Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report

Background: In 2019, WHO reported that the prevalence of HIV-1 drug resistance to first-line regimens of non-nucleoside reverse transcriptase inhibitors is increasing in countries with a low number of therapeutic options. This increasing prevalence of drug resistance is an important threat to ending the AIDS pandemic, as it compromises individual clinical outcomes and increases the risk of transmission. In countries with a high number of therapeutic options, little global information is available regarding the prevalence of multidrug-resistant HIV-1 infections, which presents a potential challenge for the clinical management of people with HIV. Even after the approval of two new antiretroviral drug classes in 2007, which were intended to help alleviate this problem, some cases of infection with HIV-1 that show limited susceptibility to the five available antiretroviral classes have been described. We did a thorough in-vitro evaluation of the drug resistance profile of HIV-1 from an observational case to show that five-class pan-resistant clinical cases do exist.

Methods: We investigated a case of a highly treatment-experienced Caucasian male with HIV-1 who had a poor virological response to previous combination antiretroviral therapy (ART) and who was not responding to a dolutegravir-based regimen. For the complete panel of approved antiretrovirals, we examined genotypic resistance using the Stanford HIV Drug Resistance Database interpretation algorithm, and we examined phenotypic resistance using the PhenoSense and Trofile assays. Using viral gp160 sequence analysis, we also explored the potential susceptibility of this virus to novel therapeutic drugs targeting viral envelope binding.

Findings: The individual was diagnosed with HIV-1 on Sept 29, 1989. Since starting antiretroviral treatment in 1995, the individual had received more than 14 different antiretroviral drugs over the course of his illness. In November, 2017, a blood sample was collected from the individual and we did drug resistance analysis tests. We found that this individual was infected with a pan-resistant HIV-1 subtype B strain that showed broad genotypic and phenotypic cross-resistance to all approved antiretroviral drugs, including the newest second-generation integrase inhibitors, dolutegravir and bictegravir. With no remaining clinical options available, except for investigational drugs, this case provides evidence that new antiretroviral drugs with different mechanisms of action are needed.

Interpretation: Our case report shows that HIV-1 multidrug cross-resistance remains an important concern, despite the extensive number of antiretroviral drugs currently available. Highly treatment-experienced patients, especially those who have been given suboptimal combination ART, can develop highly complex resistance-associated mutation patterns, conferring cross-resistance to all widely available ARTs. The identification and reporting of cases, such as the one described in this report, are needed to increase awareness of emerging trends that have the potential to affect patient management.

Funding: None.