Evaluating the Impact of Antiretroviral and Antiseizure Medication Interactions on Treatment Effectiveness Among Outpatient Clinic Attendees with HIV in Zambia

Abstract

Objective:

Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant HIV among people living with HIV in Zambia.

Methods:

Eligible participants were ≥18 years of age, concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data was obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVL), and HIV genotype and resistance profile in participants with a pVL> 1000 copies/ml were obtained. Pearson’s test of independence was used to determine whether treatment with EI-ASM was associated with pVL>1000/mL copies.

Results:

Of 50 participants, 41 (82%) were on carbamazepine (37 on monotherapy), all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a TDF/3TC backbone. The majority (94%) were on a stable ARV regimen for > 6 months. Median CD4 nadir was 205 (IQR 88–389) cells/mm3, and 60% of participants had commenced ARVs treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm³ (SD 226.3). Seven participants (14%) had a CD4 count<200 cells/mm³. Four (8%) had a pVL >1000 copies/mL, all were on carbamazepine. Three participants with elevated pVL had a CD4 count < 200 cells/mm³. None had documented adherence concerns by providers; however, 2 had events concerning for clinical failure. HIV genotype testing showed mutations in 3 participants. Carbamazepine was not found to correlate with elevated pVL (p=0.58).

Significance:

EI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts > 200 cells/mm3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.

Introduction

Epilepsy is a common comorbid diagnosis for people living with HIV in many low- and middle-income countries (LMIC) around the world, where rates of HIV are also high.^{1, 2} Once a diagnosis of epilepsy is made, people with HIV who already require lifelong treatment with antiretrovirals (ARVs) usually also require antiseizure medications (ASMs). In resource limited settings (RLS), epilepsy treatment options are often limited to older medications such as phenobarbital and carbamazepine, which have enzyme inducing properties.^{3, 4} Concern that enzyme-inducing ASMs (EI-ASMs) may increase the risk of drug-resistant HIV is of great clinical importance in areas with high rates of HIV.⁸ However, there is limited data on ASM-ARV interactions in RLS, with most studies being pharmacokinetic reports or clinical studies focusing on newer ASMs that are not commonly available in resource-limited settings.^{5, 11}

Effective HIV care requires lifelong treatment using a combination of ARVs, preferably agents with different mechanisms of action.⁶ Clinically significant drug interactions between EI-ASMs and ARVs may result in inadequate ARV levels, viral replication, and development of ARV resistance.^{7, 8, 9} Drug resistant HIV complicates disease management substantially for the individual and represents a serious public health threat if/when such resistant strains of HIV are transmitted to others. Concerns that EI- ASMs may decrease ARV levels for non-nucleoside reverse transcriptase inhibitors (NNRTIs) through induction of the P450 system have been previously reported.¹⁴ However, agents for epilepsy care in most LMIC are primarily EI-ASMs.^{2, 10, 11}

In 2012, evidence-based guidelines for ASM selection in people with HIV were published by the American Academy of Neurology and endorsed by the International League Against Epilepsy.¹² While an important first step, the guidelines were limited by a lack of strong supporting evidence from which to make recommendations, particularly when it comes to EI-ASMs.

Given the absence of epidemiologic data to guide care for persons with seizures and co-morbid HIV/AIDS, as well as the potential public health impact of the development of ARV resistant HIV due to the concurrent use of EI-ASMs and ARVs, we conducted a study to assess whether, within the context of routine care, the co-usage of EI-ASMS and ARVs is associated with ARV failure and/or ARV resistance.

Methods

Participants:

Participants were recruited from three institutions in Zambia- University Teaching Hospital (UTH), the country’s tertiary care referral center in Lusaka, and two large rural hospitals- Chikankata Hospital and Monze Mission Hospital, in Zambia’s Southern Province.

Inclusion/Exclusion Criteria:

Participants were ≥18 years of age with co-administration of ARVs and ASMs for ≥1 month within the past 6 months. Written informed consent provided in the patient’s preferred language was also required.

Clinical Data:

Participants provided blood samples for CD4 count and plasma viral load (pVL) with additional blood stored for HIV genotyping if pVL >1000 copies/ml. Genotype testing included clinically relevant ARV resistance mutations or polymorphisms as defined by the International Antiviral Society.¹³ Copies of all laboratory results were provided to participants’ clinical care providers. Medical records were reviewed for previously utilized ASM or ARV regimens, chronic usage of other enzyme-inducing agents and signs of clinical failure as defined by new or recurrent clinical events indicating severe immunodeficiency (WHO stage 4 condition) after 6 months of effective ARV treatment.¹⁴ Potential relevant covariates including gender, use of other concurrent enzyme-inducing agents, lapses in adherence as determine by staff ratings and lapses in ARV collection were extracted from the chart.

Statistical Analysis:

Descriptive statistics were performed using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA), while the test of statistical independence was performed in R, version 3.5.3 (www.r-project.org). The primary outcome variable was HIV viral suppression defined as a pVL>1000 copies/mL per 2018 Zambian Guidelines published by the Ministry of Health.¹⁵ For those with a pVL >1000 copies/mL, secondary outcome was the prevalence of ARV-resistance.¹⁶ A Pearson’s test of independence, where the p-value is computed by Monte Carlo simulation (based on 5000 replicates) was used to calculate the association between ASM and ARV regimens and the presence of viremia.

Results

We enrolled 50 participants across the 3 sites. Demographic information is provided in Table 1. The median CD4 nadir was 205 (IQR 88–389) cells/mm3, with 24 (49%) participants having a CD4 nadir < 200 cells/mm3. The majority (60%) had a highest documented WHO HIV stage of 1 or 2. Nineteen percent had a documented WHO HIV stage of 4 indicating AIDS.

Table 1.

Demographics and Clinical Characteristics of Participants

	Participants (n=50)*
Sex, male	21 (42%)
Mean age, yrs.	39.9 (SD 12.7)
Median CD4 nadir (cells/mm3)	205 (IQR 88–389)
Worst WHO stage
I	19 (40%)
II	10 (21%)
III	10 (21%)
IV	9 (19%)
Unknown	2
Current ASM
Carbamazepine	37 (74%)
Phenobarbitone	7 (14%)
Valproic Acid	1(2%)
Carbamazepine/Valproic acid	2 (4%)
Phenobarbitone/Valproic acid	1 (2%)
Carbamazepine/Phenobarbitone	1 (2%)
Carbamazepine/Phenobarbitone/Valproic Acid	1 (2%)
% on enrollment ASM for ≥6 months	34 (72%)
Median Total Duration ASM (months)	7 (5–34)
Current ARV
TDF/3TC/EFV	19 (40%)
TDF/3TC/NVP	8 (17%)
TDF/FTC/EFV	5 (11%)
TDF/3TC/DTG	4 (9%)
Other	11 (24%): 8 (16%) containing PI
Missing	3 (6%)
% on ARV for ≥6 months (n=49)	46 (94%)
Median Total Duration ARV (months)	76 (IQR 34–132)
Adherence Documentation
Missed appointments	6
Lapses obtaining ARVs	1
Documented concern for adherence	2

TDF, tenofovir disoproxil fumarate; 3TC, lamivudine; EFV, efavirenz; NVP, nevirapine; DTG, dolutegravir; PI, protease inhibitor

The majority (82%) of participants were taking carbamazepine, either as monotherapy or part of a multi-drug regimen, at the time of enrollment. The second most common ASM prescribed was phenobarbital (14%). The majority (72%) of participants had been taking ASMs for at least 6 months. Prior ASM usage included carbamazepine, phenobarbital and valproic acid; however, none of the patients had switched their ASM regimen within the prior 6 months to enrollment. The median duration of any ASM treatment was 7 (IQR 5–34) months.

Complete data on ARV exposure was missing for three participants, whose HIV clinic files were not available at the study visit and who were also unaware of their ARV regimen. There were thirteen different ARV regimens recorded among all participants, with 40% taking tenofovir disproxil fumarate/lamivudine/efavirenz (TDF/3TC/EFV). Thirty-two (68%) were on a regimen containing TDF/3TC. Eight (17%) participants were on a regimen containing a protease inhibitor (e.g. atazanavir [ATV], lopinavir/ritonavir [LPV/r]), and only 4 (9%) were on an integrase inhibitor-based regimen containing dolutegravir DTG). The majority (94%) had been on their ARV regimen for at least 6 months, and only 1 participant had been taking their current ARVs for 1 month. The median total duration on ARVs was 76 months (range 7 months-20 years). Regarding adherence, 6 participants had documented missed appointments at the HIV clinic but clinic visits are generally scheduled to provide some additional bridging medications in case an appointment is missed and only one participant had documented concern for adherence noted by their HIV clinic provider.

The mean CD4 count at study enrollment was 464 (±226.3) cells/mm3. Seven participants (14%) had a CD4 <200 cells/mm3, with the minimum being 33 cells/mm3. Thirty-four (68%) participants had undetectable HIV viral loads. Only 4 participants (8%) had a pVL >1000 copies/mL, all of whom were on carbamazepine monotherapy. Table 2 shows the clinical characteristics of the 4 viremic patients who underwent HIV genotype testing. The viremic participants showed minimal resistance to protease inhibitors, with more mutations conferring resistance found in the nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) classes. Participant 1 was the only person in the cohort on an ABC/3TC/NVP regimen, and they had no resistance mutations to their regimen. Participants 2 and 3 were both on TDF/3TC/EFV with mutations conferring high- or intermediate-resistance to all their ARVs. The K65R mutation was found in 3 of 4 viremic participants. This mutation causes intermediate/high level resistance to TDF and low/intermediate resistance to 3TC, the most common ARV backbone within the research cohort. Participant 4 had resistance to two anchor classes (PIs and NNRTIs) which suggests a prior history of ARV resistance and higher likelihood of failure on his current regimen. Pearson’s chi-square test of independence showed an association between ARV regimen and viremia (p=0.003 for all 4; p=0.002 excluding the participant with unknown ARVs); however, carbamazepine was not found to be significantly associated with viremia (p=0.58).

Table 2.

Demographics and Clinical Profile of Participants with Virological Failure

	1	2	3	4
Age	23	45	42	40
Sex	Female	Male	Female	Male
ASM	Carbamazepine	Carbamazepine	Carbamazepine	Carbamazepine
Duration on ASM within past 6 month	6 months	1 month	6 months	5 months
ARV	ABC/3TC/NVP	TDF/3TC/EFV	TDF/3TC/EFV	Unknown*
Duration on ARV within past 6 months	6	6	6	6
Total Duration on ARVs	40 months	30 months	7 months	240 months
Documented CD4 nadir	628	96	48	88
Documented Adherence Problems	None	None	None	None
Clinical Failure Events	None	Worsening seizures	None	TB
Other enzyme-inducing medications	None	None	None	None
Current CD4	642	96	33	110
Current Viral Load	1864	10,692	104,700	416,145
HIV sub-type	C	C	C	A+J
Resistance Mutations	PI=none NRTI=none NNRTI=none	PI= none NRTI= K65R, M184V NNRTI= K103N, V188L	PI=none NRTI=K65R, D67DGNS, Y115F NNRTI= K103N, V106M, E138A	PI= M46I, I54V, V82A NRTI= K65R, M184V NNRTI= K103S, V108I, V179T, V181C, G190S

TB, tuberculosis; PI; protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor

^*Patient unaware of regimen and HIV clinic file not available for medication review

We included participants who were concurrently taking other enzyme-inducing, or inhibiting, medications apart from their ASMs given the high prevalence of those medications within the population. In total, 8 participants were on concurrent enzyme-inducing medications (2 on TB treatment, 4 on Bactrim, and 2 on TB treatment and Bactrim). Of these eight, none had a pVL >1000 copies/mL indicating virological failure and thus they were not included in statistical analysis of viremic participants.

Discussion

Epilepsy disproportionately affects LMIC throughout the world.^1, Given the limited number of ARV regimens in many LMIC, development of ARV-resistant HIV carries a strong public health concern and complicates the clinical decision making regarding when to start EI-ASMs in these patients.¹⁷ As a result, we undertook this cross-sectional study in an effort to better understand the risk of EI-ASMs on developing HIV resistance.

The finding that 92% of participants receiving dual EI-ASM and ARVs in routine care context did not meet criteria for virological failure is somewhat reassuring despite the small sample size. Previous studies in Zambia have shown that people presenting with new onset seizures were often disengaged from care, and had immunosuppression, and only 29% of people in Zambia who initiate ARVs showed consistent adherence and retention within the clinical system in follow up.^{18, 19, 20} Although we did not include a control group, our rate of 8% of patients having elevated viral loads meeting virological failure is comparable to what has previously been reported in patients in Sub-Saharan Africa taking ARVs without EI-ASMs.^{21, 22, 23}

Carbamazepine was the most commonly used EI-ASM within our cohort. Despite 82% of participants taking carbamazepine, only 8% had an elevated pVL concerning for virological failure. However, analysis of these participants showed no association between carbamazepine use and their elevated pVL. While ASM co-usage was not associated with an elevated pVL, the ARV regimen taken was associated with elevated plasma viral load and ARV failure.

One potential reason for the association between ARVs and elevated pVL was that one of the viremic participants was the only person in the cohort on ABC/3TC/NVP. However, this individual did not harbor any resistance mutation on genotype analysis, suggesting another etiology such as poor ARV adherence as the cause of elevated pVL and not ARV-resistant HIV. While there were no documented concerns for adherence in this participant, they may have not been taking medications regularly and not disclosing this to their provider. Further, without prior pVL information for this participant, we cannot rule out that the pVL was trending down and responding to their ARV regiment.

Studies looking at ARV-resistance mutations have shown high rates of baseline HIV expressing mutations to NRTIs.²⁴ Furthermore, the K65R reverse transcriptase mutation found in the majority of the viremic patients is a multidrug resistance mutation that has been shown to have increasing incidence in NRTI-experienced patients on TDF and 3TC containing regimens.^{25, 26} While the prevalence of K65R mutations is quoted in studies outside of sub-Saharan Africa at ~2% of ARV-experience patients,²⁰ one study in South Africa of HIV-1 subtype-C showed patients on a TDF- containing regimen to be 5-times more likely to have a K65R mutation compared to those on other first-line regimens.²⁷ As a result, our findings of ARV regimen being correlated with elevated pVL, especially in the TDF/3TC participants with a K65R mutation, is in agreement with other studies. However, the low number of participants with virological failure limits our ability to draw additional conclusions.

Current guidelines assessing ARV and ASM interactions often discuss the pharmacokinetics of these interactions, particularly serum concentrations of the drugs. In this study, we focused on the pharmacodynamics of these drug interactions that may lead to clinical failure and ARV-resistant HIV, which is more relevant to clinical practice. The International League Against Epilepsy’s guidelines on ASM selection in people with HIV comments on ARV dosage adjustments that may be needed to maintain appropriate drug concentrations.¹² ARV levels in the serum are not monitored in regular clinical practice, particularly in LMIC where access to healthcare, diagnostic testing and drug formulations are limited. However, the enzyme-inducing effects of EI-ASMs, as well as concurrent medications like Bactrim and TB treatment, might lead to decreased blood levels of ARVs, which would decrease their efficacy in inhibiting HIV replication.^{12, 28, 29} This decreased efficacy would lead to higher viral loads, and potentially propagation of resistance mutations to the ARVs being used, particularly the NNRTI class of ARVs which includes efavirenz and nevirapine- both of which were part of the ARV regimen in over half of our participants. Fortunately, ARV-resistant HIV development was not seen in most of our participants.

Limitations to our findings include the small sample size, cross-sectional design and lack of a control group not taking EI-ASMs. In addition, we included participants on EI-ASMs and ARVs only within the previous 6 months with the ASM most commonly used being carbamazepine, and not phenobarbital, an enzyme inducer that acts on different CYP substrates.³⁰ While we included participants on other enzyme-inducing medications (e.g. Bactrim and TB treatment), none had evidence of virological failure in this study and were not included in statistical analysis, despite theoretical concern that they may compound effects of the EI-ASMs and lead to HIV resistance. Three of those participants did have low but detectable pVL that is potentially consistent with a viral blip, a low level of viral replication that can occur with ARVs of unclear clinical significance; however, we cannot rule out the onset of virological failure in those participants. Future work should include prospectively following patients on dual ASM-ARV therapies to see if risk of developing ARV-resistant HIV increases with prolonged exposure. Furthermore, a case-control study would help elucidate the true effect of ARV regimen versus EI-ASMs on ARV-resistance. While a small study, we found that EI-ASMs result in neither ARV failure nor resistance.

Key Points:

• The majority of participants on concurrent EI-ASMs and ARVs showed viral suppression of their HIV

• Use of carbamazepine and ARVs does not appear to increase the risk of developing HIV resistance

• HIV resistance is associated more with ARV regimen than EI-ASMs