Outcomes of the three-month weekly isoniazid with rifapentine (3HP) versus the six-month isoniazid preventive therapy (6H) among people newly enrolled in HIV care in western Kenya

In western Kenya, the three-month weekly isoniazid with rifapentine (3HP) regimen significantly improved TB preventive therapy initiation among people with HIV compared to the six-month isoniazid (6H) regimen, though completion rates remained similar for both, highlighting the need for targeted support for patients with advanced HIV disease.

The Gist

Imagine you have a garden (your body) and a very dangerous weed called Tuberculosis (TB) that loves to grow, especially if your garden's soil is weak because of HIV. To stop the weed, doctors give you a special fertilizer called Preventive Therapy.

For a long time, the only fertilizer available was a slow-acting one you had to water every single day for six months (called 6H). It was hard to stick to, and many people stopped watering before the job was done.

Recently, scientists invented a new, faster fertilizer: a powerful mix you only need to water once a week for three months (called 3HP). It sounded like a dream, but nobody knew if it actually worked better in the real world, especially in places like Western Kenya where resources are tight.

This study is like a report card comparing the old six-month method against the new three-month method for over 1,900 people newly starting HIV care.

The Main Story: Getting Started vs. Finishing the Job

1. The "Start" Line: 3HP Wins
Think of starting treatment like signing up for a marathon.

• The Old Way (6H): People were hesitant. Because it was a long, daily grind, about 16% of eligible people never even signed up.
• The New Way (3HP): Because the new plan is shorter and less frequent, more people were excited to start. The sign-up rate jumped to 90%.
• The Lesson: The new, shorter plan is much better at getting people to start the treatment.

2. The "Finish" Line: It's a Tie
Once people started, the story changed.

• The Expectation: Everyone thought the shorter plan (3HP) would be easier to finish, like running a 5K is easier than a marathon.
• The Reality: Surprisingly, both groups finished at almost the exact same rate (about 89%). Whether they took the daily six-month pill or the weekly three-month pill, most people who started successfully finished the course.
• The Twist: The new plan didn't magically fix the problem of people dropping out; it just got more people to the starting line.

The "Heavy Backpack" Problem (Advanced HIV)

The study found a major hurdle: Advanced HIV Disease (AHD).
Imagine some people are carrying a massive, heavy backpack (severe illness) when they arrive at the clinic.

• The Struggle: People with these heavy backpacks were much less likely to start the treatment and much more likely to drop out, regardless of whether it was the 3-month or 6-month plan.
• Why? When you are very sick, your body is fighting a war on many fronts. It's hard to focus on a new medicine when you are dealing with immediate, life-threatening infections. The study suggests we need special "porters" (extra support) to help carry the backpack for these patients so they can take their medicine.

The Cost of Dropping Out

The most important finding is about safety.

• The Finishers: People who finished their fertilizer (treatment) had a very low chance of getting the weed (TB).
• The Dropouts: People who started but quit, or never started at all, were 20 times more likely to get sick with TB.
• The Danger: Sadly, people who didn't finish their treatment were also much more likely to die within two years. It's like leaving a hole in your roof; even if you fix half of it, the rain still gets in.

The "Big Hospital" vs. "Local Clinic" Surprise

The study noticed something interesting about location.

• People treated at large, fancy referral hospitals were actually less likely to start or finish their treatment than those at smaller, local clinics.
• Analogy: Think of a big hospital like a massive, busy airport. It has great planes (doctors), but it's so crowded and complicated that people get lost in the terminal. A small clinic is like a local bus stop; it's simpler, faster, and easier to navigate. The study suggests we might need to move more care to these simpler, local "bus stops."

The Bottom Line

1. Shorter is better for starting: The 3-month weekly plan (3HP) is a great success at getting people to say "Yes, I'll do this."
2. Support is key for finishing: Once people start, the length of the plan matters less than having support. We need to help the sickest patients (those with the "heavy backpacks") stay on track.
3. Don't quit halfway: If you start the treatment, you must finish it. Stopping halfway offers almost no protection against TB and puts your life at risk.

In simple terms: The new medicine is a great way to get people to the starting line, but we still need to build a better support system to help everyone, especially the sickest ones, cross the finish line safely.

Technical Summary

1. Problem Statement

Tuberculosis (TB) remains a leading cause of mortality among people living with HIV (PLHIV). While Tuberculosis Preventive Treatment (TPT) reduces TB risk by 60% and mortality by 39%, programmatic uptake and completion rates remain suboptimal, particularly in low- and middle-income countries (LMICs).

• The Challenge: The traditional regimen, six months of daily isoniazid (6H), suffers from low completion rates due to its long duration and daily pill burden.
• The Proposed Solution: The World Health Organization (WHO) recommended a shorter regimen, three months of weekly isoniazid and rifapentine (3HP), to improve adherence.
• The Knowledge Gap: While clinical trials demonstrated 3HP's superiority in adherence, real-world programmatic data regarding its implementation, specifically among PLHIV with Advanced HIV Disease (AHD) in sub-Saharan Africa, is limited. There is a need to evaluate the "TPT cascade" (screening, initiation, and completion) in routine care settings.

2. Methodology

Study Design & Setting:

• Type: Retrospective cohort study analyzing routine medical records.
• Location: Seven high-volume HIV clinics in Kisumu County, Western Kenya (HIV prevalence: 17.5%).
• Population: 1,930 PLHIV aged ≥15 years newly enrolled in HIV care between January 2022 and September 2023.
• Comparison Groups:
  • 6H Period (Jan 2022 – Sept 2022): Only the 6-month daily isoniazid regimen was available.
  • 3HP Period (Oct 2022 – Sept 2023): The 3-month weekly isoniazid/rifapentine regimen was implemented as the preferred option.

Data Collection & Definitions:

• Data Source: Electronic medical records and hard-copy registers abstracted via REDCap.
• AHD Definition: WHO clinical stage 3 or 4, or CD4 count <200 cells/µL.
• TPT Eligibility: Determined via WHO Intensive Case Finding (ICF) algorithm to rule out active TB.
• Outcomes:
  • Initiation: Proportion of eligible patients starting TPT.
  • Completion: Proportion of initiators finishing the full regimen (excluding loss to follow-up, death, or transfer).
  • Mortality: All-cause death within 24 months of enrollment.
  • TB Incidence: New TB diagnoses post-enrollment.

Statistical Analysis:

• Comparisons: Chi-square tests for proportions across the cascade.
• Correlates: Poisson regression with generalized linear models to identify factors associated with non-initiation and non-completion (stratified by regimen).
• Survival Analysis: Cox proportional hazards regression to assess predictors of mortality within 24 months.

3. Key Contributions

• Real-World Validation: This is one of the first studies to evaluate the programmatic rollout of 3HP in Kenya, moving beyond clinical trial settings to routine care.
• Focus on AHD: It specifically highlights the challenges of delivering TPT to patients with Advanced HIV Disease, a high-risk group often excluded from or poorly served by standard protocols.
• Mortality Correlation: It quantifies the mortality risk associated with TPT non-initiation and non-completion, reinforcing the life-saving potential of full adherence.

4. Key Results

Demographics:

• Median age: 33 years; 65.8% female.
• 19.5% presented with Advanced HIV Disease (AHD) at enrollment.
• 99.6% were screened for active TB; 97.5% were deemed eligible for TPT.

TPT Cascade Performance (3HP vs. 6H):

• Initiation: Significantly higher with 3HP (89.8%) compared to 6H (84.2%; p<0.001).
• Completion: No statistically significant difference between 3HP (89.2%) and 6H (88.8%; p=0.77).
• Adverse Events: Discontinuation due to adverse effects was rare and similar for both regimens (<1%).

Factors Associated with Non-Initiation and Non-Completion:

• Advanced HIV Disease (AHD): The strongest predictor of failure.
  • AHD increased the risk of non-initiation (aRR=2.14).
  • AHD increased the risk of non-completion for both 6H (aRR=2.56) and 3HP (aRR=1.68).
• Socio-Economic Factors: Primary education level and unemployment/student status were associated with non-initiation.
• Facility Type: Care at referral hospitals was associated with lower initiation and completion rates compared to non-referral facilities.
• Marital Status: Being widowed or divorced was associated with higher non-completion rates.

Mortality and TB Incidence:

• TB Incidence: Dramatically lower among TPT completers (0.22 per 1,000 person-months) compared to those who did not initiate (4.25) or did not complete (3.75).
• Mortality: The crude mortality rate was 5.0 per 100 person-years.
  • Risk Factors: Age ≥35, male sex, referral hospital care, and higher WHO stages (3 & 4) were significant predictors.
  • TPT Impact: Patients who were eligible but did not initiate TPT had a 22-fold higher risk of death (aHR=22.31) compared to completers. Those who initiated but did not complete had a 13.75-fold higher risk (aHR=13.75).

5. Significance and Conclusion

• 3HP Improves Access: The implementation of 3HP successfully increased the initiation of TPT among PLHIV in a programmatic setting, addressing a major bottleneck in TB prevention.
• Completion Parity: Contrary to some trial expectations where 3HP showed superior completion, this real-world study found completion rates were similar between 3HP and 6H. This suggests that while 3HP is easier to start, the "completion" barrier in routine care is driven by factors other than just regimen duration (e.g., AHD complexity, social support, facility capacity).
• Critical Vulnerability of AHD: Patients with Advanced HIV Disease face a "double burden": they are less likely to start TPT and less likely to finish it, yet they suffer the highest mortality rates. The study indicates that simply switching regimens is insufficient for this group; targeted, intensive support is required.
• Policy Implication: To maximize the impact of TPT, health systems must:
  1. Prioritize AHD patients for TPT initiation and completion support.
  2. Decentralize care to lower-level facilities to improve uptake.
  3. Implement social support mechanisms (e.g., peer support for widowed/divorced individuals) to improve adherence.
  4. Recognize that incomplete TPT offers limited protection against TB and mortality, emphasizing the need for robust retention strategies.

In summary, while 3HP is a successful tool for increasing TPT initiation in Kenya, achieving high completion rates requires addressing systemic barriers, particularly for patients with advanced disease, to fully realize the mortality benefits of preventive therapy.