 5). From Table 1 also, we can see that there is a pregnant patient who receive EFV based regimen for initial therapy. Considering the teratogenic side effect of EFV, the selection of EFV regimen in this case seems not appropriate. But, may be there is a reason behind the giving of this regimen. The patients may be not pregnant or planning for pregnancy when the therapy starts. From the mean of initial hemoglobin, the patients starting ARV regimen therapy commonly have low level of hemoglobin or anemia. The mean of initial CD4+ of patients starting ARV regimen therapy is very low. But, the mean onset of therapy is less than 6 months. It assumes that most of the patient has already had a low level of CD4+ when they are diagnosed as HIV positive. It may because of the patients are late in order to seek medical care, so they come in more severe stage of disease. It also proved by the frequency of clinical manifestations appears in patients receiving the three regimens is more than half. May be the number of patients who are asymptomatic when seeking medical attention is still far less than the symptomatic ones. Mostly, CD4+ of the patients after receiving 6 months of ARV regimen therapy increases. It is shown in the Table 1 that the mean of after 6 months of therapy increases about 2 times in patients receiving NVP based therapy, 3 times for EFV based, and more than 7 times in TDF based regimen. However, the mean of initial CD4+ level of the patients receiving TDF based regimen is far below the others. Based on Table 7, we can see that not all of the changes of CD4+ after 6 months of therapy is an increase. Four patients using NVP based regimen and two patients of EFV based regimen experience a decrease in CD4+ level after 6 months of therapy. It assumes that the decrease of CD4+ level after therapy is caused by resistance to the drug which is part of these regimens. NRTIs and NNRTIs are groups of drugs which have high potency of resistancy. 7 Side effects mostly happen in patients receiving NVP based regimen. The most frequent side effect of NVP based regimen is anemia, but it is usually caused by the zidovudine (AZT) drug. So, it also happens in patients receiving EFV based regimen. NVP drug usually causes hypersensitivity reaction, such as erythema macule or Stevens-Johnson Syndrome (SJS). Other side effects, such as nausea, itching, and dizzy are less frequent and can happen in all of those 3 regimens. Side effects appearance is significantly different among the three regimens. It is related to high number of regimen changes during 6 months of therapy with this regimen. The number of regimen changes of NVP based also is significantly different with the other two regimens. Individuals with a CD4 cell count above 350 cells/μl have been shown in a number of studies to be at low risk of progression to AIDS or death. 8 Based on this study, the mean of CD4+ even initially and after 6 months of therapy is still below 350 cells/µl. The risk of progression to AIDS or death is very 9

10 high. However, the number of death cases in this study is only 7 out of 127 patients. It may be caused by the early initiation of ARV regimen therapy. But, the progression of HIV disease to AIDS among the patients may be high. Results of this study is expected to be useful as consideration in selecting the most appropriate initial ARV regimen for the patients and also improving the clinical condition of patients who seek medical attention after suspected to be infected by HIV through a good socialization. The author realizes that this study is still far from perfection. Limitations of this study especially caused by limited time in collecting and processing data. Some data needed in this study also sometimes not available in the medical records because of the patients rarely come to the clinic or the data itself is not recorded when the patients come to the clinic. CONCLUSIONS The initial ARV regimens commonly used for HIV-infected patients at VCT- CST RSUP Sanglah are NVP based regimen (AZT/3TC/NVP) which is 69.3%, EFV based regimen (AZT/3TC/EFV) which is 21.3%, and TDF based regimen (TDF/3TC/NVP or TDF/3TC/EFV) which is 9.4%. Initial hemoglobin count and opportunistic infections, such as lung tuberculosis and hepatitis B, are related to the selection of initial ARV regimen. The initial ARV regimen also related to the appearance of side effects and tendency to change ARV regimen. Most of patients treated with initial ARV regimens have an increase of CD4+ count after 6 months of therapy. However, few other patients experience a decrease in CD4+ count. Mortality happens to 7 out of 127 patients receiving initial ARV regimen therapy in The author suggests that the newest guidelines for initial ARV regimen can be used as consideration in cilical setting. Patients initial condition should be recorded completely before receiving ARV therapy. Socialization for early seeking of medical attention if suspected as HIV infected should be increased in order to improve the outcome of HIV-infected patients after ARV therapy. Monitoring of patients outcome during initial ARV regimen therapy should be done closely and regularly in order to prevent unexpected outcome, resistancy to the initial drugs, and tendency to change to second line drugs. REFERENCES 1. Join United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic NLM. 2013: Wood E, Hogg RS, Harrigan PR, Montaner JSG. When to initiate antiretroviral therapy in HIV-1- infected adults: a review for clinicians and patients. Lancet Infect Dis. 2005;5: Jain V, Hartogensis W, Bacchetti P, et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis. 2013;208: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1- infected adults and adolescents. Department of Health and Human Services. Available at AdultandAdolescentGL.pdf. Section 10

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