HIV risk – where do perception and reality overlap?

Editor’s notes: Whereas pregnancy occurs quite frequently after unprotected sex, as discussed in the previous commentary, HIV is not transmitted so easily.  In their guidance on PrEP [1] in 2015, WHO refers to substantial risk at a level of around 3% per year, which of course means that 97% of people in that risk group do not become HIV-positive in that year.  However, risk can only be measured at a group level.  Not only does this mean that there may be unrecognized risk factors, but also at the individual level we seldom calculate a mathematical risk of something happening to us.  So a better understanding of how people perceive their risk and how this relates to their actual likelihood of becoming HIV-positive is important for many aspects of HIV prevention and behaviour change communication.  Among gay men and other men who have sex with men in Europe, Australia and the US, self-identification, combined with a few screening questions could distinguish men at very high risk for whom PrEP is an obvious choice.  Adherence in this group tends to be good and the benefits far outweigh the costs, both financial and other.

In other populations, the equation is not so straightforward.  People at lower risk of HIV may still choose to take PrEP (or use other prevention technologies in the future) but the financial costs of preventing new HIV infections will always be higher for people who adhere less and are at lower risk.  Two papers this month consider aspects of this question.  Haberer et al. considered the overlap between PrEP adherence and risky periods within the Partners Demonstration Project, in Kenya and Uganda.  In this project, serodiscordant couples were recruited and offered PrEP if they met criteria that showed that the seronegative partner had a risk of seroconversion modelled at 3-4% per year.  Thus the seronegative population as a whole was at substantial risk.  The authors then further classified those periods where the HIV-positive participant had not yet had six months of ART and the couple had not used condoms all the time as high risk.  Prevention-effective adherence was defined as taking sufficient PrEP tablets to be effective during the periods when sex could be considered high risk.  The authors found that, reassuringly, during 75% of the time periods in their study, participants should have been protected.  This helps to explain the overall high effectiveness observed in the study and suggests that in this context people make rational decisions about when to adhere to their PrEP and when they do not need to worry so much.

The study contrasts somewhat with a study from South Africa by Maughan-Brown and Venkataramani.  The authors were able to use some of the most detailed information to have been collected on perceived risk of HIV infection among participants in the Cape Area Panel Study which ran from 2002 – 2009.  Detailed questionnaires on risk perception and behaviours were collected in successive surveys.  In the final survey in 2009, HIV testing was included which allowed the authors to test whether perception of risk translated into HIV seroconversion.  Their conclusions are that perception of risk did NOT translate into actual risk.  They acknowledge that perceptions may have changed over the ensuing years but it is a cautionary study that challenges our assumptions that people who consider themselves at risk are the most likely beneficiaries of prevention efforts.  On the other hand, it is impossible to offer prevention technology to people who do not consider themselves at risk.  The challenge is to find communication and delivery systems that will encourage the perfect combination of people who are genuinely at risk, people who want to use the technology and people who will adhere to it faithfully.  A key determinant remains the costs.  Focusing on this perfect combination maximizes the cost-effectiveness of prevention technologies, but that should not preclude allowing people who want to use it to do so at their own cost.

Some potential technologies are still very expensive.  Infusions of broadly neutralizing antibodies are being tested in the Antibody Mediated Prevention (AMP) study [2] in order to define the level and duration of protection of such a strategy.  This will help design future vaccine strategies or could be used for specific protection needs if the cost of antibody production falls.  So, the study from Sok et al. is exciting if still a long way from the field.  Until now, generating broadly neutralizing antibodies in the laboratory has proved challenging.  Standard approaches require multiple sequential immunogens to be administered to drive the antibody maturation process in rabbits or macaques, followed by purification of the relevant monoclonal antibody.  However, cows have a rather different antibody configuration, and in this study, four cows developed useful cross-clade coverage after regular boosts with just a single immunogen.  Of particular interest was the fact that the antibody response continued to evolve so that the later antibodies showed broader activity, despite no additional immunogens.  During the Paris IAS HIV Science conference [3], Dr Fauci [4] foresaw a future where people living with HIV might be maintained in long-term remission without ART by regular doses of powerful antibodies possibly given subcutaneously.  Science fiction or a realistic avenue?

Finally, we need to remember that some risk factors for HIV transmission are only just being elucidated.  There has been considerable interest in the vaginal microbiome.  Women whose vaginas are largely colonized by lactobacilli are less likely to become HIV-positive, whereas women with bacterial vaginosis, or dysbiosis are more likely to.  Liu et al. have study the microbiome of the foreskin in uncircumcised men in the control arm of one of the large randomized trials of voluntary medical male circumcision in Uganda.  The authors show that men in whom they could demonstrate bacterial species such as prevotella, dialister, finegoldia, and peptoniphilus were significantly more likely to become HIV-positive on follow up than men who did not have these anaerobic microorganisms.  Furthermore, they point out that these same bacteria can be passed on to the woman, where they may also cause colonization and thus transmit an increased susceptibility to the female partner too.  The challenge is that while a simple course of antibiotics may kill the relevant organisms in both men and women, recurrence is common.  Microbiomes are an essential part of sexual and reproductive health.  Another up and coming area for research. 

 

Alignment of adherence and risk for HIV acquisition in a demonstration project of pre-exposure prophylaxis among HIV serodiscordant couples in Kenya and Uganda: a prospective analysis of prevention-effective adherence.

Haberer JE, Kidoguchi L, Heffron R, Mugo N, Bukusi E, Katabira E, Asiimwe S, Thomas KK, Celum C, Baeten JM. J Int AIDS Soc. 2017 Jul 25;20(1):1-9. doi: 10.7448/IAS.20.1.21842.

Introduction: Adherence is essential for pre-exposure prophylaxis (PrEP) to protect against HIV acquisition, but PrEP use need not be life-long. PrEP is most efficient when its use is aligned with periods of risk - a concept termed prevention-effective adherence. The objective of this paper is to describe prevention-effective adherence and predictors of adherence within an open-label delivery project of integrated PrEP and antiretroviral therapy (ART) among HIV serodiscordant couples in Kenya and Uganda (the Partners Demonstration Project).

Methods: We offered PrEP to HIV-uninfected participants until the partner living with HIV had taken ART for ≥6 months (a strategy known as "PrEP as a bridge to ART"). The level of adherence sufficient to protect against HIV was estimated in two ways: ≥4 and ≥6 doses/week (per electronic monitoring). Risk for HIV acquisition was considered high if the couple reported sex with <100% condom use before six months of ART, low if they reported sex but had 100% condom use and/or six months of ART and very low if no sex was reported. We assessed prevention-effective adherence by cross-tabulating PrEP use with HIV risk and used multivariable regression models to assess predictors of ≥4 and ≥6 doses/week.

Results: A total of 985 HIV-uninfected participants initiated PrEP; 67% were male, median age was twenty-nine years, and 67% reported condomless sex in the month before enrolment. An average of ≥4 doses and ≥6 doses/week were taken in 81% and 67% of participant-visits, respectively. Adherence sufficient to protect against HIV acquisition was achieved in 75-88% of participant-visits with high HIV risk. The strongest predictor of achieving sufficient adherence was reporting sex with the study partner who was living with HIV; other statistically significant predictors included no concerns about daily PrEP, pregnancy or pregnancy intention, females aged >25 years, older male partners and desire for relationship success. Predictors of not achieving sufficient adherence were no longer being a couple, delayed PrEP initiation, >6 months of follow-up, ART use >6 months by the partner living with HIV and problem alcohol use.

Conclusions: Over three-quarters of participant-visits by HIV-uninfected partners in serodiscordant couples achieved prevention-effective adherence with PrEP. Greater adherence was observed during months with HIV risk and the strongest predictor of achieving sufficient adherence was sexual activity.

Abstract [5]  Full-text [free] access  [6]

 

Accuracy and determinants of perceived HIV risk among young women in South Africa.

Maughan-Brown B, Venkataramani AS. BMC Public Health. 2017 Jul 21;18(1):42. doi: 10.1186/s12889-017-4593-0.

Background: HIV risk perceptions are a key determinant of HIV testing. The success of efforts to achieve an AIDS-free generation - including reaching the UNAIDS 90-90-90 target - thus depends critically on the content of these perceptions. We examined the accuracy of HIV-risk perceptions and their correlates among young black women in South Africa, a group with one of the highest HIV incidence rates worldwide.

Methods: We used individual-level longitudinal data from the Cape Area Panel Study (CAPS) from 2005 to 2009 on black African women (20-30 years old in 2009) to assess the association between perceived HIV-risk in 2005 and the probability of testing HIV-positive four years later. We then estimated multivariable logistic regressions using cross-sectional data from the 2009 CAPS wave to assess the relationship between risk perceptions and a wide range of demographic, sexual behaviour and psychosocial covariates of perceived HIV-risk.

Results: We found that the proportion testing HIV-positive in 2009 was almost identical across perceived risk categories in 2005 (no, small, moderate, great) (χ 2 = 1.43, p = 0.85). Consistent with epidemiologic risk factors, the likelihood of reporting moderate or great HIV-risk perceptions was associated with condom-use (aOR: 0.57; 95% CI: 0.36, 0.89; p < 0.01); having ≥3 lifetime partners (aOR: 2.38, 95% CI: 1.53, 3.73; p < 0.01); knowledge of one's partner's HIV status (aOR: 0.67; 95% CI: 0.43, 1.07; p = 0.09); and being in an age-disparate partnership (aOR: 1.73; 95% CI: 1.09, 2.76; p = 0.02). However, the likelihood of reporting moderate or great self-perceived risk did not vary with sexually transmitted disease history and respondent age, both strong predictors of HIV risk in the study setting. Risk perceptions were associated with stigmatising attitudes (aOR: 0.53; 95% CI: 0.26, 1.09; p = 0.09); prior HIV testing (aOR: 0.21; 95% CI: 0.13, 0.35; p < 0.01); and having heard that male circumcision is protective (aOR: 0.38; 95% CI: 0.22, 0.64; p < 0.01).

Conclusions: Results indicate that HIV-risk perceptions are inaccurate. Our findings suggest that this inaccuracy stems from HIV-risk perceptions being driven by an incomplete understanding of epidemiological risk and being influenced by a range of psycho-social factors not directly related to sexual behaviour. Consequently, new interventions are needed to align perceived and actual HIV risk.

Abstract [7]  Full-text [free] access  [8]

 

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows.

Sok D, Le KM, Vadnais M, Saye-Francisco KL, Jardine JG, Torres JL, Berndsen ZT, Kong L, Stanfield R, Ruiz J, Ramos A, Liang CH, Chen PL, Criscitiello MF, Mwangi W, Wilson IA, Ward AB, Smider VV, Burton DR. Nature. 2017 Aug 3;548(7665):108-111. doi: 10.1038/nature23301. Epub 2017 Jul 20.

No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP, have improved the elicitation of potent isolate-specific antibody responses in rabbits and macaques, but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg ml-1. Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

Abstract access [9] 

 

Penile anaerobic dysbiosis as a risk factor for HIV infection.

Liu CM, Prodger JL, Tobian AAR, Abraham AG, Kigozi G, Hungate BA, Aziz M, Nalugoda F, Sariya S, Serwadda D, Kaul R, Gray RH, Price LB. MBio. 2017 Jul 25;8(4). pii: e00996-17. doi: 10.1128/mBio.00996-17.

Sexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, specifically CD4+ T cells or dendritic cells. The foreskin is a major site of viral entry in heterosexual transmission of HIV. Although the probability of acquiring HIV from a sexual encounter is low, the risk varies even after adjusting for known HIV risk factors. The genital microbiome may account for some of the variability in risk by interacting with the host immune system to trigger inflammatory responses that mediate the infection of mucosal immune cells. We conducted a case-control study of uncircumcised participants nested within a randomized-controlled trial of male circumcision in Rakai, Uganda. Using penile (coronal sulcus) swabs collected by study personnel at trial enrollment, we characterized the penile microbiome by sequencing and real-time PCR and cytokine levels by electrochemiluminescence assays. The absolute abundances of penile anaerobes at enrollment were associated with later risk of HIV seroconversion, with a 10-fold increase in Prevotella, Dialister, Finegoldia, and Peptoniphilus increasing the odds of HIV acquisition by 54 to 63%, after controlling for other known HIV risk factors. Increased abundances of anaerobic bacteria were also correlated with increased cytokines, including interleukin-8, which can trigger an inflammatory response that recruits susceptible immune cells, suggesting a mechanism underlying the increased risk. These same anaerobic genera can be shared between heterosexual partners and are associated with increased HIV acquisition in women, pointing to anaerobic dysbiosis in the genital microbiome and an accompanying inflammatory response as a novel, independent, and transmissible risk factor for HIV infection.

Importance: We found that uncircumcised men who became infected by HIV during a 2-year clinical trial had higher levels of penile anaerobes than uncircumcised men who remained HIV negative. We also found that having higher levels of penile anaerobes was also associated with higher production of immune factors that recruit HIV target cells to the foreskin, suggesting that anaerobes may modify HIV risk by triggering inflammation. These anaerobes are known to be shared by heterosexual partners and are associated with HIV risk in women. Therefore, penile anaerobes may be a sexually transmissible risk factor for HIV, and modifying the penile microbiome could potentially reduce HIV acquisition in both men and women.

Abstract [10]  Full-text [free] access  [11]

 

 [SC1] [12]Unsure if this matters as they mean the same – but the guidelines literally refer to “substantial risk” which is what you also use in line 8 of the para that follows

Africa [22]
Kenya [23], South Africa [24], Uganda [25]
  • [26]