Two vs Three: The Magic Number for HIV Therapy

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I know I used the “De La Soul” version of the song previously, but its pretty good. But three is not the magic number here. Or for pseudomonas.

HIV therapy has undergone many iterations. Long gone are the days of AZT and semi-literal drug cocktails and we have entered into an era where HIV treatment is as easy as just getting one pill per day with Triumeq, Biktarvy, and Atripla which include three-active components. Newcomer, Cabotegravir, may change the game going forward as a long acting injectable that may reduce the pill burden in these patients. One of the concerns about long-term antiretroviral therapy (ART) is toxicity and adverse events such as bone demineralization, renal injury, metabolic disturbances (i.e. weight gain and dyslipidemia) and cardiovascular disease. As a result of this, along with new drugs with long half-lives and high barrier to resistance, there has been a movement towards simplifying to two-drug regimens. Here, we will look at the data thus far and how this concept may not be that crazy after all.

The rationale behind multi-drug therapy is the same as that for tuberculosis; both are “slow burn” diseases that require long-term therapy and single-drug treatment allows the organism to achieve resistance via different mechanisms. Just like “RIPE”, ART prevents the development of resistance in the long term. The advent of integrase inhibitors, which tend to have long half-lives and a high barrier to resistance have allowed people to transition to a dual-therapy regimen. 

Boosted Protease Inhibitors:

The earliest randomized data on dual therapy came from trials involving protease-inhibitors. These are typically given in conjunction with things such as ritonavir or cobisistat, allowing the parent drug to be given at lower doses as the latter components inhibit metabolism by the P450 cytochrome family. In the GARDEL trial, therapy with lopinavir/ritonavir + lamivudine was compared to triple therapy that included lopinavir/ritonavir on top of 2 additional drugs in HIV-therapy naive patients, whose viral load was at least 1000 copies/mL (1). Primary endpoint was virological response (<50 copies/mL) at 48 weeks. 416 patients were randomized in the trial, and there was no difference in the viral suppression response between groups at week 48:

The OLE trial randomized patients in an open-label manner to therapy with either lopinavir-ritonavir + Lamivudine and triple therapy with two NRTIs and lopinavir-ritonavir (2). These enrolled patients had been on stable ART for at least 2 months with viral loads <50 copies/mL for at least 6 months prior to enrolling. Primary endpoint was response to treatment at 48 weeks in an ITT fashion. 239 patients were enrolled, much smaller than the originally planned 336. At week 48, there was no difference between groups in terms of treatment response to either dual or triple ART (difference -1.2%, 95% CI -9.6 to 7.3):

Further, dual therapy had more favorable eGFR profile changes at the expense of increase in LDL and total cholesterol:

The SALT trial (3; not to be confused with the SALT-ED Trial) randomized patients with chronic HIV and viral suppression for at least 6 month to either atazanavir-ritonavir + lamivudine or triple therapy  that included atazanavir-ritonavir. Primary outcome was non-inferiority of virologically response at 48 weeks, with 286 patients being randomized. Non-inferiority was demonstrated across all groups at 48 weeks:

This suggest that a combination of two different antiretrovirals in a select population of HIV-positive patients is a reasonable approach, which allows less toxicity and adverse events down the line. With boosted PIs, however, there tends to be a lot of drug-drug interactions, including with things that are metabolized by the liver (namely, statins). Due to this, there was been interest in pursuing dual ART with an integrase inhibitor backbone, as these have been shown to have a high barrier to resistance and being fairly well tolerated without significant drug-drug interactions.

Integrase Inhibitors

One of the first open-label trials evaluated the integrase inhibitor, raltegravir (4). Here, darunavir-ritonavir and raltegravir were compared with TDF/FTC + darunavir/ritonavir and patients were randomized in a 1:1 fashion for this trial. Patients needed to have a viral load >1000 copies/mL and a CD4 count <500. Primary endpoint was time to virological or clinical failure or change in therapy before week 32. 805 patients were enrolled, with no statistical difference in the primary endpoint at week 96, adjusted difference 4.0 (95% CI -0.8 to 8.8). Not surprisingly, when looking at patients who have both viral loads >100,000 and CD4 <200, there was a higher rate of treatment failure in the raltegravir group:

This isn’t surprising; raltegravir is an inferior integrase inhibitor to dolutegravir, but this suggested that integrase inhibitors could be a backbone to dual ART regimens. Following this study, retrospective cohorts using dolutegravir as the integrase inhibitor of choice started to pop up. For instance, in a retrospective study evaluating the efficacy of dolutegravir + rilpivirine in 104 treatment experienced patients, 88% achieved virologic suppression at 24 weeks in the ITT protocol, with the efficacy increasing to 96.8% in the per protocol population (5). In another multicenter cohort study, 145 patients were evaluated for 96 weeks after switching to dolutegravir and rilpivirine (6). After eliminating 7 patients who dropped out of the study, none of the remaining patients had a viral load >50 copies/mL with 138 (95.2%) achieving viral suppression. Here, there was a notable decrease in eGFR by a mean of -5.9, though total cholesterol also decreased by a mean of -11.3. 

A single-center retrospective study (7) enrolled 374 patients who were switched from ART to dual therapy; of these 307 were placed on lamivudine + dolutegravir, while the rest were placed on rilpivirine + dolutegravir. The incidence of virologic failure was 2.98 per 100-person years follow up overall; 3.34 per 100-person years follow up in the lamivudine group vs 1.78 per 100 person follow up years in the rilpivirine group. Notably, a Cox proportional hazard model did not find the presence of M184V mutation to have an effect on the incidence of treatment failure (aHR 0.503, 95% CI 0.195 to 1.303), nor did any TAM (aHR 0.962, 95% CI 0.389 to 2.379).  An observational  cohort of 35 patients (8) with a median treatment duration of 14 years, switching to DTG + rilpivirine was associated with 91.4% rate of virological suppression at 48 weeks. Moreover, a significant proportion of patients in this cohort had significant baseline resistance profiles, though none to integrase inhibitors:

Here, there is some degree of noise as to the utility of dolutegravir for dual ART in certain patients. What was needed was robust, randomized data to push the needle forward in terms of efficacy when compared to the standard 3 drug regimen. Notwithstanding, 4 trials were on the horizon which sought to answer this specific question.

SWORD and GEMINI:

The largest trials, SWORD 1 and 2, which evaluated dolutegravir and rilpivirine (now known as Juluca) and GEMINI 1 and 2, which evaluated dolutegravir and lamivudine (now known as Dovato; thank drug manufacturers for having to learn new combinations), have provider fairly convincing evidence that dual-therapy with a later generation integrase inhibitor and another agent is a fairly safe option for certain individuals.

In the SWORD 1 and 2 studies, which were a phase 3, randomized, open label, multicenter trials, patients were randomized in a 1:1 fashion to receive DTG +RPV or continue their regular ART for 52 weeks. In the first published trial (9), the primary endpoint was the proportion of patients with a viral load <50 copies/mL at week 48 in the ITT population with the studies being powered as an non-inferiority trial. Across the two studies, 1028 patients were randomized to each arm, with no difference in virological success in either arm of each study:

Notably, patients in this group were relatively treatment naive, and on their first or second ART regimen though needed to have suppressed viral loads for 6 months or more at screening. Further, insomnia and depression were more commonly reported in the DTG-RPV group compared to the normal ART group, though there were no changes in metabolic parameters at the end of the study. Moreover, when stratifying patients per baseline characteristics, there was no difference in virological suppression either:

In the continuation of the SWORD 1 and 2 trials (10), the patients who were initially in the regular ART arm of the study were switched at week 52 to DTG-RPV for the rest of the study, which was 148 weeks. This created an early switch and a late switch group. Virological suppression was achieved in 89% of patients in the early switch group at 100 weeks (95% CI 86-92) and in 93% of the late switch group (95% CI 91-95):

The results were also consistent when classifying the patients based on their baseline characteristics:

There were no changes between groups in terms of lipid panels, though the early switch group had a decrease in some bone turnover markers, suggesting it may prevent increased bone turnover. 

In the GEMINI trials, dolutegravir and lamivudine was compared to DTG + Truvada in a phase 3, randomized, non-inferiority trial (11). Patients who were ART naive were assigned in a 1:1 fashion to either the two drug or three drug regimen. Patients were able to be enrolled even if their viral load were greater than 500,000 copies/mL. Primary outcome was virological efficacy at week 48. 1441 patients were randomized across both trials, with both studies meeting the primary efficacy endpoint of non-inferiority virological efficacy at week 48:

In the pooled per protocol population, 93% in the two-drug regimen and 94% in the three-drug regimen achieved the primary endpoint. When looking at the patients with more than 100,000 copies/mL, 92% of those in the two-drug regimen achieved virological success compared to 90% in the three drug regimen.

 Moreover, there was lower bone turnover in the two-drug regimen, as well as a less decrease in eGFR when compared to three drug regimen. Similar findings were reported in the follow-up at 96-weeks (12), with 86% in the dual-therapy group and 89.5% in the triple-therapy group achieving viral suppression in the ITT population (adjusted treatment difference -3.4%, 95% CI -.67 to 0.0007). The adjusted differences were greater in the GEMINI 1 trial (84% vs 89%, adjusted treatment difference -4.9% (95% CI -9.8 to 0.03) than in the GEMINI 2 trial (88% vs 90%, adjusted differences -1.8% 95% CI -6.4 to 2.7)

When stratifying by CD4 count and viral load, there were also no differences in the snapshot and “Treatment-related discontinuation equals failure” with the exception for those whose CD4 count were <200, which was primarily due to non-treatment related reasons:

In a post-hoc analysis of the GEMINI studies (13), the median change in viral load from baseline at week 4 in those with viral loads >100,000 copies/mL were -3.38 log10 copies/mL in the two drug regimen and -3.40log10 copies/mL in the three drug regimen. Viral suppression was achieved in the entire population at a median of 29 days whereas in those whose viral loads were >100,000 copies/mL it was achieved at a median of 57 days in both groups. Overall, there was no difference between groups in terms of achievement of viral suppression regardless of the baseline viral load:

An Israeli retrospective cohort evaluated 173 patients who had received dual antiretroviral therapy, with the cohort being a heavily treated experienced group with a median of 8.57 years of prior therapy (14). Most patients were switched to dolutegravir + rilpivirine (55.1%) and dolutegravir + darunavir/ritonavir (18.2%). There was a steady rise in the cohort who had a switch to two-drug regimen in CD4 count over 96 weeks:

Notably, when looking at each type of dual-regimen, integrase inhibitor protease inhibitor had the lowest rates of suppression:

It should be noted, however, that patients in the PI + INSTI group had the highest rates of resistance detected, with 57% compared to 27.2% in the overall cohort. 

Cabotegravir

We have talked about how integrase inhibitor-based dual ART is a reasonable approach. Lately, a new integrase inhibitor has made headlines as it may be the first long-acting injectable to be on the market for HIV therapy. Cabotegravir, a new-generation integrase inhibitor, has been studied in this regard. A phase 2b, randomized, multicenter trial evaluated the utility of cabotegravir in treatment naive patients whose CD4 count was at least 200 and viral load was at least 1000 copies/mL in a 1:1:1:1 ratio, with patients randomized to receive oral cabotegravir either at a dose of 10mg, 30mg, 60mg per day or efavirenz 600mg per day in combination with background NRTI (15). There was an induction phase that lasted 24 weeks, and those who achieved viral suppression went on to the next phase of the arm, where those in the cabotegravir arms had theri NRTIs stopped and put on rilpivirine with the efavirenz arm remained the same. Primary endpoint was the proportion of patients with viral loads <50 copies/mL at 48 weeks in an ITT population. 243 patients were enrolled, with the proportion of patients who achieved the primary endpoint being higher in the cabotegravir arms compared to the efavirenz arm (82% vs 71%). At week 96, there was a higher proportion of patients in the cabotegravir arm that achieved viral suppression:

Moreover, those in the cabotegravir group tended to achieve viral suppression faster:


The increase of CD4 at 24 weeks in the cabotegravir was 185 in the cabotegravir group compared to 159 in the efavirenz group. This suggests that oral cabotegravir was a fairly potent therapy for HIV patients. A pair of studies published in NEJM evaluated its role along with rilpivirine for long-acting injectable therapy. In a randomized, multicenter, open label trial, patients were enrolled in a 1:1 fashion to long-term injectable or to continue their ART (16). The scheme is as follows:

Those randomized into the long-term injectable therapy had a lead-in period of PO therapy for 4 weeks (to monitor for side effects) followed by a loading dose of 600mg of cabotegravir and 900mg of rilpivirine injected and then 400/600 every 4 weeks through 52 weeks as maintenance. Primary endpoint was percentage of patients with viral load >50 copies/mL. 618 patients were randomized, with no difference in patients with >50 copies/mL at week 48 in the ITT analysis:

Most of the adverse events here were related to injections, but not different outside of that. The accompanying study was a randomized, multicenter, open-label trial of long-acting injectable therapy in patients with HIV with viral loads of >1000 copies/mL who had not been on any ART prior to enrollment (17). Patients were first induced with triumeq (abacavir, lamivudine, dolutegravir) for 16 weeks, and those with undetectable viral load then were entered into the study, which randomized patients in a 1:1 fashion to either injectables or continuing their PO therapy (loaded in a similar fashion as above):

Primary endpoint was the percentage of patients with viral load >50 copies/mL at the end of 48 weeks. 566 patients were randomized, with both groups being fairly well balanced. There was no statistical difference in the primary outcome between groups:

And as above, the main side effects related to those in the injection site.

Two different dosing schedules have been studies for cabotegravir. In this randomized, multicenter trial, IM cabotegravir + rilpivirine at 2 different intervals (4 vs 8 weeks) were compared (18). Two groups were evaluated here; one who had received standard of care ART, and the other from the original ATLAS study, who had received the long-acting regimen at 4 week intervals. Here, eligible patients had to have been on ART for 6 months without clinical failure. Patients were randomized in a 1:1 fashion to either a 4 week or 8 week interval. Primary endpoint was percentage of virological failure (>50 copies/mL) at week 48. 1049 patients were randomized, of which 391 were in the previous ATLAS study. At 48 weeks, 2% of patients in the 8 week interval group and 1% of patients in the 4 week interval group had virological failure, with an adjusted difference being 0.8 (95% CI -0.6 to 2.2)

Most of the adverse events were mild. In the LATTE-2 trial, ART naive patients with a viral load of at least 1000 copies/mL patients were randomized in a 2:2:1 fashion to either injectable cabotegravir and injectable rilpivirine at either a 4 or 8 week interval or oral cabotegravir plus abacavir-lamivudine (19). Following an induction period of 20 weeks where all patients received oral cabotegravir and abacavir-lamivudine, those who achieved viral suppression underwent randomization. Primary outcome was the proportion of patients who had achieved viral suppression at week 32, though the trial extended up to week 96. 309 patients were randomized, with 286 of these undergoing the maintenance period. At week 32, 94% of patients in the 4 week cohort, 95% in the 8 week cohort, and 91% in the oral cohort had achieved viral suppression. The proportion remained similar through week 96:

The 5-year results of the LATTE trial found that, at the end of the study, 88% of patients in the q 8 weeks and 74% of patients in the every 4 week group achieved viral suppression (20). Similarly, in those who switched from oral to IM therapy, 94% of the q8w and 90% of the q4w cohort achieved viral suppression.

In a pooled analysis of both ATLAS and FLAIR studies (22), which compared cabotegravir and rilpivirine with ART in those who had prior treatment experience, 1184 randomized patients were evaluated. At 48 weeks, primary endpoint was not statistically different between both cohorts, suggesting non-inferiority of long-acting therapy compared to standard ART in the treatment experienced population:

While both cohorts had several adverse events, most were from injection site reactions, with the proportion of adverse events being fairly equal between groups:

Look out for cabotegravir and injectables to be a new go-to regimen in certain clinics.

TL;DR
– Dual ART is an upcoming therapy option for certain HIV-patients

  • The combination of dolutegravir with either rilpivirine or lamivudine has the best data for safety and efficacy in comparison to standard ART.
  • Cabotegravir in combination with rilpivirine will be a long-acting injectable that can be dosed up to every 8 weeks

References:

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  20. Graham H R Smith, W Keith Henry, Daniel Podzamczer, Maria Del Mar Masiá, Christopher J Bettacchi, Keikawus Arasteh, Hans Jaeger, Marie-Aude Khuong-Josses, Maria Luisa Montes-Ramírez, Hans-Jürgen Stellbrink, Yazdan Yazdanpanah, Gary J Richmond, Kenneth C Sutton, Feifan Zhang, Cynthia C McCoig, Marty H St Clair, Kati Vandermeulen, Rodica Van Solingen-Ristea, Kimberly Y Smith, David A Margolis, William R Spreen, Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study, Open Forum Infectious Diseases, Volume 8, Issue 9, September 2021, ofab439, https://doi.org/10.1093/ofid/ofab439
  21. Overton ET, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F, Bredeek F, García Deltoro M, Swindells S, Andrade-Villanueva JF, Wong A, Khuong-Josses MA, Van Solingen-Ristea R, van Eygen V, Crauwels H, Ford S, Talarico C, Benn P, Wang Y, Hudson KJ, Chounta V, Cutrell A, Patel P, Shaefer M, Margolis DA, Smith KY, Vanveggel S, Spreen W. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021 Dec 19;396(10267):1994-2005. doi: 10.1016/S0140-6736(20)32666-0. Epub 2020 Dec 9. PMID: 33308425.

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