Expenditures for the care of HIV-infected patients in rural areas in China's antiretroviral therapy programs

According to the most recent estimates by the Ministry of Health and the Joint United Nations Program on HIV/AIDS (UNAIDS), China had 560,000-920,000 people living with human immunodeficiency virus (HIV) and 97,000-112,000 people living with acquired immunodeficiency syndrome (AIDS) as of the end of 2009. A total of 320,000 HIV/AIDS cases have been reported from the national infectious disease surveillance system from 1985 to 2009 [1]. The first wave of AIDS cases was reported in China around 2002, and the majority of these AIDS patients contracted the virus in the 1990s, through either the injection of drugs or plasma donation. In response, the Chinese government launched the China Comprehensive AIDS Response (CARES) in 2003, a community-based HIV treatment, care and prevention program that provides free HIV treatment, including antiretroviral (ARV) therapy and treatment of opportunistic infections (OIs) to the indigent in urban areas and to everyone in rural areas [2].

China CARES provides first-line ARV regimens, including two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), the generics of which are produced in China. According to national guidelines, ARV treatment is provided by designated infectious disease hospitals, and patients in rural areas in some provinces may go to village clinics to receive counseling and treatment for OIs. Staff from the local Centers for Diseases Control and Prevention (CDC) provides education on ARV treatment compliance and disease prevention intervention. An estimated 97% of AIDS patients (>50,000) who initiated highly active antiretroviral therapy (HAART) in China received free treatment through this national program by 2008; 3% of these patients received treatment via self-pay or through some nongovernmental organization-sponsored treatment programs that may use different regimens [3, 4]. The central government increased funding for HIV prevention and treatment from US$56 million in 2003 to US$142 million in 2008, while local governments increased funding from US$14 million to US$86 million in the same period [1]. Recent analyses of national data from China CARES have shown that it significantly decreased mortality among HIV-infected patients from 27 deaths per 100 person-years before treatment to 4-5 deaths per 100 person-years after 6 months of HAART [3, 5].

The Comprehensive International Program for Research on AIDS (CIPRA) is an initiative sponsored by the U.S. National Institutes of Health (NIH). China CIPRA comprises five interrelated projects. The overall goal of China CIPRA is to strengthen the existing HIV research infrastructure in China and to build the capacity to conduct multidisciplinary research to explore promising strategies for HIV prevention, treatment and control. Subproject 4 is "A Feasibility Study of Lamivudine/Zidovudine (3TC/ZDV) plus Efavirenz (EFV) as Initial Therapy of HIV-1-infected Patients in Rural Areas of China." The project was conducted between June 2005 and June 2007. The primary objective of Subproject 4 was to determine the efficacy and safety of a potent combination ARV regimen (3TC/ZDV + EFV) for the treatment of HIV-1-infected patients in a rural area of China. China CIPRA covered all of the costs for patients during the research period.

However, there are no publications on the expenditures and cost-effectiveness of treating HIV-infected patients in China. Considering the fact that treatment providers, targeted clients and economic assistance policies may vary across different areas, the actual expenditures of this program are largely unknown. Such information is needed for future financial planning and possible reform of AIDS-related policies. Therefore, the current study determined the expenditures associated with two ARV treatment programs in rural China.

Although funding for HAART has expanded in recent years, the resources are still limited and costs typically increase with time. On the basis of our research, the expenses for ARV medications were the largest component of AIDS treatment. Among first-line agents, only AZT, D4T, DDI and NVP are generic ARVs produced by pharmaceutical companies in China, while EFV is purchased by the Chinese central government. Although 3TC was donated by GlaxoSmithKline, we still added its price into the total expenses to show the actual expenditures for ARVs. The high cost of ARVs has been the main obstacle for China in considering free second-line agents. Indinavir without a booster, Kaletra (lopinavir/ritonavir), tenofovir, emreicitabine and abacavir are used in cases of drug resistance. Some of these ARVs are now available as cost-free treatment. Merito et al. [8] showed that the average annual cost of ARVs increased with the duration of treatment, while inpatient costs decreased. Bruno et al. [9] showed the total expense shifted from inpatient costs to ARV medication expenses. China will also face this same issue, along with the progression of HIV infection and the increasing number of AIDS patients in the near future. Duraisamy et al. [10] showed that the median direct cost of treatment and services was US$610 for 6 months in south India for patients who received HAART in 2001. According to the report from the CDC center of the Health Ministry of Iran [11], the direct cost of HIV treatment was US$1,025 per person in 2005. A Philippines study [12] reported that during the early symptomatic stage, the cost per case per year was US$301, and in the late symptomatic stage the cost increased to US$5,774 in 1996. Compared with these studies, the mean expenditure in this study was a little higher because many patients in the last symptomatic stage received HAART at the inception of China CARES. A greater number of AIDS patients receive HAART because of free ARVs and reimbursement for laboratory tests and transportation. Thus, some insurance policy should be developed to lower the patients' financial burden and promote compliance.

A higher level of education was associated with a higher cost of HAART-related expenses in our study, which was consistent with the results of Bozzette et al. [13]. In rural China, patients with a higher level of education may receive more information about AIDS and related health care policies. Therefore, they may use more health services than patients with a lower level of education.

ADEs contribute significantly to HIV/AIDS treatment costs, which can be mitigated through early symptom assessment and management. The ADEs associated with ARVs have been reported in many studies [14‐20]. Besides financial constraints, ADEs are also important factors which affect HAART compliance [21‐23], but few studies have determined the monitoring and treatment expenses of ADEs [24]. We explored the expenditures for ADEs in our study and showed that the expenditures for the treatment of peripheral neuritis were the highest because of high costs of medications. Hepatotoxicity was the most common AIDS-related ADE, thus regular laboratory monitoring for hepatotoxicity in many ARV regimens is standard. NVP was more likely to induce hepatotoxicity, which is consistent with studies in China and other countries [14‐20]. Expenditures for the treatment of anemia were the third highest among the ADEs. The main components of the increased expenditures for the treatment of anemia were blood transfusion and hospitalization expenditures. More attention should be paid to regular monitoring of the blood cell count. Early detection and early treatment will decrease the expenditure of hospitalization.

HAART has been shown to be effective in increasing the CD4 cell count and reducing the incidence of OIs [25‐27]. In the current study, OIs still occurred in some patients who received ARVs. The expenditures for some OIs with a lower incidence, such as CMV and fungal infections, were higher than the treatment costs of other OIs. Long-term hospital stays and higher expenditures for antiviral and antifungal drugs and special laboratory tests result in higher expenditures for OIs. HIV/TB coinfections deserve particular attention because of the high prevalence and cost. The treatment of HIV/TB coinfection was the second highest expenditure of all OIs in this study. China has the second-highest prevalence rate of TB in the world. According to a WHO report [28], the incidence of TB increased at an average rate of 7% per year in those countries with a high prevalence of HIV (≥5%), but the average rate of increase was only 1.3% in countries with a low prevalence (≤5%). HIV-infected patients are at a markedly increased risk for progressive disease following primary TB infection [29‐31]. Thus, screening and treatment of TB at the time of HIV infection is beneficial to patients and improves the efficacy of HAART. With respect to the optimal time to initiate HAART, it is worth noting that the immune reconstitution syndrome tends to be worse in patients initiating HAART with lower CD4 cell counts. Some of the patients in our study were in the last symptomatic stage, which may increase the incidence of OIs and sequentially increase the expenditure for treatment.

When to begin HAART is an important issue which has been much discussed in recent years. Studies in high-income countries have verified that initiating HAART in patients with higher CD4 cell counts can improve the efficacy of treatment [32]. However, for resource-limited countries, where viral load testing is often not available for the diagnosis of AIDS, the CD4 cell count and symptoms are the main indicators for initiating HAART. As a result, some patients are not diagnosed in a timely manner. A lower CD4 cell count was associated with higher treatment expenditures. This effect has also been shown in patients with CD4 cell counts <50/μl in other studies [13, 33]. In our study, we noted a similar result, although the sample size was limited. Over the long term, initiating HAART to patients with higher CD4 cell counts is likely to effectively control AIDS treatment expenses for ADEs and OIs, but it will also increase the treatment costs over a longer period of treatment. Thus, factors, such as the financial burden of patients, care policy and compliance should be generally considered when initiating HAART.

In our study, we pooled the data from two distinct programs, the only difference in program design of which was the enrollment criteria for CD4 cell counts. However, the CD4 cell count was similar in the two programs after considering the WHO's clinical stages. Pooling data can increase the sample size and yield more information about HAART expenditures. Moreover, the price of medications and medical services was similar in the different sites of the program, although the different frequencies of follow-up may produce heterogeneity in expenses (that is, a greater number of follow-up visits in the China CIPRA).

The main limitation of the study was that the results cannot be extended to all of China because of the differences in the cost of living across China [34]. Second, Chinese public hospitals are classified into three levels according to the national hospital administration standard. Higher-level hospitals had more choice of medications, ancillary examinations and higher medical service prices. In our study, Mangshi Hospital was the highest-level hospital and was associated with a higher cost of HAART-related expenses. However, other AIDS treatment expense data were from county-level hospitals, which were usually second-level hospitals. Thus, our results are likely to have underestimated the costs of hospital care compared with the highest-level hospitals in cities and overestimate the costs compared with township hospitals and village clinics. Third, our research did not address the opportunity cost, expenses outside the hospital system and the association between compliance and cost because of the difficulty of collecting data.

Despite the above limitations, this study is the first to provide important information on the cost of rural AIDS patients in China. The ARVs expense was the largest part of HAART cost, averaging US$2,242 per patient in the first ARV treatment year. These costs appear to increase over time in China, as consequences of the increasing number of possible occurrences of drug resistance in the continuing period of HAART and more second-line regimens are used. Over the long term, initiating HAART in patients with a higher CD4 cell count is likely to effectively control AIDS treatment expenses on ADEs and OIs, but some factors should be generally balanced when initiating HAART.