Pan-resistant HIV-1: what's next?
Authors: Raph L Hamers, Seth C Inzaule
Journal: The Lancet Microbe (2020)

In The Lancet Microbe, Maria C Puertas and colleagues1Puertas MC Ploumidis G Ploumidis M et al.Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report.Lancet Microbe. 2020; (published online June 11.)https://doi.org/10.1016/S2666-5247(20)30006-9Google Scholar report the first well documented clinical case of a male patient infected with a pan-resistant HIV-1 subtype B strain, which showed broad genotypic and phenotypic cross-resistance to all approved oral antiretrovirals from five drug classes, including the widely used second-generation integrase strand transfer inhibitor (INSTI), dolutegravir. The most recently approved drugs (in 2018), doravirine (a next-generation non-nucleoside reverse-transcriptase inhibitor [NNRTI]) and bictegravir (an INSTI), would be impeded by the pre-existing drug resistance mutations in reverse transcriptase (doravirine) and integrase (bictegravir) coding regions. This highly treatment-experienced patient acquired the complex pan-resistant HIV-1 strain over the course of 28 years of antiretroviral therapy (ART), following initial exposure to suboptimal therapy, poor viral suppression to subsequent potent regimens, and current virological failure on a dolutegravir-based regimen. Although the patient regularly attended his clinic visits and had no recorded mental health problems, no further details were provided regarding the underlying causes of the patient's dire situation, such as any challenges around medication adherence, the adequacy of plasma drug concentrations, the occurrence of adverse drug effects, or any behavioural or social issues. Appreciating the individual patient's sociocultural context is an important prerequisite for achieving long-term HIV treatment success. To date, clinical reports of five-class multidrug-resistant HIV-1 are scarce. The first reported case was of a man with advanced disease who had received treament for 18 years and who had received an experimental salvage regimen, which included the anti-CD4 monoclonal antibody, ibalizumab, with limited success.2Fessel WJ Anderson B Follansbee SE et al.The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment.Antiviral Res. 2011; 92: 484-487Crossref PubMed Scopus (23) Google Scholar The second case was an antiretroviral-naive individual who provided the first evidence of the transmission of a HIV-1 variant with resistance to five drug classes.3Volpe JM Ward DJ Napolitano L et al.Five antiretroviral drug class–resistant HIV-1 in a treatment-naïve patient successfully suppressed with optimized antiretroviral drug selection.J Int Assoc Provid AIDS Care. 2015; 14: 398-401Crossref PubMed Scopus (16) Google Scholar Furthermore, the TMB-301 ibalizumab trial4Emu B Fessel J Schrader S et al.Phase 3 Study of ibalizumab for multidrug-resistant HIV-1.N Engl J Med. 2018; 379: 645-654Crossref PubMed Scopus (118) Google Scholar included five patients who carried viruses that were resistant to all approved antiretroviral drugs at time of study enrolment (2015–16), although no genotypic or phenotypic data were reported in this study. Together, these cases provide evidence that multidrug cross-resistance remains an important clinical concern, despite the extensive number of treatment options available in the current ART landscape. These cases also underline the need for the continuous discovery of new drugs with new mechanisms of action, and the inclusion of highly treatment-experienced patients in clinical trials. Of note, Puertas and colleagues1Puertas MC Ploumidis G Ploumidis M et al.Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report.Lancet Microbe. 2020; (published online June 11.)https://doi.org/10.1016/S2666-5247(20)30006-9Google Scholar did ultrasensitive resistance genotyping by next-generation sequencing, which is an emerging powerful diagnostic tool that can improve the ability to detect drug-resistant minority variants archived in the patient's latent viral reservoir. This method could help to improve the prediction of drug susceptibility by identifying the lowest concentrations of drug-resistant minority variants that still have clinical relevance.5Inzaule SC Hamers RL Noguera-Julian M et al.Clinically relevant thresholds for ultrasensitive HIV drug resistance testing: a multi-country nested case-control study.Lancet HIV. 2018; 5: e638-e646Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar Ultrasensitive resistance genotyping might therefore be particularly useful for heavily pretreated patients whose drug resistance history is unknown or not well documented, to help identify archived drug-resistant minority variants and enable accurate selection of the most effective drug regimen. Puertas and colleagues1Puertas MC Ploumidis G Ploumidis M et al.Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report.Lancet Microbe. 2020; (published online June 11.)https://doi.org/10.1016/S2666-5247(20)30006-9Google Scholar make a valid point that insufficient data are available about the epidemiology of multidrug-resistant HIV infections globally and about the effects that these infections have on public health, highlighting the need for robust global drug resistance surveillance systems that continuously inform treatment guidelines.6WHOGlobal action plan for HIV drug resistance 2017–2021.http://apps.who.int/iris/bitstream/10665/255883/1/9789241512848-eng.pdf?ua=1Date: 2017Date accessed: May 12, 2020Google Scholar, 7WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance.http://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: 2018Date accessed: May 9, 2020Google Scholar The emergence of HIV drug resistance following the rollout of life-saving ART to millions of people in low-income and middle-income countries (LMICs) remains an important threat to ending the global HIV epidemic, and risks compromising individual outcomes and increasing onward transmission. Triple-class drug-resistant HIV-1 strains, which are resistant to nucleoside reverse transcriptase inhibitors, NNRTIs, and protease inhibitors, have already been reported in treatment cohorts in LMICs, particularly among children and adolescents.8Boender TS Hamers RL Ondoa P et al.Protease inhibitor resistance in the 1st three years of second-line antiretroviral therapy for HIV-1 in sub-Saharan Africa.J Infect Dis. 2016; 214: 873-883Crossref PubMed Scopus (38) Google Scholar In addition, a number of cases with resistance to all four classes of antiretrovirals available in LMICs have already been reported in sub-Saraharan Africa, meaning that these cases are essentially untreatable in this context.9Steegen K Van Zyl G Letsoalo E Claassen M Hans L Carmona S Resistance in patients failing integrase strand transfer inhibitors: a call to replace raltegravir with dolutegravir in third-line treatment in South Africa.Open Forum Infect Dis. 2019; (published online August 21.)DOI:10.1093/ofid/ofz377Crossref PubMed Scopus (4) Google Scholar, 10Seatla KK Avalos A Moyo S et al.Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana.AIDS. 2018; 32: 1899-1902Crossref PubMed Scopus (15) Google Scholar, 11Chimbetete C Chirimuta L Pascoe M Keiser O A case report of untreatable HIV infection in Harare, Zimbabwe.South Afr J HIV Med. 2019; 20: 1-4Crossref Scopus (2) Google Scholar, 12Rossouw TM Hitchcock S Botes M The end of the line? A case of drug resistance to third-line antiretroviral therapy.South Afr J HIV Med. 2016; 17: 454Crossref PubMed Google Scholar These cases include one individual in Zimbabwe11Chimbetete C Chirimuta L Pascoe M Keiser O A case report of untreatable HIV infection in Harare, Zimbabwe.South Afr J HIV Med. 2019; 20: 1-4Crossref Scopus (2) Google Scholar and one individual in Botswana,10Seatla KK Avalos A Moyo S et al.Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana.AIDS. 2018; 32: 1899-1902Crossref PubMed Scopus (15) Google Scholar both of whom had virological failure to a salvage regimen containing ritonavir-boosted darunavir and dolutegravir after previous exposure to raltegravir. The third individual was a perinatally infected adolescent in South Africa who had virological failure on a salvage regimen containing raltegravir, and who had dolutegravir cross-resistance mutations.12Rossouw TM Hitchcock S Botes M The end of the line? A case of drug resistance to third-line antiretroviral therapy.South Afr J HIV Med. 2016; 17: 454Crossref PubMed Google Scholar A 2019 study done in South Africa reported three patients with intermediate-to-high level dolutegravir resistance, two of whom had been exposed to raltegravir, and the remaining patient had been exposed to a salvage regimen containing dolutegravir.9Steegen K Van Zyl G Letsoalo E Claassen M Hans L Carmona S Resistance in patients failing integrase strand transfer inhibitors: a call to replace raltegravir with dolutegravir in third-line treatment in South Africa.Open Forum Infect Dis. 2019; (published online August 21.)DOI:10.1093/ofid/ofz377Crossref PubMed Scopus (4) Google Scholar The magnitude of the impact that emerging multidrug-resistant HIV could have on public health is a function of the number of available therapeutic options, with the important caveat that HIV treatment is a lifelong intervention. There is thus a strong imperative for LMICs to safeguard the limited number of available drug options, especially among groups that are most at risk of multidrug resistance. The recent (2018) recommendation to use dolutegravir in both first-line and second-line treatment regimens in LMICs reflects major progress towards improving long-term treatment success and helping address the challenge of the high prevalence of pretreatment drug resistance to NNRTIs in many settings.7WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance.http://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: 2018Date accessed: May 9, 2020Google Scholar Nonetheless, a strong preventive framework is needed to ensure that large-scale multidrug resistance will be avoided.6WHOGlobal action plan for HIV drug resistance 2017–2021.http://apps.who.int/iris/bitstream/10665/255883/1/9789241512848-eng.pdf?ua=1Date: 2017Date accessed: May 12, 2020Google Scholar Robust patient-centred care models are crucial for delivering high-quality services to people living with HIV over their lifetime, and across diverse health systems and contexts. These care models include the use of simple, highly potent regimens, close individual viral load monitoring, and improved attention to mental health and adherence challenges, especially in populations that are most at risk of multidrug resistance, such as children and adolescents.6WHOGlobal action plan for HIV drug resistance 2017–2021.http://apps.who.int/iris/bitstream/10665/255883/1/9789241512848-eng.pdf?ua=1Date: 2017Date accessed: May 12, 2020Google Scholar We declare no competing interests. Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case reportOur 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. Full-Text PDF Open Access