We observed an overall TDR prevalence of 9.8% (95% CI: 7.2–12.3%) in this meta-analysis. Western developed countries have relatively high TDR prevalence due to the earlier popularization of ART. Among different categories of HIV drugs, patients show the highest resistance to NNRTIs, while shows lowest to the TDRAMs in INIs. This will help inform donors and policymakers on the urgent need to address drug resistance in AHI/ EHI/ PHI people without ART in an environment where high epidemic resistance has emerged.
At present, the antiretroviral regimen for treatment-naive patients generally consists of two NRTIs plus a third active agent selected from INIs, NNRTIs or boosted PIs with pharmacokinetic enhancers[13, 14, 29]. NRTIs plays a central role in ART and was widely used in the treatment of HIV infection. In the era of pre-combined ART, TDR was mainly targeted at NRTIs[23]. In our analysis, the TDR prevalence to NRTIs was second to NNRTIs. NRTI-related mutations, especially those that reduce the fitness of the virus, can gradually disappear (such as M184V)[27]. Since NNRTIs were widely used, the prevalence of TDR to NNRTIs has increased over time. Our analysis indicates that the TDR of NNRTIs was the highest among the four types of inhibitors, and the prevalence is as high as 10% in developing countries. In our study, the most common NNRTIs-associated mutations are K103N/S, which can largely reduce the susceptibility or virological response, and develop
resistance to NVP or EFV[18]. A single amino acid mutation can produce resistance to NVP or EFV, and the DRMs in NNRTIs are particularly important in predicting the effectiveness of first-line regimens[20, 30]. Besides, a few variants may persist and have a negative impact on the response to treatments[12, 31]. But in some developing countries, NNRTs-based (e.g. EFV-, or rilpivirine-based) programs, are still the choice for some AIDS patients to begin their treatments[32]. Although the TDR prevalence to PIs was second only to NNRTIs, the clinical consequences caused by the increase of single PIs resistance mutations are very limited because of the high genetic barrier[27, 33, 34]. Nowadays, the two-drug regimens containing dolutegravir (DTG) + lamivudine (3TC) have become a relatively new scheme recommended as first-line ART[14]. The existing data have shown that the TDR of INIs was the lowest in all kinds of inhibitors. Since 2014, INIs was listed as the preferred option for ART-naive patients due to their excellent efficacy and safety[35–38]. It is worth mentioning that although cases of drug resistance transmission of INIs have been reported, major INIs mutations are rarely found[21, 22]. By this token, a PI-based and/or an INI-based combination over NNRTI-based regimens should reduce the risk of early failure[1]. At the same time, as more and more patients choose INIs-based regimens, we should also be prepared for a possible increase in the spread of INIs mutations[21].
The emergence of HIV drug resistance may impair the effectiveness of antiretroviral drugs[39] and further impact global HIV response and ART promotion[22]. According to current guidelines, drug resistance tests were
recommended in all cases right after the diagnosis is made[13, 14]. Detection of drug resistance mutations in AHI patients may be an important means to predict future drug resistance patterns[10] and help provide information on both global guidelines for the treatment and management of HIV.
As far as we know, this is the first meta-analysis of TDR and mutations in ART-naive person with PHI, AHI, or EHI. We applied a systematic, comprehensive and quantitative method in the analysis and collected relatively comprehensive data and results of DRMs in acute phase of HIV infection.
There are also limitations in our study. Firstly, similar to most meta-analyses, the analyzed data were extracted from the literature, rather than the original data, which may lead to a small bias in data selection. Secondly, because there were relatively few tests for DRMs in ART-naive patients with PHI, AHI or EHI, the analysis only includes a small number of studies. Thirdly, the data used in the study were mostly from urban and peri-urban areas, so the analysis mainly reflects the situation of DRMs in these areas. Despite these limitations, our meta-analysis can still provide references for ART-naive patients with AHI to choose antiretroviral regimens before starting treatment, especially in countries with NNRTI-based ones.