It has been over four decades since the first case of the human immunodeficiency virus (HIV) was reported. According to the joint United Nations Programme on HIV/AIDS (UNAIDS), there are approximately 39 million people currently living with HIV, and the virus has claimed the lives of over 40 million individuals globally. In 2022, there were 1.3 million new cases of HIV. This statistic signifies a high incidence rate, given the wealth of knowledge we have accumulated over the years regarding HIV prevention and education. Like most unprecedented disease outbreaks, the HIV epidemic has presented a range of complex challenges that extend across political and societal spheres. However, it is important to recognize the remarkable progress and contributions made in HIV diagnostic services and pharmacotherapy. With the appropriate treatment regimen, what was once a life-threatening disease is now manageable, and individuals with HIV can achieve a life expectancy comparable to those uninfected by the virus. The available HIV interventions, comprising a combination of various classes of antiretroviral therapy (ART), not only enhance the quality of life but also lower the viral load to undetectable levels, thereby preventing the transmission of the virus. Thus, the United States has implemented the “Ending the HIV Epidemic in the U.S. (EHE) initiative to stop the spread of HIV, improve access to care, and end associated stigma by 2030 [1].
Ongoing research continually reinforces the role of ART as a preventive measure against HIV acquisition, a concept commonly termed "Treatment as Prevention" (TasP). TasP, as a preventative tool, stands on the solid empirical foundation of ART's effectiveness, exemplified by the landmark HPTN 052 study in 2016 [2]. This study revealed a staggering 93% reduction in HIV transmission among HIV serodiscordant couples when the HIV-positive partner was on ART and achieved suppressed viremia (below 400 copies/ml) [3]. Furthermore, three groundbreaking studies—PARTNER, PARTNER2, and Opposite Attract—likewise documented zero genetically linked infections among serodiscordant couples engaging in condomless sex when the HIV-infected partner was on ART and achieved an undetectable viral load (below 200 copies/ml) [4, 5, 6]. These pivotal publications gave rise to the concept known as "undetectable equals untransmittable" colloquially referred to as “U=U”. This means that individuals with an “undetectable” viral load are non-infectious, even after engaging in sexual activity without barrier protection and/or preexposure prophylaxis.
The widespread endorsement of "U=U" by various medical associations and learned societies, including the World Health Organization and UNAIDS [7], represents a significant milestone in the battle against HIV and its associated stigma. Furthermore, the “U=U” messaging is gaining traction as a valuable public health tool to combat HIV-related stigma and promote widespread access to ART. Thus, the CDC is working collaboratively to amplify the message through social media [8]. Nonetheless, some healthcare providers remain hesitant to discuss “U=U” with their patients. Their concerns stem from the difficulty of accepting the absolute lack of transmission risk associated with being HIV undetectable, and they worry that this status might inadvertently encourage risky behavior, potentially contributing to the further spread of HIV during instances of viral load blips. Additionally, it is important to note that “U=U” exclusively pertains to sexual transmission, and risks still exist through other modes of transmission, including breastfeeding. Furthermore, “U=U” does not protect against other sexually transmitted diseases.
It is important to emphasize that HIV testing, which is within the domain of clinical laboratories, is crucial to advancing the goals of TasP and “U=U”; hence, acknowledging the pivotal role of laboratory testing in curbing the HIV epidemic. Therefore, to attain the goal of zero HIV incidences and adhere to the "U=U" principle, HIV diagnosis and care must be complemented by viral load testing. Viral load measurement stands as the cornerstone for assessing the clinical progression of HIV infection and the effectiveness of therapy. According to the aforementioned PARTNER and Opposite Attract studies, the threshold for an undetectable viral load was set at less than 200 copies/ml. The measurement of HIV viral load involves quantifying HIV RNA levels in plasma using nucleic acid amplification tests. The test results are typically reported as undetected if the assay was unable to detect HIV RNA; less than the lower limit of quantitation (typically 20 or 30 copies/ml); or if the viral RNA is detected and quantifiable, the number of viral copies is reported. The lower limit of quantitation for viral load testing can vary across different laboratories, typically within the 20-200 copies/ml range. It is important to note that clinical laboratories report HIV viral tests based on their instrument analytical sensitivity, regardless of whether they are above or below the established cut-off that supports the U=U messaging, which is 200 copies/ml. The implication of this is that patients with viral load below 200 copies/ml but above the limit of detection for the assay utilized would receive a detectable result. According to the information provided on the test directories of the major reference laboratories in the United States, Mayo Clinic Laboratories, LabCorp, and Quest Diagnostics have a quantitative range of 20-10 million copies/ml for HIV viral load testing, while ARUP Laboratories utilize a quantitative range of 30-10,000,000 copies/ml. Consequently, a patient with a viral load of 35 copies/ml will receive a detectable result at all the aforementioned laboratories. The incongruence in the analytical sensitivity variation of viral load testing and the <200 copies/ml cut-off for the U=U initiative may limit the success of the campaign and create confusion in the interpretation of lab results.
While it is acknowledged that the onus is on the healthcare provider to interpret laboratory results in the context of the patient's clinical picture, some providers, particularly practitioners in resource-limited settings where HIV is endemic, may rely heavily on lab reports and comments. Furthermore, with the increasing use of mobile electronic reporting, patients sometimes may have access to their test results before their clinical appointments, allowing room for patient-initiated investigations, potentially leading to misinterpretation and anxiety in the case of inconsistent results.
The ongoing endeavors to eliminate HIV and its associated stigma call for a universal approach. Efforts to align the laboratory interpretation of HIV viral load testing with the U=U campaign are encouraged. As lab testing technologies continue to become more sensitive, the laboratory medicine community is encouraged to lend its expertise to the better application of the U=U initiative; by proposing universal interpretive comments that correlate HIV viral load reports with disease transmissibility. This comment would help patients understand that detectable viral loads below 200 copies per ml, while reported as such, do not alter their non-transmissible status. Furthermore, the U=U language could be revised to “viral suppression at <200 copies/ml equals untransmittable” which is less ambiguous. Ultimately, implementing these changes would require concerted efforts by the laboratory and other clinical stakeholders and in compliance with the applicable public health regulations.
The HIV epidemic has been met with collaborative efforts from multidisciplinary teams of scientists, clinicians, laboratory professionals, peer researchers, and advocacy groups. While a cure for HIV is on the horizon, the collective strengths of these HIV stakeholders have already led to the containment of one of the most devastating epidemics in human history. However, we must remain vigilant, as true success will only be achieved when we attain zero HIV transmission globally.
References
1. Centers for Disease Control and Prevention. Ending the HIV Epidemic in the U.S. (EHE). https://www.cdc.gov/endhiv/about-ehe/index.html. Accessed November 9, 2023
2. Cohen, M.S., et al., Prevention of HIV-1 Infection with Early Antiretroviral Therapy. New England Journal of Medicine, 2011. 365(6): p. 493-505.
3. Cohen, M.S., et al., Antiretroviral Therapy for the Prevention of HIV-1 Transmission. New England Journal of Medicine, 2016. 375(9): p. 830-839.
4. Rodger, A.J., et al., Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. Jama, 2016. 316(2): p. 171-81.
5. Bavinton, B.R., et al., Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV, 2018. 5(8): p. e438-e447.
6. Rodger, A.J., et al., Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet, 2019. 393(10189): p. 2428-2438.
7. World Health Organization. Joint statement Ministry of Public Health of Thailand, World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS). https://www.who.int/docs/default-source/searo/hiv-hepatitis/joint-moph-unaids-who-uu.pdf?sfvrsn=8378cd0_2. Accessed November 9, 2023
8. Centers for Disease Control and Prevention. Amplifying U=U Message Through Social Media. https://www.cdc.gov/globalhivtb/who-we-are/features/amplifying-undetectableuntransmittable.html. Accessed November 9, 2023