Building Global HIV/AIDS Clinical Pharmacology Research Capacity

HIV and TB: Capacity Challenges to the use of Current

Drugs and Developing New Drugs

Kimberly Scarsi, PharmD, MSNorthwestern University Feinberg School of Medicine

Center for Global Health

Presentation Outline

• Overview of HIV and TB therapeutic challenges

• Drug Interaction considerations in HIV-TB coinfection

• Challenges in TB therapeutics research and drug development

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Tuberculosis and HIV Prevalence

WHO. Global TB Control. 2010

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Paradigm of Disease Progression in Patients with HIV-TB Coinfection

Slide adapted, courtesy of Dr. H

olly Rawizza

HIV-TB coinfection dilemma Related challenges with current therapy

Coinfection increases the risk of progression from

latent to active TB

Inadequacies in both screening and diagnostic tools and

prophylaxis

Higher rates of highly-drug resistant TB

in HIV infected patients

Inadequate therapeutic options for drug resistant TB

TB coinfection leads to more rapid HIV disease progression

Anti-TB therapy is less efficacious without concomitant ART

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

SAPIT

Abdool Karim et al. NEJM 2010;362:697

HIV-positive, CD4 <500new TB infection

HIV-positive, CD4 <500new TB infection

Early integrated (IP)Early integrated (IP) Late Integrated (CP)Late Integrated (CP)

N = 642

Sequential (> 6m)N = 213

Sequential (> 6m)N = 213

Combined IntegratedN = 429

Combined IntegratedN = 429

Slide courtesy of Saye Khoo

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Treatment of TB Infection

Initiation Phase (2 months) Continuation Phase (4 months)*

First-line Regimens

Rifampicin (RIF) or Rifabutin (RFB)Isoniazide (INH)Pyrazinamide (PZA)Ethambutol (EMB)

Rifampicin (Rifabutin)Isoniazide (INH)

Second-line Options

ethionamide, cycloserine, para-aminosalacylic acid, quinolonesInjectables: streptomycin, capreomycin, kanamycin, amikacin(Usually a minimum of 12-18 months therapy required)

* Some countries use INH + ETB for 6 months for continuation phase as an alternative.

Slide courtesy of Holly Rawizza, MD, 2009.

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Pharmacology Challenges of Current TB Therapy

• Complex regimens with high pill burden, particularly with concomitant HIV therapy– May impact adherence

• Overlapping toxicities create clinical management challenges– Importance of pharmacovigilance programs

• Lack of clinical PK-PD data– Urgent need to confirm “therapeutic” target concentrations

• Unique Pediatric Challenges:– Suboptimal drug concentrations with standard doses– Absence of PK and PD data on 2nd-line TB agents

• Significant HIV-TB drug interactions limit the effective options

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

A Focus on Drug Interactions

DRUG INTERACTION POTENTIAL No clinically significant interaction expected Potential interaction – may require close monitoring or dose alteration These drug should NOT be coadministered No clear data

Risk factors for Clinically Significant Drug Interactions in Kenya

Clinically Significant Drug Interaction Odds ratio (95% CI) [p-value]* Variable

no yes adjusted

Sample size 662 334

Sex: male n (%) 239 (36.1) 107 (32.0) ---

female n (%) 423 (63.9) 227 (68.0) 1.506 (1.097 - 2.065) [ 0.010]

Age (y) mean (sd) 38.9 ( 9.2) 39.5 ( 8.6) 1.010 (0.992 - 1.028) [ 0.243]

Weight (kg) mean (sd) 59.1 (10.7) 56.0 (10.5) 0.984 (0.970 - 0.998) [ 0.023]

CD4 (log units) mean (sd) 4.79 (1.10) 4.46 (1.21) 0.839 (0.739 - 0.954) [ 0.006]

WHO stage: 1

n (%)

277 (42.2)

86 (26.1)

---

2 n (%) 109 (16.6) 47 (14.2) 1.203 (0.776 - 1.865) [ 0.400]

3 n (%) 224 (34.1) 161 (48.8) 1.886 (1.327 - 2.683) [<0.001]

4 n (%) 46 (7.0) 36 (10.9) 2.085 (1.213 - 3.586) [ 0.007]

Regimen:

1st line

n (%)

573 (86.6)

307 (91.9)

---

2nd line n (%) 89 (13.4) 27 (8.1) 0.742 (0.457 - 1.203) [ 0.218]

*: missing observations replaced using multiple imputation (100 iterations)

Slide courtesy of Saye Khoo.Kigen et al. HIV8, 2008 Abstract O121

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

-100

-80

-60

-40

-20

0

20

40

60

80

100

SQV RTV IDV NFV APV LPV ATV DRV NVP EFV ETR RIL MVC RAL

- 86%

- 35%

- 89%

- 82%

- 82%

- 73%

- 63%

- 80%

- 72%

Change (%) in AUC of ARVs when given with rifampicin

www.hiv-druginteractions.org

- 40%

- 26%

- 40%

• No significant interactions – NRTIs and T20• Data are lacking with intermittent or high dose rifampicin regimens

ND ND

Slide adapted, courtesy of Saye Khoo

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Clinical outcome data: Essential to evaluate the impact of some

pharmacokinetic changes

Nevirapine Efavirenz

JAMA 2008. 300(5):530-9.

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Drug Interaction Research Questions• Ongoing research with accumulating data:

– Avoidance of NVP lead-in dose with rifampicin– Optimal nevirapine dose escalation strategy with rifampicin– Use of LPV/r dose escalation strategies to overcome rifamipicin

induction in both adults and children– Establishing the correct dose of TB agents for use in children– Appropriate rifabutin dose with protease inhibitors

• Questions remaining to be answered:– Rifapentine drug interactions with antiretrovirals– Defining new TB agent drug interaction profiles– If twice daily atazanavir/r can overcome rifampin induction– Drug interactions with 2nd line TB agents and ART

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

One example of practical PK evaluations of rifampicin plus nevirapine

• PK study in 18 adult Ugandan patients who had been on RIF-containing TB therapy for ≥ 2 wks– Lead-In (n = 9): NVP 200 mg x 14 days, then 200 mg bd– Full-dose (n = 9): NVP 200 mg bd from initiation

• Full dose had more favorable PK: NVP minimum concentration and overall exposure was approximately 40% lower than Full-dose in the Lead-In group at Day 7

• Both groups had median trough levels below target at day 21Lamorde M et al. CROI 2010 and JAC 2010.

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

A focus on new drug development

Goals of New TB Drug Regimens• Shorten and simplify TB treatment• Improve the treatment of MDR-TB and latent TB infection• Optimize TB therapy in combination with HIV treatment

Working group on new TB drugs. http://www.newtbdrugs.org

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Examples of the role of pharmacology in TB drug development

• TB trial design: Combination therapy should be investigated early in the development process– Consider pharmacokinetic evaluations in TB co-infected

patients when possible• Pediatric studies: Dose identification and optimization • Clinical trial capacity: Both clinical and analytic pharmacology

resources must be an area of focus• Considerations for the practical constraints: Dose finding

studies to overcome existing drug-drug interactions appropriate for resource limited settings

Ma et al. Lancet 2010

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs

Summary• Significant challenges exist in TB therapy, both with and

without HIV co-infection.• New drugs and treatment strategies are encouraging,

however capacity building is an essential component of the drug development process.

• There is a significant role for pharmacology research in both current and future TB and TB-HIV therapy.

• A few acknowledgements:– Saye Khoo and Holly Rawizza for slide contributions– Kristin Darin for assisting with presentation development– The AIDS International Training and Research Program for

sponsoring this program

HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs