Background
The “Four Frees and One Care” policy implemented in China in 2003, which provided free antiretroviral (ARV) drugs, has been credited for significantly reducing the rate of morbidity and mortality attributed to HIV infection in the country [
1,
2]. By August 31st 2013, HIV-1 patients living in 31 provinces and 2215 counties had received antiretroviral therapy (ART) and greatly benefited from this program. The accumulative total of treatment-experienced patients was 234,655, with 188,126 being treated in China.
Characterized by a high replication rate [
3] and the error-prone reverse transcriptase [
4,
5], HIV-1 is extensively genetically diverse. Like those in developed countries, the emergence and transmission of drug-resistant HIV-1 strains is of considerable concern with the widespread use of ART in developing countries. It has been reported that many treated patients developed resistance to a specific drug within a class or an entire class of ART drugs [
6], which may lead to treatment failure and limitation of alteration of treatment regimen. Furthermore, transmitted drug resistance (TDR), which is the transmission of drug-resistant variants to individuals who have never undergone ART can occur. TDR can compromise the efficacy of combination ARV regimens in the management of HIV disease, becoming a major obstacle to ART. The prevalence of TDR varies worldwide ranging from 3.2 % to 24.1 % [
2,
7‐
22]. In China, free therapy was provided to AIDS patients in 2004, which means that there might be transmission of drug-resistant variants. Some reports have demonstrated the increasing TDR rate [
22,
23]. So in this study we focused on the compare of the prevalent ratio of drug-resistant variants before and after 2004 in China to provide some guidelines for the TDR prevention.
Discussion
We report here the drug susceptibility of 521 treatment-naïve HIV-1-infected individuals at the Peking Union Medical College Hospital from 1991 to 2009. Four hundred and seventy eight gag-pol gene sequences (478/521) were sequenced successfully and the results of subtype and genetic resistance were obtained.
Various HIV-1 strains have been identified in China, of which CRF07_BC, CRF01_AE, CRF08_BC, and B/B’are the most common. Other reported strains include subtype G, subtype C, CRF55_01B and numerous unique recombinant forms (URFs) [
26,
27]. Various HIV-1 subtypes/CRFs have been disseminated among different high risk populations. Our findings found that the most common subtype was CRF01_AE among the patients who were infected by sexual contact, and subtype B was found to circulate mainly in the blood-borne transmission population, which were consistent with previous Chinese studies [
28,
29]. In the present study, we found that the main route of transmission remained blood-born route for the subjects in Henan province, of which subtype B was dominant, as a result of HIV infection outbreak in the mid-1990s in paid blood donors in Henan.
Our studies determined that the TDR prevalence in China was 6.7 %, a level classified as “intermediate” according to the WHO thresholds, and which was slightly lower than that observed in some industrialized countries. In the present study, we found no significant differences in the presence of TDR by demographic characteristic, which was similar with a previous study [
8]. Here we showed that there was no significant difference in the prevalence of drug-resistant mutations among the three antiretroviral classes (PI, 2.7 %; NRTI, 2.5 %; and NNRTI, 2.3 %). In addition, we noted that the prevalence of HIV-1 strains with high level of resistance mutations to NNRTIs were significantly higher than those to NRTIs and PIs (
p < 0.0050). The higher prevalence may be related to mutations associated with decreased susceptibility to NNRTIs with a low genetic barrier, which are rapidly generated and emerge early in the selection process [
30].
It is known that there is an approximate 8–10 % genetic diversity exists in pol gene among various subtypes; therefore drug resistance susceptibility of genotype virus may be different. Here we showed a strong association between the prevalence of TDR and subtypes. There was different prevalence of resistance among subtype B, CRF_01AE and CRF_07BC/08BC. Resistance was significantly higher in ARV-naïve patients who were infected with subtype B than in those infected with CRF01_AE viruses (
p = 0.0030), which was similar with previously published studies [
17‐
19,
31,
32]. Although subtypes may vary in mutational pathways, it is unclear whether subtype B was more prone to mutation [
33]. As the predominant prevalence in China, HIV-1 subtype B viruses have been exposed to ARV drugs for a longer period than other subtypes [
26,
34].
This study was performed on ART-naïve individuals. It has been reported that resistance testing prior to the initiation of treatment in untreated populations with HIV infection is cost-effective and may be beneficial to the patient [
35,
36]. It is commonly considered that resistant HIV-1 variants in ART-naïve patients are transmitted from ART-experienced patients or other ART-naïve individuals with drug-resistant strains. There are some studies indicating that drug resistant mutations among treatment-naïve patients were associated with ART used prior to and early in the HAART era [
16]. As the ART use has been extended in China in recent years, it becomes increasingly important to monitor HIV-1 genetic diversity and TDR. Hence, we also tested whether the free ART program, which was implemented in 2003, has influenced the prevalence of overall TDR among ART-naïve patients in China. It should be noted that contrary to the reports from other countries that have implemented broad-access programs to ART [
37,
38], results of our analysis showed that there was no time-dependent trend in the overall TDR, origins, or in any class of drug resistance. Although we did not observe evidence of an increasing prevalence of TDR over years in the sampling patients, the number of HIV-1-infected individuals in our study may be small.
While we did not study a random sample of HIV-1-infected individuals, this was a large, diverse population with a wide time span from a widespread referral network in China, and our study well reflects the time trend and demographic characteristics of TDR.
Conclusions
In summary, in this study, we fulfilled the comprehensive investigation on the circulation of TDR of three ARV classes in China. The overall prevalence of TDR remains intermediate in ART-naïve individuals, and has a stable TDR time trend. These findings enhance our understanding of HIV-1 drug resistance prevalence and time trend, and provide some guidelines for proposing efficacious and effective programs to prevent transmission of HIV-1drug resistant strains.
Acknowledgments
We thank the patients who participate in the study; and the physicians and nurses for excellent patient care.