HIV and STDs: November 2018

Single-dose Zoliflodacin effectively treats urogenital gonorrhea. N.gonorrhea has long been a contender in the race to become the first completely antibiotic-resistant bacteria. Enter zoliflodaxin, a novel antimicrobial inhibiting DNA replication via topoisomerase (so, a cousin of the fluoroquinolones). After showing promise in preclinical studies, the authors took this agent to a phase 2 trial for the treatment of uncomplicated gonorrhea.

A total of 179 patients (167 men and 12 women) with gonorrhea were randomized to receive either a single oral dose of zolifodacin (2g or 3g) or a single 500mg IM dose of ceftriaxone. Test of cure was performed 4-8 days after treatment, and subjects returned for a second safety visit one month after treatment. The primary outcome of interest was microbiologic cure of urogenitial gonorrhea.

One hundred and forty-one patients were included in the intention-to-treat analysis. Rates of urogenital gonorrhea cure were 96% with zolifodacin at either the 2g or 3g doses versus 100% with ceftriaxone. Fifteen patients had rectal gonorrhea across the three treatment arms and all were cured. Pharyngeal gonorrhea cure rates were lower with the novel agent, occurring in 4/8 (50%) of the 2g zoliflodacin, 9/11 (82%) of the 3g zoliflodacin, and 4/4 (100%) of the ceftriaxone groups. About a fifth of patients receiving zolifodacin had an adverse event deemed likely to be associated with drug, most of which were gastrointestinal.

Even with said side effects, this is an important addition to our STD armamentarium – though perhaps more than a single dose will be needed for pharyngeal disease. Hopefully we see the phase 3 trials and FDA approval follow in short order. 30403954

When do people with HIV and syphilis but no neurologic symptoms still need an LP to rule out neurosyphilis? The authors performed a retrospective review of people living with HIV (PLWH) treated for syphilis at their medical center over a 10-year period. They collected demographic data, the documented neurological signs and symptoms, and whether an LP was performed; the primary outcome of interest was whether neurosyphilis was diagnosed at the initial presentation or later followup.

A total 261 episodes of syphilis were identified among 230 patients; all patients had a positive treponemal and nontreponemal test and a clinical diagnosis of syphilis at any stage by an ID physician. Ninety-five percent of the cohort were men, and of the remainder 10 were transgender women and 3 cisgender women; most had acquired HIV via sex with men, and only 42% had a suppressed viral load on ART. The overall prevalence of neurosyphilis was 10%, and of these 78% had neurologic signs or symptoms. Patients with neurosyphilis had lower mean CD4 counts (314 vs 500 cells/ml; p<0.001), higher RPR titers (2.1 vs 1.7 log; p=0.019 - no, they didn’t give dilutions, and no, I don’t know why), and were less likely to be on effective ART (31% vs 61%, p=0.003).

Lumbar puncture was performed in 36% of syphilis cases, including 31% of cases without signs or symptoms of neurosyphilis. Neurosyphilis was diagnosed in 9% of cases in the latter group, giving a number needed to diagnose of 12; the authors point out that, had they performed an LP in every case of HIV and syphilis co-infection and not found any additional cases, the NND would have increased to 38.

The authors conclude in favor of the current CDC recommendation that the majority of PLWH who have syphilis but no evidence of CNS infection do not need an LP. However, lumbar puncture should still be considered in asymptomatic patients when the patient’s CD4 count is low, the viral load is not suppressed, or the RPR titer is high. 30402918

How effective is the proviral HIV DNA genotype at detecting resistance mutations in people with HIV who have achieved low or undetectable viral loads? Occasionally I’ll see a patient with HIV who is either controlled or has persistent low-level viremia on one of our old, cumbersome salvage regimens (e.g.; etravirine, raltegravir, and darunavir-ritonavir – a whopping 8 pills a day). For these folks I usually wonder: can I simplify their ART? Not being able to obtain a traditional HIV genotype in these situations because the serum viral load is too low can be frustrating; however, even a virologically controlled patient should still have detectable proviral HIV DNA. But how reliable is the DNA genotype?

The authors reviewed the outcomes of HIV DNA genotype testing in a 100 patients seen at their university hospital who had either a low or undetectable RNA viral load as well as some reason to need to change their current ART regimen. The resistance mutations detected by the DNA genotypes were compared to those that had been identified either on previous RNA genotypes (for 76 patients) or on a same-day RNA genotype (for 24 patients). Most patients had had known HIV infection and been on ART for over a decade.

“Loss of information,” defined as a resistance mutation detected in the RNA genotype but not in the DNA genotype, was identified in 38% of cases when comparing the DNA genotype to the historical RNA genotypes, and in 11% of cases when comparing to the same-day RNA genotype. Longer durations of ART were associated with loss of information, and no particular class of mutation (e.g. RT, protease, or integrase) was more or less susceptible. Bottom line: the DNA genotype is better than nothing, but misses a large proportion of archived resistance mutations when compared to historical RNA genotype records. 30137336

Speaking of low-level viremia, how low does it have to be before it stops being a risk factor for virologic failure?  This analysis of the African Cohort Study evaluated 1,511 participants with viral loads ranging from <200 to 999 copies/ml across 4,382 years of patient followup. Subjects were stratified by viral load (<200, 200-499, and 500-999).  Compared to those with an undetectable viral load, patients with viral loads >200 were more than twice as likely to have virologic failure during followup (HR 11.8 for viral loads 200-499; HR 22.4 for viral loads 500-999; p<0.05 for both).  The authors conclude that care for patients with persistent low-level viremia should target viral loads <200 copies/ml. 30462188

More and more data suggest that two drugs are enough to maintain HIV viral suppression, so long as one of them has a high barrier to resistance. Coformulated dolutegravir-rilpivirine was approved for the maintenance of HIV suppression in 2017, and the long-acting injectable combination of cabotegravir and rilpivirine has been in the works for a while. This month brought data supporting two more dual-drug regimens.

The first, combination dolutegravir and lamivudine, demonstrated a high degree of efficacy of in the single-arm, open label LAMIDOL trial. One hundred and four patients (86% male, mean age 45, baseline CD4 count 743, mean duration of viral suppression 4.5 years) were switched from their current regimen to dolutegravir and lamivudine over 8 weeks in a two-step manner – first switching the third agent in their current regimen to dolutegravir, then switching their two-NRTI backbone to lamuvidine alone. The duration of follow-up was 48 weeks, and virologic failure was defined as two consecutive viral loads >50 copies/ml. The overall success rate was 97%; of the three failures, one occurred at week four, one was due to loss to follow-up, and one was due to change in regimen after a single virologic blip. No new dolutegravir or lamivudine resistance mutations were detected. 30476165

The second, a meta-analysis of previous trials, demonstrates the effectiveness of dual therapy with a ritonavir-boosted protease inhibitor plus lamivudine. The authors reviewed trials of maintenance therapy with PI/r lamivudine conducted between 1990 and 2017, identifying four studies with a total 1051 patients and collaborating with those studies’ authors to pool data. At week 48 from randomization to either continuation of a three-drug regimen or switch to PI/r plus lamivudine, rates of virologic failure were similar (3% for the continuation group vs 4% for the switch group). Virologic failure was not influenced by patient gender, HCV infection, or the type of PI using in the switch group. 30085184

Genetic engineering of vaginal and rectal microbiota: a novel strategy to prevent HIV transmission? Sometimes I read an article and am left feeling jealous that the world is full of people cleverer than me. This is one of those times.

The authors took two probiotic strains of Lactobacillus rhamnosus and tried to make them express two HIV-inhibiting lectins (proteins that bind polysaccharides), actinohivin and griffithsin. Efforts to make L. rhamnosus express the former lectin were unsuccessful as the lectin proved toxic to the bacteria, but the griffithsin-expressing bacteria were successfully constructed. The authors then purified proteins produced by cultures of the engineered Lactobacillus and added them to cell cultures that were then infected with either T-tropic (X4) or M-tropic (R5) strains of HIV-1. Interestingly, while the protein made by bacteria engineered to produce extracellular griffithsin showed no antiviral activity, the protein made by bacteria expressing intracellular griffithsin potently inhibited both strains of HIV-1.

Obviously, this technology is a long way off from use in humans. First, they used antibiotic resistance genes to maintain selection of the griffithsin gene in the Lactobacillus – not something you want in a product you plan to slather on people’s genitals. Second, they’ll need to tie the protein expression to a promoter that’s reliably activated in the vaginal and rectal environments (because not all bacterial genes are turned on in all situations). Third, they’ll need to demonstrate in vivo protection against HIV transmission in an animal model. But if this works and can pass regulatory hurdles, we could have a cheap, easily distributed, totally discrete form of PrEP with no systemic side effects. How cool would that be? 30040991