With the advent of ART, HIV infection has been transformed from a death sentence to a chronic but treatable disease for most of the HIV-infected individuals. However, around 30% of ART-receiving patients fail to exhibit CD4 + T cell recovery to a normal level despite achieving a sustained HIV suppression (7, 8). Persistently low CD4 + T cell counts are associated with an increased risk of both AIDS-related and non-AIDS-related morbidity and mortality (9). Thus, identification of all the possible risk factors involved in poor CD4 + T cell recovery may provide clinicians guidance in choosing the most effective treatment approaches for these critical patients (8). In the present study, of the 277 HIV-infected Chinese Yi ethnic patients evaluated after a mean 3.77 ± 1.21 years of ART, we demonstrated that only 32.9% patients achieved optimal immune recovery with the CD4 + T cell count ≥ 500 cells/µL at the last follow-up visit, whereas the suboptimal immune recovery at CD4 + T cell counts less than 200 cells/µL, and less than 350 cells/µL occurred in 9.8%, and 36.2% of the included patients, respectively.
To our knowledge, this is the first study to analyze the risk factors potentially associated with suboptimal immune recovery among HIV-infected Yi ethnic patients in Liangshan Prefecture, Southwest China. Through multivariable logistic regression analysis, we demonstrated that low pre-ART CD4 + cell count is an independent risk factor for suboptimal immune recovery, which is consistent with previous studies (6, 8, 10, 11). Compared with patients having baseline CD4 + cell count ≥ 350 cells/µL, patients with baseline CD4 + cell count between 200 and 350 cells/µL, and between 100 and 200 cells/µL at ART initiation are more likely to have suboptimal immune recovery (Table 2). This is consistent with previous studies showing that many individuals who start ART at CD4 + cell count < 350 cells/µL never achieve a normal CD4 + cell count ≥ 500 cells/µL even after up to10 years of effective ART (11, 12). In addition, compared with patients in WHO clinical stage I and II, patients in WHO clinical stage III and IV are less likely to achieve a CD4 T cell count ≥ 200 cells/µL (Table 2). The above results corroborate the current international guideline recommending that prompt or even immediate ART initiation on the day of HIV diagnosis is of great importance to individuals living with HIV before they have markedly declined CD4 + T cell counts and progressed to AIDS (13).
In the present study, the prevalence of HBV/HIV coinfection was 11.9%, which was comparable to the HBV/HIV coinfection rate (13.85%) recently reported among HIV-infected patients in Guangxi Zhuang Autonomous region (14). The HBV infection rate among the HIV-infected individuals is much higher than that of the general population (5–6%) in China (15). Consistent with previous studies (16–18), our study revealed that HBV status did not influence CD4 + T cell response upon ART initiation (Table 2). However, it needs to emphasized that the progression of chronic HBV infection to severe end-stage liver diseases including liver failure, cirrhosis, and hepatocellular carcinoma is more rapid in individuals with HBV/HIV coinfection that in individuals with HBV mono-infection (9, 19). Thus, in patients with HBV/HIV coinfections, TDF or TAF in combination with FTC should be the ART backbone because these three drugs are active against both viruses (9, 13). The ART backbone used in this study was mostly TDF/3TC (66.4%) with the remaining 33.6% being AZT/3TC (Table 1). It is expected that the ART backbone AZT/3TC will be gradually removed from China NFATP and replaced by TDF/emtricitabine (FTC).
The prevalence of positive anti-HCV antibody among the included 277 HIV-infected Yi patients in this study was 43.7%, which could be explained by the fact that 48.7% of the patients were infected through injection drug use. Both HCV and HIV are blood-borne viruses, and the presence of HIV infection increases the transmission efficiency of HCV (20). It has been reported that HCV prevalence in HIV-infected individuals is much higher than HIV-negative individuals, especially in people in who inject drugs (82·4%, 55·2–88·5) (20). HIV co-infection accelerates HCV progression as patients with HCV/HIV coinfection had a 2.92-fold greater risk of progression to severe liver diseases than patients with HCV mono-infection (21). However, the effect of HCV infection on CD4 + T cell recovery after efficient ART remains controversial. Some studies reported that the CD4 + T cell recovery was comparable between HCV/HIV co-infected patients and HIV-mono-infected patients on efficient ART (22), or that the clearance of HCV replication did not influence immune recovery (23). On the contrary, several studies found that despite sustained HIV suppression on efficient ART, HCV/HIV co-infected patients had lower probability to achieve optimal immune recovery as compared with patients with HIV mono-infection (24–28). Our present study also revealed a negative correlation between HCV infection and the optimal CD4 + T cell recovery (Table 2), suggesting that all patients with HCV/HIV co-infection should be evaluated for curative HCV treatment (9). With the advent of direct-acting antiviral (DAA) therapies, HIV/HCV co-infection is no longer a difficult to treat population (29). Of note, when concurrent treatments for both HIV and HCV are indicated, careful consideration needs to be taken for drug-drug interactions between ART drugs and HCV DAAs. In the present study, more than 95% of the ART regimens are EFV and NVP-based (Table 1), the DAA regimen sofosbuvir/ledipasvir is recommended for HCV eradication, whereas the DAA regimens including sofosbuvir/velpatasvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir are contraindicated. As velpatasvir, elbasvir, grazoprevir, and glecaprevir are substrates of cytochrome P450 3A (CYP3A), their serum concentrations will be reduced when co-administrated with EFV and NVP (the CYP3A inducers) (9, 30).
Our study has limitations. First, all the included patients were on NNRTI-based or protease inhibitor-based ART regimens, precluding the assessment of immune recovery in patients on integrase-based ART regimens. Second, HCV-RNA levels were not measured in this study, and therefore patients with positive anti-HCV antibody but negative HCV RNA viral load may be included. Third, the number of Yi patients on efficient ART but with suboptimal immune recovery included in this study was relatively small, which may limit the identification of other determinants associated with suboptimal CD4 + T cell count recovery. Future studies are needed to include more Yi patients from Liangshan Prefecture to investigate more factors (e.g., age, gender, BMI, alcohol consumption, CD4+/CD8 + T cell counts ratio, CD8 + T cell counts, and ART regimens) that are likely to influence immune recovery of HIV-infected patients on efficient ART (8, 10, 31, 32).
In summary, we demonstrated that low pre-ART CD4 + cell count and HCV infection were associated with suboptimal CD4 + count recovery among HIV-infected Yi people on efficient ART in Liangshan Prefecture. Our study support prompt ART initiation after HIV diagnosis, and the HCV eradication treatment in HCV/HIV co-infected patients by appropriate DAA regimens (compatible with HIV ART antiretrovirals) not only for HCV cure per se but also for improving the immunological effectiveness of ART.