We know that early HIV treatment initiation is a good idea—not just for the health of a person living with HIV, but from an HIV prevention standpoint as well. We also know that integrase inhibitors have developed a pretty sterling reputation as an excellent first-line option.
But when it comes to brass tacks—for instance, the ability of a person’s first HIV treatment regimen to quickly suppress their viral load and eliminate the risk for secondary sexual HIV transmission—how well do integrase inhibitors really measure up relative to the other excellent antiretroviral options we have on the menu?
Quite well, it appears, according to recently published research.
A large modeling study appearing in PLoS One in July found that initiating HIV treatment with an integrase inhibitor–based regimen immediately after a person is diagnosed led to an 88% reduction in onward HIV transmission risk over the next eight weeks among men who have sex with men (MSM), when compared to starting treatment 28 days after diagnosis. That’s a moderately higher rate reduction than the researchers found for efavirenz-based therapy (76%) and considerably better than for boosted darunavir–based therapy (58%).
To discuss the findings in more detail and examine their clinical ramifications, we spoke with two HIV experts: Juan Berenguer, M.D., Ph.D., and Antonio Urbina, M.D.
Berenguer, the lead author of this study, is a consultant physician in infectious diseases at Hospital General Gregorio Marañón in Madrid, Spain, and head of the HIV Clinical Research Group at the Instituto de Investigación Sanitaria Gregorio Marañón. Urbina, who was not involved in this study, is the medical director for the Mount Sinai Institute for Advanced Medicine Downtown Clinic in New York City and is an associate professor of medicine at the Icahn School of Medicine at Mount Sinai.
[Editor’s note: These interviews were conducted separately by Terri Wilder but were edited together for logical flow. Interview transcripts were also edited for length and clarity.]
Study Background and Construction
Terri Wilder: Can you tell me about the background behind this research? Why did you and your coauthors decide to look into this issue?
Juan Berenguer: Early initiation of antiretroviral therapy [ART]: In the last few years, we have learned that it reduces the risk of AIDS and non-AIDS-related morbidity and mortality, irrespectively of the CD4 T-cell counts. We also learned that antiretroviral therapy and viral suppression reduces sexual transmission of HIV to negligible levels. These two facts are probably the main reasons which have moved the WHO [World Health Organization] to recommend universal antiretroviral therapy for all people living with HIV.
On top of that, there has been a lot of discussion and research about accelerated treatment initiation, including starting even the same day as diagnosis. This has proved, in resource-limited settings, to increase the rates of retention of care; to a better virologic outcome; and to reduce mortality. However, in high-resource settings, this approach of rapid initiation of ART so far only has demonstrated to shorten the time to virologic suppression.
Our hypothesis was that rapid initiation of ART, including same-day antiretroviral therapy, could decrease transmission of HIV to negative partners, particularly in a group of patients such as MSM. However, data confirming this benefit are lacking.
As a clinical trial to analyze, or to test, this hypothesis probably is unfeasible, we decided to explore this issue by mathematical modeling.
Wilder: Tell me about the model you used.
Berenguer: It’s a discrete-event simulation model. Sexual behavior during the first eight weeks after initiation of antiretroviral therapy; this was our time scenario. We got this information from the MSM population recruited in the START trial. The START trial was the clinical trial published in New England Journal of Medicine in 2015 that, let’s say, cast in stone the benefits to individuals of rapid initiation of antiretroviral therapy, irrespective of CD4 cell counts.
We got information on the number of HIV-negative sexual partners, and also the frequency of insertive and receptive anal intercourse for their partner.
As for the viral decay curves after initiation of therapy, we used the databases of three clinical trials: the SINGLE trial, that compared dolutegravir versus efavirenz; the SPRING-2 trial, that compared dolutegravir versus raltegravir; and the FLAMINGO trial, that compared dolutegravir versus darunavir.
Lastly, the risk of transmission per sexual exposure for each HIV RNA level: This was based on a mathematical model with the data of the Rikai study. The Rikai study is a study that was carried out in Africa, and studied the HIV transmission in heterosexual couples. The adjustment of probabilities of transmission from vaginal intercourse to insertive or receptive anal intercourse was based on the data from a systematic review from Patel et al, a group from the CDC in Atlanta, Georgia. These were the input variables in our model.
Wilder: How many theoretical individuals did you use in the model?
Berenguer: We modeled 5 million, for stability of the data. Javier Parrondo, the specialist in medical mathematics; he’s our pharmaceutical doctor, one of the three authors. He recommended this number.
According to the data from the START trial, of the MSM that participated in that study, 20% acknowledged [condomless] sexual activity during an eight-week period with HIV-negative patients. So, in order to have at least 1 million theoretical individuals with sexual activity, we decided to model 5 million. These 5 million were cloned 87 times, because we needed 29 clones for each regimen type: integrase inhibitors, efavirenz, and darunavir.
Wilder: Why did you pick eight weeks after treatment initiation to look at your endpoints?
Berenguer: One of the reasons is that, by eight weeks, most of the people who initiated antiretroviral therapy should be suppressed or have viral loads under 200. This is the main reason.
The second reason is because, as I mentioned, we have solid data from the START trial about sexual behavior during eight weeks’ time.
Study Results
Wilder: Tell me what you found out.
Berenguer: Talking about the first output: As I mentioned, 20% of MSM initiating ART engaged in condomless sex with serodiscordant partners. So, the number of partners was 1.92 during these eight weeks. And the number of sexual encounters per partner was 3.08 to 3.09, depending on the three arms.
The number of incident-simulated HIV transmission events during the eight-week period following initiation of therapy—and now I’m talking about per 100 patients, to make it easier:
With integrase inhibitors, if you initiate therapy on Day 0, there were 1.2 transmissions [per 100 patients] on same-day therapy, [going] up to 9.8 if you initiate it on Day 28.
For efavirenz, the figures were 3.0 and 12.2. And for boosted darunavir, it ranged between 5.4 and 12.7.
We also took a look at the differences between the treatment arms another way: taking initiation of darunavir/ritonavir at Day 28 as the reference. This sounds odd, but several years ago, doctors, when they encountered [new] patients, they took the labs; they ordered special tests, such as resistance; and they made follow-up appointments. And when everyone decided that the patient was ready, [antiretroviral] therapy was started. So it was not uncommon to initiate therapy three or four weeks after the first visit.
[Compared to] initiation on Week 4 [i.e., Day 28], if you initiated therapy on Day 0 with integrase inhibitors, the reduction of infections was 88%. If you initiated therapy with efavirenz on Day 0, the reduction was 76%. And initiation of therapy with darunavir on Day 0, in comparison with initiation on Day 28; the reduction was 58%.
Clinical Significance of the Study Results
Wilder: What do you think that this means for a medical provider, in terms of thinking about particular medications to start their newly diagnosed patient on?
Berenguer: Well, this is mathematical modeling. These are not observed data. There is a saying that all models are wrong, but some are useful.
We think that the results of our simulation support a notion that rapid initiation after diagnosis of HIV-1 in MSM has the potential to impact horizontal transmission. This is the first conclusion.
The second is that, probably, in this situation there are meaningful advantages of integrase inhibitors over efavirenz or darunavir. We found this difference, and I think that probably this could be another reason for preferring integrase inhibitors over these two drugs in this population group.
Third, probably, is that rapid—if not same-day—initiation of therapy based on integrase inhibitors in newly diagnosed HIV-infected MSM has the potential for substantial public health benefits from [decreases] in secondary transmission events.
Wilder: Dr. Urbina, what is your analysis of the findings?
Antonio Urbina: I found the study to be very interesting. It really validated a lot of these rapid start programs that I’ve been part of at Mount Sinai. I think it bridged this whole treatment-as-prevention continuum, with U=U, or Undetectable=Untransmittable.
I think the study was the first to demonstrate that rapidly initiating antiretrovirals has the potential to really impact secondary transmissions. This is something that all of us kind of knew; but to see this paper, through its mathematical modeling, prove this concept is a big breakthrough for people involved with the care of HIV patients.
Wilder: Part of the conclusion in this paper was that there was a small but statistically significant advantage of integrase inhibitors [INSTIs] over the efavirenz and darunavir/ritonavir. Could this information influence what medical providers actually choose for an ART regimen for a newly diagnosed person with HIV?
Urbina: Yes, absolutely. These INSTI-based regimens have, throughout the guidelines—not just national, but the international guidelines—have preferentially become the backbone ARTs of choice. Primarily, it was due to their potency, efficacy, and safety; and also lack of adverse events.
But what I think this data now supports, too, is that because of their mechanism of action—in terms of [how] they produce the rapid decay of virus after initiation of therapy—that because of that, and what this modeling has shown, it statistically improves decreasing secondary transmission.
So, as a practitioner working in a clinic, I would use this paper and its results here to preferentially put integrase-based regimens up front in treating MSM that are newly diagnosed with HIV.
Wilder: Recently, new data were presented on the feasibility of dolutegravir/lamivudine (Dovato) as a treatment option for rapid initiation after diagnosis in adults with HIV-1. Can you talk a little bit about how this intersects with the study that we’ve just been discussing?
Urbina: [Dolutegravir/lamivudine] is a two-drug regimen. Typically we start with three-drug regimens; in most of the rapid start protocols, that’s what’s been used.
One of the criticisms with [dolutegravir/lamivudine] has been that, although it can be used in patients [who are] newly diagnosed, can it be used very early on—for example, in a rapid start protocol—before we have information about what type of mutations this person living with HIV has potentially become infected with? Or information about their hepatitis B status, as [dolutegravir/lamivudine] doesn’t have full treatment activity against hepatitis B; it just contains one drug [that works against hepatitis B].
This study, which looked at rapid initiation of [dolutegravir/lamivudine] in patients newly diagnosed with HIV, demonstrated that not only was it safe and effective; but that in those few cases where there was identification of drug-resistant virus and/or active hepatitis B, that as long as those laboratory tests were performed and that quick changes could be made to these regimens—meaning, changing from two to three drugs—that all patients maintained virologic suppression.
So, I think it further put [dolutegravir/lamivudine] on the playing field with the preferred three-drug regimens in the guidelines.
Study Limitations and Caveats
Wilder: In the summer of 2012, the U.S. Food and Drug Administration approved PrEP in adults as an intervention for reducing the risk of HIV acquisition. Dr. Berenguer, you mentioned in the section near the end of your publication about some of the limitations of your model, and that you didn’t consider PrEP use in the analysis. What impact do you think it may have had on the results?
Berenguer: [With] PrEP, one thing is approval; [another] is the penetration. For example, in the U.S., it’s not the same, the proportion of MSM—or other populations at risk—taking PrEP in California as in the Southern states. This also holds true for other parts of the world.
Dr. [Anthony] Fauci said several years ago: Theoretically, if you diagnose everybody with HIV and you put everybody on therapy, you could reach a point in which all the transmission could stop. In our model, PrEP could have influenced the results, diminishing the effects on transmission of rapid initiation of therapy, irrespectively of which regimen you use.
I have talked about the limitations; I would probably emphasize the strengths: All the inputs come from well-curated clinical trial data, from meta-analyses, and we performed several sensitivity analyses. These confirmed the main result.
Urbina: I know that there were some limitations to the study design. One, it was a mathematical model. Two, it didn’t really include the concept of the role that PrEP, or pre-exposure prophylaxis, can lead in decreasing secondary transmissions.
But I thought the study also highlighted that the earlier we start—in particular, if you can start the same date of diagnosis—that you can really dramatically decrease horizontal transmissions in that first month. So, again, I think we really have to look at these interventions that we have for scaling up these rapid start programs.
Now, one of the caveats to that, to this paper, is that INSTI-based regimens work well with MSM, [but] we know that in persons of childbearing potential—for example, cisgender women or trans men—that some of the INSTI-based regimens have a small, but statistically increased, chance of neural tube defects [in infants].
Subsequent data have shown that that risk has further been decreased; but it’s still statistically higher than other [antiretroviral] agents. So I think that’s one caveat to this study: It doesn’t apply to all populations, or at least it needs to be studied a little bit more in different populations.
Implications for Public Health
Wilder: When you think about the publication, Dr. Urbina, could you speak to what these results could mean in terms of impact on public health?
Urbina: Just remember that our ultimate goal here is really ending the epidemic—not just here in the U.S., but across the globe. I think what this study further supports is that the earlier that we can initiate antiretroviral therapies, not only do we benefit the patient—individually, in terms of preventing HIV from penetrating further into the reservoir—but that we also have this huge public health impact of decreasing secondary transmission.
I think this study also highlights for me the importance of scaling up rapid start protocols in different settings; and also making sure that we have support systems so that we can scale them up. And that means looking at insurance; looking at how well we counsel patients about the importance of adherence; and then also further studying long-term retention.
One other thing that I think is very important, which this paper did not really comment on, is: How can rapid start protocols improve health disparities and health inequities?
In this study, the modeling that they used to look at the effects of ART on these transmission events was from a cohort called the START trial. Now, although 30% of participants in those trials were Black, only 10% of those were American.
So, biologically, we know that starting earlier can decrease transmission events. But how can we then further these conclusions by looking at how this information can also improve health inequities?