HIV and ID Observations

Photo by Justine Camacho on Unsplash.

As I noted last week — and you did read last week’s post, didn’t you? — the International AIDS conference first took place in Mexico City in 2008. Last week we returned to this sprawling, vibrant city for the 2019 meeting.

It was an excellent, well-run conference — with one small complaint.

But more on that later… On to the content, a Really Rapid Review® of the highlights.

• The risk for neural-tube defects in babies born to women who conceived while receiving dolutegravir is lower than first estimated. In last summer’s report from Botswana, it was 4 out of 426 (0.9%); now with a larger surveillance population (covering over 70% of nationwide pregnancies in that country), it was 5 (one additional case since the original four) in 1684, or 0.3%. This is still higher than in women taking EFV at pregnancy, or women without HIV (around 0.1%), but good news overall. So the relative risk is still higher, but the absolute risk is low. (Linked is the full paper, published when the study was presented.)
• Additional cohorts from Botswana and Brazil also demonstrated a lower risk than the original estimate. The cumulative effect of these three studies enabled the WHO to go forward and recommend “TLD” — tenofovir, lamivudine, dolutegravir — to all people starting HIV treatment, even women of childbearing potential. Bottom line — we clearly should not be switching all women of childbearing potential off their dolutegravir-based regimens. But what if a woman says she wants to become pregnant, and is actively trying? Then we’ll need to have a discussion, and I believe her preference should dictate what we do.
• Could PrEP with TAF/FTC work faster and be more forgiving of poor adherence than TDF/FTC? In this sub-analysis of incident HIV from the DISCOVER study comparing the two, poor adherence was responsible for breakthroughs in both treatment arms. But the onset to protective concentrations was faster for TAF than TDF, and duration of protection after the last dose of tenofovir was 60% longer as well. TAF/FTC is currently under review by the FDA for PrEP; for now, I would recommend its use in people who have some clinical reason for not taking TDF — such as known renal disease, low bone density, or perhaps during the time of bone formation (adolescents and young adults).
• Raltegravir is not quite as good as efavirenz as initial therapy for people with HIV who have active TB. Or, in the pedantic words of clinical trialists (i.e., people like me), it was “not noninferior.” Another finding — no increased risk for IRIS with the RAL-based approach. So efavirenz will remain standard-of-care for now, but given our general move to second-generation integrase inhibitors, how would efavirenz compare with twice-daily dolutegravir?
• Dolutegravir/lamivudine remains noninferior to dolutegravir plus TDF/FTC at 96 weeks. The key finding from this extended follow-up of the GEMINI (as in the twins, two drugs, ha!) study is that still no participant developed resistance in the two-drug arm. It will be interesting (and important) to see if this resistance barrier is just as durable in clinical practice, where adherence tends to be lower than in clinical trials.
• In a large US cohort study (n=2038), DTG-based regimens achieved a higher rate of viral suppression than any of EVG, RAL, or DRV. This certainly would reflect current clinical practice for these patients, though some would use bictegravir/FTC/TAF (which is very similar to DTG + 2 NRTIs). An ongoing prospective study (cleverly called LAPTOP) compares bictegravir/FTC/TAF to
  darunavir/c/FTC/TAF in patients with advanced HIV disease.
• A randomized, three-armed study in South Africa compared TDF/FTC/EFV, TDF/FTC plus DTG, and TAF/FTC plus DTG. Results — noninferior virologic efficacy across the three arms, and a bit more failure with resistance in the EFV arm. Two important additional comments: 1) The study was over 60% women, differentiating it from USA/European studies, which are overwhelmingly in men; 2) Weight gain was significantly different per study arm. The DTG regimens gained more weight than the EFV regimen, and the TAF/FTC plus DTG regimen gained the most weight (10 kg at 96 weeks in women). (Link to the published paper, published as the study was being presented.)
• A focused analysis on weight changes in the ADVANCE (previous link) and NAMSAL studies confirms that initial therapy with DTG leads to more weight gain than EFV. The NAMSAL trial compared DTG with low-dose EFV in Cameroon, with a very advanced HIV disease population and again more than 60% women. The cause of excessive weight gain associated with certain ART (in particular DTG and TAF) remains unclear, but it is certainly more than just a “return to health” — these changes shift more people into the overweight or obese categories. The big question is why? And why more in women — especially black women — than men? Leading theories include a possible appetite-suppressive effect of TDF and/or a still undefined off-target toxicity of integrase inhibitors, or TAF, or both.
• Bictegravir/FTC/TAF is safe and effective in women. Regulatory studies of this commonly used single pill treatment did not include many women, so data from this study of over 400 women are important. Analysis of weight changes are ongoing.
• Switching people on TAF-based, three-drug ART to dolutegravir/lamivudine is noninferior to continued triple therapy. This study — called TANGO, because it takes two (ha) — further demonstrated a very low risk for treatment failure and no emergent resistance in either treatment arm. Importantly, eligibility criteria excluded participants with a history of treatment failure or resistance — so people who have never failed are the appropriate target of this regimen switch.
• For people on TAF/FTC or TDF/FTC plus dolutegravir, switching to bictegravir/FTC/TAF was noninferior to TAF/FTC plus dolutegravir. (Disclosure: I was the presenting author.) To contrast with the prior study, here participants were eligible even with prior treatment failure and/or resistance — and approximately 25% did have NRTI resistance, as evidenced by either investigator-provided genotypes or an assessment of proviral DNA (“archive”) resistance testing. The study results suggest that the resistance barrier of bictegravir is comparable to dolutegravir, as it was able to maintain viral suppression even with NRTI resistance.
• The two-drug regimen of DTG plus DRV/r maintains virologic suppression as well as continued three-drugs. This strategy should perhaps be called a three-drug regimen (two active drugs) since the DRV needs to be boosted with either ritonavir (as in this study) or cobicistat.
• Patient-reported outcomes with long-acting injectable cabotegravir plus rilpivirine demonstrate very high rates of treatment satisfaction. With the caveat that those entering this study of oral vs. injectable therapy knew they had a 50% chance of getting the latter — and hence that’s probably why they entered the study — these data show that this first version of injectable therapy will be highly popular among those who want it. FDA approval likely in early-mid 2020.
• An implant of the antiviral agent MK-8591 (islatravir, ISL) provided sustained drug levels that could be sufficient for PrEP for up to 1 year. Yes, this meeting was the first time we’d learned the name of the potent nucleoside reverse transcriptase translocation inhibitor we’ve been hearing about for a few years. The same company makes an FDA-approved long-acting contraceptive (Nexplanon), which should hasten development of this novel approach to prevention.
• Islatravir, doravirine, and lamivudine demonstrated comparable virologic suppression to a control arm of tenofovir DF/3TC/doravirine. A dose-finding phase 2 study, so a sample size small (roughly 30 per arm). The goal will be to move this to a two-drug regimen of daily islatravir/doravirine — though clearly the former could be administered less frequently, provided it finds an appropriate dance partner.
• The attachment inhibitor fostemsavir induced viral suppression at 96 weeks in 60% of people with only one other active drug. Importantly, most participants received dolutegravir (fully or partially active), and a multi-drug optimized background regimen (OBR). Perhaps even more remarkably, 37% of a smaller group with no active drugs (but still given with an OBR) achieved viral suppression. Fostemsavir has not yet been submitted to the FDA for review, where the intent is to seek approval as a therapy for people like those in this study — with limited treatment options.
• A single subcutaneous dose of the capsid inhibitor GS-6207 induced a viral load decline of 1.8 to 2.2 log at day 10. At that point in the study, all started BIC/FTC/TAF. This agent could be part of a once-weekly or even much less frequently administered regimen; it also may have a role in people with limited treatment options. Except …
• There aren’t many people left in the USA who have limited treatment options. As I wrote last week, this has become increasingly rare — <1% of people in care, according to this comprehensive evaluation of over 27,000 ART-experienced people with HIV in the USA. Finding those who are also viremic and eligible for clinical trials of novel agents will be a challenge!
• In low-to-moderate cardiovascular risk individuals with HIV, rosuvastatin did not slow progression of atherosclerosis as estimated by carotid artery intima-media thickness. These negative results are relevant for the much larger REPRIEVE study, which is testing pitavastatin in a similar population, but using clinical endpoints.

One big plus to this year’s conference — the number of research posters was smaller than usual, increasing the quality of accepted studies.

Also, being in Mexico City in the summer remains a joy, with cool weather (remember the altitude!), friendly people, extraordinary sites and cuisine, and relatively reasonable prices.

My only complaint? No, not the traffic — that’s terrible in every big city.

It was the conference Wi-Fi, which tortured every attendee in a particularly excruciating way. Your computer and/or phone would indicate everything A-OK, no problem, then give access to the internet in brief spurts, lasting at most seconds — followed by prolonged periods of unresponsiveness. Completely impossible to do anything.

WiFi at #IAS2019 worse than early versions of WiFi on flights. Yes, #FirstWorldProblems, but still plenty frustrating!
(p.s. great conference otherwise.) https://t.co/G6fxaWkGPj

— Paul Sax (@PaulSaxMD) July 24, 2019

Yes, I’ll get over it.