April 2019: HIV and STDs

Complera (tenofovir DF/emtrictabine/rilpivirine) is adequate post-exposure prophylaxis for HIV.  I have a soft spot in my heart for rilpivirine and its three coformulated one-pill-once-a-day regimens.  Rilpivirine got a bad rap for reduced efficacy as initial therapy among patients with high viral load or low CD4 in the ECHO and THRIVE trials, which were done before we understood rilpivirine’s pharmacology, and specifically that it is much better absorbed when taken with a fatty meal.  If you can look past that historic blemish, you’ll find rilpivirine a relatively high resistance barrier antiretroviral with few side effects and once daily dosing.  If only Tibotec had invested in some ice cream sandwiches for their clinical trial participants, I think we’d see rilpivirine maintaining a fair bit of the ART market share to this day.  As it is, RPV-based regimens remain a great switch option for patients who are suppressed on other regimens and are either having medication side-effects or want to simplify therapy to reduce their pill burden.

But enough waxing poetic about rilpivirine.  This was an observational, prospective multicenter study of five French HIV centers over a one-year period.  The authors followed the outcomes of patients referred for HIV post-exposure prophylaxis (PEP) after either sexual (n=150) or non-sexual (n=13) exposures. All patients received a 28-day course of rilpivirine-tenofovir DF-emtricitabine.  Five participants stopped PEP early because the source patient was found to not have HIV; of the remainder, 15 were lost to follow-up and 7 stopped PEP prematurely due to either simple nonadherence (n=3) or medication side effects (GI disturbance, n=3; fatigue, n=1).  By four months of follow-up, no patient had acquired HIV.

Are we going to see uptake of rilpivirine-based PEP in a world with easy access to dolutegravir and other INSTIs? Probably not.  But I think this article was worth mentioning because it demonstrates the efficacy one of my favorite much-maligned antiretrovirals.  It also reinforces an important point about transmitted HIV resistance – while transmitted NNRTI resistance is relatively common, transmitted rilpivirine resistance is not, as RPV is robust against most single NNRTI mutations, and particularly the common transmitted mutation K103N. 30689937

Here’s more epidemiologic evidence underlining why a diagnosis syphilis or gonorrhea is an indication for PrEP in someone without HIV. The authors collected public health surveillance data from Baltimore spanning 2009 to 2016 in order to assess the risk of new HIV diagnosis after a first or repeat diagnosis of either syphilis at any stage or gonorrhea in men. Records from a total 1531 men were analyzed, among whom there were 898 syphilis diagnoses and 1243 gonorrhea diagnoses.  Of these men, 104 (7%) were subsequently with HIV.  Overall, 1 in 10 MSM with a diagnosis of gonorrhea or syphilis received a diagnosis of HIV in the following 2 years; for non-MSM men, that rate was 1 In 50.  Among non-MSM, repeated diagnosis of STDs (e.g. being diagnosed with syphilis or gonorrhea after having been diagnosed and treated for gonorrhea) was associated with 5.4-fold higher incidence of HIV acquisition (95% CI 2.4-12.1) versus having had a single STD diagnosis.

So, if you see a man in clinic for syphilis or gonorrhea, and he doesn’t already have HIV, his risk of acquiring it in the next couple of years is 2-10%. Offering PrEP is a no-brainer. 30870326

Speaking of PrEP, a recent study in JAMA that looked at STI incidence after initiation of PrEP in 2892 gay and bisexual men (mean age 34) found that while the post-PrEP incidences of chlamydia, gonorrhea, and syphilis did increase (the total STI incidence went from 69.5 infections per 100 person-years to 98.4 per 100 person-years), just 25% of subjects accounted for 76% of all STI diagnoses.  In multivariate analysis, younger age, greater number of partners, and group sex were all associated with greater STI risk. while condom use was not.  So, consider more frequent STI testing for men on PrEP who are younger, have multiple partners, and/or engage in group sex - or simply those who have recurrent STIs. 30964528

M. genitalium seems to be mainly associated with urethritis, not proctitis, in MSM.  This study is out of Australia.  The authors run a clinic with a large population of men who have sex with men (MSM), and decided to interrogate the epidemiology of Mycoplasma genitalium in this population. Over a year they enrolled asymptomatic MSM to receive urine and rectal screening for M. genitalium, and compared the rates of test positivity among this population to that of MSM presenting to the clinic for proctitis and nongonococcal urethritis.

 Of 1,001 asymptomatic men in the cohort, 95 (10%) had M. genitalium; of these, 17% had a coinfection with gonorrhea or chlamydia, and 84% had M. genitalium isolates that were macrolide-resistant.  MSM with proctitis (n=355) were no more likely to have M. genitalium on rectal swab than the asymptomatic cohort (6% vs 7%); on the other hand, MSM with nongonococcal urethritis (n=1019) were more than twice as likely as asymptomatic patients to have M. genitalium in their urine (8% vs 3%). 

So, M. genitalium seems to be an important cause of nongonococcal urethritis, but not proctitis, among men who have sex with men. 30882306

Speaking of M. genitalium, this retrospective review from China found that 11% of men presenting to clinic with urethritis had an M. genitalium infection, that rates of resistance to macrolides AND quinolones for this pathogen approached 90%, and that 97% of isolates were resistant to macrolides among men recently exposed to that medication (p=0.03).  Yikes. Here’s hoping they have access to spectinomycin. 30972419

This modeling study shows that avoiding dolutegravir in pregnant women in the developing world is likely to kill more people than it saves.  So, there is this small prospective observational study in Botswana that’s collecting data on dolutegravir use in pregnancy, and in an interim analysis of their data the researchers found a signal toward higher rates of neural tube defects in patients taking dolutegravir (4/426, 0.95% - now down to 0.67% after additional recruitment - vs 14 of 11,300, or 0.12%).  Yes, you read that right: the increase in incidence was detected (and a shift in global HIV treatment policy has been made) on the basis of pregnancy outcomes in four women.  To be fair, there is some in vitro data suggesting that dolutegravir may antagonize folate metabolism – I think this is questionably relevant in areas with access to folate-fortified foods, but possibly an issue where access to folate is more limited. 

Anyway, the international HIV community flipped out over these data, with experts cautioning against dolutegravir use in women with reproductive potential and recommended second-line options for ART among women in the developing world.  These recommendations have not been widely embraced across said developing nations, though, because dolutegravir is still by far their best available drug for treating HIV.  The authors of this paper performed a modeling study using published data to shed some further light on the issue.

The goal of the paper was to predict the clinical outcomes of 3 ART strategies for South African women of child-bearing potential over a 5-year period.  The strategies were efavirenz-based ART for everybody (EFV), dolutegravir-based ART for everybody (DTG), or a choice of efavirenz without contraception or dolutegravir with contraception (WHO approach).  Their data sources were published data on neural tube defect risks and 48-week ART efficacy rates for efavirenz (0.05% and 60-91%, respectively) and dolutegravir (0.67% and 96%, respectively).  The outcome measures of interest were deaths among women and children, sexual and vertical HIV transmissions, and the incidence of neural tube defects.

The model found that the DTG approach, compared to the EFV approach, would lead to 4400 excess deaths among children due to neural tube defects but avert 13,700 deaths due to HIV among women, and would further prevent 57,700 HIV transmissions.  The WHO approach offered similar tradeoffs vs the EFV approach but to a more limited degree.  Overall, cumulative mortality was highest with EFV (367.3k deaths) followed by the WHO approach (362.8k deaths), and lowest with DTG (358k deaths).  In a sensitivity analysis, the authors calculated that the DTG approach would prevent more deaths than it caused unless the excess risk of neural tube defects associated with dolutegravir exceeded 1.5%.

It seems that the women in the developing world have it right: even if dolutegravir does pose increased risk of neural tube defects in early pregnancy, it’s still their best option overall.  One final note – remember that the neural tube finishes forming 4-6 weeks after the start of the mother’s last menstrual period.  So, by the time a woman realizes she’s pregnant, there’s no reason to hesitate in giving her dolutegravir. 30934067