Care of HIV-infected patients in China
1The AIDS Research Center, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing 100730, China2Department of Infectious Diseases, Shanghai/FuDan Public Health Center & Huashan Hospital, Fudan University, Shang-hai 201508, China ABSTRACT
Compared with high infection areas of the world, the total HIV infection rate in China is relatively low. Nonetheless, because of China’s vast territory and large population, the potential infection risk must be taken seriously. In the nextfew years, needle sharing among injection drug users will remain the most common route of transmission for the HIV/AIDS epidemic in China. Unprotected sex is gradually becoming a major route of transmission. China began to imple-ment HAART in 1999 according to international standards. Prior to 2003, there were only about 150 HIV/AIDS patientswere treated with HAART in some clinical trials and about 100 HIV/AIDS patients were treated by private sources.
Results of those treatments are the scientific basis for development of the therapeutic strategies in China. In March of2003, the Chinese government initiated China CARES program. In November of 2003, the Chinese Ministry of Healthannounced a national policy of free ARV treatment to all HIV+ Chinese citizens who were in poverty and required ARVtherapy. There are total of 19,456 HIV/AIDS patients received free ARV drugs to date in 159 regions and 441 towns.
Current challenges are how to follow-up and evaluate those patients in the clinical settings. The longer the therapy ispostponed, the more side effects and the higher probability of drug resistance are going to occur. It remains unclear,therefore, when HAART regimen should be started in the HIV/AIDS population in China.
Keywords: HIV/AIDS, needle sharing, unprotected sex, HAART, China CARES program.
Compared with other areas with high HIV infection rate 2. Many risk factors of HIV transmission remain in the world, the total HIV infection rate in China is rela- tively low. Nonetheless, in light of China’s vast territory 1) In the next few years, needle sharing among injec- and large population, the potential infection risk must be tion drug users will remain the most common route of taken into account seriously. The clinical features of the transmission for the HIV/AIDS epidemic in China.
HIV/AIDS epidemic in China include the followings [1]: 2) Unprotected sex is gradually becoming a major route 1. HIV/AIDS has begun to spread from specific groups of transmission for the HIV/AIDS in China.
into the general populations. Since 2001, some areas in 3) With increases in the number of female HIV patients China have been confronted with a particularly high mor- infected through sex, mother-to-child transmission is boundto increase. Since the first case of mother-to-child trans-mission (MTCT) to be acknowledged in 1995, MTCT rateshave been rising year by year. Currently, mother-to-child transmission mainly occurs in areas with severe HIV epi- Tel: +86-10-65105182/65105179-22; Fax: 65105179-12; E-mail: [email protected]: HCV (Hepatitis C Virus); TB (Tuberculosis); CPC 3. High HIV-HCV co-infection rates present a major (Communist Party of Chinese); HAART (Highly Active Anti-Retroviral Therapy); STD (SexuallyTransmitted Disease); ARV (anti-retroviral 4. The complexities of HIV-TB co-infection must also therapy); CDC (Centers for Disease Control and Prevention); HLA be addressed. Confronted with a severe HIV/AIDS (major histocompatibility complex); CAMS (Confederation of Austra-lian Motor Sport); .ADARC (Aaron Diamond AIDS Research Center); epidemic, the Chinese government has been making great NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor) efforts to reinforce the prevention of HIV/AIDS in recent | Cell Research, 15(11-12):883-890, Nov-Dec 2005 years. After the establishment of China’s Medium-& Long- sizes both prevention and treatment, which has been a rather term Strategy for HIV/AIDS Prevention and Control (1998- complicated and difficult systematic project. In 2003-2004, 2010) [5] in 1997 and China’s Action Plan for Reducing the Chinese government directly invested 1.2 billion RMB and Preventing the Spread of HIV/AIDS (2001-2005) in in the prevention and treatment of HIV/AIDS, and is plan- 2001[6], the State Council established the State Council ning to spend 3.86 billion RMB in 2005-2007 to further Coordinating Committee for HIV/AIDS/STD Prevention promote the implementation of HIV/AIDS prevention and and Control in 2004, so as to fortify the leadership and to mobilize all resources towards prevention. This commit-tee is led by Yi, WU member of CPC Central Committee HIV/AIDS PREVENTION AND CONTROL IN
and Vice Premier of the State Council. After using a pre- THE PAST 20 YEARS
vention-oriented strategy for several years, the Chinese In the past 20 years, since HIV was first considered as government has shifted towards a strategy that empha- the cause of AIDS to the present, scientific researches Tab. 1 Drugs used in the treatment of HIV infection [7]
(A )Nucleoside reverse transcriptase inhibitors (NRTIs); (B)Nonnucleoside reverse transcriptase inhibitors (NNRTIs); (C)Protease inhibitors(PIs); (D)Fusion inhibitors.
Cell Research, 15(11-12):883-890, Nov-Dec 2005 | Tab. 2 HAART clinical trail in China
encouraging. Up to now, nearly 20 patients have been tak- ing medicine for 6 years. Moreover, the areas of the treat-ment covered have spread from Beijing beginning in 1999 to Shanghai, Guangdong, Henan, Yunnan, Fujian, and Xinjiang. There were four main clinical trial groups (Tab.
1) The first pilot study was conducted in 1999 [8]: “Triple therapy Combivir (AZT and 3TC) plus Indinavir in Chinese individuals with HIV infection” (Tab. 1). There were 23 chronically HIV-infected patients included in thisstudy. In the first year, patients were given Combivir andIndinavir, followed by Combivir and Abacavir, and in thelast two years Trizivir (a combination of Abacavir, 3TC and clinical practices for HIV/AIDS prevention and treat- and AZT) was administered. Among the 23 patients, 17 ment have achieved great success, yet we are still con- are male and 6 are female; mean age is 40.2 (40.17±8.
fronted with a number of challenges. Concerning the 28). Among them, 17 were infected through sexual mechanism of HIV/AIDS as well as prevention and treat- transmission, including four homosexual, and four het- ment measurements, many difficult problems remain erosexual (by spouse). There were four intravenous-drug unsolved, such as ARV. The public no longer considers users (IVDUs) infected due to sharing used syringes; the HIV/AIDS a fatal illness. In the mid 1990s, HAART, in other two were infected through blood transfusion. Based which several drugs are combined, heralded a new era for on the US CDC diagnosis standards for AIDS (1983), 16 anti-HIV-I therapy. The AIDS mortality rate subsequently of 23 patients were diagnosed with asymptomatic HIV-1 declined. Twenty-five drugs have been authorized by FDA infection, while the other 7 were diagnosed with AIDS or the HIV/AIDS therapy and can be categorized into three (five of the seven AIDS patients had opportunistic infec- kinds, namely nucleoside reverse transcriptase inhibitors, tions before treatment, and the CD4+ cell count was < non-nucleoside reverse transcriptase inhibitors and pro- 200/mL in two patients). The following parameters were examined every three months: HIV-1 RNA in plasma was Adequate treatment for HIV-infected patients is impor- quantitatively detected by bDNA (branched-DNA magni- tant for controlling the source of infection and preventing fication technique; Branched-DNA,Company Bell, HIV re-transmission. Treatment of AIDS patients is the Quantiplex TM System 340) with a sensitivity range of < primary means for improving patients’ quality of life, pro- 50 ~ >500,000 copies/mL. The cell counts of CD3, CD4 longing patients’ lives, and reducing mortality. Clinical and CD8 in peripheral blood and the CD4, CD8 subsets of therapy for HIV/AIDS is one of the essential measure- T-lymphocyte were detected with relative counting, (FACS ments for the prevention and control of HIV/AIDS pro- calibur flow cytometer and fluorescent-labeled monoclonal posed in China’s Medium- & Long-term Strategy for HIV/ antibodies, Company Beckman-Dickson). Routine blood AIDS Prevention and Control (1998-2010).
tests, liver function, renal function, blood lipid and bloodglucose were measured. (ABBOTT CD1600£»Hitachi CLINICAL TRIALS FOR HIV/AIDS TREAT-
7170); The drug resistance trial through genotype assay is MENT IN CHINA
using the Trugene HIV-1 Genotyping System and In 1999, China began to implement HAART according OpenGene DNA Sequencing System (Bayer HealthCare, to international standards. Before 2003, there were about 150 HIV/AIDS patients using free imported anti-virus Of 23 cases, 12 continued taking medicine after com- drugs for treatment in HAART clinical trial groups and pleting four years of HARRT. Before therapy, the average about 100 HIV/AIDS patients using imported drugs on CD4+ T cell count and virus load (HIV-1 RNA) of the 23 their own. China imported thirteen kinds of ARV drugs.
cases were 372.1/ml and 525,765.5 copies/ml in the blood These patients, who spent about 100,000 to 120,000 RMB plasma, respectively. After four years’ treatment, the av- per capita per year on therapy, were treated under doc- erage CD4+ T cell count rose to 615.7/ml and the average tors’ strict follow-up and guidance. They were therefore HIV-1 RNA level decreased by 5.7 log10 to 1904.8 cop- able to overcome the initial common side effects of the ies/ml in the blood plasma. The HIV-1 RNA level in the drugs and take medicine on time, which helped them pro- blood plasma of 75% patients remained undetected all the long their lives, enhance their quality of life, control viral time. During the therapy, 19 patients had gastrointestinal replication and rebuild their immunity. These results were tract complications and the amounts of aminotransferase | Cell Research, 15(11-12):883-890, Nov-Dec 2005 885 of 3 patients increased by a factor of 5, yet no clinical However, obvious side effects were observed, including hepatitis symptoms appeared. Only two patients had to severe gastrointestinal reactions, peripheral neuritis, and discontinue medication because of hypersensitivity reac- tions due to drug resistance and taking Abacavir, 4) The trial, “Triple therapy Trizivir (AZT, 3TC, respectively. In concert with the results from foreign clini- Abacavir) in Chinese with HIV infection” began in Oct cal reports, the HARRT regimen achieved distinctive ef- 2002. Trizivir® is a three-antiretroviral drug with limited fects of decreasing virus load, increasing CD4+ T cell clinical experience in Chinese HIV/AIDS patients. Yunnan count, and reducing opportunistic infections among HIV/ Infectious Disease Hospital is carrying out an HIV treat- AIDS patients. Due to its convenient administration, Trizivir ment program in collaboration with CAMS and ADARC to greatly enhanced patients’ adherence and improved their evaluate the safety and efficacy of the regimen in HIV-1 infected Chinese patients. 80 HIV/AIDS patients (35 female, 2) The second clinical trial was conducted in Bejing, 45 male) were enrolled into a single-center, open-label Henan Province, Yunnan Province and Xinjiang Uighur study. The mean age was 36.4±9.3 years old. HIV infec- Autonomous Region in China in 2001 [10]: “Combination tion was acquired through heterosexual transmission therapy with once a day Stocrin™ (Efavirenz) and three (n=62), injection drug use (n=11), homosexual contact times a day Crixivan™ (Indinavir) in HIV-1 infected pa- (n=2), blood transfusion (n=3), or unknown routes (n=2).
tients in China”. In this open-label study, a combination of Trizivir™ is supplied as one tablet twice daily for three EFV and IDV was administered in 20 chronically HIV-1 years. The study is ongoing. To date, 38 and 23 patients infected patients. The average age of the subjects was 39 have completed >24 and 12-24 months of treatment, years, and 60 percent (12/20) were men. Among 20 respectively. At this time, treatment has been interrupted patients, 45 percent (9/20) were infected through sexual or changed in 19 cases, 17 (89.5%) due to adverse events.
activity, and 40 percent (8/20) through blood transfusion.
A rebound in viremia was noted in 4 of the 17 patients. All Changes in HIV-1 viral load and immunological param- the samples showed resistance to the RT inhibitors.
eters were examined longitudinally over a period of 48 Trizivir™ treatment has shown potent ARV activity in weeks. We found that the drug regimen was generally Chinese HIV/AIDS patients with varying levels of viral load, well tolerated, was efficient at reducing HIV-1 plasma vi- even those with viremia level above 500,000 copies/ml.
ral load, and at increasing total CD4+ T cell counts. The Prolonged treatment has resulted in greater increases in percentage of CD4+ and CD8+ T cell subsets expressing CD4+ counts and improved the control of opportunistic CD38 and HLA-DR activation markers was positively cor- infections. A marked decrease in hematocrit occurred in related with plasma viral load, suggesting there is a gener- approximately 10% of the patients. Overall, Trizivir™ alized T cell activation during HIV-1 infection. However, yielded reasonably good control of HIV replication [13].
soon after the initiation of treatment, the levels of CD38and HLA-DR expression on T cells tended to normalize.
Based on these observations, it is anticipated that this com- TIONAL FREE ANTIRETROVIRAL THERAPY
bination regimen has potential to translate into long-term General information about the national free ARV
3) In May, 2001, the third clinical therapy group, “Early, aggressive therapy of HIV-1 infected adults in China with It has been two years since the national free ARV therapy DDI, D4T and Neveripine (NVP) assessing the effect on was put into effect in 2003. Generally speaking, this ur- viral load and immune function”, started with 30 cases, gent and helpful action was quite meaningful to the pro- including 11 from Guangdong, 6 from Yunnan, 8 from motion and extension of the China’s AIDS prevention and Henan, 3 from Beijng, 1 from Shanxi and 1 from Shanghai.
control project. After 2003, generic drugs made domesti- For 20 patients with effective therapy, the lab studies cally were put on the market. The China Stop, Prevention, showed that after 48 weeks of treatment, CD4+ T cell and Treatment of AIDS Action Plan (2001-2005) was count increased by 177/mL on average and the average unveiled, suggesting establishment of general demonstra- HIV-1 RNA level reduced from 134816 copies/ml before tion districts for AIDS prevention and treatment, building therapy to 196 copies/ml in the blood plasma after therapy.
up health education, behavior intervention, medical care Yet according to the lab monitoring results, 10 patients and consultant care. As of July 30th, 2005, 127 general did not show improvements. Compared with previous demonstration districts for AIDS prevention and treatment methods, this method had the advantage of easier had started, encompassing 28 provinces and 83.25 million administration, fewer administrations per day, and no di- people. All together 19,456 HIV/AIDS patients received etary limitations, which led to good patient compliance.
free ARV drugs offered by the national government in 159 Cell Research, 15(11-12):883-890, Nov-Dec 2005 | regions and 441 towns. The enrollment standard for therapy in each region was in accordance with the enroll- Effective AZT requires almost perfect compliance to ment standard of the national free therapy [14]. Eligibility its complex therapeutic approach. During the course of for antiretroviral therapies is based on a combination of taking ATR, patients’ high compliance was very essential clinical (WHO Stage III, IV) and laboratory criteria (CD4 to reduce virus load in the plasma, to enhance immunity < 200 cells/mm3). Clinical criteria are identified through a function, to maintain the concentrations of therapeutic careful physical examination and medical history. Labo- drugs and to retard the development of the disease. Many ratory criteria rely primarily on a CD4 test, or a total lym- reports indicated that only when the compliance increased phocyte count (< 1200 cells/mm3) when a CD4 is not to 90% - 95% or above, the virus replication in the body available. Note that a CD4 test is preferable to a lympho- could be effectively repressed [15]. Therefore, in order to cyte count, and CD4 counts should be used when they enhance the compliance and achieve ideal therapeutic effects, the main measures were to reduce the amount There are four pharmaceutical manufacturers involved and times of administration to as few as possible and to in the production of the national free ARV drugs, including select drug combinations with few side effects and con- five kinds of generic drugs (DDI, D4T, AZT, NVP, and venient administration. However, it proved very difficult IDV). The Ministry of Health imported large amounts of to maintain high levels of compliance during therapy. Pa- Combivir, 3TC and EFV from GSK and MERCK. In light tients taking ARVs must tolerate several side effect syn- of the strict control of long-term application of HAART, dromes with varying degrees, from mild to life-threatening.
the approach and the selection of the formula from the Moreover, ARV therapy requires patients to take different National Free AIDS ARV Drug Therapy Manual were based drugs at different times in a day in some cases. Compli- on the drugs that the government could provide for free.
ance is affected by many factors, such as the patient’s I. First-line Approach for ARV-Naïve Patients: psychosocial and economic situations, opportunistic D4T+DDI+NVP or AZT+DDI+NVP was selected for pa- infections, therapeutic approaches (side effects, drug tients without obvious hepatic diseases (jaundice, ascites, dosage, drug type, dietary restrictions, etc), the quality of or the increase of baseline serum aminotransferase) and the doctor-patient relationship, and accessibility to the clinics. Since compliance varies from patient to patient II. First-line Approach for ARV-Experienced Patients: with different social, economic and cultural backgrounds, Due to its milder toxicity and side effects, 3TC was rec- the optimal approach is to take each patient’s individual ommended to replace DDI in the original approach so as situation into account. Research on compliance has been to improve or avoid toxic and side effects attributed to mainly conducted in western developed countries, but little DDI or the combination of DDI/D4T. Other drugs were information about compliance in the developing countries is available. China has no data or information concerning 80% of patients were given the combined approach of patient compliance. At present, it is necessary in general AZT/D4T+DDI+NVP. Among them, the approach con- demonstration districts for AIDS prevention and treatment taining AZT was most common, accounting for 77%. As to start health education and behavioral interventions. This 3TC was distributed for free and new therapy guidelines includes promotion of HIV-1 voluntary test and counseling, were implemented, the number of patients taking AZT/ provision of pre- and post-test counseling. Imparting d4T+3TC+NVP/EFV gradually increased, and among knowledge about ARV drugs, the best time to start HARRT, them, d4T+3TC+NVP was the predominant drug combi- direct monitoring of ARV therapy, drugs availability, meth- ods of drug administration, side effects of the drugs, nec-essary lab tests, etc, would enhance compliance and Factors affecting the therapeutic effects of ARV drugs
Tab. 3 Criteria for ART in adults/adolescents [14]
Patients with active TB and CD4 >200 < 350** Pregnancy – see “special case-pregnant women” | Cell Research, 15(11-12):883-890, Nov-Dec 2005 887 drug resistance testing for the patients. As for these pa- Since several kinds of ARV drugs became available and tients with poor compliance, we should adequately super- HAART was adopted, anti-HIV/AIDS therapy has achieved vise the administration of their medicines and re-test the good clinical effects, drastically reducing the morbidity viral load and CD4+ T cell count monthly so that curative and mortality rate of HIV/AIDS patients. However, HIV-1 drug resistance is not only a major obstacle to sustaining On Aug 20, 2004, we conducted CD4/CD8 and VL tests HAART in the long-term, but also the main reason for the for 320 patients who had been receiving therapy for more failure of anti-HIV/AIDS treatment [16]. We collected the than 6 months in 5 sites: Shangcai County (Guodun and sample from 100 patients who started HAART between Wenlou), Xincai County of Zhuma City in Henan Province, 1999 and 2003 [17], including 10 cases with therapy more Suizhou City in Hubei Province and Lixin City in Anhui than 5 years of duration, 62 cases with over 2 years Province. The results demonstrated that among those re- duration, and 53 cases with over 1 year duration. Among ceiving therapy for more than half a year, VLs of 141 them, 19 cases showed rebounding viral load, defined by samples were higher than 500 copies/ml, including 126 at least 2 successive viral load detections remaining above samples that were high enough to qualify for drug resis- 500 copies/ml (bDNA) or unchanged CD4+ cell count, tance testing. There were four drug combinations among and persistence of clinical symptoms. We conducted the t h o s e p a t i e n t s , i n c l u d i n g 1 . D 4 T + d d I + N V P , 2 .
drug resistance test at 47 time points for 19 patients.
D4T+ddI+EFV, 3.AZT+ddI+NVP, and 4.AZT+ddI+EFV.
Trugene HIV-1 Genotyping System and OpenGene DNA The results indicated that of the 126 samples with viral Sequencing System (Bayer HealthCare£¬USA) were load > 500 copies/ml after 6 months therapy in these 5 employed. Through RT-PCR, sample RNA was amplified locations, 67.46% (85/126) showed drug-resistance and into target DNA, which was the protease gene fragmentof 297bp and reverse transcriptase gene fragment of1680bp in HIV-1 pol gene. After the Clip reaction as wellas the mapping, OpenGene DNA Sequencing System com- Tab. 4 Test results of 19 cases with clinical therapy failure [17]
bined and analyzed the sequence automatically. By manual proofreading, clinical test reports and lab research reports were obtained. The results suggested that among 19 patients, 3 of them were not detected with drug resis- tance in the samples at each time point. Among the 16 patients who developed drug resistance after HAART, 14 cases were those in which plasma samples were taken before the therapy. Only one of them indicated resistance to NNRTIs before therapy. The test results of the 16 pa-tients showed that resistance to different drugs had dif- ferent degrees at different times after the therapy. And among the 11 cases that had been treated previously with NNRTIs, all of them showed resistance to NNRTIs, and nine of them became resistant within one year of adminis- Drug resistance emerges mainly through two routes: one is the transmission of drug-resistant strains (initial drug resistance); the other is the transformation from HIV-sen- sitive strains to drug-resistant strains (induced drug resistance). Our results indicated that during the early stages, the majority of HIV/AIDS patients were not drug- resistant before therapy in China. Among the 19 clinical cases that had rebounding viral load, three cases weredetected not to be drug-resistant. By detailed interviews with patients, it was verified that their administration com- +: Highly resistant; -: Not resistance; ±: Possibly resistant;1) The tested single point was not enough to produce resistance to pliance was poor. They frequently took medicine discontinuously, suggesting that patient compliance should 2) This point was found in clinical experiment that it could only lead be well understood before clinicians decide to conduct to resistance of some patients to certain drug.
Cell Research, 15(11-12):883-890, Nov-Dec 2005 | the percentage was as high as 80.95% in Guotun of sion ability of HIV by alleviating viremia and thus benefit Shangcai County. Cases without viral load reduction were public health [19]. Controversy remains regarding how attributed to the emergence of drug-resistant strains in the early therapy should be initiated. Although evidence indi- patient, rendering therapy ineffective for them.
cates that the immunity functions of HIV-infected patients Furthermore, the majority demonstrated resistance or pri- without HAART decrease progressively, HAART cannot mary resistance to NNRTI. Currently, China is conduct- completely restore immune function in some patients.
ing ARV therapy on a large scale and NVP is one of very Therefore, currently it cannot be predetermined to what important components. Because of cross drug resistance, extent the immunity function will be restored by therapy.
drug resistance mutation sites for NVP could lead to resis- It also cannot be determined how delayed therapy will in- tance to other NNRTIs [18]. Careful attention should be fluence the restoration of the immunity function. If the paid by clinical personnel to avoid the spread of strains ongoing comparative research on early therapy and de- resistant to these drugs in China. Ideally, all patients hav- layed therapy fails to yield useful conclusions, clinical de- ing received therapy should be tested with HIV drug resis- cisions must rely on the existing evidence. The existing tance since drug resistance test is very helpful for the es- optimal approach still bears some uncertain factors. Our tablishment of rational therapy measurements. However, knowledge of the ideal time for starting therapy is limited current HIV drug resistance testing is still unavailable in [20]. Currently, China (and other developing countries) almost all areas. Therefore, it is crucial for China’s HIV/ should offer treatment to patients with CD4 counts be- AIDS therapy to involve drug resistance testing in the HIV/ tween 200 to 350/mm3, who are on the verge of clinical AIDS clinical routine tests as soon as possible.
AIDS stage. The longer therapy is postponed, the more 3) Follow-up and evaluation are big problems for ARV the side effects and the higher the possibility of drug resistance. China does not have standardized data for Chi- Follow-up and evaluation in the clinical setting are press- nese CD4 and CD8 cell counts. Therefore it remains un- ing problems for ARV therapy. The objectives of the clear when HAART regimen should be started in the HIV/ antiretroviral therapy are as follows: 1. Virological objective: to reduce viral load to the greatest possible extent and tomaintain undetectable levels for as long as possible; 2.
Immunological objective: to reestablish immunity function We thank the GSK, Merck, BMS and Boehringer and/or maintain immunity function; 3. Ultimate objective: Ingelheim pharmaceutical company for their supplied all to prolong life and improve quality of life for the patient.
ARV drug in our for clinical trial study. We also thank the However, currently in China’s rural areas, viral load and Office of AIDS for fuddling us to set up the clinical train- drug resistance tests are not available either because of lack of equipment, reagents or technology. Regarding im-munity testing, the nation tries its best to support it, but REFERENCES
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