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The introduction of highly active antiretroviral therapy (HAART) has markedly decreased mortality and morbidity in patients infected with HIV/AIDS Acquired Immunodeficiency syndrome) (11). However, HAART cannot completely eradicate HIV from the body, results in long-term toxicity and eventually leads to the emergence of drug-resistant HIV strains under the drug pressure in vivo, which was the main obstacle to the effectiveness of antiretroviral therapy (ART) (3). HAART therapy was introduced in Feb 2003 in Queshan, Henan, the first province to implements free ART in China under the policy of "Four Free and One Care". We performed drug resistance studies on several patients in this place to examine the prevalence of drugresistance mutations, resistance to antiretroviral drugs, and the subsequent virological response to therapy in HIV-1 infection.
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The results of CD4+ cell count and measurement of viral load in untreated and treated groups are shown in Table 1. 38.5% of treatment-naïve patients had undetectable plasma viral load (VL), which signify-cantly increased to 61.9% in 0 to 6 months treatment patients (mean 3 months) (χ2=10.987, P=0.001), but again significantly decreased to 38.6% in 6 to 12 months treatment patients (mean 9 months) (χ2= 12.444, P < 0.001) and 40.0% (χ2=8.926, P=0.003) in treatment more than 12 months patients (mean 16 months) (χ2=8.248, P=0.004). With the increase of viral load in each group, the prevalence of drug resistance was getting higher and higher. The drug resistance rates increased with time of treatment in the same range of viral load.
Table 1. Viral load and drug resistance analysis in each group
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The plasma samples with detectable viral load were tested for drug resistance genotypes. In the 241 samples with detectable viral load, only 199 had corresponding sequences, so the genotyping results were limited to these samples. Within each patient group, there were large quantity of PI minor mutations, including types of L63P/S、A71V/T、V77I and I93L. Only one PI major mutation, V82I was found in the untreated group. The results are detailed in Table 2 and Table 3.
Table 2. Frequency of drug resistance mutations in each group
Table 3. Description of drug resistance mutations in each group
No mutation associated resistance to NRTIs was found in untreated and 0-6 months therapy groups. The mutation rates of resistance to NRTI were 8.3% and 19.0% in 6-12 months therapy group and greater than 12 months therapy group, respectively. The most common mutation was T215Y, with a rate of 12.8% found in the greater than 12 months therapy group. Other NRTI mutations were found at a lower frequency less than 5% in each group.
NNRTI mutations emerged quickly after therapy begun, and increased significantly in patients treated for more than 6 months (χ2=9.646, P=0.002). In the untreated group, K101Q/R was more common than for the treated groups. The most frequent mutations were K103N, V106A, Y181C and G190A after therapy, and the rates of K103N, Y181C and G190A increased with the continuation of treatment. The frequency of K103N was 32.4% in patients treated for less than 6 months, and increased to 52.8% and 55.3% in 6-12 months therapy group and the greater than 12 months therapy group, respectively. Table 4 showed the mutation patterns of NNTRI in each group: in patients treated for less than 6 months there were mostly single mutations, while the strains with two or more NNRTI mutations increased with the continuation of therapy(χ2=4.320, P=0.038).
Table 4. Frequency of NNRTI mutations in treated patients
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The prevalence of drug resistance in patients who had detectable VL with sequences available were 7.0% (3/43), 48.6% (18/37), 70.8% (51/72) and 72.3% (34/47) respectively in untreated group, 0-6 months therapy group, 6-12 months therapy group and the greater than 12 months group, among which the rates increased dramatically in patients treated for more than 6 months (χ2=6.529, P=0.011). The rates of drug resistance in each group were a little lower than the mutation rates presented in Table 3, for some mutations do not reduce drug susceptibility. No patients with resistance to PIs were detected in this study. NRTI resistant strains were found only in patients treated for more than 6 months, with the rates of 7.0% (5/72) and 19.0% (9/47) in 6-12 months therapy group and the greater than 12 months therapy group (χ2= 4.080, P=0.043), respectively. In the greater than 12 months therapy group, resistance to different NRTIs were all higher than that in the 6-12 months therapy group, among which the drugs with resistance rates more than 10% were Abacavir (Abc), Azt, Stavudine (D4t), Ddi and Tenofovir (Tdf), and high-level resistance to Lamivudine (3tc), Azt and Emtricitabine (Etc) were found at a low frequency ( < 5%). The rates of resistance to NNRTIs in treated patients were high, almost all were high-level resistance, and the rates increased significantly after 6 months therapy (χ2= 9.646, P=0.002). Resistance to Delavirdine (Dlv) and Efavirenz (Efv) were slightly lower than Nvp. Resistance to both NRTIs and NNRTIs were found in patients treated for more than 6 months (Table 5).
Table 5. Drug resistance analysis in each group
For the Azt+Ddi+Nvp regimen under treatment, patients mainly presented resistance to Nvp, which increased significantly in patients treated for more than 6 months (χ2=6.529, P=0.011). Resistance to Azt and Ddi was only present in patients with Nvp resistance and were seen after 6 months of therapy. Resistance to all three drugs was 4.2% (3/72) and 12.8% (6/47) in patients treated for 6 to 12 months and treated for more than 12 months, respectively (Fig. 1).