Thursday 1 November 2018
Broadly neutralising antibodies
Lynn Morris at HIVR4P 2018. Photo by Gus Cairns.
The HIV Research for Prevention conference (HIVR4P
2018) was dominated
by studies of one type of molecule – broadly neutralising antibodies (bNAbs).
These complex molecules, which develop in some people with HIV after years of
infection, are natural entry inhibitors, stopping the virus from attaching to
and infecting cells. They target highly conserved parts of the virus –
parts of its proteins that are important to its functioning and which it finds
difficult to alter.
HIVR4P heard about a large number of studies of bNAbs. They
can be infused ‘passively’, i.e. made outside the body and given in drips as
long-lasting drugs. The reason researchers are interested in bNAbs for HIV is
not only because they could treat virus resistant to other kinds of drugs –
which they could. Neither is it simply because a single infusion of antibodies
can last weeks in the body – though it can, and bNAbs are therefore of interest
as a kind of new-generation pre-exposure prophylaxis (PrEP).
It is also because of the way they alert other parts of the
immune system, with an effect that can be maintained for long after they
have disappeared from the body. Most exciting is the possibility that – since
they arise naturally in response to infection – a finely tuned vaccine could
induce people to make their own bNAbs. In theory a bNAb-stimulating vaccine
could prevent HIV infection altogether.
The prevention potential of bNAbs is being tested in the
(Antibody-Mediated Protection) studies, with results anticipated by
late 2020. Participants are receiving a bNAb called VRC01 or a placebo. It is
unlikely that that AMP will be the last study of its type: further studies are likely
to test combinations of bNAbs.
The Miami monkey
Image from José Martinez-Navio's presentation slides at HIVR4P 2018
conference heard about a University of Miami study that used sophisticated gene
therapy to induce monkeys to make their own broadly neutralising antibodies
(bNAbs) and produced an apparently functional cure in one animal.
The two antibodies used were the same two bNAbs, 10-1074 and
3BNC117, that were recently
used in a promising experiment in humans. They were given as a gene
therapy – two modified genes introduced into the monkey’s own immune system by
means of a vector, the shell of an inert virus called AAV (adeno-associated
virus), which induced the monkey’s immune system to express the bNAbs.
The monkeys were infected with SHIV-AD8, received no
treatment for 86 weeks and were then given the AAV-vector vaccine. One
of four animals developed a viral load that was consistently undetectable and
still is just over three years after vaccination. The monkey still appears to
have HIV in some of its cells but the persistent levels of antibody and the
presence of a functional anti-SHIV CD8 response indicate prolonged recession of
HIV infection or even a permanent functional cure.
HIV prevention choices
Jim Pickett leading a protest at HIVR4P 2018. Image credit: @HIVpxresearch
‘Choices’ was the buzzword of the conference. Activists took
to the stage during both the opening and closing sessions to express their
concern about decisions by the US National Institutes of Health to reduce
funding for the development of microbicides and other topical products.
Investment will be concentrated on systemic and long-acting products, such as
injectables and implants, as well as vaccines (which have always received the
lion’s share of funding).
Activist Lillian Benjamin Mwakyosi told delegates: “The
research agenda is moving away from what people want: choices.” Jim Pickett
expressed his concern about “an HIV prevention research agenda that does not
include choices that are user controlled, that does not include short acting
choices and that neglects options that are non-systemic.”
Craig Hendrix of Johns Hopkins University made an eloquent
plea for research to continue into topical pre-exposure prophylaxis (PrEP), calling
on the National Institutes of Health, the HIV Prevention Trials Network
and other actors to ensure that topical products can be chosen for PrEP. He
said the lesson from contraception was clear – an increased range of
contraceptive options is associated with higher levels of usage and better
health outcomes. For each additional contraceptive method provided, there is a
12% increase in the proportion of women using contraception.
He asked: “I wonder how much this increase will be for every
additional product we license for PrEP?”.
Future PrEP products
Raphael Landovitz at HIVR4P 2018. Photo by Roger Pebody.
Landovitz of the University of California gave the conference a high-level
overview of the pipeline of potential future pre-exposure prophylaxis (PrEP) products. Oral
PrEP based on tenofovir disoproxil fumarate/emtricitabine (Truvada) has
set a high bar for prevention effectiveness, but a range of alternative
products are in development, he said.
An ongoing trial is evaluating the use of oral tenofovir
alafenamide/emtricitabine (Descovy) as an alternative to Truvada. While the newer formulation of
tenofovir is an attractive option for HIV treatment, it remains to be seen
whether it will work well for PrEP. Intracellular drug levels are high, but
they are relatively low in plasma and genital tissues, he said.
Long-acting injectable formulations of PrEP drugs are likely to
become available imminently, with cabotegravir furthest along the development
process. However the ‘long tail’ of injectable PrEP (see next item) may be a
Long-acting implants may not have the same drawbacks as
injectables: they do not have a ‘long tail’ and can be removed in the event of
intolerance. Studies are at an earlier stage but the technology of implants is
progressing rapidly, including multipurpose implants that could deliver a
contraceptive together with an antiretroviral. Combining protection against
unwanted pregnancy and HIV in a single device may make it more attractive to
The dapivirine vaginal ring has demonstrated partial
efficacy and is under review by regulatory agencies. The conference heard that
adherence has been higher in the ongoing open label study than in the
placebo-controlled trials; this is likely to have a positive impact on
effectiveness. Different types of vaginal
rings may also be used as multipurpose devices.
At earlier stages of development are vaginal films, vaginal or rectal inserts, rectal gels and
Injectable cabotegravir’s long tail
Image from Raphael Landovitz's slides at HIVR4P 2018.
four in ten women and one in ten men taking injectable cabotegravir as
pre-exposure prophylaxis (PrEP) still have evidence of the drug in their body
around 18 months after their last injection, the conference heard.
The findings raise concerns about the potential development
of drug resistance. If people stop receiving PrEP injections, they will be
vulnerable to HIV unless they start or continue another method of HIV
prevention, such as oral PrEP. The ‘long tail’ means that there could be a
lengthy period during which, if they caught HIV, individuals could develop drug
resistance. Drug resistance only arises in situations like this when there is
some drug in the body but not enough to fully suppress an infection.
Data were collected from participants in the phase II HPTN
077 study for up to 76 weeks after participants’ last injection.The median time
for drug levels to fall below the lower limit of quantification (LLOQ) in women
was 66 weeks, ranging from 18 to 182 weeks. In men, the median was 43 weeks,
ranging from 20 to 134 weeks.
People who have used injectable cabotegravir could be
recommended to take oral PrEP for a period after their last injection, to cover
the long tail, but will this be a feasible approach in routine clinical care?
Women's product preferences
Ariane van der Straten at HIVR4P 2018. Photo by Roger Pebody.
A number of studies presented at HIVR4P investigated
people’s preferences for possible prevention products. A
study conducted with young women in South Africa and Zimbabwe found that there
is no single formulation which will suit everyone – after trying
four different vaginal products, there was no one product that was much more
popular than the others.
The participants tried four different placebo products for a
month at a time. Ratings for all products improved over time and after using
After trying all four, they
were asked to rank them in order of preference:
- The vaginal ring was the preferred choice of
29%, but also the least favourite of 42%.
- The vaginal
film was preferred by 29%, but also the least favourite of 23%.
- The vaginal
insert was preferred by 26%, but the least favourite of 12%.
- The vaginal
gel was the preferred choice of 16%, but also the least favourite of 23%.
“Young women want choice,” commented researcher Ariane van
der Straten. “They want a product that is low burden, provides peace of mind,
is fool proof and multi-purpose, but what form this product takes does vary.”
Rising uptake of PrEP
Laura Fitch at HIVR4P 2018. Photo by Roger Pebody.
least 380,000 people have started to take pre-exposure prophylaxis (PrEP) in 68
countries, but most of them are in the United States and African
countries, according to a global analysis tracking demonstration projects,
implementation initiatives and national programmes.
The latest figures show that 225,000 people who are taking
PrEP are in the United States, most of whom are men who have sex with men
(MSM). A further 103,000 are in sub-Saharan Africa, with usage overwhelmingly
concentrated in Kenya, South Africa, Uganda, Zimbabwe and Lesotho. Numerous
other African countries have hardly any PrEP users. The majority of African
PrEP users are adolescent girls and young women.
Only around 22,000 people are taking PrEP in Europe, mostly
in England, France and Germany. The exercise identified 8000 PrEP users in
Asia, over half of whom are in Thailand.
many more gay men and MSM may be using PrEP than
these figures suggest, some believe. The figures do not include people
obtaining PrEP informally (for example, purchasing medication online), but the
practice appears to be widespread. Large numbers of gay Chinese tourists are visiting
Thailand to buy PrEP there. Surveys conducted by the dating app Hornet have
found that 7% of Brazilian respondents were taking PrEP and that 18% of
European respondents who were taking PrEP were living in Russia (not a country
frequently mentioned in relation to PrEP).
“PrEP is available online everywhere,” Michelle Rodolph of the World Health
Organization said, “and its use is not monitored”.
is emerging of the real-world impact of providing PrEP to clinic populations.
The Fenway clinic in Boston is a community health centre with a special focus on
sexual and gender minorities; it was one of the first to institute a large PrEP
programme. Their figures show that HIV incidence in people never prescribed
PrEP is 1.34%.
In those with a current PrEP prescription, incidence is 0.13%,
a reduction of 90%. The handful of infections which occurred in PrEP users
appear to be either people with acute HIV infection at the time they started
PrEP or people with adherence difficulties.
Stop talking about ‘risk’
Sarit Golub at HIVR4P 2018. © HIVR4P/ Leon Gutierrez
unhelpful to frame the use of pre-exposure prophylaxis (PrEP) in terms of
‘risky behaviour’, Sarit Golub, professor of psychology at the City
University of New York told the conference. She argued that while risk
assessment tools may have validity across a population, they tend to be quite
poor at accurately predicting an individual’s risk of acquiring HIV. As many
people are not comfortable discussing their sexual behaviour with clinicians,
the information they gather is not always complete.
Moreover, the language is stigmatising and alienating.
“People do not ‘engage in risk behaviour’, we ‘have sex’,” she said. Public
discussions about ‘risk compensation’ and ‘behavioural disinhibition’ are
particularly damaging, she believes. Healthcare providers who have concerns
about PrEP being associated with more condomless sex and increases in sexually
transmitted infections are less willing to prescribe PrEP than other
Instead of conducting risk assessments, Golub said that
healthcare providers should ask patients about their sexual health concerns and
their sexual health goals. Providers should focus on the reasons why people
might want to take PrEP other than because they are ‘high risk’, including
reducing anxiety, increasing intimacy and taking control of their health.
Barriers to PrEP
Image from Albert Liu's slides at HIVR4P 2018 promoting a PrEP demonstration project for transgender people.
conference heard about barriers that are slowing access to pre-exposure prophylaxis (PrEP) and
preventing it having as great an impact as hoped.
In the United States, the persistent inequalities of the
healthcare system continue to mean that PrEP is not reaching those who need it
most. Whereas 26% of white men who have sex with men (MSM) have an indication for PrEP and 14% are taking
it, 44% of black MSM have an indication, but only 1% are taking it.
There are also substantial
gaps in the PrEP care continuum for transgender women. A San Francisco
study found that 79% were aware of PrEP, 35% had discussed it with a healthcare
provider, 12% were using it and 10% were adherent to PrEP. Social disparities
and medical mistrust are likely to contribute to this situation.
Brazil, political and structural conservatism have led to slow
uptake of PrEP. A failure to integrate the PrEP programme with the existing HIV
treatment programme was slowing down implementation. It’s unclear what will
happen to the programme following the election of right-winger Jair Bolsonaro
In eastern Europe there have only been a couple of small
implementation studies. One of the challenges is establishing a network of supportive
and knowledgeable healthcare professionals to provide PrEP.
Poor retention and adherence could also severely limit PrEP’s
impact. A number of American studies have reported problems with retention,
while a study with female sex workers in Benin, west Africa found that
only one in seven women stayed in the study and remained on PrEP.
Ethel Weld at HIVR4P 2018. Photo by Roger Pebody.
There is interest in developing prevention products that are
‘behaviourally congruent’ so that people do not need to make substantial
changes to their lifestyles. Craig Hendrix said that adding fluoride to
drinking water and fortifying milk with vitamins A and D were examples of ‘behaviourally
congruent’ health interventions.
an active pre-exposure prophylaxis (PrEP) drug to a rectal douche would fit in with people’s existing
sexual practices. A survey of users of a gay hook-up app found that 80%
reported douching before having receptive anal sex. The respondents were very
interested in the idea of a douche to prevent HIV and sexually transmitted infections – 98% of men who
currently douche and 94% of men who do not said that would be very interested
in such a product.
In a phase I study of a tenofovir rectal douche, the product
achieved adequate coverage, i.e. it travelled as far up the colon as semen was
likely to go. High tissue concentrations of tenofovir were achieved.
NAM's news reporting services from HIVR4P 2018 have been made possible thanks to support from Merck & Co., Inc., ViiV Healthcare and the organising committee of the HIVR4P conference.