A highly unusual case of someone recently acquiring HIV that was resistant to four different classes of antiretroviral drugs has been reported in France. The case is unusual not only because of the degree of resistance displayed by the virus, but also because it appears to have undamaged ability to replicate.
Dr Stéphanie Raymonde and colleagues from Toulouse University Hospital were also able to trace a long-term diagnosed patient with a virus that had exactly the same pattern of resistance, though they could not show that this patient was the source of the infection; they regard it as more likely that there are untraced intermediaries.
Treatment-limiting multi-drug resistance is now rarely seen in HIV strains.
Until the mid-2000s, HIV treatment meant taking drugs with a rather low barrier to developing resistance, or with problematic side effects, or both. Resistance only develops in HIV and similar pathogens if someone takes some of the treatment prescribed to them, but not enough. This means that the virus is able to continue to reproduce, but the pressure from the drug 'selects' drug-resistant mutations that emerge randomly but which can reproduce better under the poorly suppressive regimen.
Soon the resistant viruses form most or all of the viral population and the efficacy of the regimen the patient is taking is effectively lost, and can’t be regained even if their adherence becomes perfect: the only solution is to switch to a regimen containing drugs the virus is not resistant to.
Starting in the late 2000s, several developments made antiretroviral regimens both easier to take and less 'fragile'. In 2007 the first of a fourth class of drug, the integrase strand transfer inhibitors (INSTIs), appeared in the shape of the twice-daily raltegravir, to be followed by the more robust, once-a-day elvitegravir and dolutegravir in 2014.
In 2008 the first of the ‘second generation’ non-nucleoside reverse transcriptase inhibitors (NNRTIs) appeared in the shape of etravirine – which was somewhat less likely to generate resistance than its predecessors.
And in 2012 boosted darunavir, the first protease inhibitor (PI) that was both highly resistance-proof and relatively free of side effects, appeared.
Between them, these drugs were able to provide enough coverage so that the successive development of resistance mutations to all four classes – NRTIs, NNRTIs, PIs, and ISTIs – became uncommon enough that the development of four-class resistance in one long-term diagnosed patient with a history of successive partially suppressive regimens became worth noting in a report in The Lancet Microbe two months ago.
This was a virus acquired during treatment. The transmission of multi-drug resistant (MDR) HIV is even rarer. This is because most drug resistance mutations impair the virus’s ability to replicate. MDR-HIV generally produces a lower viral load in patients who are not virally suppressed, and is not often transmitted.
This is why the present case is so uncommon. A 23-year-old gay man was diagnosed with HIV in September last year. He was HIV negative in June 2019 and his September test had an antibody signature that suggested recent infection. His viral load was higher than average at 5.1 logs (126,000 copies/ml) and his CD4 count was high, at 821.
Resistance tests taken before starting treatment showed his HIV had extensive drug resistance. It had high-level resistance to all NRTIs, NNRTIs, PIs (unusual in itself) and high-level resistance to the INSTIs raltegravir and elvitegravir. He had lower-level resistance to dolutegravir and bictegravir, though some dose adjustment would be needed.
The researchers subsequently identified a 54-year-old gay man who was diagnosed in 1995 who had acquired an identical pattern of resistance mutations on treatment. At the time his HIV was sequenced his viral load was 316,000 copies/ml and his CD4 count 205, despite taking an antiretroviral therapy (ART) regiment of tenofovir, emtricitabine, dolutegravir, and boosted darunavir. Phylogenetic sequencing showed the viruses to be closely related but direct transmission could not be shown to have happened, suggesting at least one intermediary link.
The one difference between the two patients was that the transmitted virus was an R5 virus, meaning it could only enter cells via the CCR5 co-receptor, whereas the virus acquired on treatment was partially X4, meaning it could also use the CXCR4 co-receptor.
The patients’ physicians have put together an ART regimen that should in theory work for both of them. However, the inconvenience or the regimen, which involves daily injections and fortnightly attendances for an infusion, harks back to the early days of HIV therapy.
They have kept dolutegravir for both but have doubled the dose to twice-daily. They have added three drugs of the entry-inhibitor class, which block HIV from entering cells.
These are the long established injectable drug enfuvurtide (Fuzeon, T-20), which blocks the last stage of viral entry; the recently licensed HIV attachment inhibitor fostemsavir (Rukobia), an oral drug; and the post-attachment inhibitor ibalizumab (Trogarzo), which has to be administered via an intravenous drip every 14 days. The younger patient will also be given the oral drug maraviroc (Celsentri), which blocks the CCR5 co-receptor but not CXCR4.
The physicians are awaiting viral load results to see if this regimen works; they express interest in also using lenacapavir (GS-6207), a long-lasting, injectable drug of a new class (capsid inhibitor), which has yet to be licensed.
The last time the transmission of such an extensively drug-resistant virus was reported, according to the writers, was in 2004 when a virus resistant to all drugs apart from enfuvirtide and the protease inhibitor tipranavir was found in a patient who rapidly developed AIDS. But INSTIs were not available at that time.
There have been cases of people being infected with HIV resistant to several classes, including a widely reported PrEP breakthrough case in Toronto where the patient acquired a virus resistant to some NRTIs, NNRTIs, and INSTIs. This was unusual in itself but offers more treatment options, and the patient became undetectable on dolutegravir, rilpivirine and boosted darunavir.
The writers say they are seeing some signs of falling viral load in the newly infected patient which may indicate some loss of replicative capacity after all. In the meantime, however, they urge that an expert epidemiological surveillance network needs to keep tabs on this 'XDR-HIV' strain to ensure there are no further infections.
Raymond S et al. Sexual transmission of an extensively drug-resistant HIV-1 strain. The Lancet HIV 7: E529-E530. August 2020. https://doi.org/10.1016/S2352-3018(20)30205-8.