STI / HIV Prevention in the Era of Biomedical Interventions

STI Prevention in the Era of Biomedical HIV Intervention

 

 

 Part I

 Incident chlamydia, gonorrhea, and syphilis have risen sharply among men in the United States and other industrialized countries, with syphilis disproportionately high among MSM.1 This study investigates the relationship between biomedical HIV interventions and recent increases in STI incidence in AIDS-affected communities across the U.S. As Truvada (and now, Descovy) and concepts like U=U (undetectable equals untrasmittable) move across continents and into local formularies, traditional methods of HIV prevention are being destabilized. For the past 40 years, under the guidance of CDC and WHO, public health departments have focused primarily on preventing HIV by promoting abstinence, behavior change, and condoms (ABCs). However, the biomedical paradigm is shifting global strategies to address this disease. Anti-retroviral drugs can reduce the infectiousness of people living with HIV by about 96%--treatment as prevention or TasP--and can reduce the risk of being infected by an HIV positive person by about 70%--pre-exposure prophylaxis or PrEP--raising the prospect of using anti-retroviral drugs to stop the epidemic of HIV.

 

PrEP is a biomedical interventional strategy in which healthy people routinely take one or more antiretroviral (ARV) drugs to reduce their risk of getting HIV through sex. Three RCTs have studied the effects of PrEP on the acquisition of HIV infection***. The first landmark study, the Pre-exposure Prophylaxis Initiative (iPrEX) looked at the effect of daily use of tenofovir-emtricitabine in 2499 MSM from six countries (Peru, Ecuador, South Africa, Brazil, Thailand, and the USA) and was published in 2010. The PRe-exposure Option for reducing HIV in the UK, immediate or Deferred (PROUD) trial enrolled 544 MSM in the UK and randomly assigned them to immediate or a 1 year delayed start of daily oral tenofoviremtricitabine. In the Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (Ipergay) trial, ** **MSM were randomly assigned to either tenofovir-emtricitabine or placebo for intermittent use in France and Canada. In all PrEP trials, adherence was a strong determinant of PrEP effectiveness. **

 

The currently validated PrEP method involves interventional use of ARVs, tenofovir and emtricitabine, taken daily in a single pill marketed as Truvada, and Descovy. PrEP is a powerful intervention for HIV prevention, but it has the potential to reduce commitment to primary prevention strategies, result in risk compensation and increase proportions of at-risk populations with STIs. For example, new data about PrEP uptake confirms that of approximately 500,000 Black people who could potentially benefit from PrEP, only 7,000 prescriptions have been filled. This data underscores the need to ensure that a policy shift to prophylactic treatment is not producing inequities. The role of PrEP in relation to STI incidence is somewhat easier to assess than with TasP, because PrEP is an individual intervention rather than a population-based one. PrEP is, however, only in the early stages of implementation. Individuals who receive PrEP will need to be followed up carefully over time with the use of quantitative and qualitative research methods to establish whether and how risk compensation and changing patterns of sexual partnerships and practices are affecting STIs.

 

The long-term effect of PrEP for risk, incidence and prevalence of STIs are not yet known. Widening of PrEP use, together with other behavioral changes could affect sexual networks and proportions and patterns of STI. For example, if non-condom sex partnerships between individuals using PrEP who are not infected with HIV and individuals using TasP who are HIV infected become more common, outbreaks of syphilis, lymphogranuloma venereum, hepatitis, and shigellosis that have occurred mostly in those infected with HIV could spread to networks of individuals without HIV infection. STIs that increase HIV infectiousness through inflammatory mechanisms could then reduce the effect of biomedical HIV prevention methods.

 

TasP methods are designed to reduce HIV infectiousness and involve starting ARV drug therapy as soon as HIV infection is diagnosed to prevent sexual transmission to uninfected partners. The success of TasP depends on people with HIV having the needed access to health care and taking their medications as prescribed every day of their lives. So, strict adherence to ARV drug treatment over the long term is absolutely essential. The concept of U=U means that people living with HIV who achieve and maintain an undetectable viral load- the amount of HIV in the blood- by taking and adhering to the pharmaceutical regime as prescribed cannot sexually transmit the virus to others. To extrapolate these benefits to a whole population, a sufficiently high proportion of all individuals infected with HIV would need to receive and adhere to effective ARV drug treatment from very early in the course of infection.

 

The landmark NIH-funded HPTN 052 clinical trial showed that no linked HIV transmissions occurred among HIV serodifferent heterosexual couples when the partner living with HIV had a durably suppressed viral load. Subsequently, the PARTNER and Opposites Attract studies confirmed these findings and extended them to male-male couples. Validation of the TasP strategy and acceptance of the U=U concept has numerous behavioral, social and clinical implications. There is a consensus that knowledge about the effects of ARV treatment on reduced infectiousness of HIV is contributing to risk, incidence, and prevalence of STIs 3.

 

The shift from condoms to medication as the primary form of prevention does not eliminate human behavior as a limit to effective prevention. The success of these strategies is dependent upon strict adherence to the pharmaceutical regime. Recent studies investigating the interventional use of ARVs suggest a relationship between PrEP uptake and TasP strategies like U=U to increasing STI prevalence. These findings have experts questioning the possible unintended negative consequences of using ARV drug treatment for HIV prevention. A disadvantage inherent to TasP is that its success depends on the behavior of others.** The uninfected individual has to trust that their sexual partners infected with HIV are adherent to ARV treatment, and that this treatment is sufficiently effective to mitigate transmission risk. By contrast, with PrEP, the at-risk individual takes the preventive treatment. Biomedical solutions may be an important tool to “treat our way out of this epidemic,” but increasing rates of HIV and STIs raise questions about the influence of PrEP and TasP strategies on STI epidemiology once implemented more broadly.

 

Summary points

·         Persons living with HIV who achieve sustained viral suppression with antiretroviral therapy can avoid sexual transmission of HIV without using condoms.

·         Similarly, pre-exposure prophylaxis with tenofovir-emtricitabine in HIV-uninfected persons is highly effective.

·         With this background, rates of sexually transmitted infections are increasing in some HIV-infected populations, and in some at risk for HIV acquisition.

·         The implications require reassessment of the alignment and prioritization of HIV research funding, public health policy, and community engagement.

 

Key research questions.

Overall	• Is the high incidence of STI likely to undermine the success of TasP or PrEP in the long term, in certain populations, or with new PrEP agents? • Can approaches focused on broader spectrum prevention (i.e., agents that inhibit HIV and other viruses) be effective for both HIV and STI PrEP? • What are the broad implications, including funding and trial design, for clinical research in STIs and HIV?
Biology and HIV–STI synergy	• When mucosal injury occurs, does the immune environment influence healing time? • What does hormonal contraception do to the interaction of STI and HIV and to the vaginal microbiome? • Are these processes different in the adolescent genital tract? • How does asymptomatic rectal STI and its treatment perturb the rectal mucosal environment and its receptivity to HIV infection? • For non-TDF-FTC PrEP regimens, can inflammation facilitate breakthrough replication that could overcome the effect of PrEP or promote the risk of HIV/STI transmission? • Could HIV cure strategies that involve interventions to “shock” the virus from latent reservoirs release transmissible virus in the genital tract?
Epidemiology of STIs and sexual behavior in the PrEP era	• To what degree is the increased detection of STI in persons on PrEP due to increase screening (ascertainment bias) versus a true increase in acquisition? • How will prolonged PrEP use impact sexual behavior and sexual networks? • How is PrEP utilized in the context of multiple sexual partnerships? • What is the relative contribution of enhanced detection through routine screening among PrEP users and HIV-infected MSM in care versus absolute increases in STI acquisition due to increases in unprotected sex?
Implementation science	• What innovative testing strategies improve STI diagnosis among individuals on PrEP? • What will be the economic and workforce implications of the increase in STI screening we will continue to see with expanding use of PrEP? • Can STI clinics integrate the provision of PrEP as part of their menu of services? • Can primary care settings seeing patients at risk for HIV improve the quality of STI screening and service provision? • What interventions decrease racial/ethnic disparities in PrEP uptake and STIs?
Study design	• How can we leverage HIV prevention studies using the factorial design strategy to “layer on” STI prevention interventions? • What STI prevention strategies are amenable to more efficient studies focused on operational endpoints (i.e., coverage) instead of effectiveness? • Can the stepped wedge cluster randomized trial approach be used more widely to study clinic-based and population-based STI prevention strategies?

 

 

The specific aims of this study are to:

·         Assess the real-world efficacy of PrEP to prevent sexually-acquired HIV-1 infection

·         Examine the relationship between TasP strategies and risk of STIs

·         Evaluate the impact of biomedical interventions on HIV and STI rates in AIDS-affected community

·         Examine the relationship between increased PrEP uptake and STI crisis

 

 

References

 

2018 CROI PrEP Press Release | CDC. Centers for Disease Control and Prevention. https://www.cdc.gov/nchhstp/newsroom/2018/croi-2018-PrEP-press-release.html. Accessed October 8, 2019.

Correction to Lancet Infect Dis 2017; 17: 330–38. The Lancet Infectious Diseases. 2019;19(4). doi:10.1016/s1473-3099(19)30079-9

Eaton LA, Kalichman SC. Risk compensation in HIV prevention: Implications for vaccines, microbicides, and other biomedical HIV prevention technologies. Current HIV/AIDS Reports. 2007;4(4):165-172. doi:10.1007/s11904-007-0024-7

Oldenburg CE, Nunn AS, Montgomery M, et al. Behavioral Changes Following Uptake of HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in a Clinical Setting. AIDS and behavior. https://www.ncbi.nlm.nih.gov/pubmed/28150120. Published April 2018. Accessed October 8, 2019.

The science is clear: with HIV, undetectable equals untransmittable. National Institutes of Health. https://www.nih.gov/news-events/news-releases/science-clear-hiv-undetectable-equals-untransmittable. Published January 10, 2019. Accessed October 7, 2019.

Chen Y-H, Snowden JM, McFarland W, Raymond HF. Pre-exposure Prophylaxis (PrEP) Use, Seroadaptation, and Sexual Behavior Among Men Who Have Sex with Men, San Francisco, 2004-2014. AIDS and behavior. https://www.ncbi.nlm.nih.gov/pubmed/26983951. Published December 2016. Accessed October 8, 2019.

Marrazzo JM, Dombrowski JC, Mayer KH. Sexually transmitted infections in the era of antiretroviral-based HIV prevention: Priorities for discovery research, implementation science, and community involvement. PLoS medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761829/. Published January 10, 2018. Accessed October 8, 2019.

Oldenburg CE, Nunn AS, Montgomery M, et al. Behavioral Changes Following Uptake of HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in a Clinical Setting. AIDS and behavior. https://www.ncbi.nlm.nih.gov/pubmed/28150120. Published April 2018. Accessed October 8, 2019.

Stolte IG, Dukers NHTM, Geskus RB, Coutinho RA, de Wit JBF. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS (London, England). https://www.ncbi.nlm.nih.gov/pubmed/15075549. Published January 23, 2004. Accessed October 8, 2019.