Consensus statement on human immunodeficiency virus pre-exposure prophylaxis in China

Introduction Although the global human immunodeficiency virus (HIV) epidemic has been effectively curbed, preventing and managing HIV infection in high-risk populations remains challenging.[1] In China, HIV is primarily transmitted through sexual contact.[1,2] Pre-exposure prophylaxis (PrEP) is a new and effective method for preventing HIV infection using antiretroviral drugs[3]; data from multiple clinical trials worldwide have shown that using antiretroviral drugs for PrEP can limit HIV transmission.[4–7] The World Health Organization (WHO) issued guidelines in 2015 recommending PrEP in populations with an HIV incidence above 3/100 person-years (PY) and in individuals engaging in high-risk behaviors.[3] According to existing studies, the HIV incidence among key populations in China was 5.6/100 PY for men who have sex with men (MSM),[8] 1.6/100 PY for intravenous drug users (IDUs),[9] and 1.4/100 PY for female sex workers.[10,11] As of July 2020, 54 countries and regions have issued PrEP guidelines for adults to prevent HIV infection, and 36 of these have also published guidelines for children and adolescents. However, there are no PrEP guidelines or related consensus statement in China. As such, there is a strong need for standardized guidance on the implementation of PrEP pertaining to medical selection criteria, PrEP timing, drug safety, and consultation and testing programs. Here we present the consensus statement on the implementation of PrEP in China based on the opinions and suggestions of health policy-makers, scientists, clinical experts, community-based organizations of key populations, and the latest reports in PrEP researches. HIV PrEP Effectiveness A number of clinical trials and real-world studies of PrEP have been carried out globally in MSM, transgender (TG) women, heterosexual populations engaging in high-risk behavior, and IDUs. Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (iPERGAY), a double-blind randomized controlled trial (RCT)[5] conducted in France and Canada, found that the risk of HIV infection in MSM populations who took tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on demand was 86% lower than that in the placebo group. The Participatory Research in Ottawa: Understanding Drugs study found that the risk of HIV infection was 86% lower in MSM taking daily TDF/FTC than in those who were treated after a 1-year delay.[12] In the Partners PrEP phase III double-blind RCT conducted in Uganda and Kenya that enrolled 4758 HIV serodiscordant couples,[13] the effectiveness of TDF/FTC and TDF monotherapy for preventing HIV infection was 66% and 71% in females, and 84% and 63% in males, respectively. In the TDF2 study conducted in Botswana,[14] the effectiveness of TDF/FTC was 62%; however, 33.1% of subjects failed to complete the follow-up study according to the protocol. In the Bangkok Tenofovir Study, a phase III double-blind RCT of IDUs in Thailand,[15] the overall effectiveness of TDF monotherapy for preventing HIV infection was just 48.9%, although the rate was higher (73.5%) in subjects with high adherence (ie, taking the prescribed medication for ≥71% of days and missing no more than two consecutive days of doses). Safety and drug side effects As TDF/FTC is a prescription drug combination, PrEP must be used under the supervision of doctors and with laboratory monitoring to ensure standardized dosing and safety; it is inappropriate for non-clinical staff to provide guidance on the use of PrEP. TDF/FTC drugs have excellent safety and tolerability as preventive drugs before HIV exposure. Some people taking this medication may experience mild nausea, headache, weight loss, and other symptoms within four weeks of starting the PrEP, but most of the symptoms will disappear or alleviate over time. The side effects of TDF/FTC compound preparations are lighter than other antiviral drugs, but they still have the potential risk of severe adverse reactions. Physicians need to communicate with PrEP participants in detail before prescribing PrEP drugs. Common side effects of TDF are headache, diarrhea, fatigue, slight loss of kidney function, lactic acid metabolic poisoning, and osteoporosis.[16,17] The possible cause of renal dysfunction caused by TDF is proximal renal tubular lesions. In the guidelines for the treatment of HIV infection, it is not recommended to use TDF or TDF/FTC to subjects with the estimated creatinine clearance rate less than 60 mL/min, and PrEP users need to follow up renal function at least once every 6 months. If abnormal renal function occurs, the cause of abnormal renal function should be carefully examined. If suspected to be caused by TDF, discontinuation of the drug should be considered. Also, subjects taking TDF/FTC also had a slight decrease in bone mineral density, and the risk of fracture did not increase. Common side effects of FTC include headache, nausea, diarrhea, fatigue, skin pigmentation, and lactic acid metabolism. Even if TDF/FTC had the above adverse reactions, in the iPrEx clinical study,[6] the subjects taking TDF/FTC had no significant differences in adverse drug reactions, including side effects of grade 3 or above, and fracture incidence (vs. the placebo group). In the iPERGAY study,[5] a higher proportion of subjects taking the TDF/FTC trial group had gastrointestinal adverse reactions, such as nausea and vomiting, and a higher proportion of subjects had increased creatinine. In contrast, other clinical indicators had no statistically significant differences in adverse reactions such as increased aminotransferases, fractures, proteinuria, and urine glucose between the two groups. A meta-analysis of ten RCTs showed no significant difference in the frequency of adverse events (odds ratio: 1.01, 95% confidence interval [CI]: 0.99–1.03, P = 0.27) and no difference in grade 3 or 4 adverse events between the PrEP and placebo groups.[18] In conclusion, the side effects of people taking PrEP are not common, and they are usually relieved within the first month of taking the drug (“priming syndrome”). Physicians or public health personnel may use over-the-counter drugs to treat symptoms such as headache, nausea, and flatulence. PrEP participants should also be consulted about symptoms requiring urgent evaluation (indicating that they may have symptoms of acute kidney injury or acute HIV infection). Drug resistance A meta-analysis of six RCTs evaluating drug resistance by analyzing the genotypes of TDF- or FTC-resistant HIV strains reported that selective resistance was rare and that drug resistance could occur in subjects who were in the acute stage of HIV infection at the time of enrollment.[18] For example, in the TDF2 study, a patient who showed resistance to TDF and FTC was later found to be in the acute infection stage at baseline, which was not detected during the so-called window period.[14] It was also shown that some patients taking TDF/FTC did not develop secondary resistance but were directly infected with resistant strains.[19,20] Medication adherence The effectiveness of PrEP is highly dependent on adherence to the regimen. A systematic review and meta-analysis of 18 international observational studies including RCTs comprising different key populations showed that PrEP regimens that included TDF (mainly TDF/FTC) reduced the risk of HIV infection.[21] Moreover, adherence was associated with a rate of protection against HIV infection of >70% (infection risk ratio of 0.30 compared to the placebo), while no protective effect was observed when the adherence rate was <40%.[18,22] Another meta-analysis of MSM demonstrated that PrEP reduced HIV infection rate by >80% and up to 98.8% after adjusting for adherence.[23] Thus, a higher adherence to PrEP reduces the risk of HIV infection. Additionally, drug adherence in daily PrEP was shown to be critical for achieving a maximal benefit and reducing the risk of drug resistance, while poor adherence increased the risk of HIV infection.[4,24–26] PrEP with drugs other than TDF/FTC The results of the DISCOVER study—a double-blind phase III RCT evaluating the effectiveness and safety of tenofovir alafenamide (TAF)/FTC PrEP in MSM—showed that the risk of HIV infection was reduced by 98% and 89% with TAF/FTC and TDF/FTC, respectively, compared to the control; the two-drug combinations were similarly effective according to the non-inferiority analysis, and no FTC or TAF resistance was observed among seroconverts in the two treatment groups.[27] However, detectable intracellular drug concentrations are achieved more rapidly with TAF/FTC than with TDF/FTC (ie, median tenofovir-diphosphate concentration can exceed the 90% effective concentration [EC90] within 1 to 2 h after taking TAF/FTC compared to 3 days for TDF/FTC, and additional pharmacokinetic data confirmed that after drug discontinuation, the EC90 was maintained for a longer period of time with TAF/FTC than with TDF/FTC [16 vs. 10 days]),[4,27–29] supporting the effectiveness of TAF/FTC for PrEP. Additionally, in an RCT (HIV Prevention Trials Network 083)[30] of long-acting (LA) injectables for PrEP that enrolled 4570 subjects in several countries who engaged in high-risk behaviors, the risk of new HIV infection was lower in cabotegravir (CAB) taken every 8 weeks than in daily TDF/FTC injection group (incidence rate 0.38% vs. 1.21%; hazard ratio: 0.31, 95% CI: 0.16–0.59). These results demonstrate the non-inferiority or superiority of CAB LA to TDF/FTC for PrEP. Indications and Preparations for Starting PrEP On August 11, 2020, Truvada (emtricitabine and tenofovir disoproxil fumarate tablets, emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg, FTC/TDF) was approved by China's National Medical Products Administration for PrEP in people at high risk of HIV infection, so as to reduce the risk of HIV infection in adults and adolescents (weighing at least 35 kg). PrEP is only suitable for individuals who are at high risk of HIV exposure; this should be determined and a medical evaluation performed before initiating a PrEP regimen. HIV risk assessment International guidelines for PrEP usually include the following questions to help healthcare workers identify individuals who engage in high-risk behaviors and are; therefore, eligible for PrEP. In the past 6 months: – Have you engaged in homosexual or heterosexual activities without using condoms? – Have you ever injected illegal drugs or shared needles with others? – Have you ever had a sexual partner who was infected with HIV? – Are you newly diagnosed with sexually transmitted diseases (STDs) such as syphilis, gonorrhea, or chlamydia? – Have you previously used PrEP/post-exposure prophylaxis (PEP), or are you willing to use PrEP/PEP to prevent HIV infection through sexual or injection transmission? In the above five questions, sexual activities refer to anal or vaginal sex. If one of the five questions is answered “yes,” the person is considered as being at high risk for HIV infection. A person who is in a monogamous heterosexual relationship with an HIV-positive partner who is already receiving antiretroviral therapy and has had an undetectable viral load within the previous 6 months can be ruled out as being at high risk for HIV infection. Medical evaluation Eligibility criteria for PrEP determined in the medical evaluation are as follows: age ≥18 years; negative for HIV antibody; at high risk for HIV infection based on the risk assessment; no contraindications for PrEP medications; and agreement to take PrEP as prescribed, with adherence to treatment and scheduled follow-ups. Being conscious, mentally stable, and able to independently make decisions HIV antibody testing must be performed before initiating PrEP to ensure that the person is not already infected with HIV, as PrEP in undiagnosed HIV-positive patients can lead to drug resistance and have adverse consequences for further treatment. Additionally, baseline laboratory examinations are required before initiating PrEP to exclude individuals with contraindications or other related conditions. HIV antibody test HIV antibody testing should be performed in adults and teenagers (>14 years old) according to the National Guideline for Detection of HIV/acquired immunodeficiency syndrome (AIDS) (2015 version) issued by the Chinese Center for Disease Control and Prevention.[31] HIV self-test results cannot be used as a basis for initiating PrEP. Healthcare providers should be taken to exclude the possibility of infection in the acute phase of HIV [Figure 1].Figure 1: Flowchart of HIV algorithm for PrEP provision. EIA: Enzyme linked immunosorbent assay; HIV: Human immunodeficiency virus; PrEP: Pre-exposure prophylaxis.Renal function test In previous clinical trials, an inclusion criterion for initiating PrEP was estimated creatinine clearance rate ≥60 mL/min.[32] Serologic detection of hepatitis virus Sexually active populations (especially MSM) and IDUs have an elevated risk of hepatitis B virus (HBV) and hepatitis C virus infection. As the PrEP regimen includes drugs that are used to treat HBV, people who are infected with HBV (ie, positive for hepatitis B surface antigen) may experience hepatitis flares upon cessation of PrEP. It is, therefore, necessary to check HBV status before initiating PrEP. HBV infection is not a contraindication for PrEP, but doctors should perform a medical evaluation before PrEP and consult with a hepatitis specialist if necessary. STDs In China, institutions providing free HIV testing usually offer syphilis screening; the rapid plasma regain (RPR) test is the most commonly used method. If the result is negative, syphilis can be excluded; if it is positive, additional testing—for example, with the Treponema pallidum particle agglutination (TPPA) test—should be performed to confirm infection status. The TPPA test can also be used for screening; if the result is negative, syphilis can be excluded and if it is positive, an RPR test is required to determine whether it is a previous or existing infection so as to inform the treatment strategy. Other STDs, including Gonococcal urethritis and Nongonococcal urethritis, can be diagnosed and treated according to individuals’ needs and the availability of resources. History of STD infection in the last 6 months is one of the indicators of the priority recommended for PrEP. Pregnancy test Pregnancy is not a contraindication for PrEP but pregnancy status should be recorded before initiating PrEP. Consultation relating to pregnancy (including contraception and perinatal care) should be offered to women before and during PrEP. Recommendations for PrEP Regimens PrEP drug regimens recommended in the European AIDS Clinical Society (EACS) and US Food and Drug Administration (FDA) guidelines both include the combination of TDF and FTC. In 2019, the EACS and US FDA further approved oral TAF/FTC to the MSM and TG women as a new alternative opinion to PrEP. WHO guidelines also recommend TDF combined with lamivudine (also known as TDF/3TC), as FTC and 3TC are considered equivalent in terms of prevention and treatment of HIV infection. However, with the exception of one phase I study, there are insufficient clinical data on 3TC-based PrEP. At present, China, the United States, and the European Union have not approved the drug indications of PrEP based on 3TC. Therefore, we recommend that 3TC be considered when FTC is not readily available. The present guidelines focus on the TDF/FTC regimen for PrEP. On-demand and daily oral TDF (300 mg) and FTC (200 mg) administration are the two recommended PrEP regimens. Daily regimen: One dose of TDF/FTC per 24 h. On-demand regimen: Double dose of TDF/FTC (or TDF/3TC) 2 to 24 h before an anticipated sexual activity and one dose of TDF/FTC (or TDF/3TC) at 24 and 48 h after the activity [Figure 2].Figure 2: On-demand PrEP. In the typical “2 + 1 + 1” on-demand PrEP regimen, PrEP users take two tablets of TDF/FTC (or TDF/3TC) orally within 2 to 24 h before sex, and one tablet of TDF/FTC (or TDF/3TC) at 24 and 48 h after the last dose of medication. FTC: Emtricitabine; PrEP: Pre-exposure prophylaxis; TC: Lamivudine; TDF: Tenofovir disoproxil fumarate.Studies have shown that the daily regimen is effective in preventing HIV infection in all high-risk groups, while on-demand PrEP was effective only in MSM populations,[33–36] which may be related to the sexual behavior of these groups is mainly anal sex, and the blood concentration in the rectum tissue reaches the protective effect for a shorter time than the concentration of vaginal secretions in women. The 2019 WHO guidelines recommend the use of daily or event-driven (on-demand) PrEP in the MSM population,[36] with daily medication recommended only for the heterosexual population and IDUs. On-demand PrEP is most suitable for MSM who have less frequent (<2 per week) sexual activities that are planned at least 2 h in advance or can be delayed for at least 2 hs; it is not recommended for other high-risk groups such as heterosexuals and IDUs [Table 1]. Table 1 - Target populations for on-demand PrEP. Suitable for on-demand PrEP • MSM with the following characteristics: –Those who think on-demand PrEP is more effective and convenient –Have less frequent sexual activity (ie, <2 encounters per week) –Can plan sex at least 2 hs in advance, or can delay sex for at least 2 hs Not suitable for on-demand PrEP • Women, including those who identify themselves as TG or are identified by society as TG • TG men who engage in vaginal sex • Men who have vaginal or anal sex with women • Individuals with chronic hepatitis B virus infection PrEP: Pre-exposure prophylaxis; MSM: Men who have sex with men; TG: Transgender. Follow-up for PrEP and Frequently Asked Questions Follow-up frequency and testing Most guidelines recommend monitoring HIV and STD status every 3 months after initiating PrEP. Side effects of the medications should be recorded for the duration of PrEP treatment. At each outpatient follow-up (every 3 months), relevant should be by medical staff and creatinine clearance and should be [Table Table 2 - recommended at each up every 3 months HIV assessment STD testing and clearance rate Pregnancy Side effect assessment risk consultation evaluation and consultation PrEP PrEP are HIV acid testing to out the so-called of HIV testing should include urine testing and blood testing and testing and for or infection). renal function every 6 months. For individuals with renal function or it may be necessary to check renal function more and include testing for other indicators urine A in creatinine clearance not discontinuation of PrEP. If the creatinine clearance rate to remains the should be to a for consultation and treatment. testing should include hepatitis and Individuals not for hepatitis A and B should be treatment with chronic hepatitis on-demand PrEP should not be to hepatitis B the frequency of the hepatitis C virus infection status based on of can be as number of a follow-up period for PrEP should not be recommended to individuals who have not been and by HIV: Human immunodeficiency virus; PrEP, Pre-exposure prophylaxis; Sexually transmitted monitoring and is critical for the effectiveness of PrEP in preventing HIV infection. for evaluating PrEP adherence in published studies include tablet and of blood drug concentrations blood and blood Although the an assessment of it should be that blood drug concentrations only drugs that were taken of drug concentrations in has been used in some studies to adherence over an but this should be PrEP treatment. medication consultation and adherence should be at the time of PrEP with adherence by during the follow-up should be carried out in of poor Medication and medication are additional for adherence PrEP regimen in MSM The 2019 WHO guidelines recommend two different PrEP and between regimens should be recorded every 3 with of relevant HIV infection during PrEP Although PrEP can effectively prevent HIV infection, HIV negative to positive infection can occur during PrEP, in of poor Clinical trials and other studies have shown that during PrEP is mainly to the so-called window period of HIV infection before or to poor PrEP must be upon of HIV infection. recommend that positive be to and at In to of HIV infection, HIV resistance testing should be performed and antiretroviral therapy PrEP follow up in the of the Disease 2019 In the of public health such as the when follow-up is not medical for PrEP can be through blood can be and for the recommended of for drug concentration and HIV testing during HIV self-test are also the monitoring of HIV infection status and drug concentrations in the Chinese MSM population was achieved in real-world PrEP studies using HIV self-test and blood with was by a from the of National Research for the of

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