Phanuphak, Nittaya MD*; Pattanachaiwit, Supanit MSc*; Pankam, Tippawan MMA*; Pima, Warabhorn MS*; Avihingsanon, Anchalee MD†; Teeratakulpisarn, Nipat MD*; Phanuphak, Praphan MD, PhD*
Access to antiretroviral treatment (ART) has expanded rapidly during the past years with an estimation that, around 4 million people worldwide were receiving ART at the end of 2008.1 In 2009-2010, both the World Health Organization and the United States Department of Health and Human Services revised their guidelines to recommend earlier initiation of ART than previously recommended.2,3 These recommendations were largely based on the large cohort studies which demonstrated higher risk for AIDS or death among HIV-infected patients with CD4 count between 351 and 500 cells per cubic millimeter or >500 cells per cubic millimeter who deferred ART than patients with similar CD4 counts who started ART immediately.4,5 The 2010 Thai National HIV/AIDS Diagnostic and Treatment Guidelines now recommend CD4 count <350 cells per cubic millimeter as the threshold for ART initiation in Thai patients.6
In both developed and developing countries, practitioners may find it quite challenging to implement the new recommendations to initiate ART earlier due to the limited feasibility to diagnose HIV-positive patients at high CD4 counts. The expansion of the national ART program has occurred since 2000 in Thailand.7 By 2009, 200,000 Thai patients (75% coverage) have started ART.8 The number of people who undergo anti-HIV testing in Thailand, however, did not increase during the past years although free ART is made widely available.1 The average CD4 count at which patients started ART in Thailand is 41cells per cubic millimeter.7 Late HIV testing and/or delayed CD4 count measurement after HIV diagnosis may explain delayed initiation of ART in many settings. We evaluated the distribution of the first CD4 count of clients who were diagnosed with HIV infection for the first time at the Thai Red Cross Anonymous Clinic (TRC-AC) which also had the facility of CD4 count measurement within the same setting along with time duration between HIV diagnosis and CD4 count measurement. Factors that might affect late HIV testing and prolonged time duration between HIV diagnosis and CD4 count measurement were also evaluated. The information gained from this study would be valuable in guiding the policies to promote early HIV testing and early CD4 count measurement after HIV diagnosis.
Study Setting and Study Population
In 1991, the Thai Red Cross AIDS Research Centre in Bangkok established a voluntary counseling and testing (VCT) clinic called the Thai Red Cross Anonymous Clinic (TRC-AC) where clients are not required to disclose their identity. The TRC-AC's goal is to decrease stigmatization associated with HIV and to bridge HIV positive persons into care. Over the years, the TRC-AC has provided comprehensive health care services for all regardless of HIV status. In addition to VCT, the services, from which each client can choose from, include annual health check-up, nutritional assessment and counseling, tuberculosis screening, prophylaxis and treatment, anal and cervical Pap smear, sexually transmitted disease (STD) testing and treatment, antiretroviral clinic, and a wide range of laboratory testing including CD4 count, HIV viral load, hepatitis serology, lipids, chemistry, and others. In 2008, the provider-initiated testing and counseling (PITC) for HIV was officially implemented using annual health check up, nutrition, anal and cervical Pap smear, and STD services as entry points to HIV testing. Clients who came in for these services were routinely offered HIV testing by the TRC-AC's health care providers regardless of clients' initial intention to have HIV testing.
Client confidentiality was maintained via the current anonymous system in which clients do not have to disclose their identity. All clients were asked to voluntarily provide their initials, date of birth, birthplace, and gender. The information provided cannot be linked to the tested subjects and was used only to determine if the client is a new or former client. As part of the registration, clients were given a TRC-AC identification (ID) number which is a 7-digit number with the first 2 digits representing the year and the following 5 digits representing the sequence of which the client sought care in that calendar year. This unique ID number was used for all clinical and laboratory services, including HIV testing and CD4 count measurement, each client received at the TRC-AC. TRC-AC counselors provided VCT clients with HIV pretest and posttest counseling consistent with TRC-AC operating procedures and nationally accepted VCT guidelines. The counseling process included HIV risk assessment, risk reduction plan, psychosocial implications of HIV infection, and sources of HIV care and treatment.
To derive the scenario that is applicable to the Thai setting, only clients who identified themselves as having Thai nationality were included into the analyses in this study.
Diagnosis of HIV Infection
HIV-1 screening and confirmatory testing was performed by venipuncture according to the TRC-AC procedures. A fourth-generation enzyme immunoassay (AxSYM, Abbott Laboratories, Wiesbaden, Germany), designed to simultaneously detect antibodies against HIV-1 and/or HIV-2 and HIV p24 antigen, was used for HIV screening. The second blood draw was done on the same day for confirmatory testing of HIV-reactive samples. Confirmatory tests were performed using a recombinant antigen enzyme immunoassay (Genscreen HIV 1/2, Marne-la-Coquette, France) and a particle agglutination assay (Serodia HIV 1/2, Fujirebio, Tokyo, Japan). HIV infection was confirmed if both or at least 1 of the 2 confirmatory tests was reactive from the second blood sample. If the first test was reactive, clients would receive posttest counseling as “positive” on the same day of their tests and would be asked to return for confirmatory test results and for additional posttest counseling 7-10 days after the initial visit. According to the TRC-AC's policy, prompt measurement of CD4 count was generally advised at the confirmatory visit. Clients could choose to have CD4 count measurement at the TRC-AC in an anonymous manner described above or to be referred to the other health care facilities of their own choice.
Demographic data including gender, age, marital status, HIV risk factors, educational level, occupation, birth place and current living place, monthly income, history of STD, and HIV-related symptoms were extracted from the database. The demographic information was collected using self-administered paper questionnaire during the registration process. Laboratory results of HIV testing and CD4 count measurement along with date of testing were also extracted and linked to the demographic information by TRC-AC ID number. CD4 count at first HIV diagnosis was defined as the earliest CD4 count measured at the TRC-AC after HIV diagnosis.
Data were collected from Thai clients who had HIV testing at the TRC-AC during June 1, 2006, to May 31, 2009. Data on CD4 count were collected until August 31, 2009. Duration between HIV diagnosis and CD4 count measurement was calculated from the date of HIV testing to the date of CD4 count measurement.
Logistic regression analysis was used to determine risk factors of low CD4 count and late CD4 count measurement. Continuous variables were transformed into categorical variables using cut-off values of clinical significance. Adjacent categories were then grouped if the coefficients obtained through the univariate analysis were similar. All variables with a P value <0.20 in the univariate analysis were included into the multivariate analysis.
During the 3-year study period, 21,255 clients came to the TRC-AC for HIV testing; of which, 19,525 (91.9%) were Thais. Out of the Thai clients, 6218 (31.8%) were women, 3485 (17.8%) were men who have sex with men (MSM), 9819 (50.3%) were heterosexual men, and 3 (0.02%) did not report gender. There were 2580 unique individuals diagnosed with HIV infection. This gave the overall HIV prevalence of 13.2%, with the prevalence of 13.2% (818 of 6218) in women, 29.1% (1014 of 3485) in MSM, and 7.6% (748 of 9819) in heterosexual men.
Demographic characteristics of 2580 clients who were first diagnosed with HIV infection at the TRC-AC are presented in Table 1. Mean (±SD) age was 32.4 years (±8.4). The main route of HIV acquisition was reported to be through sexual intercourse with less than 1% reported intravenous drug use. The majority of MSM were single, whereas almost half of women and heterosexual men were married or living together with their partners. Around 69% were employed and 3.3% reported sex workers as their occupation. Twelve percent reported history of STD and 2.7% ever had HIV-related symptoms. MSM tended to be younger, have higher educational level, have higher income, and be more likely to currently live in Bangkok than the other groups.
CD4 Count After First HIV Diagnosis and Time Duration Between HIV Diagnosis and CD4 Count Measurement by Gender
Among 2580 clients who were firstly diagnosed with HIV infection during the study period, 1890 (73.3%) had CD4 count measurement at the TRC-AC after HIV diagnosis (Table 2). Median CD4 count among 1890 clients with available results was 287.0 (IQR = 114.0-434.3) cells per cubic millimeter. Median CD4 count was lower in heterosexual men (213.5 cells/mm3, IQR = 57.0-375.3) as compared with women (311.0 cells/mm3, IQR = 129.5-499.5) and MSM (311.0 cells/mm3, IQR = 173.0-442.0) (P < 0.001). CD4 count was found to be <200, 200-350, 351-500, >500 cells per cubic millimeter in 681 (36.0%) clients, 491 (26.0%) clients, 371 (19.6%) clients, and 347 (18.4%) clients, respectively. Median duration between HIV diagnosis and CD4 count measurement was 1.0 (IQR: 0-11.0) day for women, 3.0 (IQR: 0-11.0) days for MSM, and 1.0 (IQR 0-10.0) day for heterosexual men (P = 0.369). CD4 count measurement was performed within 30 days of HIV diagnosis among 91.4% of the clients, and 95.3% had CD4 count measurement within 90 days of HIV diagnosis.
CD4 Count After First HIV Diagnosis and Time Duration Between HIV Diagnosis and CD4 Count Measurement by Year
Median CD4 count among 1054 clients who had HIV diagnosis in 2006-2007 was 287.5 (IQR = 113.0-435.5) cells per cubic millimeter, whereas it was 287.0 (IQR = 117.3-434.0) cells per cubic millimeter among 836 clients who had HIV diagnosis in 2008-2009 (P = 0.529) (Table 2). A higher proportion of clients who had HIV diagnosis in 2008-2009 had CD4 count measurement within 30 days of HIV diagnosis (89.3% if HIV diagnosed in 2006-2007 versus 93.9% if HIV diagnosed in 2008-2009, P < 0.001).
Risk Factors Associated With First CD4 Count ≤350 Cells Per Cubic Millimeter After HIV Diagnosis
By univariate logistic regression, risk factors significantly associated with CD4 count ≤350 cells per cubic millimeter were being heterosexual men [odds ratio OR = 1.8; 95% confidence interval (CI): 1.4 to 2.3], age older than 30 years (OR = 1.7; 95% CI: 1.4 to 2.0), being employed (OR = 1.7; 95% CI: 1.4 to 2.1), and having HIV-related symptoms (OR = 2.3; 95% CI: 1.1 to 5.1). HIV-related symptoms, however, were excluded from further analysis as there were more than 50% missing data (Table 3). Being heterosexual men (OR = 1.7; 95% CI: 1.3 to 2.2), age older than 30 years (OR = 1.5; 95% CI: 1.2 to 1.9), and being employed (OR = 1.5; 95% CI: 1.2 to 1.8) remained significant risk factors for having first CD4 count ≤350 cells per cubic millimeter after HIV diagnosis in the multivariate logistic regression model.
Risk factors significantly associated with advanced HIV disease (CD4 count <200 cells/mm3, data not shown) after HIV diagnosis in the multivariate analysis were similar to those associated with CD4 count <350 cells per cubic millimeter and included being heterosexual men (OR = 1.7; 95% CI: 1.2 to 2.3), age older than 30 years (OR = 1.9; 95% CI: 1.5 to 2.5), and being employed (OR = 1.4; 95% CI: 1.0 to 1.9).
Risk Factors Associated With Delayed CD4 Count Measurement ≥30 Days After HIV Diagnosis
By univariate logistic regression, risk factors significantly associated with delayed CD4 count measurement (≥30 days) after HIV diagnosis were age older than 30 years (OR = 1.4; 95% CI: 1.0 to 2.0), being single/separated/divorced (OR = 1.5; 95% CI: 1.0 to 2.3), high education (OR = 1.4; 95% CI: 1.0 to 1.9), currently living in Bangkok (OR = 1.6; 95%CI: 1.1 to 2.4), and having HIV diagnosis in 2006-2007 (OR = 1.5; 95% CI: 0.7 to 2.8) (Table 4). Being single/separated/divorced (OR = 1.6; 95% CI: 1.0 to 2.5) and having HIV diagnosis in 2006-2007 (OR = 2.3; 95% CI: 1.5 to 3.5) remained significant risk factors for delayed CD4 count measurement after controlling for other confounding variables in the multivariate logistic regression analysis.
Late HIV testing is not uncommon in developed countries with 25%-70% of HIV-infected persons already had advanced immunosuppression when diagnosed with HIV infection.9-15 Around 39% of patients in Italy had CD4 count <200 cells per cubic millimeter or clinically defined AIDS when presented to the hospital-based setting within 6 months of the first HIV diagnosis.16 In our VCT setting, the first measured CD4 count was <200 cells per cubic millimeter among 36% of those newly diagnosed with HIV infection, and ≤350 cells per cubic millimeter among 62%. A smaller proportion of HIV-infected pregnant women in Thailand had advanced immunosuppression at their first antenatal care visit with 28.3% of them had CD4 count ≤250 cells per cubic millimeter.17 CD4 count at first HIV diagnosis may partly be driven by the reasons for seeking HIV testing. In a study from the Southern part of Thailand, 62% of males sought HIV testing because of symptoms, whereas 46% of women sought HIV testing because they were pregnant.18 Older age was found to be associated with late HIV testing in many studies,10,11,13,14,16 whereas previously negative HIV test and injection drug use were associated with earlier HIV testing in the Italian study.16 Our study found age older than 30 years to be one of the significant risk factors for late HIV testing. In addition, we also identified being heterosexual men and being employed as other significant risk factors for late HIV testing. New HIV testing strategies, including provider-initiated counseling and testing, are needed to enhance earlier HIV testing among people with HIV risk behaviors, especially those who may consider working more important for themselves or their families than seeking health care (heterosexual men, aged older than 30 years, and being employed). Given that confidentiality of HIV test result could be ensured, inclusion of HIV testing as one optional test available in the annual health check-up program for employees19,20 or delivery of rapid HIV tests to workplaces through the use of mobile health clinic21,22 may be effective ways to improve access to HIV testing among those at risk for late HIV testing.
HIV prevalence among women (13.2%) and heterosexual men (7.6%) in our study were much higher than the national HIV prevalence (<1.0% among Thai blood donors, military recruits, and pregnant women during the study period).8 This indicated that clients who received HIV testing at our VCT setting might represent a population with higher risk for HIV infection than general Thai population. Nevertheless, the proportions of women, MSM, and heterosexual men newly diagnosed with HIV infection in our study were very similar to the projected proportions of new HIV cases in Thailand during the same period.8 Therefore, data on CD4 counts from our study (CD4 count <200 cells/mm3 among 36% and <350 cells/mm3 among 62% of newly diagnosed HIV cases) are likely to be important for country's health care planning as they indicate that the number of HIV-infected persons who need ART in Thailand will be almost doubled when we start to implement the new treatment guidelines to initiate ART earlier. However, it is expected that the number of HIV-infected persons who actually access treatment facilities for ART will be slowly increased as strategies to enhance early HIV testing and linkage to care are increasingly implemented.
Delayed CD4 count measurement after HIV diagnosis has been reported in both developed and developing countries. In the United States, 39% of HIV-infected persons delayed over 12 months before entering care and receive CD4 count measurement.23 Only 34% and 47% of patients diagnosed with HIV infection in the hospital-based setting in the Southern part of Thailand received CD4 count measurement within 6 and 12 months of HIV diagnosis, respectively.18 Our study showed that, among 73.3% of HIV-positive clients who had CD4 count measurement at our clinic, 91.4% and 95.3% had CD4 count measurement within 1 month and 3 months of HIV diagnosis, respectively. Delayed CD4 count measurement was repeatedly shown to be strongly associated with the lack of posttest counseling.16,18,23 The much shorter duration between CD4 count measurement and HIV diagnosis shown in our study might be the results of our routine posttest counseling which always includes the recommendation of immediate CD4 count measurement and the availability of CD4 count measurement in the same clinic. Although our clinic has been able to provide CD4 count measurement at the lowest cost in Thailand, it is still of interest to see a high percentage of HIV-infected clients who chose to have CD4 count measurement at our clinic given that they can access the same test without charge at public hospitals under the governmental health care programs. Concerns about exposure to too many staff in different health care facilities during the early stage of knowing HIV diagnosis may explain this finding. Efforts must be made widely to ensure effective referral to CD4 count service at the time of posttest counseling. CD4 count measurement should be considered as a crucial and practical linkage from HIV testing to HIV care. Although previous studies reported the association of delayed CD4 count measurement with route of HIV infection, older age and unemployment,16,18,23 we could not identify any of these associations. Being single/separated/divorced (OR = 1.6; 95% CI: 1.0 to 2.5) was significantly associated with delayed CD4 count measurement >1 month after HIV diagnosis in our study. HIV-infected persons may need supports from partners or spouses to get early access to CD4 count service. Having HIV diagnosis in 2006-2007 (OR = 2.3; 95% CI: 1.5 to 3.5), before our clinic implemented the PITC using various services available as entry points to HIV testing, was also found to be associated with delayed CD4 count measurement. It is likely that PITC clients received repetitive messages from different health care staff in the clinic regarding the importance of early access to both HIV testing and HIV care and, therefore, had early CD4 count measurement.
Compared with high-income countries, patients starting ART in low-income countries had lower CD4 counts (median 108 vs 234 cells/mm3) and higher mortality in the first year of ART.24 Among developing countries, HIV-infected Thai patients started ART later than other countries. The average CD4 count at which patients started ART in Thailand is 41 cells per cubic millimeter,7 whereas these are 87 cells per cubic millimeter in South Africa,25 112 cells per cubic millimeter in Malawi,26 and 141 cells per cubic millimeter in Zambia.27 In the hospital-based setting in the Southern part of Thailand, median CD4 count was 36 (IQR: 10-116) cells per cubic millimeter, 22 (IQR: 9-85) cells per cubic millimeter, and 73 (IQR: 16-169) cells per cubic millimeter among all, symptomatic and asymptomatic patients with HIV infection, respectively.18 Although we could not infer that clients who had CD4 count measurement in our VCT setting were linked to HIV care and had ART initiation if eligible, we found that the median first CD4 count after HIV diagnosis of 287.0 (IQR = 114.0-434.3) cells per cubic millimeter was much higher than those previously reported in Thailand and was almost equal to those reported from the United States and Canada in the recent years.28 Baseline CD4 count is a strong prognostic factor for mortality after ART.24-27 Therefore, strategies to enhance earlier HIV testing and earlier CD4 count measurement and to ensure better linkage to HIV treatment facilities are urgently needed to improve survival of HIV-infected patients after ART. The median first CD4 count after HIV diagnosis in our centre did not increase from 2006 to 2009 although free access to ART has rapidly expanded in the country during the same period. Previous study also showed that ART availability did not motivate earlier HIV testing among people at risk for HIV in New York City.12 Median CD4 count in our study was significantly lower in heterosexual men than in women and MSM. Similarly, a study from Brazil reported that females were diagnosed with HIV earlier, followed by MSM and heterosexual men.29 Many previous studies also reported male gender as an independent factor associated with late or symptomatic HIV diagnosis.11,13,14,18
There are several limitations in our study. First, we did not have the system to track down if our HIV-positive clients who did not have CD4 count measurement at our clinic did actually receive CD4 count measurement elsewhere as the cost of CD4 count measurement is currently covered under various governmental health care programs. The proportion of HIV-positive clients who had CD4 count measurement could, in fact, higher than reported in this study if CD4 count measurement carried out elsewhere were to be included or if CD4 count measurement was provided free of charge at our clinic. Second, during the study period, reasons for HIV testing were not recorded systematically. Therefore, we could not study in detail the potential effect of reasons for HIV testing on delayed CD4 count measurement or delayed HIV testing. Third, we only allowed 3-month period after the last HIV diagnosis for CD4 count measurement. It might be possible that some of HIV-positive clients had CD4 count measurement after that period. However, given the very high proportion (95.1%) of HIV-positive clients who had CD4 cell count measurement at our clinic within 3 months of HIV diagnosis, this missing number would be very small. Last, our setting was a VCT clinic and results may not be generalized to other settings. Compared with the hospital-based setting, clients receiving HIV testing at a VCT clinic may represent a higher risk population although people seeking HIV testing or care at a hospital-based setting may be more likely to have already perceived illnesses. Also, it was not possible to infer that all clients who had CD4 count measurement at our VCT setting were linked to HIV care, as patients with low CD4 count might not yet access ART even if they were eligible.
The major strength of our study is the ability to collect data from a large number of clients who enrolled consecutively in a 3-year period. Our group of 2580 HIV-positive clients was composed of balanced proportions of women, MSM, and heterosexual men, very similar to the projected proportions of new HIV infection in Thailand during the same period.8 Our clients reported currently living both in and outside Bangkok. These factors altogether helped reducing potential biases due to samplings of specific risk groups or from specific clinic settings or specific periods.
To implement the new international and national recommendations to initiate ART earlier, early HIV testing and early CD4 count measurement after HIV diagnosis are essential steps. Waiting until having HIV-related symptoms before getting HIV testing is definitely too late. Efforts are needed to increase uptake of routine HIV testing among people who practice “behavioral risks” for HIV infection, and not to only confine the efforts among the “high risk groups”. Integrating non-HIV services, such as cervical Pap smear, anal Pap smear, nutritional counseling, and health check-up packages, as part of the VCT clinic may prove effective in getting lower risk clients into early HIV testing. Availability of HIV-related services beyond HIV testing, such as CD4 count measurement, tuberculosis screening, ART provision and HIV viral load at the VCT clinic or having an effective referral system is an important step in linking HIV-positive clients into HIV care. Early HIV testing can save costs by preventing morbidities and mortalities occur in advanced immunosuppressed patients. In addition, early HIV testing and early HIV care can prevent unintentional HIV transmission related to delayed HIV diagnosis although also allow enough time to prepare readiness in the majority of HIV-infected patients for life-long successful ART.
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. Presented at: 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, CA; 2007.
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