First case of HIV resistant to all antiretroviral treatment combinations described

The Lancet Microbe publishes the first case reported of an HIV-positive person whose virus is resistant to all five families of oral anti-HIV drugs, and who was not sensitive to 25 of the 26 drugs tested. To eliminate the virus, the therapies need at least a combination of two drugs blocking different important pathways for the virus. Thus, the paper highlights the importance of developing new drugs that work in alternative ways and against which these viruses have not developed resistance. The article also highlights the need to perform studies that detect these resistant viruses and prevent their transmission.

HIV resistance to antiretrovirals is caused by at least one mutation in the genetic structure of the virus, which impairs the effectiveness of a drug - or a combination of drugs - in blocking viral replication. Resistance can occur in people in whom the treatment is not fully effective, people who for various reasons do not take the treatment continuously, or people who are already infected with a resistant virus. In 2019, WHO warned that in some countries more than 10% of new HIV infections occur with drug-resistant virus.

So far, the scientific literature had recorded 2 cases with resistance to certain drugs belonging to each of the 5 existing families of antiretrovirals, but not to all drugs simultaneously.

Partial infection control

The case described in The Lancet Microbe refers to a man diagnosed as HIV-positive in 1989, at the age of 41. He began taking antiretroviral treatment in the 1990s, with the first low-efficacy drugs, and to date has taken 14 different drugs that have only partially controlled the infection. In November 2015 he received a new generation integrase inhibitor, which is more effective and less likely to generate resistance, but after an initial improvement, the treatment failed again in June 2016.

Using sequencing techniques and experiments on cell cultures, IrsiCaixa researchers have shown that this person's virus samples are resistant to all but one of the approved oral drugs. "A single drug is not effective against HIV because the virus easily finds other ways to escape. This is why it is necessary to administer therapies that combine various families and block various phases of the virus' infection cycle", explains Mª Carmen Puertas, IrsiCaixa researcher and first author of the work.

Scientists suggest that HIV resistances in this case are due to two reasons: exposure during the first years to antiretroviral drugs that were not as effective as the current ones and a possible lack of regularity in taking the drugs. "It is not that there is a pan-resistant virus circulating, but rather that it was generated in this specific case", specifies Javier Martínez-Picado, ICREA researcher at IrsiCaixa and leader of the study.

Prevent the transmission of pan-resistant viruses

The scientists point out that, in this specific case, the only therapeutic alternative would be the use of antibodies that block the virus or drugs with new mechanisms of action, but for the moment both options are still in the development phase. "This clinical case illustrates the potential risk of multi-resistance in the field of HIV, despite the diversity of antiretrovirals that exist. As there are no therapeutic options available, with the exception of some injectable drugs that are not viable for daily use, it is clear that there is an urgent need to develop new antiretroviral drugs to which no variant of HIV has ever been exposed, so that it is impossible for the virus to generate resistance against them", indicates Puertas.

The work also highlights the need to monitor HIV patients in order to detect resistant cases early and prevent their transmission. In this sense, the study stresses that the identification of this isolated case does not necessarily pose a risk to public health, "but epidemiological surveillance must be maintained because as one case has appeared, others may appear. The current prevalence of pan-resistant HIV is not known, and it is essential to do so in order to stop the chain of transmission on time and thus avoid HIV infection when there are no therapeutic options, as used to be the case in the 80s", concludes Martínez-Picado.

• Reference: Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report. The Lancet Microbe. Maria C Puertas, George Ploumidis, Michalis Ploumidis, Emilio Fumero, Bonaventura Clotet, Charles M Walworth, Christos J Petropoulos, Javier Martinez-Picado. Doi: S2666-5247(20)30006-9