Articles tagged as "Basic science"

Next generation PrEP—multipurpose technologies in macaques

Editor’s notes: Adherence is an issue not only for oral PrEP but also for topical PrEP.  Two large studies of an intra-vaginal ring releasing dapivirine both showed some overall efficacy in the primary analysis, but suggested that very high adherence would be needed to achieve reliable protection from HIV.  One reason for poor adherence, particularly among the youngest women in the studies, may be that young women do not seriously consider the chance that they might acquire HIV infection from a romantic partner.  Adherence to modern family planning methods has been improved through the use of long-acting reversible products including injections, implants, rings and intra-uterine devices. This has led to enthusiasm for multipurpose technologies that might offer women not only protection against unwanted pregnancies, but also protection from HIV or from other sexually transmitted such as herpes simplex virus.  Smith and colleagues present some data from early studies of one such device.  They made silicone rings with pods that could deliver hormonal contraception as well as tenofovir alafenamide (against HIV) and acyclovir (against HSV).  These rings were shown in macaques to release their different components satisfactorily into the vaginal tissues and systemic circulation at levels that would be predicted to be highly effective.  Modern contraceptives are highly effective and hugely important as a means for women to regulate their own fertility.  As has been seen with the dapivirine ring studies, adherence to intravaginal products is likely not be as high as can be achieved with injections or implants.  So the balance between contraceptive efficacy and the potential benefits of additional prevention tools for HIV and other sexually transmitted infections will need to be weighed carefully.  On the other hand, the increasing worry that DMPA may actually increase the risk of HIV acquisition (as discussed in previous issues) makes research to broaden the choices for women’s reproductive and sexual health even more important.

Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model.

Smith JM, Moss JA, Srinivasan P, Butkyavichene I, Gunawardana M, Fanter R, Miller CS, Sanchez D, Yang F, Ellis S, Zhang J, Marzinke MA, Hendrix CW, Kapoor A, Baum MM. PLoS One. 2017 Oct 5;12(10):e0185946. doi: 10.1371/journal.pone.0185946. eCollection 2017.

Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

Abstract  Full-text [free] access

Basic science
Northern America
United States of America
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Beyond PrEP—immune technologies for prevention

Editor’s notes: Last month, we discussed developments in antibody technology.  This month there is a useful perspective paper in Science from Cohen and Corey that lays out the rationale and history of the development of broadly neutralising antibodies for the prevention of HIV.  Animal studies show that lower doses of antibody are needed to prevent HIV infection than to control it after the infection has occurred.  However, many animal studies are conducted with a narrow range of viruses in the infecting inoculum. Humans are generally exposed to a whole swarm of viruses, meaning that greater breadth of coverage may be needed to protect from infection.  Nonetheless, the rapid advances in synthesis of molecules that have additional active sites, such as the bioengineered triphasic antibody, combined with the ongoing proof of concept studies such as antibody-mediated prevention (AMP) mean that we can hope that biomedical prevention beyond PrEP is only just over the horizon.

Broadly neutralizing antibodies to prevent HIV-1.

Cohen MS, Corey L. Science. 2017 Oct 6;358(6359):46-47. doi: 10.1126/science.aap8131.

Advances in technology—especially single-cell antibody cloning techniques—have led to the isolation and characterization of antibodies from people with HIV infection that can neutralize many variants. These are referred to as broadly neutralizing antibodies (bnAbs). Such antibodies can be detected in about 25% of persons with untreated HIV-1 infection, reflecting a host immune response to unremitting viral replication, generation of large numbers of viral variants, and shifting antigen exposure. Although bnAbs may exert some selective pressure as they develop, they generally do not reduce viral burden, improve health, or slow the progression of disease. However, they offer considerable opportunities for treatment and prevention of HIV-1 infection in others. At this time, hundreds of bnAbs have been identified; those that have attracted the most attention are bnAbs with the greatest breadth, neutralizing the largest number of HIV-1 strains, including those traditionally most neutralization resistant; or bnAbs that have the greatest potency, requiring the smallest concentration to neutralize resistant strains of HIV-1.

Abstract access 

Northern America
United States of America
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Exciting biomedical advances – keep your eyes on the longer-term opportunities for HIV prevention and treatment

Editor’s notes: An important advance on the road to effective immune therapies may have been published in the journal Science. We have now entered the era of antibodies for the prevention, and possibly the treatment of HIV.  The AMP study is the first large scale study of antibodies being used to try to prevent HIV infection.  However, most researchers agree that just like antiretroviral therapy, a cocktail of different antibodies is likely to be needed to prevent HIV escaping from immune control, just as it does from individual medicines.  Xu and colleagues at Sanofi have managed to engineer a molecule that is an antibody except that instead of having a single specific target antigen, had three different targets.  In other words, it might function as a cocktail despite being a single agent.  This is important because it might speed up the critical pathway for research.  With multiple antibodies, the regulators naturally want to be certain that each of them is safe and effective before approving trials that combine them.  This can take many years, despite the researchers predicting that the single antibody studies are proofs of concept on the longer pathway to a combination that might make a real difference to treatment or prevention programmes. In studies in macaques, the novel tri-specific antibody molecule provided complete immunity to infection with a range of simian-human immunodeficiency viruses (SHIVs), whereas single antibodies only protected against some of the SHIVs.  This approach to immunotherapy is also an example of HIV science leading to discoveries that might have a much wider field of application in other diseases such as cancer and autoimmune disease.

In addition to making the best antibodies (or T-cell responses), a vaccine also must deliver the antigen or DNA in such a way that the antibodies are made effectively and in high concentrations by the host’s cells.  This is done by means of the vaccine vector.  Previous HIV vaccine candidates have had to be withdrawn from the research pipeline because their vectors appear to have caused harm, possibly by stimulating the immune system in such a way that HIV replication was actually enhanced.  So, the study by Capucci and colleagues is a useful example to show how different vectors work in animal models.  In this study, two vectors that are usually utilized to stimulate T-cell responses were used.  A non-replicating chimpanzee adenovirus or a non-replicating modified vaccinia virus Ankara both produced good antibody responses using an HIV glycoprotein trimer that is known to produce neutralizing antibodies.  The implication might be that these vectors could carry antigens that could provoke useful antibody responses in addition to useful T-cell responses, thus mimicking the most likely way that HIV is controlled in the human host.

Many studies of new biomedical approaches to HIV prevention are tested first in animal models.  Many of us know little of the details of these models.  In order to compare different prevention technologies, it is important that the same or comparable models are used.  Many studies now use simian-human immunodeficiency virus (SHIV).  This is a virus that is genetically modified so that it expresses many aspects of HIV, but still has enough of the SIV components to infect monkeys.  SHIV is often inserted into the vagina of rhesus macaques that have been treated with a new prevention technology or a control to determine whether the technology prevents the establishment of infection.  In the past most macaques used for this research were from India.  However, there is now a shortage of such laboratory monkeys, so Veazey and Ling have done a simple comparison of Indian macaques with Chinese macaques.  With this particular common laboratory strain of SHIV, the authors found no important differences between the two sub-species.

Delving further into the comparative immunology of macaques and humans, Fu and colleagues have performed a comprehensive profiling of lymphocyte receptors from a Chinese macaque.  These sorts of studies allow vaccine scientists to understand how immune responses in macaques can generate antibody and T-cell responses.  They are a building block for future development of vaccines and immune based therapies.  And they remind us how advanced the technology is becoming for ever more detailed understanding of the interactions between primates’ immune systems and the environment to which these systems are exposed.

 

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Xu L, Pegu A, Rao E, Doria-Rose N, Beninga J, McKee K, Lord DM, Wei RR, Deng G, Louder M, Schmidt SD, Mankoff Z, Wu L, Asokan M, Beil C, Lange C, Leuschner WD, Kruip J, Sendak R, Do Kwon Y, Zhou T, Chen X, Bailer RT, Wang K, Choe M, Tartaglia LJ, Barouch DH, O'Dell S, Todd JP, Burton DR, Roederer M, Connors M, Koup RA, Kwong PD, Yang ZY, Mascola JR, Nabel GJ. Science. 2017 Oct 6;358(6359):85-90. doi: 10.1126/science.aan8630. Epub 2017 Sep 20.

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

Abstract  Full-text [free] access

HIV-1-neutralizing antibody induced by simian adenovirus- and poxvirus MVA-vectored BG505 native-like envelope trimers

Capucci S, Wee EG, Schiffner T, LaBranche CC, Borthwick N, Cupo A, Dodd J, Dean H, Sattentau Q, Montefiori D, Klasse PJ, Sanders RW, Moore JP, Hanke T. PLoS One. 2017 Aug 9;12(8):e0181886. doi: 10.1371/journal.pone.0181886. eCollection 2017.

Rabbits and monkeys immunized with HIV type 1 (HIV-1) native-like BG505 SOSIP.664 (BG505s) glycoprotein trimers are known to induce antibodies that can neutralize the autologous tier-2 virus. Here, we assessed the induction of HIV-1 trimer binding and neutralizing antibody (nAb) titres when BG505s trimers were also delivered by non-replicating simian (chimpanzee) adenovirus and non-replicating poxvirus modified vaccinia virus Ankara (MVA) vaccine vectors. First, we showed that approximately two-thirds and one-third of the trimers secreted from the ChAdOx1.BG505s (C) and MVA.BG505s (M) vaccine-infected cells, respectively, were cleaved and in a native-like conformation. Rabbits were immunized intramuscularly with these vaccine vectors and in some cases boosted with ISCOMATRIX™-adjuvanted BG505s protein trimer (P), using CCC, MMM, PPP, CPP, MPP and CMP vaccine regimens. We found that the peak trimer-binding antibody and tier-1A and autologous tier-2 nAb responses induced by the CC, CM, PPP, CPP, MPP and CMP regimens were comparable, although only PPP induced autologous tier-2 nAbs in all the immunized animals. Three animals developed weak heterologous tier-2 nAbs. These results demonstrate that ChAdOx1 and MVA vectors are useful delivery modalities for not only T-cell, but also antibody vaccine development.

Abstract  Full-text [free] access

Comparative susceptibility of rhesus macaques of Indian and Chinese origin to vaginal SHIV transmission as models for HIV prevention research

Veazey R, Ling B. AIDS Res Hum Retroviruses. 2017 Aug 10. doi: 10.1089/AID.2017.0173. [Epub ahead of print]

Historically, Indian origin rhesus macaques (iRM) have been preferred for SIV/HIV prevention, pathogenesis, and treatment studies, yet their supply is limited. Chinese origin rhesus macaques (cRM) are currently more available yet little is known regarding the relative susceptibility of this subspecies to vaginal transmission of SIV or SHIV. Here we compared the susceptibility of 40 cRM and 21 iRM to a single vaginal challenge with SHIVsf162P. Our results showed cRM have comparable primary SHIV infection as iRM, underscoring their equal importance in studies of HIV transmission and prevention.

Abstract access

A comprehensive profiling of T- and B-lymphocyte receptor repertoires from a Chinese-origin rhesus macaque by high-throughput sequencing

Fu L, Li X, Zhang W, Wang C, Wu J, Yang H, Wang J, Liu X. PLoS One. 2017 Aug 16;12(8): e0182733. doi: 10.1371/journal.pone.0182733. eCollection 2017.

Due to the close genetic background, high similarity of physiology, and susceptibility to infectious and metabolic diseases with humans, rhesus macaques have been widely used as an important animal model in biomedical research, especially in the study of vaccine development and human immune-related diseases. In recent years, high-throughput sequencing based immune repertoire sequencing (IR-SEQ) has become a powerful tool to study the dynamic adaptive immune responses. Several previous studies had analyzed the responses of B cells to HIV-1 trimer vaccine or T cell repertoire of rhesus macaques using this technique, however, there are little studies that had performed a comprehensive analysis of immune repertoire of rhesus macaques, including T and B lymphocytes. Here, we did a comprehensive analysis of the T and B cells receptor repertoires of a Chinese rhesus macaque based on the 5'-RACE and IR-SEQ. The detailed analysis includes the distribution of CDR3 length, the composition of amino acids and nucleotides of CDR3, V, J and V-J combination usage, the insertion and deletion length distribution and somatic hypermutation rates of the framework region 3 (FR3). In addition, we found that several positions of FR3 region have high mutation frequencies, which may indicate the existence of new genes/alleles that have not been discovered and/or collected into IMGT reference database. We believe that a comprehensive profiling of immune repertoire of rhesus macaque will facilitate the human immune-related diseases studies.

Abstract  Full-text [free] access

Basic science
Asia, Northern America
China, United States of America
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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 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 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, Dr Fauci 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  Full-text [free] access 

 

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  Full-text [free] access 

 

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  

 

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  Full-text [free] access 

 

 [SC1]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
Kenya, South Africa, Uganda
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How are we going to get to our prevention targets? Old tools, new tools and a more nuanced understanding of transmission dynamics.

Editor’s notes: By 2020, the Fast-Track strategy is aiming to reduce new HIV infections to 200 000 per year.  There is increasing recognition that if we are to succeed, we will need to do much more than simply putting people onto HIV treatment.  Despite the massive impact of ART on infectiousness, the decline in new infections at the community level is still not fast enough, even in countries like Botswana (see above) where 90-90-90 has almost been reached.  Renewed enthusiasm for primary prevention has also followed key trials of biomedical prevention tools including voluntary medical male circumcision and ARV-based prevention.  It is all too easy for us to forget the crucial role that condoms have played from the early days of the epidemic.  More recently, with HIV seen as a less terrifying infection, many programmes suffer from “condom fatigue”.  So it is good to see papers on the key importance of condoms as well as perspectives on how they are perceived by young men.

The magic of ARVs does not end with treatment.  We are finally moving to wider use of pre-exposure prophylaxis (PrEP).  There is no doubt that PrEP works when taken, but there are still plenty of questions for policy-makers about how to adopt it whole-heartedly into their national strategic plans and for financiers about how to pay for it.  Papers this month cover a range of experiences with PrEP from the US, where the huge majority of PrEP users still live, to Europe and Australia, where policies are finally moving towards wider use.  Long acting PrEP remains a key objective for many, as it might improve regular adherence, which has proved the Achilles’ heel of oral and topical PrEP in several of the large studies.

One of the ways to make PrEP most cost-effective is to ensure that it is available to people who are most likely to acquire HIV.  So the hope continues that phylogenetic analyses will allow more sophisticated understanding of the dynamics of the multiple overlapping networks of HIV transmission in communities.  Papers this month cover Australia and the PANGEA consortium of African research sites along with a cautionary comment about establishing the ethical framework for such studies, particularly among populations who are already subject to discrimination and criminalization.

When used correctly and consistently, condoms are highly effective not only to prevent HIV but also to prevent pregnancy and to prevent sexually transmitted infections.  Stover and colleagues have tried to capture all three benefits in one model.  They explore three potential scenarios for condom programming between now and 2030 in 81 countries that are priorities for family planning or HIV programmers or both.  The benefits of greater investment in condoms are huge.  In their most optimistic scenario, the authors suggest that if the entire gap between people who would like to use condoms and people who currently use them was filled (almost 11 billion condoms over the period), this could prevent up to 400 million unwanted pregnancies; 16.8 million new HIV infections and more than 700 million sexually transmitted infections.  The costs are quite modest, and at $115 per DALY averted this is an investment that everyone should support.  There are of course limitations in such a broad brush model, but it provides an excellent starting point.

The challenges in provision of condoms to young people go well beyond the cost and effectiveness considerations that underpin the previous analysis.  In an interesting qualitative study in South Africa, de Bruin and Panday-Soobrayan report their findings from focus group discussions with learners in 33 public schools.  Most of the learners were not in favour of provision of condoms at school, although they were keen on more youth friendly sexual and reproductive health and rights services within the public sector.  Many thought that provision of condoms would lead to earlier and more frequent sexual contacts, despite considerable experience showing that this is not the case in other settings.

Multiple trials have shown that PrEP is extremely effective when it is used consistently and correctly.  Many countries in all continents are now beginning to work out where it fits within their combination prevention package.  To date, the large majority of PrEP users are in the United States of America (USA), where more than 140 000 people have started.  It is much harder to measure how many are still taking it regularly.  Patel and colleagues analysed utilization at three months after the initial prescription of PrEP in three major PrEP clinics in three states in the USA.  18% of the 201 people (90% male) seen at baseline did not use their PrEP and this was strongly predicted by insurance status, with around a four-fold risk of dropping out among those who were not insured.  Although the numbers are small, this is an important study.  The authors suggest that increased insurance cover might make PrEP have a greater impact.  More broadly it raises the challenge that PrEP is often needed most by people least able to access it.  This will be a real challenge in countries where people most at risk, such as gay men and other men who have sex with men and sex workers, are criminalized or discriminated against in many health care settings.

In Australia, PrEP has been provided through large demonstration projects while awaiting decisions about how to include it in routine practice.  Lal and colleagues report results from 114 (one transgender woman, the rest male) people taking PrEP in the Victorian PrEP Demonstration project.  Participants have to pay an equivalent of an insurance co-payment, in order to make the situation more like the “real world”.  The participants were recruited because they were at high risk of HIV engaging in condomless anal sex with partners who were known to be living with HIV or of unknown status.  Adherence to PrEP was excellent as measured by a variety of reported and biological measures.  They observed one seroconversion in a man with exposure two weeks before starting PrEP who was already in the process of seroconverting and whose virus was found to be resistant to emtricitabine.  The only other seroconversion occurred in someone who had not yet started PrEP.  The authors found a substantial increase in rates of gonorrhoea and chlamydia once participants were “stable” on PrEP after three months.  There was also a significant reduction in condom use with both regular and casual partners.  This is one of the first studies to document important risk compensation among PrEP users.  Of course, preventing HIV is a huge benefit that generally outweighs the harms of additional treatment for sexually transmitted infections.  However, the study emphasizes the importance of enhancing sexual health services alongside PrEP and reminds us that people most at risk of HIV are also at high risk of other infections (and also of pregnancy in the context of heterosexual transmission.)  If PrEP is integrated within a broad sexual health service, there could be considerable synergistic benefits.

Gay men and men who have sex with men who enrolled in the PrEP demonstration project in Amsterdam also had high concomitant rates of hepatitis C virus (HCV).  Hoorenborg and colleagues found that around 5% of the 375 men enrolled in the project were co-infected.  The HCV found among these men were genetically similar to those circulating in the population of gay men and other men who have sex with men living with HIV, and more distinct from HCV from other risk groups.  This is good evidence that HCV and HIV both circulate in this population, and emphasizes once again the need for more integrated services, including hepatitis screening.

The ÉCLAIR study is a phase 2a trial of cabotegravir injections in healthy HIV-negative male volunteers.  As noted, adherence is a major challenge in many PrEP trials; although notably less of a problem when people choose to take PrEP in demonstration projects.  It is hoped that cabotegravir could be the first long acting PrEP.  Markowitz and colleagues presented the results of this study at CROI 2017.  The authors point out that although the injections are painful, many men stated that they would be happy to continue if the injections were effective.  No serious safety challenges emerged. The pharmacokinetics suggests that a dose given more frequently will be needed – and subsequent trials will use a two monthly regimen. 

One group for whom PrEP has been recommended by WHO for some years are serodiscordant couples (SDCs).  The Partners PrEP study, which forms one of the cornerstones for the evidence that PrEP works for both men and women, was conducted in SDCs.  The idea is to protect the HIV-negative partner from infection until such time as the partner living with HIV has been on ART consistently and suppressed their viral load.  So a study from the Centers for Disease Control USA is relevant to discussions of PrEP.  Crepaz and colleagues found that around 6000 new HIV infections occur each year in the USA among men and women having heterosexual sex and are aware that their partner is living with HIV.  They point out that viral suppression is achieved by only around 50% of heterosexuals living with HIV and that an additional proportion does not know their HIV status.  So the importance of HIV testing, and of focusing efforts on serodiscordant couples is clear.  Such efforts include both improving HIV treatment effectiveness, and providing a range of prevention choices including PrEP until viral suppression is achieved.

While the study above used traditional epidemiological surveillance reports, phylogenetics may provide additional insights into the dynamics of transmission.  In Australia, where notifications with HIV are rising steadily,  Castley and colleagues have examined the sequence data from almost 5000 viruses collected across the country from 2005-2012.  This sample is drawn from around 1200 new HIV infections per year (and around 27 000 people living with HIV).  The sample is not random, but reflects samples that were sent for sequencing to determine drug resistance.  Around one quarter of sequences are found in tight clusters (pairs, triplets or more) with other sequences, making it likely that they are closely connected by transmission.  Of course, all HIV sequences have been transmitted, so a longer time period and complete sampling would be expected to give a much higher proportion in clusters.  Indeed the more recent samples are around twice as likely to be in clusters as those collected at the start of the time period. Nonetheless, the large sample and the time period of collection allows some clear observations to be made.  In all states, the proportion of non-B subtypes is increasing, which must relate to travel and migration to and from Asia and Africa.  There is little evidence that the C subtypes (originally from Africa) are found in all male clusters suggesting little spill over into the community of gay men and other men having sex with men.  Larger clusters are more common among younger, all male networks. Like most molecular epidemiological studies, there are a small number of large clusters which represent highly active transmission.  These clusters are also most likely to be all male.  Taken together, the results suggest that the steady rise in notifications in Australia is probably due to increasing migration and travel and to ongoing active transmission networks among young gay men.  The challenge is to turn this sort of analysis into clear policy recommendations that can improve HIV prevention.

UNAIDS joined an interesting meeting on the ethics of phylogenetic studies in Africa organised by the PANGEA consortium.  Many of the issues discussed are also covered in a comment by Cohen on the importance of thinking through the risks inherent in these studies.  A key issue is to ensure that systems are reinforced to monitor any unexpected harms and to establish mitigation strategies to minimize them.  The challenges are not necessarily different to traditional epidemiological studies which may highlight networks and locations of groups that are criminalized or discriminated against.  In community consultations, prior to agreeing to go forward with phylogenetic studies, some potential participants even say that they would be keen to “know who infected them” in order to punish them.  This is clearly NOT the aim of such studies and emphasizes the importance of clear information about the limitations of the techniques which cannot usually rule out the possibility of additional links in the transmission chain.  Issues of anonymised information and what to do if clinically relevant results such as drug resistance mutations are uncovered as incidental findings also need to be discussed.

Furthermore, Ratmann and colleagues, reporting on the first 4000 sequences from the PANGEA consortium (largely from the Rakai project in Uganda), also emphasize some of the technical challenges that may lead to erroneous results in creating phylogenies.  There is little doubt that as the cost of sequencing falls and as the technologies and software become increasingly straightforward, we will see more and more studies of sequence data.  It is likely that analysis of these data will lead to more nuanced approaches to HIV prevention, particularly as the overall incidence falls, and sharper tools are needed to dissect the pathways of ongoing transmission.

The case for investing in the male condom

Stover J, Rosen JE, Carvalho MN, Korenromp EL, Friedman HS, Cogan M, Deperthes B. PLoS One. 2017 May 16;12(5):e0177108. doi: 10.1371/journal.pone.0177108. eCollection 2017.

When used correctly and consistently, the male condom offers triple protection from unintended pregnancy and the transmission of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). However, with health funding levels stagnant or falling, it is important to understand the cost and health impact associated with prevention technologies. This study is one of the first to attempt to quantify the cost and combined health impact of condom use, as a means to prevent unwanted pregnancy and to prevent transmission of STIs including HIV. This paper describes the analysis to make the case for investment in the male condom, including the cost, impact and cost-effectiveness by three scenarios (low in which 2015 condom use levels are maintained; medium in which condom use trends are used to predict condom use from 2016-2030; and high in which condom use is scaled up, as part of a package of contraceptives, to meet all unmet need for family planning by 2030 and to 90% for HIV and STI prevention by 2016) for 81 countries from 2015-2030. An annual gap between current and desired use of 10.9 billion condoms was identified (4.6 billion for family planning and 6.3 billion for HIV and STIs). Under a high scenario that completely reduces that gap between current and desired use of 10.9 billion condoms, we found that by 2030 countries could avert 240 million DALYs. The additional cost in the 81 countries through 2030 under the medium scenario is $1.9 billion, and $27.5 billion under the high scenario. Through 2030, the cost-effectiveness ratios are $304 per DALY averted for the medium and $115 per DALY averted for the high scenario. Under the three scenarios described above, our analysis demonstrates the cost-effectiveness of the male condom in preventing unintended pregnancy and HIV and STI new infections. Policy makers should increase budgets for condom programming to increase the health return on investment of scarce resources.

Abstract  Full-text [free] access

Learners' perspectives on the provision of condoms in South African public schools.

de Bruin WE, Panday-Soobrayan S. AIDS care. 2017 May 16:1-4. doi: 10.1080/09540121.2017.1327647. [Epub ahead of print]

A stubborn health challenge for learners in South African public schools concerns sexual and reproductive health and rights (SRHR). In 2015, the Department of Basic Education (DBE) proposed the provision of condoms and SRHR-services to learners in schools. This study aimed to contribute to the finalisation and implementation of DBE's policy by exploring learners' perspectives on the provision of condoms and SRHR-services in schools. Sixteen focus group discussions were conducted with learners (n = 116) from 33 public schools, to assess their attitudes, social influences, and needs and desires regarding condom provision and SRHR-services in schools. The majority of learners did not support condom provision in schools as they feared that it may increase sexual activity. Contrarily, they supported the provision of other SRHR-services as clinics fail to offer youth-friendly services. Learners' sexual behaviour and access to SRHR-services are strongly determined by their social environment, including traditional norms and values, and social-pressure from peers and adults. Learners' most pressing needs and desires to access condoms and SRHR-services in school concerned respect, privacy and confidentiality of such service provision. Implementation of DBE's policy must be preceded by an evidence-informed advocacy campaign to debunk myths about the risk of increased sexual activity, to advocate for why such services are needed, to shift societal norms towards open discussion of adolescent SRHR and to grapple with the juxtaposition of being legally empowered but socially inhibited to protect oneself from HIV, STIs and early pregnancy. Provision of condoms and other SRHR-services in schools must be sensitive to learners' privacy and confidentiality to minimise stigma and discrimination.

Abstract  Full-text [free] access

Impact of insurance coverage on utilization of pre-exposure prophylaxis for HIV prevention

Patel RR, Mena L, Nunn A, McBride T, Harrison LC, Oldenburg CE, Liu J, Mayer KH, Chan PA.  PLoS One. 2017 May 30;12(5):e0178737 . doi: 10.1371/journal.pone.0178737. eCollection 2017.

Pre-exposure prophylaxis (PrEP) can reduce U.S. HIV incidence. We assessed insurance coverage and its association with PrEP utilization. We reviewed patient data at three PrEP clinics (Jackson, Mississippi; St. Louis, Missouri; Providence, Rhode Island) from 2014-2015. The outcome, PrEP utilization, was defined as patient PrEP use at three months. Multivariable logistic regression was performed to determine the association between insurance coverage and PrEP utilization. Of 201 patients (Jackson: 34%; St. Louis: 28%; Providence: 28%), 91% were male, 51% were White, median age was 29 years, and 21% were uninsured; 82% of patients reported taking PrEP at three months. Insurance coverage was significantly associated with PrEP utilization. After adjusting for Medicaid-expansion and individual socio-demographics, insured patients were four times as likely to use PrEP services compared to the uninsured (OR: 4.49, 95% CI: 1.68-12.01; p = 0.003). Disparities in insurance coverage are important considerations in implementation programs and may impede PrEP utilization.

Abstract  Full-text [free] access

Medication adherence, condom use and sexually transmitted infections in Australian PrEP users: interim results from the Victorian PrEP demonstration project

Lal L, Audsley J, Murphy D, Fairley CK, Stoove M, Roth N, Moore R, Tee BK, Puratmaja N, Anderson PL, Leslie D, Grant RM, De Wit J, Wright E; VicPrEP Study Team. AIDS. 2017 May 1 doi: 10.1097/QAD.0000000000001519. [Epub ahead of print]

Objective: HIV Pre-exposure prophylaxis (PrEP) decreases risk of HIV acquisition however its efficacy is closely dependent on adherence. There is also concern that the preventive effect of PrEP may be offset by risk compensation, notably an increase in condomless anal sex.

Design: Multi-site, open-label demonstration study that recruited people at current or recent risk of HIV infection in Melbourne, Australia.

Methods: Participants were recruited from three general practice clinics and one sexual health clinic in Melbourne and consented to take daily tenofovir/emtricitabine for 30 months. Sexual practice data, HIV and sexually transmitted infection (STI) test results were collected at baseline and 3-monthly during follow up. PrEP adherence was evaluated by self-report at clinical visits, online surveys, refill-based assessments and dried blood spot (DBS) testing. We present a 12-month interim analysis.

Results: 114 people were recruited. We observed a significant decline in condom use which occurred concomitantly with a significant increase in STIs over the first 12 months of PrEP. Incidence (per 100PY) of any STI was 43.2 and 119.8 at m0-3 and M3-12, respectively (IRR 2.77 (1.52, 5.56)). Adherence to PrEP medication was high by all measures, including six month TDF-FTC levels in DBS.

Conclusions: We found significant reduction in condom use and an increase STIs over the first 12 months of follow-up. High medication adherence rates coupled with a decline in condom use and a rise in STIs, suggests that prevention, early detection and treatment of STIs is a chief research priority in the current era of HIV PrEP.

Abstract

Men who have sex with men starting pre-exposure prophylaxis (PrEP) are at risk of HCV infection: evidence from the Amsterdam PrEP study

Hoornenborg E, Achterbergh RC, Van Der Loeff MF, Davidovich U, Hogewoning A, de Vries HJ, Schinkel J, Prins M, Laar TJWV; Amsterdam PrEP Project team in the HIV Transmission Elimination AMsterdam Initiative, MOSAIC study group. AIDS. 2017 May 1. doi: 10.1097/QAD.0000000000001522. [Epub ahead of print].

Objectives and Design: Hepatitis C virus (HCV) has been recognised as an emerging sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). However, HIV-negative MSM at high risk for HIV might also be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start pre-exposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM.

Methods: At enrolment in the Amsterdam PrEP (AMPrEP) demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis.

Results: Of 375 HIV-negative MSM enrolled in AMPrEP, 18 (4.8%, 95%CI 2.9%-7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15/18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%) and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV.

Conclusion: HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs.

Abstract

Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial.

Markowitz M, Frank I, Grant RM, Mayer KH, Elion R, Goldstein D, Fisher C, Sobieszczyk ME, Gallant JE, Van Tieu H, Weinberg W, . Margolis DA, Hudson KJ, Stancil BS, Ford SL, Patel P, Gould E, Rinehart AR, Smith KY, Spreen WR. Lancet HIV. 2017 May 22. pii: S2352-3018(17)30068-1. doi: 10.1016/S2352-3018(17)30068-1. [Epub ahead of print]

Background: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.

Methods: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.

Findings: Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237-0·385), 0·331 μg/mL (0·253-0·435), and 0·387 μg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.

Interpretation: Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.

Abstract

Examination of HIV infection through heterosexual contact with partners who are known to be HIV infected in the United States, 2010-2015

Crepaz N, Dong B, Chen M, Hall I. AIDS. 2017 Jul 17;31(11):1641-1644. doi: 10.1097/QAD.0000000000001526.

Using data from the National HIV Surveillance System, we examined HIV infections diagnosed between 2010 and 2015 attributed to heterosexual contact with partners previously known to be HIV infected. More than four in 10 HIV infections among heterosexual males and five in 10 HIV infections among heterosexual women were attributed to this group. Findings may inform the prioritization of prevention and care efforts and resource allocation modeling for reducing new HIV infection among discordant partnerships.

Abstract

A national study of the molecular epidemiology of HIV-1 in Australia 2005–2012

Castley A, Sawleshwarkar S, Varma R, Herring B, Thapa K, Dwyer D, Chibo D, Nguyen N, Hawke K, Ratcliff R, Garsia R, Kelleher A, Nolan D; Australian Molecular Epidemiology Network-HIV (AMEN-HIV).. PLoS One. 2017 May 10;12(5):e0170601. doi: 10.1371/journal.pone.0170601. eCollection 2017.

Introduction: Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia.

Methods: The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4873 patients who had genotypes performed during 2005-2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster).

Results: HIV-1 subtype B represented 74.5% of the 4873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008).

Conclusion: This nationwide HIV-1 study of 4873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia

Abstract  Full-text [free] access

HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences.

Ratmann O, Wymant C, Colijn C, Danaviah S, Essex M, Frost SD, Gall A, Gaiseitsiwe S, Grabowski M, Gray R, Guindon S, von Haeseler A, Kaleebu P, Kendall M, Kozlov A, Manasa J, Minh BQ, Moyo S, Novitsky V, Nsubuga R, Pillay S, Quinn TC, Serwadda D, Ssemwanga D, Stamatakis A, Trifinopoulos J, Wawer M, Leigh Brown A, de Oliveira T, Kellam P, Pillay D, Fraser C.. AIDS Res Hum Retroviruses. 2017 May 25. doi: 10.1089/AID.2017.0061. [Epub ahead of print].

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

Abstract  Full-text [free] access

 

Africa, Asia, Europe, Northern America, Oceania
Afghanistan, Angola, Australia, Azerbaijan, Bangladesh, Benin, Bolivia, Botswana, Brazil, Burkina Faso, Burundi, Cambodia, Cameroon, Central African Republic, Chad, China, Comoros, Congo, Côte d'Ivoire, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guatemala, Guinea, Guinea-Bissau, Haiti, India, Indonesia, Iran (Islamic Republic of), Iraq, Jamaica, Kenya, Kyrgyzstan, Lao People's Democratic Republic, Lesotho, Liberia, Madagascar, Malawi, Mauritania, Mexico, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, Niger, Nigeria, Pakistan, Papua New Guinea, Peru, Philippines, Russian Federation, Rwanda, Sao Tome and Principe, Senegal, Sierra Leone, Solomon Islands, Somalia, South Africa, South Sudan, Sudan, Swaziland, Tajikistan, Togo, Turkmenistan, Uganda, Ukraine, United Republic of Tanzania, United States of America, Uzbekistan, Viet Nam, Yemen, Zambia, Zimbabwe
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How do we know which activities make a difference to HIV prevention?

Editor’s notes: In order to be fairly certain that an intervention is responsible for changes in HIV or HIV-related behaviours, the gold standard is randomization. This allows for fair comparisons between groups, since factors that might alter the outcomes will be more or less equally balanced between the study groups.  This is true whether such confounding factors are expected, but also importantly, even those factors that are unknown, unexpected and unmeasured will also be balanced between the arms. 

A second key determinant of high quality research is to use an approach that maximizes full engagement and follow-up of participants in the study.  One such approach that is widely recognized is to use Good Participatory Practice.  

Rhodes and colleagues study condom promotion and HIV testing among the Hispanic/Latino community of gay men and other men who have sex with men in North Carolina, USA.  Although gay men and other men who have sex with men represent approximately 4% of the adult male population in the United States of America, they account for more than 80% of new HIV infections among men.  Around one quarter of gay men and other men who have sex with men are Hispanic or Latino.  The authors therefore wanted to use research to make a difference to the HIV burden of the Hispanic/Latino gay men and other men who have sex with men community in North Carolina, USA.  They found that despite the impact of HIV on Hispanic/ Latino gay men and other men who have sex with men, they were only able to identify one evidence-based behavioural HIV prevention programme focussed on this population.

The authors used an extensive community based participatory research partnership, whose members represented the Hispanic/ Latino gay men and other men who have sex with men community, AIDS service organizations, Hispanic/Latino-serving community organizations, and universities to develop, implement, and evaluate a Spanish-language, small group intervention designed to increase condom use and HIV testing among Hispanic/Latino gay men and other men who have sex with men (HOLA en Grupos).

304 participants were randomly allocated to the HOLA en Grupos intervention, or to a general health education comparison intervention having the same number of sessions (4) and duration (16 hours in total) that focussed on prostate, lung, and colorectal cancers; diabetes; high cholesterol; cardiovascular disease; and alcohol misuse. These topics for the control group were identified on the basis of identified needs and priorities of Hispanic/Latino gay men and other men who have sex with men.

HOLA en Grupos is grounded on social cognitive theory, empowerment education, and traditional Hispanic/Latino cultural values and includes four interactive modules of four hours each delivered in groups.  Participants in both intervention and control arms received reimbursement for their time, certificates of completion and meals and a celebration at the completion of the course.  In other words this was an intensive intervention that might be hard to replicate in most settings, but it follows very high standards both for developing and conducting the research and also for determining the impact of the intervention.

The intervention was associated with a large effect on both condom usage (four-fold higher in the intervention arm than the control) and HIV test uptake (an astonishing 14-fold higher, reflecting the relatively low testing rate in the control group).

A major limitation in many HIV prevention studies, including this one, is that the outcome is based on reported behaviour.  The challenge is that the real outcome of interest, which is new HIV infections, is relatively rare in almost all communities so that studies have to be huge and expensive, and the large majority of participants in both intervention and control arms do not in fact acquire HIV.  This is in contrast to most studies of treatment, where there are clearly defined biological, standardized measures which many or all participants are likely to reach.  Nonetheless, there are many examples of studies that find changes in reported behaviour that are not associated with biological markers of such change (such as incidence of HIV or other sexually transmitted infections, or pregnancy). 

There are also many observational or ecological studies that report changes in new HIV infections but that cannot truly say why the number of infections fell and whether the interventions used in the study were responsible for the changes.  For example Nwokolo and colleagues report in a short research letter on the dramatic decline in new HIV diagnoses in the large London clinic where they work.  New infections in that clinic, and in fact in other large clinics in London, have dropped by a remarkable 40% from 2015 to 2016, as originally reported in the popular science press before any scientific publication or presentation. The authors of the research letter are suitably cautious about how to account for the impressive decline.  Various systems have been improved over the past few years in this clinic to make it easier to have an HIV test and start treatment immediately.  However, most of the clinic team (and many other commentators) assume that it is also due to the rapid rise in the use of PrEP.  Although it is still not available through the UK National Health Service, the clinic has been at the forefront of encouraging gay men and other men who have sex with men who might benefit from PrEP to purchase it from on-line pharmacies.  The clinic then provides the appropriate monitoring and follow up to ensure that their clients get the best possible PrEP service given the current constraints.  Whatever the cause, we should be celebrating the rapid fall in new HIV infections across London, which is home to a substantial proportion of the new HIV infections in the UK.

The challenges of demonstrating evidence of effectiveness for HIV prevention is also felt among black women in the USA.  Although they have the highest burden of HIV among women in the USA, the incidence rates are such that a traditional randomized trial design would need to be huge, and consequently hugely expensive.  Adimora and colleagues consider whether an alternative trial design might be to use data from high HIV incidence settings and then to develop proxies of protection, such as the concentration of a PrEP medicine to infer whether black women are protected.  An alternative that has been proposed for men who have sex with men would be to look for other markers of high risk, such as sexually transmitted infections, reported partners, age, and substance use and estimate the likely risk of HIV acquisition in the absence of PrEP from these parameters.  Then the observed incidence could be compared to this modelled counterfactual, much as was done in the open label extension of the Partners PrEP study in Kenyan and Ugandan sero-different couples.  However, translating risk factors for infection across populations, and even continents when there is such heterogeneity in risk of infection is not at all straightforward.  So there is still plenty to think about and no clear answers yet!

A useful addition to the tool box for designing studies and assessing the effectiveness of interventions, would be better tools for measuring recent infection.  There are several assays all with differing characteristics but increasingly these differences and how they interact with different clades of HIV are becoming clear.  Key determinants for each assay are the mean duration of recent infection (MDRI) estimate (which does seem to vary by clade) and the false recency rate (FRR) which needs to be less than 2% to be considered useful.  Hargrove and colleagues used three different assays to test samples from 101 women who seroconverted during the ZVITAMBO trial.  The MDRI measured using standard cut-off points, were considerably shorter than those published for the general population.  The authors point out that changes in antibody properties among women who have recently given birth or other unspecified physiological states, mean that incidence assays may give different results from those published and expected.  Yet more caution when comparing incidence estimates between studies.  As an endpoint in a comparison between two groups in the same population, the assays are still attractive. Although, given typical MDRIs of around six to nine months, these assays will still need to be embedded in very large samples to give reliable estimates of incidence and statistically significant differences between groups.

This month saw the production of a useful supplement on many aspects of how data from different sources, including incidence assays are used to inform the sophisticated models on which so much HIV planning, programming and financing is based.  An example is Mahiane and colleagues’ paper on the development of a new tool to fit existing programme data into the spectrum suite of models in order to estimate incidence.

Finally in this section, for those who are keen on laboratory studies, Richardson-Harman and colleagues describe the current state of ex-vivo challenge models for assessing potential candidates as microbicides.  In these models, biopsies of rectal, cervical or vaginal tissue, taken during other procedures, or from volunteers, are kept alive in the laboratory.  The tissues can then be challenged with HIV in the presence or absence of potential microbicide products.  The current model works best for rectal tissues, in which infection occurs promptly and consistently, so that the effect of a microbicide can clearly be seen by a reduction in the production of HIV p24 antigen.  However, for cervical and vaginal tissues, the infection (in the absence of any microbicide) was less consistent, slower and lasted longer making it less easy to determine statistical differences between those tissues with microbicide and those without.  Further work of this sort may help to streamline the choice of microbicide or PrEP products that can most sensibly be taken out of the laboratory and into the (almost) real world of clinical trials.

Small-group randomized controlled trial to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Rhodes SD, Alonzo J, Mann L, Song EY, Tanner AE, Arellano JE, Rodriguez-Celedon R, Garcia M, Freeman A, Reboussin BA, Painter TM. Am J Public Health. 2017 Jun;107(6):969-976. doi: 10.2105/AJPH.2017.303814. Epub 2017 Apr 20.

Objectives: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men.

Methods: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%.

Results: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001).

Conclusions: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

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Not just PrEP: other reasons for London's HIV decline.

Nwokolo N, Whitlock G, McOwan A. Lancet HIV. 2017 Apr;4(4):e153. doi: 10.1016/S2352-3018(17)30044-9.

The reduction in HIV diagnoses in London in 2016 is attributed to pre-exposure prophylaxis (PrEP). We believe that the causes of the 42% decline seen at our clinic are likely to be multifactorial. 56 Dean Street diagnoses one in four of London's HIV cases, 50% of whom have incident infection (ie, within 4 months of infection). Because of this, and following the results of the START study, we actively recommend treatment at, or close to, diagnosis, reducing the risk of transmission in people who would otherwise be highly infectious.

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US black women and HIV prevention: time for new approaches to clinical trials.

Adimora AA, Cole SR, Eron JJ Clin Infect Dis. 2017 Apr 5. doi: 10.1093/cid/cix313. [Epub ahead of print]. 

Black women bear the highest burden of HIV infection among US women. Tenofovir/ emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV pre-exposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high incidence settings - and then applying these observations to drug concentrations measured among at risk individuals in lower incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates.

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Heightened HIV antibody responses in postpartum women as exemplified by recent infection assays: implications for incidence estimates.

Hargrove JW, van Schalkwyk C, Humphrey JH, Mutasa K, Ntozini R, Owen SM, Masciotra S, Parekh BS, Duong YT, Dobbs T, Kilmarx PH, Gonese E. AIDS Res Hum Retroviruses. 2017 May 24. doi: 10.1089/AID.2016.0319. [Epub ahead of print].

Laboratory assays that identify recent HIV infections are important for assessing impacts of interventions aimed at reducing HIV incidence. Kinetics of HIV humoral responses can vary with inherent assay properties, and between HIV subtypes, populations, and physiological states. They are important in determining mean duration of recent infection (MDRI) for antibody-based assays for detecting recent HIV infections. We determined MDRIs for multi-subtype peptide representing subtypes B, E and D (BED)-capture enzyme immunoassay, limiting antigen (LAg), and Bio-Rad Avidity Incidence (BRAI) assays for 101 seroconverting postpartum women, recruited in Harare from 1997 to 2000 during the Zimbabwe Vitamin A for Mothers and Babies trial, comparing them against published MDRIs estimated from seroconverting cases in the general population. We also compared MDRIs for women who seroconverted either during the first 9 months, or at later stages, postpartum. At cutoffs (C) of 0.8 for BED, 1.5 for LAg, and 40% for BRAI, estimated MDRIs for postpartum mothers were 192, 104, and 144 days, 33%, 32%, and 52% lower than published estimates of 287, 152 and 298 days, respectively, for clade C samples from general populations. Point estimates of MDRI values were 7%-19% shorter for women who seroconverted in the first 9 months postpartum than for those seroconverting later. MDRI values for three HIV incidence biomarkers are longer in the general population than among postpartum women, particularly those who recently gave birth, consistent with heightened immunological activation soon after birth. Our results provide a caution that MDRI may vary significantly between subjects in different physiological states.

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Improvements in Spectrum's fit to program data tool.

Mahiane SG, Marsh K, Grantham K, Crichlow S, Caceres K, Stover J.  AIDS. 2017 Apr;31 Suppl 1:S23-S30. doi: 10.1097/QAD.0000000000001359.

Objective: The Joint United Nations Program on HIV/AIDS-supported Spectrum software package (Glastonbury, Connecticut, USA) is used by most countries worldwide to monitor the HIV epidemic. In Spectrum, HIV incidence trends among adults (aged 15-49 years) are derived by either fitting to seroprevalence surveillance and survey data or generating curves consistent with program and vital registration data, such as historical trends in the number of newly diagnosed infections or people living with HIV and AIDS related deaths. This article describes development and application of the fit to program data (FPD) tool in Joint United Nations Program on HIV/AIDS' 2016 estimates round.

Methods: In the FPD tool, HIV incidence trends are described as a simple or double logistic function. Function parameters are estimated from historical program data on newly reported HIV cases, people living with HIV or AIDS-related deaths. Inputs can be adjusted for proportions undiagnosed or misclassified deaths. Maximum likelihood estimation or minimum chi-squared distance methods are used to identify the best fitting curve. Asymptotic properties of the estimators from these fits are used to estimate uncertainty.

Results: The FPD tool was used to fit incidence for 62 countries in 2016. Maximum likelihood and minimum chi-squared distance methods gave similar results. A double logistic curve adequately described observed trends in all but four countries where a simple logistic curve performed better.

Conclusion: Robust HIV-related program and vital registration data are routinely available in many middle-income and high-income countries, whereas HIV seroprevalence surveillance and survey data may be scarce. In these countries, the FPD tool offers a simpler, improved approach to estimating HIV incidence trends.

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Analytical advances in the ex vivo challenge efficacy assay.

Richardson-Harman N, Parody R, Anton P, McGowan I, Doncel G, Thurman AR, Herrera C, Kordy K, Fox J, Tanner K, Swartz G, Dezzutti CS. AIDS Res Hum Retroviruses. 2017 Apr;33(4):395-403. doi: 10.1089/AID.2016.0073. Epub 2016 Dec 16.

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n = 502), cervical (n = 88), and vaginal (n = 110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05), but a larger sample size was predicted to be needed for either cervical (n = 21) or vaginal (n = 10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.

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HIV-2 – not a global pandemic, but still causing challenges for diagnosis and treatment

Editor’s notes: HIV-2 is discussed much less than HIV-1 because it has not caused a global pandemic.  Nonetheless there are around 1-2 million people thought to be living with HIV-2, predominantly in West Africa and in Portugal and her historical connections (Brazil, Angola, Mozambique and India).  A useful review by de Mendoza C and colleagues from Spain highlights key features in the epidemiology, management and future directions for HIV-2.  The diagnosis is easy to miss and should be considered whenever routine HIV-1 tests give curious serological profiles.  There are also important differences when treating people living with HIV-2. HIV-2 cannot be treated with non-nucleoside reverse transcriptase inhibitors and some protease inhibitors do not work either. Viral load monitoring has not been commercialized, and so is often unreliable.  CD4 cell counts tend to drop more rapidly in HIV-1 and this has sometimes led to the suggestion that HIV-2 is a benign infection.  However, progression to an AIDS-like syndrome does occur, particularly in people who acquired HIV at a younger age.  The CD4 cell count recovery on antiretroviral therapy seem to be less effective in HIV-2 compared to HIV-1 infections. Failure and selection of drug resistance may be more frequent in HIV-2.

HIV-2 Epidemic in Spain - challenges and missing opportunities.

de Mendoza C, Cabezas T, Caballero E, Requena S, Amengual MJ, Peñaranda M, Sáez A, Tellez R, Lozano AB, Treviño A, Ramos JM, Pérez JL, Barreiro P, Soriano V; Spanish HIV-2 Network. AIDS. 2017 Mar 29. doi: 10.1097/QAD.0000000000001485. [Epub ahead of print]

HIV type 2 (HIV-2) is a neglected virus despite estimates of 1-2 million people infected worldwide. HIV-2 is less efficiently transmitted than HIV-1 by sex and from mother-to-child. Although AIDS may develop in HIV-2 carriers, it takes longer than in HIV-1-infected patients. In contrast with HIV-1 infection, there is no global pandemic caused by HIV-2, remaining the virus largely confined to West Africa. In a less extent and due to socioeconomic ties and wars, HIV-2 is prevalent in Portugal and its former colonies in Brazil, India, Mozambique and Angola. Globally, HIV-2 infections are steadily declining over time. A total of 338 cases of HIV-2 infection had been reported at the Spanish HIV-2 registry until December 2016, of whom 63% were male. Overall 72% were sub-Saharan Africans whereas 16% were native Spaniards. Dual HIV-1 and HIV-2 coinfection was found in 9% of patients. Heterosexual contact was the most likely route of HIV-2 acquisition in more than 90% of cases. Roughly one third presented with CD4 counts <200 cells/μL and/or AIDS clinical events. Plasma HIV-2 RNA was undetectable at baseline in 40% of patients. To date, one third of HIV-2 carriers have received antiretroviral therapy, using integrase inhibitors 32 individuals. New diagnoses of HIV-2 in Spain have remained stable since 2010 with an average of 15 cases yearly. Illegal immigration from Northwestern African borders accounts for over 75% of new HIV-2 diagnoses. Given the relatively large community of West Africans already living in Spain and the continuous flux of immigration from endemic regions, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded once in all HIV-seroreactive persons, especially when showing atypical HIV serological profiles, immunovirological disconnect (CD4 count loss despite undetectable HIV-1 viremia) and/or high epidemiological risks (birth in or sex partners from endemic regions).

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Basic science, HIV
Europe
Spain
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Phylogenetics - powerful new tools tied to ethical imperatives for key populations

Editor’s notes: There are now well over half a million HIV isolates that have been sequenced and the data stored in public accessible Genbank.  A systematic review by Hassan AS and colleagues of the methods used to define phylogenetic trees and clusters within them demonstrates the importance of using the correct criteria for the hypothesis being tested. Most articles use the pol sequence, since this is what is sequenced for drug resistance testing.  Most analyses have been done using a phylogenetic approach that uses a probability to assess the likelihood that isolates are clustered, and so depends on the cut-off value chosen.  For example, a well-studied outbreak of HIV among drug users in Finland is clearly linked to an earlier outbreak in Sweden, but because the Finnish isolates were collected later, they had already diverged somewhat from the Swedish ones.  If the threshold was set too high, they would not be recognized to be part of the same outbreak.  However for active transmission chains, a high threshold is needed to avoid falsely linking isolates.  There is no consensus on what methods to use, so caution is needed when comparing different studies.

Mark Wainberg, Professor of Medicine and of Microbiology at McGill University and a giant of Canadian HIV science, passed away this month.  So, as a tribute to his work, we have chosen a study from the McGill AIDS Centre by Brenner BG and colleagues.  The team used phylogenetic analysis to classify pre-treatment HIV isolates from 3901 men who have sex with men in Quebec according to the likelihood of being an acute or recent infection and the likelihood of clustering with other isolates.  Over the period from 2002-2015, a larger and larger proportion of the infections in this population could be linked to larger clusters, particularly involving younger men and men with recent infection, many of whom did not know their HIV status.  At least 40% of the onward spread of the epidemic in Quebec can be ascribed to just thirty clusters, varying in size from 20–140 individuals.

Using phylogenetics to understand transmission patterns requires careful attention to ethics, confidentiality and stigmatization.  A study in South Korea by Ahn MY and colleagues aimed to define the risk factors for clustering within clusters among 143 people living with HIV in four cities.  In eight out of the nine clusters identified participants did not report the same risk factors. Clusters were small, eight pairs and one quartet.  In the two tightest clusters, where the isolates were indistinguishable on the sequences examined, one man stated that he had sex with women, but the paired isolate came from another man and in the other pair, both men chose not to disclose their risk factors.  With small studies where information can sometimes be inferred even when not disclosed, it is perhaps not surprising that more than half the participants chose not to report their risk factors.

Other phylogenetic studies this month have explored the evolution of HIV recombination and the spread of different clades in communities in North-Eastern Brazil [Delatorre E et al.] and China.  In the North-Eastern states of Brazil, 72% of HIV isolates were subtype B, but rare subtypes such as D (1%) and CRF02_AG (1%) appear to be spreading within the population rather than being introduced from outside. In China studies from Sichuan [Wang Y et al.], Yunnan [Li Y and colleagues] and Zhejiang [Wang H et al.] have shown new recombinant forms of HIV with elements that suggest that viruses from different countries in the region have combined.  The widening diversity of HIV brings challenges for vaccine development, and potentially for HIV assays, such as those for recent infection that may differ in their sensitivity and specificity between different sub-types.  Understanding the migration of people and their viruses could be useful for providing better services, but careful attention to messaging will be needed to prevent such data from being used to discriminate further against migrants.

The final phylogenetic paper this month also comes from China, where Hao M and colleagues reported a study of students living with HIV in Beijing. The study demonstrated that transmitted drug resistance is still low in this setting, with just 0.8% of 237 students having virus that was resistant to non-nucleoside reverse transcriptase inhibitors that form part of the backbone of first line treatment in China.  A further 1.3% has resistance to protease inhibitors that are used in second line treatment.

Defining HIV-1 transmission clusters based on sequence data: a systematic review and perspectives.

Hassan AS, Pybus OG, Sanders EJ, Albert J, Esbjörnsson J. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001470. [Epub ahead of print]

Understanding HIV-1 transmission dynamics is relevant to both screening and intervention strategies of HIV-1 infection. Commonly, HIV-1 transmission chains are determined based on sequence similarity assessed either directly from a sequence alignment or by inferring a phylogenetic tree. This review is aimed at both nonexperts interested in understanding and interpreting studies of HIV-1transmission, and experts interested in finding the most appropriate cluster definition for a specific dataset and research question. We start by introducing the concepts and methodologies of how HIV-1 transmission clusters usually have been defined. We then present the results of a systematic review of 105 HIV-1 molecular epidemiology studies summarizing the most popular methods and definitions in the literature. Finally, we offer our perspectives on how HIV-1 transmission clusters can be defined and provide some guidance based on examples from real life datasets.

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Large cluster outbreaks sustain the HIV epidemic among MSM in Quebec.

Brenner BG, Ibanescu RI, Hardy I, Stephens D, Otis J, Moodie E, Grossman Z,Vandamme AM, Roger M, Wainberg MA; and the Montreal PHI, SPOT cohorts. AIDS. 2017 Mar 13;31(5):707-717. doi: 10.1097/QAD.0000000000001383.

Objective: HIV-1 epidemics among MSM remain unchecked despite advances in treatment and prevention paradigms. This study combined viral phylogenetic and behavioural risk data to better understand underlying factors governing the temporal growth of the HIV epidemic among MSM in Quebec (2002-2015).

Methods: Phylogenetic analysis of pol sequences was used to deduce HIV-1transmission dynamics (cluster size, size distribution and growth rate) in first genotypes of treatment-naïve MSM (2002-2015, n = 3901). Low sequence diversity of first genotypes (0-0.44% mixed base calls) was used as an indication of early-stage infection. Behavioural risk data were obtained from the Montreal rapid testing site and primary HIV-1-infection cohorts.

Results: Phylogenetic analyses uncovered high proportion of clustering of new MSM infections. Overall, 27, 45, 48, 53 and 57% of first genotypes within one (singleton, n = 1359), 2-4 (n = 692), 5-9 (n = 367), 10-19 (n = 405) and 20+ (n = 1277) cluster size groups were early infections (<0.44% diversity). Thirty viruses within large 20+ clusters disproportionately fuelled the epidemic, representing 13, 25 and 42% of infections, first genotyped in 2004-2007 (n = 1314), 2008-2011 (n = 1356) and 2012-2015 (n = 1033), respectively. Of note, 35, 21 and 14% of MSM belonging to 20+, 2-19 and one (singleton) cluster groups were under 30 years of age, respectively. Half of persons seen at the rapid testing site (2009-2011, n = 1781) were untested in the prior year. Poor testing propensity was associated with fewer reported partnerships.

Conclusion: Addressing the heterogeneity in transmission dynamics among HIV-1-infected MSM populations may help guide testing, treatment and prevention strategies.

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HIV-1 transmission networks across South Korea.

Ahn MY, Wertheim JO, Kim WJ, Kim SW, Lee JS, Ann HW, Jeon Y, Ahn JY, Song JE, Oh DH, Kim YC, Kim EJ), Jung IY, Kim MH, Jeong W, Jeong SJ, Ku NS, Kim JM, Smith DM, Choi JY. AIDS Res Hum Retroviruses. 2017 Mar 27. doi: 10.1089/aid.2016.0212. [Epub ahead of print]

Molecular epidemiology can help clarify the properties and dynamics of HIV-1 transmission networks in both global and regional scales. We studied 143 HIV-1-infected individuals recruited from four medical centers of three cities in South Korea between April 2013 and May 2014. HIV-1 env V3 sequence data were generated (337-793 bp) and analyzed using a pairwise distance-based clustering approach to infer putative transmission networks. Participants whose viruses were ≤2.0% divergent according to Tamura-Nei 93 genetic distance were defined as clustering. We collected demographic, risk, and clinical data and analyzed these data in relation to clustering. Among 143 participants, we identified nine putative transmission clusters of different sizes (range 2-4 participants). The reported risk factor of participants were concordant in only one network involving two participants, that is, both individuals reported homosexual sex as their risk factor. The participants in the other eight networks did not report concordant risk factors, although they were phylogenetically linked. About half of the participants refused to report their risk factor. Overall, molecular epidemiology provides more information to understand local transmission networks and the risks associated with these networks.

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HIV-1 Genetic diversity in northeastern Brazil: high prevalence of non-B subtypes.

Delatorre E, Couto-Fernandez JC, Bello G.AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0045. [Epub ahead of print]

The Northeastern Brazilian region has experienced a constant increase in the number of newly reported AIDS cases over the last decade, but the genetic diversity of HIV-1 strains currently disseminated in this region remains poorly explored. HIV-1 pol sequences were obtained from 140 patients followed at outpatient clinics from four Northeastern Brazilian states (Alagoas, Bahia, Ceará and Piauí) between 2014 and 2015. Subtype B was the most prevalent HIV-1 clade (72%) detected in the Northeastern region, followed by subtypes F1 (6%), C (5%) and D (1%). The remaining strains (16%) displayed a recombinant structure and were classified as: BF1 (11%), BC (4%), BCF1 (1%) and CRF02_AG-like (1%). The 20 HIV-1 BF1 and BC recombinant sequences detected were distributed among 11 lineages classified as: CRF28/29_BF-like (n = 5), CRF39_BF-like (n = 1), URFs_BF (n = 9) and URFs_BC (n = 5). Non-B subtypes were detected in all Northeastern Brazilian states, but with variable prevalence, ranging from 16% in Ceará to 55% in Alagoas. Phylogenetics analyses support that subtype D and CRF02_AG strains detected in the Northeastern region resulted from the expansion of autochthonous transmission networks, rather than from exogenous introductions from other countries. These results reveal that HIV-1 epidemic spreading in the Northeastern Brazilian region is comprised by multiple subtypes and recombinant strains and that the molecular epidemiologic pattern in this Brazilian region is much more complex than originally estimated.

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Identification of a novel HIV type 1 CRF01_AE/B'/C recombinant isolate in Sichuan, China.

Wang Y, Kong D, Xu W, Li F, Liang S, Feng Y, Zhang F, Shao Y, Ma L. AIDS Res Hum Retroviruses. 2017 Mar 13. doi: 10.1089/aid.2017.0002. [Epub ahead of print]

We report in this study a novel HIV-1 unique recombinant virus (XC2014EU01) isolated from an HIV-positive man who infected through heterosexual sex in Sichuan, China. The near full-length genome analyses showed that XC2014EU01 harbored one subtype B segment in pol region and two subtype C segments in gag-pol region in a CRF01_AE backbone. The unique mosaic structure was distinctly different from the other CRF01_AE/B'/C recombinant forms reported. Phylogenetic tree analyses revealed that the subtype B region originated from a Thailand subtype B' lineage, the subtype C regions were from an India C lineage, and the backbone was from CRF01_AE. XC2014EU01 was still identified as CCR5-tropic, and plasma of XC2014EU01 infected person had the media neutralizing activity. The emergence of XC2014EU01 may increase the complexity of the HIV-1 epidemic among high-risk populations and the difficulty of vaccine research and development.

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Identification of a novel HIV type 1 circulating recombinant form (CRF86_BC) among heterosexuals in Yunnan, China.

Li Y, Miao J, Miao Z, Song Y, Wen M, Zhang Y, Guo S, Zhao Y, Feng Y, Xia X. AIDS Res Hum Retroviruses. 2017 Mar;33(3):279-283. doi: 10.1089/AID.2016.0188. Epub 2016 Oct 18.

In recent years, multiple circulating recombinant forms (CRFs) and unique recombinant forms of human immunodeficiency virus type 1 (HIV-1) have been described in Yunnan, China. Here, we identified a novel HIV-1 CRF (CRF86_BC) isolated from three heterosexuals with no obvious epidemiologic linkage in western Yunnan (Baoshan prefecture) in China. CRF86_BC had a subtype C backbone with four subtype B fragments inserted into the pol, vpr, vpu, env, and nef gene regions, respectively. Furthermore, subregion tree analysis revealed that subtype C backbone originated from an Indian C lineage and subtype B segment inserted was from a Thai B lineage. They are different from previously documented B/C forms in its distinct backbone, inserted fragment size, and break points. This highlighted the importance of continual monitoring of genetic diversity and complexity of HIV-1 strains in this region.

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Near full-length genomic characterization of a novel HIV-1 unique recombinant (CRF55_01B/CRF07_BC) from a Malaysian immigrant worker in Zhejiang, China.

Wang H, Luo P, Zhu H, Wang N, Hu J, Mo Q, Yang Z, Feng Y. AIDS Res Hum Retroviruses. 2017 Mar;33(3):275-278.doi: 10.1089/AID.2016.0100. Epub 2016 Aug 17.

Recombinant forms contribute substantially to the genetic diversity of human immunodeficiency virus type 1 (HIV-1). Here we report a novel HIV-1 recombinant detected from a comprehensive HIV-1 molecular epidemiologic study among cross-border populations in China. Near full-length genome (NFLG) phylogenetic analysis showed that the novel HIV-1 recombinant ZJCIQ15005, which was isolated from a Malaysian immigrant worker in Zhejiang, China, clustered with CRF55_01B reference sequences but set up a distinct branch. Recombinant analysis showed that the NFLG of ZJCIQ15005 composed of CRF55_01B (as the backbone) and CRF07_BC,with 12 recombinant break points observed in the pol, vif, vpr, tat, rev, env,nef, and 3'LTR regions. This is the first detection of a novel HIV-1 recombinant (CRF55_01B/CRF07_BC) in immigrant workers in China. The emergence of this recombinant may increase the complexity of the HIV-1 epidemic in China and suggests the importance of continuous surveillance of the dynamic changes of HIV-1.

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Low rates of transmitted drug resistances among treatment-naive HIV-1 infected students in Beijing, China.

Hao M, Wang J, Xin R, Li X, Hao Y, Chen J, Ye J, Wang Y, He X, Huang C, Lu H. AIDS Res Hum Retroviruses. 2017 Mar 22. doi: 10.1089/AID.2017.0053. [Epub ahead of print]

Beijing has seen a rising epidemic of HIV among students. However, little information was known about the molecular epidemiologic data among HIV-infected students. In this study, the diversity and the prevalence of TDR in pol sequences deriving from 237 HIV-infected students were analyzed. TDR mutations were found in 5 MSM among students. The overall prevalence of TDR in students was 2.1%, comprised of 1.3% to protease inhibitors and 0.8 % to non-nucleoside reverse transcriptase inhibitors. Our finding indicates a low-level prevalence of TDR mutations among students in Beijing.

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Asia, Latin America, Northern America
Brazil, Canada, China, Republic of Korea
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Cure and vaccination – more steps forward in understanding persistence of HIV and how we might deal with it

Editor’s notes: CD32a is the exciting new marker for T-lymphocytes that seem to harbour the reservoir for HIV in peripheral blood.  These cells form a very small proportion of all CD4 T-lymphocytes, but they host copies of the virus in their DNA that can be woken up and start replicating again.  While this is still a discovery at the level of basic immunology, it raises important possibilities for measuring the reservoir and perhaps for intervening directly to drain it.  It may also lead on to further basic biological understanding of why this particular transmembrane protein should be so significantly expressed in latently infected cells but not in bystanders [Descours B et al., Richman DD].

Two papers are relevant to the push for an HIV vaccine.  A new mathematical model by Medlock J et al. highlights the potential contribution of a vaccine (or indeed other prevention technologies) over and above the impact of better diagnosis, linkage and treatment of people living with HIV as framed in the 90:90:90 treatment target of UNAIDS.  Of course, a significant advantage of a vaccine or a prevention technology is that primary prevention leads to a more rapid reduction in the number of people living with HIV and the associated costs of lifelong ART. UNAIDS strategy already includes a major push for those prevention tools that have been shown to work, with emphasis on combination prevention including structural (such as incentives to keep girls in school and improving access to condoms), behavioural (such as increasing condom usage) and biomedical (such as PrEP) elements within an approach that prioritizes the highest burdened locations and populations.  It is not clear that this new model has incorporated these wider prevention programmes in their baseline scenarios. Nonetheless the conclusion is still that we should maintain our enthusiasm for the ongoing and imminent large scale clinical trials of vaccine candidates!

And finally for this month, another encouraging immunotherapy study from NIAID.  In a macaque model using a humanized SHIV (a virus that still infects macaques but has been engineered to express HIV proteins), Nishimura Y et al. found a big difference when treatment was stopped between standard ART and infusions of broadly neutralizing antibodies infused around the time of infection.  Whereas the viral load rebounded soon after the ART was stopped, several of the macaques were able to continue to suppress the SHIV for up to two years after the infusion of antibodies.  The mechanism was shown to be through the CD8 T cell pathway, since removal of these cells led to rapid viral rebound in the antibody treated animals. With each new discovery in the animal and immunology laboratories, we get a little closer to understanding what it might take to develop an effective vaccine that could provide durable protection against HIV or provide effective treatment or therapeutic enhancement that allowed people living with HIV to no longer require ART.  That is a goal that we are all pushing towards!

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses.

Descours B, Petitjean G, López-Zaragoza JL, Bruel T, Raffel R, Psomas C, Reynes J, Lacabaratz C, Levy Y, Schwartz O, Lelievre JD, Benkirane M. Nature. 2017 Mar 23;543(7646):564-567. doi: 10.1038/nature21710.Epub 2017 Mar15.

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

Abstract access 

HIV: Finding latent needles in a haystack.

Richman DD. Nature. 2017 Mar 23;543(7646):499-500. doi: 10.1038/nature21899. Epub 2017 Mar15.

Antiretroviral therapy can keep HIV at bay, but a few cells remain infected, so the disease cannot be cured. The discovery of a protein that marks out these infected cells will facilitate crucial studies of this latent viral reservoir. 

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Effectiveness of UNAIDS targets and HIV vaccination across 127 countries.

Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Proc Natl Acad Sci U S A. 2017 Mar 20. pii: 201620788. doi:10.1073/pnas.1620788114. [Epub ahead of print]

The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035. Achieving the Joint United Nations Program on HIV/AIDS 95-95-95 target was estimated to avert 25 million [20M, 33M] of these new infections, and an additional 6.3 million [4.8M, 8.7M] reduction was projected with the 2020 introduction of a 50%-efficacy vaccine gradually scaled up to 70% coverage. This added benefit of prevention through vaccination motivates imminent and ongoing clinical trials of viable candidates to realize the goal of HIV control.

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Early antibody therapy can induce long-lasting immunity to SHIV.

Nishimura Y, Gautam R, Chun TW, Sadjadpour R, Foulds KE, Shingai M, Klein F, Gazumyan A, Golijanin J, Donaldson M, Donau OK, Plishka RJ, Buckler-White A, Seaman MS, Lifson JD, Koup RA, Fauci AS, Nussenzweig MC, Martin MA. Nature. 2017 Mar 23;543(7646):559-563. doi: 10.1038/nature21435. Epub 2017 Mar13.

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

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HIV treatment during acute infection can lead to false negative HIV antibody tests

Initiation of antiretroviral therapy during acute HIV-1 infection leads to a high rate of nonreactive HIV serology.

de Souza MS, Pinyakorn S, Akapirat S, Pattanachaiwit S, Fletcher JL, Chomchey N, Kroon ED, Ubolyam S, Michael NL, Robb ML, Phanuphak P, Kim JH, Phanuphak N, Ananworanich J. Clin Infect Dis. 2016 Aug 15;63(4):555-61. doi: 10.1093/cid/ciw365. Epub 2016 Jun 17.

Background: Third- and fourth-generation immunoassays (IAs) are widely used in the diagnosis of human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) during acute HIV infection (AHI) may impact HIV-specific antibodies, with failure to develop antibody or seroreversion. We report on the ability of diagnostic tests to detect HIV-specific antibodies in Thai participants initiating ART during AHI.

Methods: Participants with detectable plasma HIV RNA but nonreactive HIV-specific immunoglobulin G, enrolled in an AHI study, were offered immediate initiation of ART. Participants were tested at initiation and at 12 and 24 weeks following treatment using standard second-, third-, and fourth-generation IAs and Western blot (WB).

Results: Participants (N = 234) initiating ART at a median of 19 days (range, 1-62 days) from HIV exposure demonstrated different frequencies of reactivity prior to and following 24 weeks of ART depending on the IA. Third-generation IA nonreactivity prior to ART was 48%, which decreased to 4% following ART (P < .001). Fourth-generation IA nonreactivity was 18% prior to ART and 17% following ART (P = .720). Negative WB results were observed in 89% and 12% of participants prior to and following 24 weeks of ART, respectively (P < .001). Seroreversion to nonreactivity during ART was observed to at least one of the tests in 20% of participants, with fourth-generation IA demonstrating the highest frequency (11%) of seroreversion.

Conclusions: HIV-specific antibodies may fail to develop and, when detected, may decline when ART is initiated during AHI. Although fourth-generation IA was the most sensitive at detecting AHI prior to ART, third-generation IA was the most sensitive during treatment.

Clinical trials registration: NCT00796146 and NCT00796263.

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Editor’s notes: Antibodies to HIV become detectable around three weeks after HIV infection. Fourth generation HIV tests detect both HIV antibodies and the p24 HIV antigen, and can therefore detect HIV infection earlier than second and third-generation tests, which are based on detection of antibodies. Fourth generation tests therefore allow for earlier initiation of antiretroviral therapy (ART) relative to second- and third-generation HIV tests.

There have been sporadic reports of seroreversion from being HIV antibody positive to negative, or failure to seroconvert to being HIV antibody positive, following initiation of ART, particularly from paediatric populations. This study examined the impact of ART initiation during acute HIV infection on HIV diagnostic test results. Although the fourth-generation HIV test was the most sensitive at detecting acute HIV infection, it also had the highest frequency of seroreversion. Conversely, third generation HIV tests were positive prior to the start of ART in just over half of participants, compared to nearly all by 12 weeks after ART initiation. Notably, the Western blot, which was historically used as a confirmatory test for HIV, had high rates of non-reactivity in acute infection and 12% of tests were negative at 24 weeks after treatment, demonstrating that this test is not informative as a confirmatory assay in the context of acutely-treated HIV infection.   

The recent WHO guidelines recommend ART for all HIV-positive people regardless of age and disease stage.  Initiating ART as early as possible following HIV infection has also been recommended as a means to limit the size of the viral reservoir and improve prognosis. It is therefore likely that increasing numbers of individuals will start ART during early infection. There may be instances where individuals on ART may retest either due to doubts about results, or when they relocate to other HIV services. Clinicians need to be aware of the possibility of false-negative HIV antibody tests among people taking ART, particularly among individuals who initiated treatment during acute infection.    

Asia
Thailand
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