An HIV clinician’s perspective with resistance to dolutegravir among pregnant women

Scientists hoped that dolutegravir (DTG) would be a nearly resistance-proof solution when it was rolled out in South Africa in 2020. And while it has been more successful than other HIV treatments, there are reports of surprising resistance, ranging from 3.9% to 8.6% — even as high as 19.6%.

Clinical Laboratory News spoke to Natasha Davies, MD, an HIV specialist, and senior clinician at Anova Health Institute in South Africa about the problem. She works primarily with pregnant and breast-feeding women whose HIV viral loads are unsuppressed or have advanced HIV. She sits on the national 3^rd line treatment/drug resistance committee.

How do you respond to suspected HIV drug resistance?

With pregnant women that I manage, the decision needs to be made quickly, because we’re worried about exposure of the infant in utero and during delivery. If the patient has two viral loads over 1,000 copies/ml within a month of each other, is reporting full adherence, and her history indicates past unsuppressed viral loads, I request an antiretroviral drug resistance test to genotype the virus.

With the general adult population, we only order resistance tests if the patient has been on DTG-based regimens for more than 2 years, has had multiple high viral loads, and we have effectively addressed adherence issues.

How do you confirm adherence?

That’s the hardest part. Patients are often nervous about disclosing adherence problems because they expect a negative provider response. We lack a good objective measure to confirm adherence, except relying on patients' self-reports and following South African guidelines which suggest clinicians check clinic attendance records and pharmacy refill information. Research data shows both methods can be useful. However, in the real world, some patients religiously attend their clinical visits, pick up their medications, but don’t take their pills as prescribed.

Really, the only reliable way to measure adherence is with drug level testing, either using the relatively new Tenofovir urine tests or therapeutic drug monitoring. Unfortunately, in South Africa we don’t yet have easy access to these objective measures.

What are the factors contributing to the emergence of drug resistance to DTG in patients with HIV?

In high income countries with smaller programs, resistance to DTG was uncommon. Because of reports from these programs, when DTG came to South Africa in 2020, we were very excited; however, by 2021, we were already seeing early resistance cases.

In high-income countries, when an individual experiences viral rebound, a multidisciplinary team provides guidance to enhance adherence. This approach aims to ensure better outcomes for patients facing viral rebound. In contrast, lower-resource settings often deal with patients who experience prolonged viral non-suppression due to inconsistent drug pressure. Fluctuating adherence levels contribute to the replication of the virus along the mutation pathways, leading to emergent drug resistance.

Another critical consideration arose with the transition of our patients to the tenofovir, lamivudine, and dolutegravir (TLD) regimen. In 2020, upon gaining access to DTG, we faced the challenge of ensuring patients achieved viral suppression before switching medications. However, this cautious approach inadvertently slowed down the adoption of TLD.

Subsequently, three clinical trials demonstrated favorable outcomes when patients with background resistance to nucleotide reverse transcriptase inhibitors and unsuppressed viral loads were switched to TLD. These study results were extrapolated to a large-scale program serving five million people, where patients do not receive the same high level of adherence support, and some continue to grapple with longstanding adherence issues.

Based on these findings, South Africa shifted policy, allowing nearly all patients to transition to TLD, irrespective of their current viral load or antiretroviral therapy (ART). The only exceptions were patients who had been on a protease inhibitor regimen for more than two years, exhibited high viral loads, and had addressed adherence challenges. In retrospect, it appears that this broad approach may not have been optimal for certain cohorts.

How does DTG resistance impact the effectiveness of HIV treatment?

We initially anticipated that DTG would serve as a bridge for patients with fluctuating adherence while we dealt with their adherence challenges. However, recent observations indicate that even a few months of suboptimal adherence in treatment-experienced patients can lead to the development of DTG resistance.

Thankfully, for ART-naïve patients who initiate TLD as their first-ever regimen, resistance remains uncommon unless they have encountered issues related to tuberculosis and perhaps failed to receive the appropriate double-dosed DTG.

In cases where a patient becomes resistant to DTG, the next step involves transitioning to darunavir—a medication that is more difficult to administer. Notably, patients with prior protease inhibitor exposure (a relatively common scenario) may exhibit cross-resistance from lopinavir to darunavir. If these patients develop resistance to DTG and switch to darunavir, its efficacy might be compromised if administered once daily. We must look after these patients carefully to safeguard their future treatment options.

What are the current strategies employed by physicians to manage dolutegravir-resistant cases?

The current South African guidelines set a high bar for resistance testing. Patients must meet four criteria: have been on TLD for at least two years; failed a previous regimen; have at least two viral loads over 1,000 copies/ml; and their clinician must objectively confirm that they have more than 80% adherence.

The challenge with this approach is that some primary healthcare clinicians work in high volume sites with more than 10,000 patients enrolled on ART, perhaps seeing 40 to 50 patients a day. To confirm that a patient meets all four of those criteria is very challenging. The provider also needs approval to request a resistance test. Some provinces haven’t even put that process in place yet.

In my clinical practice, I encountered six pregnant women with confirmed dolutegravir resistance. Interestingly, none of them met all four criteria outlined in the guidelines. Despite this, I made the decision to perform resistance testing due to the critical implications for maternal and infant health.

Notably, emerging data from laboratories suggest a significant decline in the number of requested resistance tests following the implementation of the current guidelines. These guidelines, while setting a rigorous standard, have inadvertently led clinicians to conduct fewer resistance tests, potentially resulting in underdiagnosis of DTG resistance in South Africa.

Are there any promising advancements in HIV drug resistance and dolutegravir?

For me as a clinician, drug level testing is the most promising advancement. Being able to perform drug level monitoring gives clinicians an advantage. We can differentiate between non-adherent patients with high viral load and adherent patients with high viral load, so we know who needs resistance testing.

Drug resistance testing works very well. What we need as clinicians is a better way of quickly identifying those who need the test so we’re not wasting limited resources.

How can healthcare providers and patients collaborate to prevent or minimize DTG resistance?

Personally, I develop a rapport with my patients that helps to build trust so that they can feel comfortable telling me when adherence is the issue. Many patients hesitate to confide in their clinician when they struggle with medication adherence. Without trust--without open, honest, and supportive conversations--it can be a frustrating process to work out whether a patient is adherent or not.

Many providers think, “it’s just one pill a day, just swallow it, how hard can it be?” But there’s so much more going on in patients’ lives than their medication. Providers need to have more empathy and recognize that life-long therapy is really challenging.

From the patient’s viewpoint, optimal adherence is key in preventing resistance. Yet, it hinges on how we, as providers, and the systems we operate within, empower patients to maintain consistency over a lifetime.

To access HIV educational resources from Thermo Fisher, please visit www.thermofisher.com/hiveducation.

Jen A. Miller is a freelance journalist who lives in Audubon, New Jersey. +X: View the full CLN July/August 2024 issue.