HIV and STDs: July 2018

The International Antiviral Society (IAS) has published its 2018 recommendations for antiretroviral therapy (ART) in people with HIV infection. I can’t adequately summarize a guideline in a paragraph, but here are some highlights from the section on ART timing and selection. First, immediate initiation of ART (i.e. same day to within 14 days of diagnosis) is recommended for all non-hospitalized patients with HIV infection unless an opportunistic infection that would contraindicate ART is suspected or the diagnosis is in question. This approach has been shown to improve engagement in care and time to viral suppression, two key factors in preventing further HIV transmission. Second, immediate ART should consist of dolutegravir, bictegravir, or darunavir along with either form of tenofovir and either emtricitabine or lamivudine (remember, we aren’t starting abacavir immediately because patients need to have a documented negative HLA B5701). Third, bictegravir and dolutegravir-based regimens are recommended as first-line therapy; regimens based on darunavir, raltegravir, elvitegravir, efavirenz, and rilpivirine are considered alternative. Fourth, the alafenamide preparation of tenofovir (TAF) is preferred over the older disproxil fumurate (TDF) on account of fewer renal and bone-related toxicities (I did not see this explicitly stated in the text, but DTG + TAF/FTC is listed among the generally preferred regimens, with a footnote that TDF/FTC can be substituted if the former is not available). Fifth, PrEP on-demand has been endorsed as an acceptable strategy in addition to daily PrEP. 30043070

PrEP on demand is highly effective and as good as daily PrEP – so long as you actually take it. This study out of France followed a prospective cohort of 1049 men who have sex with men at high risk for HIV acquisition (median sex partners in the past 3mo = 10) who started either daily or on-demand PrEP. More than 75% of patients opted for the on-demand regimen, which consisted of 2 pills of tenofovir-emtricitabine taken 2-24hr before sex, then one pill each 24hr and 48hr later. Over 486 patient-years of followup, there were 4 cases of new infection, all of which occurred in patients who were non-adherent or poorly adherent to PrEP. Of the four ‘failures,’ one patient was prescribed but never started taking on-demand PrEP, one patient started taking daily PrEP during primary HIV infection, one patient was prescribed but was poorly adherent to daily PrEP due to chemsex (having sex primarily while under the influence of drugs) and one patient was lost to followup for a year after the first visit where he was prescribed on-demand PrEP, and was HIV-positive on return to the clinic.

For those who were wondering, yes, rates of condomless sex increased, but the impact on additional diagnosis on bacterial STIs was modest (14.6% at baseline versus 19.2% after starting PrEP). One important point is that more diagnoses of rectal STIs were made after PrEP initiation (probably on account of users having more condomless anal sex), so be remember to be vigilant about screening every mucosal site used for sex when monitoring patients on PrEP for STIs. On-demand PrEP has just been recommended for use in the US in the latest set of IAS guidelines (see above), which is great news. 30005015 

While we’re on the same topic, this month also saw a new prospective study examining sex behaviors after the introduction of PrEP among men who have sex with men in Amsterdam. The authors found that while the men did not seek out additional partners or engage in more sex acts overall after PrEP, they were less likely to use condoms during the sex they had. In this study, the prevalence of bacterial STIs after introduction of PrEP remained stable. Bacterial STIs are curable, which HIV is not, and usually do not reduce lifespan, which HIV does, so in my mind the potential increased risk for bacterial STIs should have no bearing on whether an otherwise eligible patient should be prescribed PrEP. 29762169

Data from the Opposites Attract study supporting the concepts of U=U and HIV treatment as prevention were published in Lancet HIV this month. U=U is shorthand for “undetectable equals untransmissible,” which refers to the principle that there is zero risk of HIV transmission between sex partners when the HIV-positive partner is taking antiretroviral therapy and has had an undetectable viral load for at least six months. This study followed an international cohort recruited from HIV clinics, including of 358 serodiscordant couples followed for a total 588.4 couple-years. During the study period the participants reported an estimated 16,800 acts of condomless anal intercourse. 34% of the HIV-negative partners were taking prep, and 74% of the HIV-positive partners had viral loads consistently below 200 copies/ml. There were no phylogenetically linked transmissions within the entire cohort. While I don't have a PubMed reference for you yet, data from the PARTNERS2 study, presented at AIDS 2018 just a few days ago, followed 779 couples for a total 1561 couple-years and found the same thing.

As I tell the partners of my patients in clinic, it is now demonstrably safer to be having sex with someone who is has HIV infection and a consistently suppressed viral load on ART than to be having sex with someone who is sure they are HIV uninfected and has not been tested since their last sexual encounter. U=U has been endorsed by the CDC and a number of other major medical organizations. Now it’s critical that HIV and general ID providers communicate these findings to other physicians and the general public to reduce the stigma associated with HIV infection, as stigma is arguably the primary driver of the HIV epidemic. 30025681

How common is Mycoplasma genitalium infection and how prevalent is antimicrobial resistance in the US? M. genitalium (MG) is a frustrating diagnosis; there is no commercially available test for it right now, so the diagnosis easily falls into the blind spot of “can’t test for it, don’t think about it.” Here's a study out of Alabama that recruited 116 men seeking care at an STI clinic and their primary female sex partners. The authors used PCR to detect MG and the presence of its macrolide and flouroquinolone resistance mutations in vaginal, oral, and anal specimens. The prevalence of MG was 11% in men and 13% in women; for comparison, gonorrhea was present in 12% and 13%, chlamydia in 20% and 21%, and trichomonas in 10% and 20% of samples. Sixty-one percent of specimens had macrolide resistance mutations and 11% of specimens had quinolone resistance mutations. Among men, MG infection was associated with higher rates of urethral discharge and was more common in gonorrhea coinfection, but neither characteristic reliably differentiated MG-positive from MG-negative men. Among women, the only significant association with MG infection was younger age.

Given the significant rates of macrolide resistance seen in this study, it seems reasonable to consider a quinolone (e.g. moxifloxacin) to treat MG in cases of infectious urethritis or cervicitis that do not test positive for gonorrhea or chlamydia or respond to combination therapy with ceftriaxone and azithromycin. 29979336

 What are the noninfectious diseases you’re most concerned with when you see patients in HIV clinic? This study was a systematic review of papers investigating the prevalence of CV disease, diabetes, cervical cancer, and depression in people living with HIV infection in mid- and low-income countries. Across 57 studies, the pooled prevalence of hypertension was 21%, various dyslipidemias were 22-52%, obesity was 8%, depression was 24%, invasive cervical cancer was 1-2%, and the prevalence of diabetes was 1-18%. This squares with what I’ve learned in our HIV clinics (which primarily serve an underinsured population) – once the HIV infection is under control, the most common life-limiting comorbidities are cardiometabolic diseases, poor mental health, and substance abuse. Someday I will quit medicine, come up with a tablet containing coformulated atorvastatin, metformin, and buproprion-naltrexone, and then become obscenely wealthy. 29952786

Cervical neoplasia treatment outcomes are better when HIV infection is under good control. This study dovetails nicely with last month’s paper demonstrating that viral-mediated cancer outcomes are worse when HIV infection isn’t suppressed. The authors performed a retrospective cohort study of Swedish women with cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer (hereafter, CIN2+) who did or didn’t have HIV infection. The women with HIV infection were stratified by whether they were receiving suppressive antiretroviral therapy at the time of their treatment for CIN2+. Compared to women without HIV infection, women with HIV infection were more likely to have treatment failure (OR 3.7) and recurrent CIN2+ after treatment (OR 5); CD4 <200 cells/ul was a strong predictor of treatment failure (OR 8.5 versus women with HIV infection and CD4 >500). On the other hand, suppressive ART was associated with significantly less treatment failure (OR 0.3). Because the study included patients from 1983 until 2015, I suppose it’s possible that advances in the care of cervical cancer over the past 30 years might be a confounding factor, but on the other hand I think the biologic plausibility of this association (that is, the association between control of HIV infection with immune reconstitution and better outcomes in another virus-mediated disease) is high. 29746299

Might PD-1 immune checkpoint inhibitors have a role in a cure for HIV infection? PD-1 inhibitors (e.g.; pembrolizumab, nivolumab) are a new class of chemotherapeutic used primarily in metastatic melanoma; they’re important for us in the ID world because one of their primary side effects is ID consultation for an inflammatory syndrome mimicking sepsis that can be accompanied by mucositis, colitis, hepatitis, or pneumonitis. The PD-1 ligand-receptor interaction deactivates regulatory T-cells, dampening immune activation, so in essence PD-1 inhibitors knock out one of the immune system’s negative feedback systems, stimulating antitumor activity as well as autoimmunity (hence the endocrinopathies and end-organ inflammation focused at microbiome interfaces like the GI tract and mucosa). One of my department’s attendings likes to call fludarabine “AIDS in a bottle”; by that logic, I suppose you could call PD-1 inhibitors graft-versus-host disease in a bottle.

Anyway, remember how CD4 T cell activation stimulates HIV reactivation from latent infection? Well, the authors in this study demonstrated that HIV latency was enriched in PD-1 expressing CD4 T cells, and that HIV latentcy could be reduced by addition of PD-1 checkpoint inhibitors prior to HIV infection of CD4 T cells in vitro. They also examined the effect of PD-1 inhibitor therapy on a patient with HIV infection on ART who underwent treatment for metastatic melanoma, observing a significant increase in cell-associated HIV RNA after the infusion without increases in HIV DNA or plasma RNA, which is consistent with reversal of HIV latency under ART suppression. So, perhaps PD-1 inhibitors could play a role as latency-reversing agents in a “kick and kill” approach to HIV cure. 29746296

Coformulated darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF aka “Symtuza”), approved this month, was as safe as its components given separately. This phase III RTC compared the combination of darunavir-cobicistat and tenofovir disproxil fumurate-emtricitabine (DRV/c + TDF/FTC) to coformulated DRV/c/F/TAF. Yes, this was a trial of giving the same regimen in two versus one tablets – or at least very nearly the same, the latter regimen containing the newer version of tenofovir, TAF, which has less renal and bone toxicity. Surprising no one, the two regimens did about as well, with 91% vs 88% viral suppression at 48 weeks favoring the single tablet regimen and similar rates of serious adverse events and treatment discontinuation. The single tablet regimen with TAF was associated with a lower urinary protein/creatine ratio, less loss of bone mineral density, and a less favorable shift in the lipid profile versus the two-tablet regimen with TDF, which again is expected.

Honestly, I don’t know how often I’m going to use DRV/c/F/TAF, because we really haven’t seen much integrase inhibitor resistance in our area and I quite like the dolutegravir and bictegravir-based regimens. I can see it having a niche role in reducing pill burden in patients with multiclass resistant HIV infection (e.g. combining DRV/c/F/TAF with dolutegravir, dolutegravir-rilpivirine, or doravirine), being a drug of a choice for immediate initiation of ART when a patient has not yet had HIV genotyping, and/or becoming a go-to single tablet regimen for patients in whom we’re concerned about intermittent adherence (as darunavir has that high barrier to resistance). Do you see a role for DRV/c/F/TAF in your practice? 29683855