Dolutegravir monotherapy: three new papers about one bad idea. I’m sympathetic to the idea of using fewer drugs to maintain suppression of HIV in the era of potent, high genetic barrier antiretrovirals, but honestly, the NRTIs are cheap and well-tolerated – why risk monotherapy when the data for dual therapy is so good?
In the first paper, the authors performed a randomized controlled trial taking patients who had started ART within 6 months of a documented primary HIV infection and achieved viral suppression for at least a year and randomizing them 2:1 to either dolutegravir or continuation of their existing regimen. The outcome of interest was the proportion of patients maintaining an undetectable HIV RNA level through week 48, and the authors prespecified an inferiority margin of 10%. A total 101 patients were randomized (68 to the monotherapy arm), and at week 48 all patients in the study maintained viral suppression. So, perhaps there is a select group of folks who do well on dolutegravir monotherapy – but keep in mind that this sample size is small and the period of follow-up is short. 30601950
The second paper analyzed data from an RTC in which researchers randomized patients on ART who had never experienced virologic failure, had CD4 nadirs >200, and had HIV RNA zeniths <100,000 copies/ml to continue their current ART or switch to dolutegravir monotherapy. This paper compared the patients in the monotherapy arm who developed virologic failure (8/95 or 8.4%) to those who did not. The authors found that the patients who experienced virologic failure on monotherapy had lower median CD4 nadirs (260 vs 380 cells/ul, p = 0.011), a longer time between HIV diagnosis and ART initiation (median 49 vs 15 months, p=0.015), and higher peripheral WBC HIV DNA levels (417 vs 147 copies per million WBCs, p=0.022). Hence, the findings in the trial above – whose patients had early start of ART with relative preservation of immune function and limited HIV reservoirs – are probably not generalizable to the broader population. 30270543
Finally, the nail in dolutegravir monotherapy’s coffin is the MONCAY trial, which randomized patients with a CD4 nadir >100 cells/ul who had been suppressed on ART for a year or more on DTG/ABC/3TC to either continue that regimen or switch to dolutegravir monotherapy. In this study, the primary outcome of interest was maintenance of viral suppression at week 24, with failure defined as two consecutive viral loads >50 copies/ml. Among a total 158 patients (n=78, switch and n=80, continuation), rates of treatment failure were 6.4% in the monotherapy arm and 3.7% in the continuation arm. However, an additional 5 patents in the monotherapy arm experienced virologic failure during extended followup, two of whom developed INSTI resistance mutations. The cumulative incidence of virologic failure over the subsequent 24 weeks (i.e. weeks 24 to 48) was 9.7% in the monotherapy arm versus 0% in the continuation arm (p=0.005), after recognition of which the investigators terminated the study. 30601976
Moral of these stories? Sure, you can you find a subset of patients with HIV and near-normal immune systems who will at least briefly tolerate dolutegravir monotherapy (note total durations of follow-up in these studies were <1 year). But why not just throw in some lamivudine and call it a day?
Here’s your pharmacokinetic proof that it’s OK to combine dolutegravir with darunavir-cobicistat. I’ve switched several patients with complex HIV genotypes on salvage ART regimens to genvoya-darunavir (EVG/c/TAF/FTC plus DRV) and have had good luck achieving and/or maintaining viral suppression with that. But do the other INSTIs and darunavir-cobi play well together? In this study, 20 healthy volunteers were randomized to take either two weeks of dolutegravir followed by a week-long washout period and then two weeks of dolutegravir + darunavir-cobi, or two weeks of darunavir-cobi followed by a week-long washout and then both drugs together. Researchers found dolutegravir levels were essentially unchanged by the addition of darunavir cobi, whereas darunavir levels were decreased by ~10% by the addition of dolutegravir, probably not clinically relevant. So, co-prescribe dolutegravir and darunavir-cobi to your heart’s content.
What I wish they’d looked at was bictegravir/TAF/FTC plus darunavir/cobi, though – to me, that seems like the simple salvage regimen of choice in 2019. 30272231
The Southern US is still terrible at caring for people with HIV. That’s my takeaway from this recent investigation of regional variations in HIV care published in CID. The authors analyzed data from patients with HIV in the National Institute on Drug Abuse Clinic Trials Network 0049 study, which enrolled patients from eleven hospitals across the US with high HIV inpatient censuses, comparing patients seen at Southern versus non-Southern sites. My one quibble with the methods of this study is that the authors defined Baltimore, Maryland as a Southern site. Really? Sure, technically it’s south of the Mason-Dixon, and they do have shrimp and grits. But Maryland fought for the Union; more importantly, if you order an iced tea there you won’t be served a sweetened beverage, which everyone knows is the true demarcation of the American South.
Anyway, the researchers included a total 1227 patients (557 from Southern sites and 670 from non-Southern sites) in their analysis. Compared with their non-Southern peers, Southern patients were more likely to be black (71% vs 63%; p<0.001), disabled (56% vs 44%; p<0.001), and uninsured (24% vs 17%; p<0.001), and less likely to be unemployed (23% vs 37%; p<0.001), to have had problematic drug or alcohol use (46% vs 60%; p<0.001), or have been incarcerated in the past six months (7% vs 11%; p < 0.01). With regards to HIV care, patients at Southern sites were more likely to have not been seen in the past 12 months (13% vs 8%; p=0.16), to have a CD4 count <200 (55% vs 43%, p < 0.001), and to not have viral suppression (65% vs 51%; p<0.001). In multivariate analysis, patients seen in the South were less likely to be taking ART (OR 0.69), more likely to have not been seen in the past year (OR 1.69), and more likely to have a CD4 count <200 (OR 1.53).
So, we’re seeing poorer HIV care outcomes in a patient population that has higher rates of employment (yet lower rates of health insurance), less drug use, and less incarceration than their Northern peers. But truly, who among us could have predicted that there might be consequences to abandoning the social safety net? 29920584
Pay it forward: an innovative approach to improve STI testing among Chinese MSM. The authors note that MSM in China rarely receive testing for gonorrhea and chlamydia (which it turns out isn’t free – at least not at the authors’ clinics). To address this issue, the researchers compared two testing strategies at their HIV testing sites, an STD clinic for MSM and a local MSM community organization. In the standard care model, the researchers offered men gonorrhea and chlamydia testing at the standard price of 150 yuan (about $20). In the pay-it-forward model, the men were offered free testing and then invited to donate money to subsidize testing for future participants. Both sites started with the pay-it-forward model and then switched to the standard model (presumably a crossover design would have been problematic here – why pay for testing once you’ve heard that free testing is being offered down the street?). The primary outcome of interest was uptake of gonorrhea and chlamydia testing.
A total 408 men participated in the study (n=203, pay-it-forward and n=205, standard care). Most participants were of Han ethnicity, under 30 years of age, and had a monthly income under 10,000 yuan; a third had had unprotected anal sex in the preceding 3 months. The pay-it-forward model resulted in a dramatically higher rate of testing uptake versus standard care (54% vs 6%; aOR 19.7, p<0.0001). Of the men tested, 80% had their first gonorrhea test and 86% their first chlamydia test; 4% were diagnosed with gonorrhea and 12% with chlamydia. When interviewed about their decision to get tested, 49% of men in the pay-it-forward group cited that model, citing subthemes such as encouraging testing in the MSM community and supporting reciprocal giving. Among those tested in the pay-it-forward model, 89% chose to contribute some amount of money for future testing, with a mean donation of 65 yuan – about half the cost of the testing. In fact, the incremental cost per additional diagnosis of gonorrhea or chlamydia was lower in the pay-it-forward versus the standard care model (3165 versus 8398 yuan).
So, this study tells us two things. First, even what seems a modest expense – in this case, half a day’s wages – can pose a significant barrier gonorrhea and chlamydia testing to low-income MSM; if you have the resources and you’re serious about controlling STIs in the community, free testing is the way to go. Second, at least in the Han Chinese MSM context, appealing to altruism / the communal good is an effective way to increase the uptake of STI testing and promote collective action to defray the costs of healthcare. 30587296