Diverse people seen from a bird's eye view gather to spell out the letters HIV

Dolutegravir (DTG), an integrase inhibitor used in combination with tenofovir and lamivudine, is a powerful treatment for HIV and has been the World Health Organization’s (WHO) preferred first and second line antiretroviral (ART) since 2018. This recommendation was based on evidence showing that DTG is highly effective in blocking HIV replication leading to high levels of viral suppression, is easier to take and has fewer side effects compared to other antiretroviral (ARV) drugs. DTG also has demonstrated a substantially lower risk of selecting for drug resistance compared to other drugs.

By July 2023, 91% of 127 low- and middle-income countries (LMIC) reporting data to WHO adopted DTG-based ART, according to the WHO.

Recent surveillance data show population levels of acquired HIV drug resistance to DTG ranging from 3.9% to 8.6% and reaching levels as high as 19.6% in one heavily treatment-experienced cohort. Overall, available data — especially from LMIC — remain limited, and more data from standardized surveillance and well characterized cohorts are needed.

Michael Jordan, MD, MPH, FIDSA is associate professor of medicine and public health and community medicine at Tufts University. He’s also a consultant to the WHO and co-chairs the WHO HIV Drug Resistance (HIVDR) Surveillance and Monitoring Working Group. CLN spoke to him about why, while these numbers require further study, drug resistance might not be as high as recent studies might indicate.

Can you discuss WHO’s current guidance and rationale for HIVDR testing at population-level public health surveillance?

With any ARV drug or combination of drugs, including integrase inhibitors, some emergence and possible transmission of drug-resistant virus is expected. Therefore, WHO recommends that, as national antiretroviral therapy (ART) programs initiate and maintain populations on ART, routine, standardized surveillance of drug resistance be part of the assessment of the overall quality of service delivery. We don’t know whether levels of HIV drug resistance are high or low unless we measure it.

What is the WHO’s current guidance and rationale for HIVDR individual-level patient testing?

WHO does not recommend individual patient HIVDR testing to guide regimen selection. The reason for this current recommendation is multi-factorial. One is that with integrase inhibitors, we see very high levels of population-level viral suppression, often greater than 95%. That kind of viral suppression at a population level is something we didn’t see with prior non-nucleoside reverse transcriptase inhibitors (NNRTI)-based regimens. The high levels of population-level viral suppression achieved with DTG-based ART is a game changer and viral suppression is drug resistance prevention.

Drug resistance testing is also expensive — in some countries a drug resistance test can be more expensive than an entire year of treatment for an individual. At present, with the low cost of the fixed dose combination of tenofovir, lamivudine, dolutegravir (TLD) and even the comparably higher cost of other regimens, such as protease inhibitors, drug resistance testing is not generally likely to be cost-effective in most settings. Clear cost benefit and cost effectiveness analyses are needed in the context of a public health approach to HIV care and treatment.

HIVDR testing in high-income countries, such as the U.S., typically involves baseline testing prior to initiation of ART and then whenever there is suspected drug resistance or a change in ART regimen. The same is not true in low- and middle-income countries where demand is greater and resources more limited. What trade-offs were considered by the WHO for HIVDR testing in resource-limited settings?

First and foremost, we look at the impact of drug resistance testing on treatment outcomes when ART is delivered following a public health approach. Does using the result of that test for clinical management lead to better treatment outcomes? The second thing we look at is the cost-effectiveness of that test. A third consideration would be capacity. If this test were to be recommended, could it be implemented, and would the results be of high quality and provided in a timely manner to guide patient management decisions?

Given what we know from clinical trials about DTG used in combination with tenofovir and lamivudine, the vast majority of people are likely to achieve viral load suppression with optimal adherence, even if some NRTI drug resistance mutations are present.

Simply put, TLD is highly potent and effective — this is why we are seeing high population-levels of HIV viral suppression, often ranging from 90% to 95% in countries reporting data to WHO.

With respect to HIV drug resistance testing in people receiving TLD who do not have viral load suppression, we need to consider adherence to treatment. Currently, data suggest that the vast majority of people in LMIC taking DTG-containing regimens with detectable virus are likely not optimally adherent to treatment. We need better ways of measuring patient and population-level adherence and better ways to support adherence. Optimal adherence to treatment and drug resistance prevention go hand-in-hand.

How does the WHO surveillance and monitoring working group treat new findings showing resistance?

To put this in perspective, let’s think about the data that we had available 5-10 years ago when most people were receiving NNRTI-based regimes (e.g., efavirenz or nevirapine-containing ART). The first point to note is that viral suppression in patients receiving ART was lower than what we see today. In the NNRTI era we saw 70-90% viral suppression. We’re now seeing levels of viral suppression at or above 90-95% among people receiving DTG-based ART.

Moreover, unlike in the NNRTI era when most people failing ART had NNRTI drug resistance associated mutations, in the DTG era we see vastly lower levels of DTG drug resistance associated mutations. As I mentioned, currently available data suggests that the majority of people who are failing DTG-containing regimens are doing so because of sub-optimal adherence.

Surveys reported in WHO’s 2024 HIV drug resistance report found 3.9% to 8.6% DTG resistance among people with viral non-suppression. If these same people had been receiving NNRTI-based therapy, we would see around 70% to 90% of the approximately 20-23% of people without viral suppression having NNRTI drug resistance. That means the absolute number of people who have acquired DTG resistance is significantly smaller than was the case when NNRTI regimens were used.

One of the challenges we have with integrase inhibitors, including DTG, is we’re still learning about the clinical relevance of some DTG-associated drug resistance mutations. Some of them probably matter more than others. We really need more data from surveillance and well-described cohort studies to understand which DTG-drug resistance associated mutations are going to be the most clinically relevant, and which could be present in a patient’s virus and that patient will still go on to achieve durable suppression while taking TLD.

What are the risks posed by this new epidemiological evidence to achieving the UNAIDS 2030 Fast Track Targets of 95-95-95?

At present, I don’t see great risks. I think there’s every likelihood that we can achieve the global 95-95-95 elimination goals for HIV, but we really need to maximize adherence to treatment and pay attention to the quality-of-service delivery (this means maximizing retention in care, preventing drug stockouts or drug shortages that may impact adherence to treatment, and scaling up viral load testing and use of viral load test results to inform patient management).

We also need to ensure that we expand access to HIV testing and deploy HIV prevention strategies like pre-exposure prophylaxis (PrEP). Concerns about HIVDR should never be a barrier to the scale up of treatment of prevention of HIV.

We also need routine, standardized surveillance of HIV drug resistance to inform national and global HIV regimen guidelines. If we look at clinical trial data, we saw levels of DTG drug resistance in ARV drug-naive people that were less than 1%. In real life, we’re seeing something closer to 4-9%.

This difference could be because in clinical trials, people were followed very closely, adherence was monitored and supported, and participants’ regimens were switched quickly if they experienced virological failure. As HIV incidence in LMIC declines, this means that more and more people are not ARV drug naïve. Many people in LMIC have also started and stopped treatment in the past and/or were treatment experienced at the time of the switch from NNRTI-based to DTG-based ART and may have had unsuppressed viral loads at time of switch. This is the real-world situation and helps to underscore the need for data from observational cohorts and from standardized and routinely implemented surveillance.

We continue to look for signals of DTG resistance, and at this point, there is no need for alarm. Observed levels of DTG resistance are so much lower than NNRTI resistance ever was, and while data are limited and more research is needed, there are reasons to believe that many individuals who are failing even with some DTG-associated drug resistance mutations, may go on to achieve viral suppression with enhanced adherence and support.

That’s not to say we can neglect people living with HIV who have DTG resistance and whose regimens are failing them, and we do need to think about what the optimal treatment is for people in whom DTG-based therapy is failing.

It is surprising to learn that people may still achieve viral load suppression when some level of DTG resistance is present. Do we understand why this is true? Was this true with NNRTIs?

There remains an important research gap — specifically, to define which, if any, DTG-associated drug resistance mutations can be present, and yet people receiving TLD are able to achieve sustained virological suppression or re-suppression. This observation is not yet fully characterized in clinical trials or observational cohort studies and remains a very important public health and clinical research question.

There is some evidence to suggest that some people with DTG-associated mutations will achieve viral suppression, but we don’t know for how long. There was some anecdotal evidence of similar situations with NNRTI drug resistance mutations in people taking NNRTI-based ART, but largely it was not clinically relevant.

NNRTI resistance levels are higher than DTG’s; however, NNRTIs were in use for 30 years while DTG has been in use for less than 10 years. Can we expect DTG resistance levels to continue to rise with continued use?

Not necessarily. These are very different drugs with different ways of working and different genetic barriers to selection of drug resistance mutations. If used correctly, evidence to date suggests that we should see far less DTG-associated resistance than we did to the NNRTI drug class.

Can you provide some sense of the cost of HIV drug resistance testing that is needed to meet the global needs for testing at both the population and the individual level?

Modelers within WHO HIVResNet are currently working to answer this question with respect to people failing TLD. It really comes down to what the cost of the next regimen would be compared to the cost of a drug resistance test. We know the price needs to be low, and we have published this target product profile with minimum and optimal criteria. Further information can be found on the WHO website.

Please remember however that there are factors other than cost that play a role such as clear clinical indication for a drug resistance test as well as the capacity for results to be of high quality and provided with minimal turnaround time.

Note to readers:

Thermo Fisher Scientific is working with global health access organizations to make HIV drug resistance testing available and affordable to all in low- and middle-income countries. To learn more about the company’s programs, visit the their global health equity website.

Jen A. Miller is a freelance journalist who lives in Audubon, New Jersey. +X: @byJenAMiller