You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Background {#Sec1}
==========

Current antiretroviral therapy (ART) requires strict life-long adherence to daily drug taking. Long-acting ART agents, capable of being administered on a weekly or less frequent basis, have the potential to improve adherence to therapy and allow a more forgiving time window of drug administration \[[@CR1]\].

Albuvirtide (ABT) is a chemically modified peptide derived from the N-terminal sequence of HIV-1 gp41, and contains a 3-maleimimidopropionic acid (MPA) group in its 13th lysine side chain \[[@CR2]\]. Previous studies demonstrated that upon intravenous injection ABT could rapidly conjugate with serum albumin and dramatically extend the peptide in vivo half-life from 1.7 to 25.8 h in rats and from 10.9 to 102.4 h in monkeys \[[@CR2]\]. A recent study using pseudoviruses showed potent inhibitory activity of ABT against a broad spectrum of HIV-1 strains, including those commonly observed in China and some variants resistant to T20 \[[@CR3]\]. A phase 1 single agent study in HIV-1 infected patients showed excellent safety profile of single and multiple dose of ABT, a half-life of 11--12 days, and a clear dose related antiviral activity \[[@CR4]\].

In this study in naive HIV-1 patients, a novel two-drug regimen combining ABT and lopinavir/ritonavir (LPV/r) was tested, their drug--drug interaction investigated, and short-term safety and efficacy profiles characterized.

Methods {#Sec2}
=======

Study population {#Sec3}
----------------

Antiretroviral treatment-naïve HIV-1-infected patients aged 18--50 years were eligible for this study if they had HIV RNA levels between 5000 and 1,000,000 copies/ml, CD4 cell counts more than 350 cells/μl, body weight more than 40 kg and body mass index (BMI) between 18.0 and 27.0 kg/m \[[@CR2]\]. They had a normal level of albumin and no severe liver and kidney damage, and had not received any antiretroviral therapy for HIV and HBV or stopped antiretroviral therapy for more than 6 months. Exclusion criteria included acute HIV infection, severe opportunistic infections and tumors, severe diseases of digestive tract, hematology, metabolism, psychology and heredity, previous treatment of other HIV fusion inhibitors, drug abuse, pregnancy, and breastfeeding. Female patients with child bearing potential and heterosexually active male patients were required to use effective contraception during the study. The study was approved by the institutional ethics committee of Beijing You'an Hospital, and all potential subjects provided written informed consent before undergoing procedures.

Study design {#Sec4}
------------

The study was a single-site, open-label, and randomized parallel study conducted in the Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University. Twenty antiretroviral treatment-naïve HIV-1 infected patients were enrolled and randomized into two dose groups (10 in each group) to receive ABT by intravenous infusion at dose levels of 160 or 320 mg, and LPV/r (400/100 mg) twice daily. On Day 5--7, ABT was given daily for 3 days, then given weekly till Day 40; and LPV/r was given from Day 1 to 46. The subjects were followed for a 47-day observation period. After the study all participants were treated with triple combination antiviral therapy containing tenofovir, lamifudine and LPV/r.

The plasma HIV-1 RNA was measured using a branched-chain DNA method (bDNA, version 3.0, Bayer Healthcare LLC, Diagnostics Division, Tarrytown, NY) with a detection limit of 50 copies/ml. CD4 cell counts were measured using a FACS count system (FACS Calibur, Becton Dickinson, USA).

Statistical analysis {#Sec5}
--------------------

This was a pilot study without power calculations or sample size estimation. Data were presented as the mean ± SD if not specified. The efficacy and safety analyses were performed for the intent to treat (ITT) population, defined as all subjects who were enrolled in the trial and received at least one dose of study medication. All statistical analyses were performed using SAS version 9.2.

Results {#Sec6}
=======

Twenty antiretroviral treatment-naïve HIV-1 infected patients (Table [1](#Tab1){ref-type="table"}) were enrolled and randomized into two dose groups (10 in each group) to receive ABT (160 or 320 mg) and LPV/r. There were no significant differences in age, body weight, HIV viral load and CD4 cell count at baseline between the two groups. Nineteen subjects completed the study with one withdrawal due to lost to follow-up. Two patients whose baseline HIV viral load did not meet the inclusion criteria and their viral load data were excluded from efficacy analysis. All 20 subjects were included in the pharmacokinetic and safety analysis.Table 1Baseline characteristics of subjects160 mg ABT + LPV/r320 mg ABT + LPV/rRandomized and treated1010Excluded11SS for safety analysis1010ITT for efficacy analysis99Sex (male/female)8/27/3Race (Han/other)9/110/0Age (years)31.9 (18\~48)37.4 (24\~47)Body weight (kg)67.8 (53\~88)65.4 (53\~76)BMI (kg/m^2^)22.8 (19\~27)22.8 (18\~26)Baseline HIV-1 RNA (log~10~ copies/ml)4.27 (3.53\~4.70)4.27 (3.32\~5.14)Baseline CD4 (cell/μl)517.0 (350\~774)566.6 (350\~1070)Data are presented as n or mean (range)

From Day 14 till the end of the study, the viral load (plasma HIV-1 RNA) of all patients decreased \>1.0 log~10~ copies/ml. At the 47th day, the mean viral load decreased from baseline was 1.91 ± 0.36 log~10~ and 2.20 ± 0.33 log~10~ copies/ml for the 160 and 320 mg groups, respectively (Fig. [1](#Fig1){ref-type="fig"}a). The percentage of subjects with viral load \<50 copies/ml was 11.1 % in the 160 mg group and 55.6 % in the 320 mg group (Fig. [1](#Fig1){ref-type="fig"}b). Pharmacokinetic/pharmacodynamic (PK/PD) relationship analysis showed that the decrease of HIV viral load was positively correlated with AUC~0-168h~, C~min~ and C~trough~ of ABT. After treatment with ABT and LPV/r for 47 days, the mean absolute CD4^+^ cell count change relative to baseline was --5 cells/μl for the 160 mg group and 52 cells/μl for the 320 mg group respectively.Fig. 1Anti-HIV activity of albuvirtide and LPV/r. **a** Mean change of plasma HIV RNA over time by dose group. **b** Percentage of patients with viral load \<50, 200 and 400 copies/ml on Day 47

The pharmacokinetic profile of co-administration of ABT and LPV/r showed weak or no interaction. The results will be reported elsewhere. There were no serious adverse events during the 47 days of treatment. Eight cases of adverse events were observed in 7 subjects in 160 mg group and nine cases in 8 subjects in 320 mg group, but only six cases were related to investigational regimen in each group. All adverse events were mild, mainly triglycerides level elevation, diarrhea, nausea and skin rash. No injection site reactions were found during the trial.

Discussion {#Sec7}
==========

In chronic management of HIV infection with ART, one of the most challenges is poor patient adherence to treatment, which often results in treatment failure and emergence of drug resistance \[[@CR5]\]. ABT is an experimental anti-HIV peptide targeting the HIV-1 envelop protein gp-41 at an area that's different from that of T20. The 13th residue of ABT contains a MPA modification that allows ABT to react with serum albumin. This extends its half-life to 11--12 days in human while retaining anti-HIV activity \[[@CR3]\]. Although long-acting AIDS drugs are much sought after, how to administer such molecules with current oral drugs remain to be studied.

In this phase 2 trial, we designed a two-drug regimen that includes a weekly given ABT and twice daily given LPV/r. It represents the first attempt to combine an approved, orally taken ART with a long-acting, injectable anti-HIV agent to treat HIV infected patients. For 47 days, the novel regimen was safe and exhibited potent anti-HIV activity. All treated patients, including one whose baseline viral load was \>5 log~10~ copies/ml, showed \>1 log~10~ copies/ml reduction of viral load. Importantly, data of the 320 mg group showed a trend of superior anti-HIV activity to that of the 160 mg group. This demonstrates clear contribution of ABT to the plasma HIV RNA reduction in the two-drug regimen.

ABT is the first long-acting antiretroviral drug developing in China. With the limitation of no long-acting drugs combined with ABT, we also chose LPV/r for the ART regimen in the phase III clinical trial, a 48-week, randomized, controlled, open-label, multicenter study to investigate the safety and efficacy of ABT, which may have potential as next-generation HIV fusion inhibitors targeting gp41 for clinical use \[[@CR6]\].

Conclusion {#Sec8}
==========

In summary, this 7-week study shows that ABT combined with LPV/r is safe and effective. Compared with regimens of 3--4 drugs, the two-drug regimen could offer a simplified therapy with better safety and less drug--drug interaction. The long half-life of ABT potentially allows a 3-day window for weekly administration and is more forgiving in adherence than daily taken drugs.

Hongwei Zhang and Ronghua Jin contributed equally to this work

Designed the study: DX and HW; conducted the study: RJ, TZ, MW, HZ, WX, R L, CW, CY, HP and XW; analyzed the data: DX, HW, CY and R J; wrote the manuscript: HZ, CY, HW and DX. All authors read and approved the final manuscript.

Acknowledgements {#FPar1}
================

The study was sponsored by Nanjing Frontier Biotechnologies Co., Ltd., and partly supported by the Beijing Municipal Science & Technology Commission (D131100005313005), the Ministry of Science and Technology of China (Grant No. D141100000314005, D141100000314002), the national "twelfth five" major projects of significant new drugs development (Grant No. 2013ZX09101001), and the national "twelfth five" major projects of AIDS and viral hepatitis and other major infectious diseases prevention and control (Grant No. 2012ZX10001-003). The study was registered at <http://www.chictr.org/>, \# ChiCTR-TRC-13003140.

Competing interests {#FPar2}
===================

C.Y., R.L., C.W. and D.X. are employees of Nanjing Frontier Biotechnologies Co., and hold stock in the company. All other authors declare that they have no competing interests.