Unintended HIV-1 Infection During Analytical Therapy Interruption

To the Editor—Analytical Therapy Interruption (ATI) performed during human immunodeficiency virus (HIV) cure–related clinical trials is currently the recommended intervention to assess efficacy [1]. Using ATI in this field has, however, been a subject of debate and criticism in recent years [2], especially since the publication of the Strategies for Management of Antiretroviral Therapy (SMART) study [3], as it raises important ethical and safety issues. There have been several adverse events identified as potential collateral damage associated with ATI, encompassing clinical, virological, and epidemiological risks [4, 5]. Recently, Lelièvre and Hocqueloux [6] reported a case of HIV-1 transmission to a sexual partner during ATI. We describe another case of unintended HIV transmission between a sero-discordant men-who-have-sex-with-men couple during ATI in a therapeutic vaccine clinical trial conducted in a tertiary hospital in Barcelona, Spain. The index case was a man in his 40s with previous episodes of sexually transmitted infections (STIs). He was diagnosed with HIV infection and started antiretroviral treatment (ART) 12 years and 4 years before entering the clinical trial, respectively. Antiretroviral treatment consisted of a single-tablet regimen containing cobicistat-boosted elvitegravir plus emtricitabine and tenofovir alafenamide (EVG/COBI/FTC/TAF). Since he started ART, viral load (VL) has been maintained at undetectable levels (≤50 copies/mL) and CD4+ T-cell count has remained at 500 cells/mm3 or greater. He was included in a therapeutic vaccine clinical trial (ClinicalTrials.gov identifier: NCT02767193) where the aim was to assess the safety and immunogenicity of a dendritic cell-based vaccine pulsed with autologous heat-inactivated virus. As scheduled, he received 3 doses of ultrasound-guided inguinal intranodal vaccine that were very well tolerated. The same day that he received the last dose of the vaccine, ART was interrupted. Due to the risk of HIV transmission this entails, the participant and his partner were informed in detail of the need to use available methods to prevent HIV transmission during the ATI period, such as condom use and postexposure prophylaxis. The index case was followed up every week for the first 2 weeks and then every 2 weeks during 2.5 months after ATI. Four weeks after ATI, the VL rebounded, and after another 4 weeks he reported diverse moderate symptoms that seemed to represent an acute retroviral syndrome; therefore, ART was restarted with the previous regimen. The index case’s partner was a man also in his 40s with a history of STIs, the last one reported 4 months before documented HIV seroconversion. At that time point HIV-1 testing was negative. He was monitored in our center as part of a sero-discordant couple and was informed of the risks of his partner’s treatment interruption. During the time of the index case ATI, he reported a flu-like syndrome, and had 2 HIV fourth-generation enzyme-linked immunosorbent assay tests that were positive. Western blot was negative, and VL was 36 300 copies/mL, with 846 CD4+ T-cell/mm3 confirming a primary infection. A genotypic drug-resistance profile reported no resistance. He immediately started ART with same regimen as his partner and the VL became undetectable after 6 weeks. Viruses from the index case and his partner were sequenced and a phylogenetic analysis was carried out, confirming that both individuals were infected with the same virus (Figure 1). Neighbor-Joining phylogenetic tree of patients’ viral sequences in C2-V5 env region. The evolutionary history was inferred using the Neighbor-Joining method and bootstrap analysis with partial C2-V5 env nucleotide sequences derived from sexual partner PBMC DNAs and HIV-1–unrelated epidemiological patients. The optimal tree is shown. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Maximum Composite Likelihood method and are in the units of the number of base substitutions per site. The rate variation among sites was modeled with a gamma distribution (shape parameter = 0.6994). Evolutionary analyses were conducted in Molecular Evolutionary Genetics Analysis software version 6 (www.megasoftware.net). Only bootstrap values of 100% are represented. Black: nucleotide sequences obtained from index case. Red: nucleotide sequences obtained from partner. Abbreviations: HIV, human immunodeficiency virus; PBMC, peripheral bloos mononuclear cell. This case highlights the risk of HIV transmission among sexual partners during ATI and stresses the importance of reinforcing HIV transmission-prevention methods during the ATI period. Despite risks being explained in detail, a secondary transmission can occur. Many authors propose different alternatives to prevent this situation in cure-related trials, such as prescribing pre-exposure prophylaxis (PrEP) to the sexual partners during the treatment interruption. However, the implementation of PrEP is still restricted in some countries because of the lack of approval from governmental authorities, which is the case in Spain. Finding the best option to prevent secondary transmission is mandatory, since ATI remains the most frequently recommended intervention to analyze the impact of cure-related strategies. Financial support. This work was partially supported by the following grants: the Spanish Ministry of Economy (MINECO) (grants: SAF2015-66193-R, RTI2018-096309-B-I00), the Fondo de Investigación Sanitaria (FIS) PI15/00480, the Fondo Europeo para el Desarrollo Regional (FEDER), the SPANISH AIDS Research Network RD16/0025/0002–ISCIII–FEDER (RIS), and the CERCA Programme/Generalitat de Catalunya SGR 615 and SGR 653. F. G. has received support from José María Segovia de Arana contracts. Work in C. L.-G.’s laboratory was supported by grants SAF (2010–17226) and (2016-77894-R) from MINECO (Spain) and FIS (PI 13/02269, ISCIII) and in part by the RIS-RETIC grants RD06/006/0036 and RD12/0017/0028 funded by the ISC III-FEDER. Potential conflicts of interest. All authors: No reported conflicts.