Drug Resistance to HIV-1 Integrase Inhibitors among Treatment-naive Patients in Jiangsu, China.

Abstract

Integrase strand transfer inhibitors (InSTIs) have been widely used in recent years because of their high genetic barrier to resistance. The World Health Organization (WHO) has recommended dolutegravir (DTG)-containing regimens as the preferred firstand second-line antiretroviral therapy (ART) regimens for people living with human immunodeficiency virus (HIV). During the long-term treatment process, the appearance of drug resistance mutations to InSTIs is inevitable. A meta-analysis has shown that the resistance rate among InSTI treatment-experienced patients is 3.9% (Raltegravir, RAL), 1.2% (Elvitegravir, EVG), and 0.1% (DTG). However, resistance to InSTIs has not been reported in treatment-naive populations. In China, the government highly values the prevention and treatment of HIV/acquired immunodeficiency syndrome (AIDS) and the “Four Free and One Care” policy was announced in and has been implemented since 2003. There are eight kinds of drug on the free list; for example, the standard first-line strategy for treatment-naïve adults and teenagers, tenofovir/zidovudine + lamivudine + efavirenz/nevirapine [two nucleoside reversetranscriptase inhibitors (NRTIs) + one non-nucleoside reverse-transcriptase inhibitor (NNRTI)], has been used for more than 10 years. Another meta-analysis has shown that, in China, the prevalence of acquired drug resistance (ADR) is 44.7%, which includes 31.4% NRTI, 39.5% NNRTI, and 1.0% protease inhibitor (PI) resistance; that of transmitted drug resistance (TDR) is 3.0%, which includes 0.7% NRTI, 1.4% NNRTI, and 0.5% PI resistance. Considering the high drug resistance rate observed under the current treatment strategy, the InSTI-containing strategy seems to be an alternative choice for HIV treatment. The Chinese Food and Drug Administration has approved the use of RAL, DTG, and fixed-dose combinations. Although no InSTIs have been included in the free drug list in China, InSTIcontaining regimens will likely be used to treat patients infected with HIV in the future. In China, new recommended drugs are usually included in the medical insurance reimbursement catalog. Although providing free InSTIs for HIV/AIDS treatment is not possible, there is the possibility to include InSTIs in the medical insurance reimbursement drug list. In March 2019, Anhui, the neighborhood of Jiangsu province, was the first province in the country to include InSTIs (including DTG and RAL) into provincial medical insurance, which greatly reduced the economic burden of patients with HIV/AIDS. However, using InSTIs also increased the economic burden of local government and used a lot of public health resources. Thus, the necessity and effectiveness of using InSTIs should be considered locally. The pol gene of HIV contains three essential enzymes for its replication, reverse transcriptase (RT), protease (PR), and integrase (IN). A previous study has shown that patients with IN-resistant viruses are more likely to have PR-RT mutations than those without an IN-resistant infection. Considering the limited use of InSTIs in China and the association between IN and PR-RT, we believe that IN-resistance mutations are more likely to be observed in samples carrying PR-RT mutations than in those without PR-RT mutations. There has not been large-scale InSTI use in patients with HIV in