Integrating human immunodeficiency virus and tuberculosis drug treatment.

Ravesh Singh, HPP laboratory for technical expertise in the use of the Roche Light cycler at the HPP laboratory. A summary of the START trial, regulatory approvals for the START trial and the PhD study analysis, informed consent forms, testing.

INTRODUCTION

Background and literature review

The HIV and TB epidemics in Southern Africa
The traditional barriers to HIV and TB treatment integration
The need for HIV and TB treatment integration
Drug interactions between TB and HIV drugs
Focusing on the RIF-EFV drug-drug interaction
Pharmacogenetic considerations for RIF and EFV

The rifamycin class of TB antimicrobial agents consists of rifampicin (RIF), rifabutin (RFB), and rifapentine (RFP). The main drug-drug interactions expected between TB treatment and ARVs are most often related to changes in hepatic elimination involving the rifamycin class of antimicrobial drugs. -TB drugs with the NNRTI and PI classes of ARV drugs [30, 32]. In this study, EFV concentrations were found to be 59% higher in blacks than in whites and 52% higher with EFV 800 mg. The likelihood of having an EFV trough concentration of less than 1 µg/mL while on RIF-based TB treatment was doubled in White patients compared with Black patients (50% vs. 23%, respectively).

Figure 1: Estimated HIV prevalence in new and relapse TB cases from the 2014 Global TB report [4]

Study rationale and objectives

All these research questions formed the basis for the PhD, the PK research that was part of the larger study 'Starting Tuberculosis and Antiretroviral Therapy' (START)1. The PhD outcome aimed to complement and strengthen evidence-based recommendations for the safe and effective integration of tuberculosis-HIV treatment in black, South African patients.

PUBLICATIONS

Paper I: Initiating antiretrovirals during tuberculosis treatment: a drug safety review

Discussion of paper I
PhD candidates’ contribution to the journal article

I designed the literature search methodology and selected articles for inclusion in the review. I performed a literature search in accordance with the set methodology, searched for, selected and reviewed all the articles that were included in the review article.

Paper II: The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV

Discussion of paper II

To our knowledge, this was one of the first studies to model the impact of TB treatment on EFV apparent clearance (CL/F) in black African patients exposed to the higher EFV 800mg dose. Article title: The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis. I contributed to the formulation of the study hypothesis in collaboration with the START study principal investigator.

I was involved in the provision of drug therapy and the collection of patient data on case report forms, which were specifically designed for the PK study. I spoke with Prof. Holford worked together to refine the model and this collaboration resulted in the discovery of the final mixture model.

Paper III: Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent TB

Discussion of paper III

This analysis builds on the findings from Paper II by studying polymorphisms in key drug-metabolizing enzymes in Black African patients, assessing the implications of these SNPs for EFV dosing and reporting on the tolerability of the higher dose. Title of the article: Dosage of efavirenz: influence of polymorphisms of drug-metabolizing enzymes and concomitant treatment of tuberculosis. I contributed to the formulation of the research hypothesis in collaboration with the principal investigator of the START study and, as a secondary objective, wrote the PK study into the main study protocol.

I designed the pharmacokinetic study with respect to the timing of the blood draws, and determined the appropriate collection and storage of samples for analysis after the study was completed. I took overall responsibility for writing the manuscript and, after completing the first full draft of the manuscript, submitted the manuscript to the co-authors for review and comment.

Commentary: Should efavirenz be dosed higher when co-administered with rifampin?

Discussion of commentary
PhD candidates’ contribution to the commentary

This comment is critical of the FDA's decision to advocate an update to the package insert that includes a new dosing recommendation for patients over 50 kg receiving RIF-based TB. A dose increase may be appropriate for Caucasian patients, but it is certainly not "one size fits all" for African and Asian patients, who make up the majority of the world's users of this drug. Although the FDA has advocated for this dosing update, global treatment guidelines, with the exception of the British HIV Association, have not changed their guidelines to follow suit.

SS Abdool Karim as a regular contributor to comment on the United States Food and Drug Administration (FDA) on January 6, 2012. I made the first draft of the response, which was reviewed and edited by Prof Abdool Karim.

Paper IV: Low rifampicin concentrations in tuberculosis patients with HIV infection

In this analysis, we measured approximate peak RIF concentrations in the START study and investigated the presence and influence of polymorphisms in drug transporter proteins on RIF plasma exposure. The incidence of TB recurrence in 43 of the 58 patients who could be followed long-term was 7.1 per 100 person-years. I contributed to the formulation of the study hypothesis in collaboration with the START study principal investigator and wrote the PK study into the main study protocol as a secondary objective.

I formulated the pharmacogenetic hypothesis for the influence of polymorphisms in drug transporter proteins on RIF exposure. This included verifying the record of the time of the RIF dose, the time of the blood collection and documenting.

OVERALL CONCLUSIONS AND RECOMMENDATIONS

Discussion of major findings

Therefore, the observed overall 29.5% reduction in EFV clearance during TB treatment was unexpected. These results indicated that, in addition to interpatient metabolic differences, concurrent TB treatment appears to play a role in the higher EFV exposure observed in our patients [125]. These findings are in contrast to those reported by others, in which mean EFV CL/F was shown to increase [58, 94] or EFV concentration was reduced [57] in the presence of TB-based treatment. RIF.

At the time these studies were conducted, it was not clear why RIF-based TB treatment would increase the variability in EFV concentrations. Although few side effects were reported with the higher EFV 800 mg dose, we do not support dose escalation during TB treatment.

Study limitations

Increasing the dose of EFV during RIF co-treatment is therefore not supported in these patients. The low peak RIF concentrations detected may place these patients at high risk of TB relapse, possibly warranting an increase in dose. Due to the premature termination of the parent study, it was not possible to assess long-term viral suppression (12 months) in both arms and thus to relate EFV concentrations and genotype to long-term viral suppression.

Finally, due to the study design, it was not possible to distinguish between reinfection and reactivation of tuberculosis when assessing RIF concentrations and tuberculosis recurrence.

Recommendations for clinical practice

Recommendations for future research

In the near future, we plan to evaluate the impact of NAT2 acetylator status in our patients. Given the high EFV concentrations we demonstrated in the presence and absence of TB treatment at 'standard' dosing, small clinical studies are needed to demonstrate that EFV dose reduction in the South African population is safe and effective and potentially cost-saving. In patients with abnormal liver function, genotype may play a role, but this needs to be confirmed in clinical studies in South Africans.

Concentrations analyzed at single time points in many patients during routine treatment must be modeled with NONMEM to generate PK parameters. If our results are validated, studies should be designed to assess the safety and efficacy of higher doses of RIF in South African patients to reduce the risk of TB treatment failure and reduce TB transmission risk for the population as a whole.

Concluding statements

Co-authored publications relevant to the PhD topic

Discussion of Paper V: Paper V is a seminal article evaluating the impact of integrated HIV and TB treatment on survival, adverse events and safety. This landmark study was an open-label RCT that assigned 642 black South African patients to start ART while on TB treatment or complete TB treatment and then start ART. This RCT showed a 56% relative reduction in the risk of death among those receiving integrated treatment, across all CD4 strata, compared with those who started HIV treatment after completing TB treatment.

In addition, the study identifies the critical period between the completion of TB treatment and the subsequent initiation of ART as a period of high risk for death. Importance of TB/HIV treatment integration: The article was timely in highlighting the need for more drug options in resource-limited settings and the need for more pharmacokinetic studies in sick individuals to better understand drug interactions and offer safer treatments. options for HIV-infected patients requiring TB treatment. Discussion of Paper VIII: This article was published on the basis of the SAPIT study and provides clear guidance on the timing of ART initiation during TB treatment, using the patient's CD4 count as a guide to determine when ART should be initiated during TB treatment phases.

One of the main concerns for co-treatment was the management of IRIS, and this result gave providers more confidence in co-treating the very ill early in TB treatment and delaying ART initiation for less ill patients in the continuation phase of TB treatment without worrying about their growth. risk of mortality.

The START Trial

Female participants who engage in sexual activity that could lead to pregnancy and who take EFV must agree to use two reliable methods of contraception: a barrier .. cap with spermicide) together with either an intrauterine device (IUD) or hormonally based. contraception while taking the drugs specified in the protocol and for 6 weeks after stopping the drugs. Another ART drug will be substituted for EFV if participants are unable or unwilling to use two forms of contraception simultaneously. Note: Female participants taking rifampicin but not taking EFV must agree to use a barrier method of contraception or an IUD while taking rifampicin.

Participants who engage in sexual activity that could result in pregnancy but do not receive EFV must use at least one barrier method of contraception or IUD while receiving protocol-specified medications. Participants who lack reproductive potential as defined above, or whose male partner(s) has undergone a successful vasectomy or has documented azoospermia for any other reason are eligible without the use of contraception.

Regulatory approvals for study conduct

Assay and NONMEM information