ASPIRE: Highly active antiretroviral therapy (ART) has played

ASPIRE:
HIV Prevention in Women

 

Introduction

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With 1 million deaths in 2016 and 1.8 million new
cases of infection, HIV remains a global health problem. By the end of 2016, more than 35
million people have lost their lives to HIV. African region bears the
heaviest burden with 25.6 million people living with HIV in 2016 and two thirds
of the global total infection cases1.

 

Sexual and parenteral exposures make up the risks of
HIV acquisition. Among sexual exposure, anal sex is the riskiest of contracting
HIV infection followed by heterosexual
vaginal sexual intercourse. For parenteral exposure,
blood transfusion and contaminated
needles sharing are riskiest non-sexual exposures for HIV infection2. Although the use of condom and antiretroviral
therapy has reduced the risk of
HIV with sexual intercourse3, the overall HIV pandemic is still worrying because fundamental
behavioural changes in preventing HIV such as traditional abstinence, loyalty
to a single partner, to the use of
condoms are not always practised.

 

Emergence
of PrEP

Highly active antiretroviral
therapy (ART) has played a vital role in decreasing HIV related mortality,
lowering viral load in the spread of the disease. New HIV infections fell
by 39% between 2000 to 2016 due to the introduction
of ART, and it is estimated that more
than 13 million lives have been saved1.

Given all efforts in creating a HIV vaccine have failed miserably, pre-exposure
prophylaxis(PrEP) – the use of oral and topical use of ART is therefore deemed
the most promising and effective methods for HIV prevention4, apart from condoms and male circumcision.

To stop the global onslaught of HIV, WHO strongly recommends initiation of ART
in the entire HIV population to reduce transmission and recommends the use of PrEP
as one of the prevention tools for those who are prone to infection1.

 

Among the newer inventions of HIV prevention, oral PrEP has emerged as one of the most
effective tools. A combination of tenofovir and emtricitabine (Truvada) has been approved for this purpose in many
countries. Although Truvada has 99% protection rate on 100% adherence, the
protection rate decreases significantly
on non-adherence. If not taken daily, oral PrEP has lower so-called
“forgiveness” rate (i.e. the tolerance for missed doses) in females as compared
to men forgiveness which could be due to a lower
concentration of these drugs in the vagina
as compared to male genitals and intestine5.

Thus some trials in African women have even failed to show any benefits due to
poor adherence6. It is also important to note that
daily oral PrEP may not be an affordable option
in resource-poor countries.

 

Other concerns with oral PrEP are the risk of
development of resistance to antiretroviral drugs; high toxicity related to antiretroviral medications; and concern that people may lose restraint by stop
using condoms while on PrEP and thus neutralizing the benefit of oral PrEP7.

 

Consequently, there is an urgent need to find alternative methods of HIV prevention. An ideal solution will be of less toxicity with
a lower risk of resistance development, better adherence, and cost-effectiveness. For this purpose,
researchers turned their attention to the topical
use of antiretroviral drugs. One of the topical
medications that has been tested in various trials is 1% topical gel
of tenofovir. In CAPRISA study it showed the safety and effectiveness in
preventing new HIV infection in women8. However, it was much less effective when compared to oral PrEP, and had
the problem of adherence as it was required to be
used on a regular basis. Therefore
it did not do well in successive trial8.

 

ASPIRE: a study to understand
efficacy of dapivirine vaginal ring

Keeping in view the highest prevalence rate of HIV-1 among sub-Saharan women, ailing economic
situation, poor adherence to oral PrEP or tenofovir gel, the need was felt for a better solution that was
effective and easy to use.

 

One option
that seems to be more practicable in sub-Saharan Africa is the use of vaginal
rings. There was a study, called ASPIRE, completed by JM Baeten and his team in
2016 to explore the effectiveness and efficacy of such rings9.

These rings can be inserted inside the female genitals, containing slow
releasing antiretroviral drug. Thus
vaginal rings containing Dapivirine (a non-nucleoside HIV-1 reverse
transcriptase inhibitor) were developed. These rings can be inserted just once
a month. Moreover, dapivirine rings provide continuous release of drug to the vaginal
mucosa, and
its deployment is not dependent on the
coital activity. Further, vaginal rings are low in cost, easier to store, transport, and have fewer requirements for supply chain, making
them a better fit over once-a-day topical gel for use in developing countries settings10. It is highly affordable
and scalable in future usage, especially in the less developed countries. 

 

In phase I and II
clinical trials, they were found to be
safe for use. With vaginal rings, plasma
level of Dapivirine is 1000 times less in comparison to the oral dose10.

Thus finally in August 2002 ASPIRE, phase III study of these vaginal rings, was
initiated to find out the effectiveness of these rings in a much more substantial population group.

 

There is an important
reason for choosing the sub-Saharan region. For the treatment studies, one has to find the people who are infected with HIV-1. But for preventive studies, areas
with high incidence and prevalence are required, as preventive measures used in such region
would provide more accurate and productive
data. Region with higher prevalence also requires smaller sample size (i.e.

participants) for the same level of accuracy. Given the fact that the
sub-Saharan region had 71% of the global HIV population (out of a total of 35
million) with a one-year incidence of new infection reaching 1.5 million in the
year of 201311, it was ideal for ASPIRE to establish its study site.

 

It was a three-year study that was carried out
between August 2012 to June 2015. Participants of ASPIRE were sexually active,
non-pregnant, non-HIV positive women from Zimbabwe, Uganda, Malawi and South
Africa. It was a multi-center study (15 sites) that enrolled women from 18 to
45 years of age. The primary aim of ASPIRE
was to find out the efficacy and safety of dapivirine vaginal ring in
comparison to placebo, in HIV prevention. These vaginal rings need to be
replaced just once every four weeks. Rings give women control over their
health, and once a month means that compliance would be less of a problem, not
to mention the lower cost and toxicity.

 

In ASPIRE, all female participants were randomly
divided into two groups, one group was given 25 mg dapivirine vaginal rings
while another group was given similar looking silicon rings
(placebo). They were provided with education on using the rings, and had to
come to the clinic once a month for
follow-up investigations and to receive the newer ring.

 

Researchers knew from experience that adherence is a
big problem in sub-Saharan Africa. Providing education and rings to women does
not necessarily improve it. Thus on a quarterly basis plasma samples were collected and measured to
confirm that ring was used for a whole month
and was not inserted just before the visit to the clinic. Women were given the
next ring only when they returned the used one to the clinic. After a year of the trial, used rings were analysed against
the objective assessment of adherence – remaining amount of dapivirine in them
to be less than 23.5mg (with at least 1.5mg released).

 

The trial was
designed to achieve 60% lower HIV-1 infection rate in those using dapivirine
vaginal rings as compared to placebo, with a confidence
level of 90%. Assuming the annual
prevalence rate of 5% in placebo group (based on earlier trials), it was calculated that at least 120 HIV-1
acquisition events among 2600 participants would be required for the clinical trial to be successful. This study enrolled 2629 women. In the study 2614 women completed at least one
follow-up test for HIV-1 infection, resulting in accumulation of total 4280
human years of follow-up. Mean follow-up in the trial
was for 1.6 years, and 1024 participants were followed up for more than two years. In the dapivirine group, drug was
detected in plasma in acceptable level in
82% of cases, and in 84% cases, the
returned rings had dapivirine less
than 23.5 mg (meaning that they were used by the
participants).

 

At the end of
the trial, 168 of the 2629 participants
tested positive for the HIV-1 virus. 97
tested positive in the placebo group and 71 in
the dapivirine group, which means that incidence of HIV-1 in dapivirine groups
was 27% less than in placebo.  In
the following analysis, data from the two
sites were excluded due to poor adherence
and follow-up, and the analysis
demonstrated that HIV-1incidence was in fact 37% less in the dapivirine group. In the trial, it was
also noted that dapivirine rings had no
effect in those below the age of 21 due to poor adherence and other behaviour
issues. Thus when the data was analysed
for participants of 25 years of age or above, it was found that HIV-1
prevalence was 61% less in the dapivirine group
as compared to those on placebo.

 

Although
the trial failed to meet the overall expectations (demonstrating just
27-37% fewer incidences against the
target of 60%), it is quite clear that results were significant. The more in-depth analysis shows if not due to
some factors, results would have been much higher and would have been above the targeted 60% protection
rate. There are several reasons for the lower protection rate in the
trial. Firstly, there was very poor adherence in those younger than 21, and
even in those of 25 or below. Secondly, real adherence in those above 25 could also be lesser as the plasma analysis or
analysis of vaginal rings do not prove that these rings were used during the whole period. Thirdly, we see that in fact
only half of the participants continued to be part of the trial after two years. Another reason for low results was that genital tract of those below 21 years
is more susceptible to HIV-1 infection9.

 

A subsequent study however demonstrates
that higher adherence might provide HIV-1 protection rate of greater than 65%
by analysing on the returned rings with residual Dapivirine ?22mg compared to
ASPIRE level ?23.5mg12. This result exceeds the 60% target
protection rate and demonstrates the efficacy of the ring in preventing HIV-1
infection and gives confidence for future studies to further explore its usage.

 

Study Limitations

When we look carefully at the methodology of ASPIRE, some deficiencies are quite visible.

Firstly, the trial has undoubtedly failed to
motivate the participants to take part in the study and convey the expected
benefits to them. Thus due to the fears of side effects or inadequate
understanding; few participants continued to use those rings for the whole
period of the clinical trial (mean follow-up period of 1.6 years, against the
targeted three years).

 

Another deficiency is that the methodology of accessing
adherence. In the trial, quarterly plasma
levels of dapivirine were checked to see if participants were using the rings
or not, but positive plasma levels can be achieved by merely inserting the ring about eight hours before giving the blood
for the test. Thus it is entirely possible that many of them were not
using the rings all the time. Instead,
they just inserted the ring a day before the visit to the clinic. Using the vaginal ring to prevent HIV-1 infection was evidently a new thing for the participants, it
is quite possible that many of them were just not comfortable in integrating the vaginal
rings into their lives.

 

Furthermore, the trial did not account for anal sex
during the study period. Anal sex is often
associated with high transmission rates. Vaginal rings would not be
protective in such case and participants were only asked about anal sex at the
beginning of the trial retrospectively but not during the trial. Thus for various reasons, it seems highly
possible that it may have distorted the result.

 

Moreover, the result of the per protocol analysis –
assessing the results of those who stuck to protocol (meeting the adherence
standards) is 37%, compared to intention-to-treat analysis of 27% (analysing
all randomized women), suggesting that non-adherence is an important factor. Given
the fact that the trial researchers have admitted that the non-adherence
threshold was set too low13 (i.e. easy to be non-adherent) – with
two sites being excluded from the per protocol analysis – it potentially distorts
the per protocol analysis and undermines the concluded efficacy (biological effect
of the treatment) of the intervention.

 

In addition, it is quite
possible that the male partners of many of the participants had a negative influence on them, given 64% of the
partners in both groups were aware of the ring use. Although dapivirine rings are for females, but this does not mean that their sexual partners have no part to play in it. It is entirely possible that male partners of some of
the participants were cynical or even
worried about the use of such thing as a vaginal
ring, for reasons of poor literacy,
superstition, or other cultural reasons. Besides, during the trial, the rate of usage of condoms by male partners was not taken into consideration, though it is possible
that due to increased HIV awareness or fear of other diseases caused by the participation
of their female partners in the trial may have led to the more frequent use of
condoms by the men.

 

Finally, it should be
noticed that trial was done in the
females of the sub-Saharan region. It is
not a multi-ethnic trial. African women are known to be more genetically
predisposed to bacterial vaginosis that natural vaginal bacteria bearing a protective role in HIV (e.g. lactobacillus crispatus) could easily be
lost14. The fact that ASPIRE was conducted in the
sub-Saharan region has altered the concluded efficacy of topical prophylaxis
and would also limit the generalisability of such conclusion to other
ethnicities.

                                       

These several deficiencies in the trial may change the results in both ways, either falsely showing higher protective
rate or a lower one. These shortcomings
are to be rectified in the future studies.

 

Considering that dapivirine vaginal ring decreased
the incidence of HIV-1 more than 50% in the age group above 21, there is real need for more clinical trials. We must understand that initial trials with oral PrEP were also poor due to low adherence. Most of the trials with oral PrEP drugs showed far better
results when they were carried on as open-label trials with a focus on compliance15.

Thus the ongoing open-label trials on dapivirine vaginal rings (e.g. DREAM,
HOPE and MTN-036)16,17 are expected to deliver more
reliable and stronger evidence for the effectiveness and efficacy of the rings
with better education and control on adherence. Such study design can hopefully
improve the non-adherent situation for all females, including the age group
from 18-21 that ASPIRE failed to address.

 

Next Steps

Focused research effort is crucial to the success of
future studies. Way before ASPIRE, dapivirine was tested on vaginal rings in combination with maraviroc (an
entry inhibitor) in 2009, which showed limitations in its efficacy (as a
combined effect). Top priority had therefore been given to dapivirine
alone in research efforts, until now18. Focused research effort can expedite the research on
dapivirine, helping us understand its role and effectiveness as a topical
antiretroviral agent in HIV-1 prevention.

 

Cognitive-based behaviour change techniques (CBCTs) have
great potential in mitigating the problem of low adherence rate of future
studies. The use of Motivational Interviewing (MI) and other types of CBCTs, has
been proved in its efficacy and effectiveness in medication adherence
intervention in community-based settings19. These techniques can be
used for the future ring studies to enhance women’s adherence behaviour through
improvements in their confidence and sense of self-efficacy in using the ring
to successfully prevent HIV infection. Studies can apply a multi-element
approach, combining CBCTs with educational (i.e. knowledge dissemination) and
behavioural (e.g. application aids) elements to improve the overall adherence.

 

 

Conclusion

In conclusion, it must be understood that African females are bearing the highest burden of HIV-1 epidemic, in the most prominent
areas of the highest proportion of HIV new infection in the world11
despite efforts like sexual education, counseling,
providing free condoms. Earlier studies also demonstrated problem in
sub-Saharan Africa. The dapivirine vaginal ring
has shown its safety and efficacy. It is less toxic than oral drugs, more importantly, it is much easier to use, meaning
adherence would be less of a problem. Studies have indicated that those who
used it found easier to adhere and
integrate vaginal ring into their day to day life, especially with the progress
of time20. Such vaginal ring would also be cost
effective. Hence the ongoing second phase III trials would be of great
importance.

 

Hopefully, this
antiretroviral ring can give us an answer to our current calling for HIV-1
prevention. It seems to give hope as a second tool for prevention (after PrEP)
which can be used under a woman’s
total control – being able to be kept secretly from men, which makes it extremely
beneficial, especially for females who are unable to get their partners to
consent to mutual monogamy or condom use.