Monthly HIV-1 infections, low adherence to the

Monthly Vaginal Dapivirine Ring:

A New PrEP Technique for
HIV-1 Prevention in Africa

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HIV
is a life-threatening disease affecting 25.6 million people in Africa. Despite
antiretroviral medications were shown to decrease HIV-1 infections, low
adherence to the regimen seems to have undermined its effectiveness. A recent,
randomized controlled trial sought to reduce the adherence challenge through a
monthly vaginal microbicide-releasing ring containing dapivirine.

Refers to Baeten J, Palanee-Phillips T,
Brown E, Schwartz K, Soto-Torres L, Govender V et al. Use of a Vaginal Ring
Containing Dapivirine for HIV-1 Prevention in Women. New England Journal of
Medicine. 2016;375(22):2121-2132.

     I.        
HIV
Pandemic and Prevention

As a type of infectious
disease, Human
immunodeficiency virus (HIV)
threats people’s life by attacking the human immune system. In 2016 alone, one
million deaths were related to HIV globally.1

HIV
heterogeneity can be observed regionally and sexually. The African region has
the highest prevalence of HIV and new infections rates. Globally, 25.6 out of
36.7 million people living with HIV were in the African region by 2016.1
Also, Africa alone makes up two thirds
of new HIV infections among all ages.2,3 African women are at an
even higher risk. In the eastern and southern African areas, 56% of adults infected with HIV in
2015 were female, and HIV infections in young females were double that of young
male’s.2 Therefore, HIV prevention in the African region, especially
for African women, is imperative.

New HIV prevention approaches have been
continually developing. In the early years, major prevention approaches
included condoms, STI treatments and HIV vaccines. Among these, condoms were
more than 70% effective in HIV serodiscordant couples.4 Male
circumcision was reported to reduce HIV transmission from men to women by 60%,
according to a randomized, controlled trial conducted by Williams et al.5
Vaginal microbicides were developed around 2008, but no significant effect was
observed at that time. HIV vaccines showed a low level of efficacy that was not
significant enough to be applied outside a trial setting.6 STI
treatments failed to show a significant effect, either.7,8

In 2010, HIV Prevention Trials Network
(HPTN) Study 052 revealed that antiretroviral therapy (ART) was significantly
effective, preventing 96% of genetically linked infections caused by HIV-1.9 This was a milestone
for antiretroviral medication (ARV), and because of its high effectiveness, it
is thought to be a promising medication for pre-exposure prophylaxis (PrEP). Consequently,
a large number of studies were conducted on the uses of ARV. Various ARV-based prevention tools have been
developed, including oral pills; ARV injections; rectal gels;
vaginal tablets, gels, films and rings; thin film polymer; nanofibre
and phosphate buffered saline.10 Active drugs include tenofovir
(TFV), tenofovir/emtricitabine (TFV/FTC), tenofovir disoproxil fumarate/emtricitabine(TDF/FTC) and Dapivirine.
A wide range of trials from pre-clinical
trials from phase? through ? clinical
trials have also been conducted.10

 

   II.        
 Low Efficacy of ARV among African Women

ARV medication is expanding its
influence around the world. In 2015, ARV was recommended by WHO as an HIV
prevention approach, and it was further approved by WHO in 2016 in its
consolidated guidelines.11 In practice, ART became more accessible
to people living with HIV (20.9 million in 2017compared to 7.7 million in
2010).2

Increasing implementation of ARV is
expected to lessen the HIV disease burdens among African women. However, ARV’s
effectiveness varies among different trials conducted in Africa. High
effectiveness was demonstrated in several trials, including the study by Baeten et al. in Kenya and Uwanda,12
in which a 67% reduction in HIV incidence was observed in the population after
taking TDF; a 75% reduction was seen with TDF-FTC in heterosexual men and women; and an
efficacy of 62.2% was observed in a daily TDF/FTC trial conducted in Botswana
with heterosexuals.13

Notably,
the effectiveness in trials among African women was relatively low. For
example, in a tenofovir-based
PrEP study of African
women, the effectiveness was –49.0%,
-4.4% and 14.5% for TDF, TDF-FTC and TFV gel, respectively.14 Moreover,
the FACTS 001 Study did not confirm tenofovir’s effectiveness in a large group
of young African women, with an outcome of 0% effectiveness.15

One
common reason for the limited effectiveness in these trials was low adherence
to medications. The adherence intervention result from a tenofovir-based PrEP
for (CAPRISA 004) trial supports this assumption. The adherence score was between
72.2% and 82.0% from low to high adherence groups, and a consequent
effectiveness score between 54% and 64% in this study. Moreover, women in the
high adherence group had the highest positive tenofovir effect.16
However, in practice, it is difficult to control people’s actual use of these
medications. For some medications, such as oral PrEP, daily dosing adherence is
essential to achieve efficacy. Eventually, even
though medications have become available to African women, HIV infection rates
will likely remain high.

In
this setting, to improve the ARV effectiveness among African women, a long-acting form of antiretroviral
prevention seems to be more desirable than daily pills.

 

III.        
Key
Details of the Study & Analysis

To
address this need, a monthly vaginal ring containing dapivirine is thought to
be able to deliver long-acting
effectiveness. To investigate this assumption, a double-blinded, randomised,
placebo-controlled trial was conducted at 15 sites in Africa.17 The researchers randomly
assigned 2629 African women, aged 18 to 45, to either an intervention or
placebo group at a 1:1 ratio. Each woman in the intervention group was given a
vaginal matrix ring made of silicone elastomer and containing 25 mg of
dapivirine. Each woman in the control group was given a placebo ring. The women
were required to return the ring monthly, and a new ring was provided. Neither
the participants nor the investigators were aware of who was in the control
group and who was in the intervention group during the trial. Drawing from findings of a 27% lower
HIV infection incidence rate on average in the intervention group, researchers
concluded that a monthly vaginal ring containing dapivirine can effectively
reduce HIV in African women, and increased efficacy was found in higher
adherence group.

Notably, the study result of 27% reduction
was drawn from a wide confidence interval from 1 to 46. And
the p-value (P=0.046) indicates the evidence is not strong. Such an outcome
suggests that the efficacy of monthly
vaginal dapivirine rings for African women varies.

One
important finding is that efficacy variations are associated with adherence.
And such adherence differences can be found across study sites and age groups.

A total of 15 sites were set at the beginning
of the study; however, two sites had a lower adherence rate than expected.
There were 29 infections among the 234 participants at these two sites.17
Of these infections, 17 were in an intervention group, and the other 12 were in
the placebo group.17 The analysis shows that, after excluding these
two sites, the incidence reduction rate increased to 37% (95% CI, 12 to 56; P=0.007) in the intervention group. 17
Compared to that of 27% in the 15 sites, a change of 12% is remarkable. Low
levels of adherence were consistent with low dapivirine levels in plasma
samples.

Additionally, the positive relationship
between dapivirine adherence and effectiveness could also be found among age
groups. During the first 30 months, in
the youngest age group (aged 18 to 21), the lowest adherence rate was observed;
the incidence rate in the youngest dapivirine group was higher than that of the
placebo group. The
protection effectiveness of dapivirine was -27% (95% CI, -133 to 31; P=0.45). 17 However, after
the 30th month, the adherence rate increased sharply from around 64%
to 70%17 as shown in the bottom right “Plasma and Ring”
chart below (this figure is on page 2129 of the original report).
Interestingly, the
incidence rate in the dapivirine group became lower than the placebo group simultaneously, as shown in the top left “Cumulative
Incidence” chart for 18–21
age group. This illustrates that increasing adherence to the ring
is likely to decrease the HIV incidence rate. Despite the fact that this change was not reported in the
study, this observation can further expand the assumption about the association
between dapivirine adherence and its effectiveness in treating African women.

 

Another key contribution of this study is its confirmation
of the safety using the monthly
vaginal dapivirine ring. It compared the frequency of primary safety points,
adverse events, incidents of sexually transmitted infections and antiviral
resistance between intervention and placebo groups. No significant difference
was observed in any of the above categories. This result paves the way for the
following larger trails.

 

 IV.        
Strengthens
and Weaknesses of the Study

In
the context of previous ARV trial limitations and the doubts raised about ARV
effectiveness in preventing HIV among African women, this study conducted by Baeten
et al was a breakthrough. It was the first study that offered evidence on the
effectiveness of sustained delivery of ARVs.

One
major strength of this study is that it added a post hoc analysis on age. As
indicated in the report, pre-specified subgroups on age included only two
groups, older or younger than 25 years. After realizing the potential influence
of age on HIV protection efficacy, three subgroups were formed. Moreover,
nearly the same number of HIV infections (around 44) were assigned by the
researchers to each group. This thoughtful design gave equal statistical power
in each age-characterized subgroup, thus avoiding the potential confounding of
age in subsequent analysis to a large extent.

Compared
to related previous studies, the study design was more enhanced and complete.
Regarding the study sample, the sample size was large for this study (5516
screened and 2629 enrolled).17 Some previous studies concerned with
the monthly dapivirine ring also conducted by IPM (International Partnership
for Microbicides) were limited to a small sample size. For instance, in trial
IPM 001, only 12 women were enrolled.18 Trial IPM 008, IPM 018 and
IPM 024 also contained less than 30 participants.18,19,20 Among all
the completed IPM studies relegated to the dapivirine ring, this study was the
largest one until now.

Of
note, the follow-up time of this study was also longer. Previous trials of the
same theme as “Safety, Acceptability and Adherence of Dapivirine Vaginal
Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in
Sub-Saharan Africa” by Nel et al. were only 12 weeks.21 To
investigate the efficacy of long-acting
HIV prevention, a relatively longer follow-up time is preferable. It allowed
the Batean’s study to consider more information, including the African women’s
growing comfort with and adaptation to the dapivirine ring over time. According to the
report’s adherence status, use of the ring by older African women (aged 22 to 45)
became stable after a short period during the study.17 This
suggested the feasibility of a monthly dapivirnie vaginal ring for African
women over the long term. Additionally, this study also benefitted from its
multi-centre design. Fifteen
study sites were based in five African countries: Malawi, South Africa, Uganda and
Zimbabwe, increasing the sample diversity and enabling researchers to compare
results among a range of population groups.

Despite
the fascinating findings, there remain some problematic points in this study.
One most noticeable issue is the measurement of adherence. Adherence was
measured by the plasma dapivirine level in this study. Less than 23.5 mg of
dapivirine in the plasma was treated as being in adherence.17 To
distinguish whether the participants only used the ring shortly before the
collection or not, the researchers tested the plasma level of dapivirine and
defined adherence as greater than 95 pg per millilitre. However, as stated in
the report, this level can be achieved after 8 hours of continuous use.17
This mean that the results could be inaccurate if participants removed the ring
during the month and put it back again before the visit –  making the adherence rate higher than the
actual rate. An overestimation of adherence rates could mislead an
investigation into the association between dapivirine ring adherence and its
performance. Compared to that, Grant et al. investigated daily doses of TDF/FTC
in preventing HIV in men who have sex with men,22 and described a
more rational study design for examining adherence. Researchers included
diverse approaches in measuring the level of pill using: self-reporting, counting pills, as
well as blood and hair measurements of drug concentration. Therefore, the
measurement of adherence in this report needs a more thoughtful consideration.

Lack of sufficient pre-specified age-characterized groups might also impair
the power of the study.
The post hoc analysis of age groups offered insightful results on age and
adherence, yet assigning the groups artificially can also lead to some
confounding. In the study, researchers designated an equal number of HIV
infected participants into each age groups. In reality, however, the incidence
could be more diverse than this artificial assignment. Thus, the analysis from
this report might not reflect the actual incidence and adherence among African
women.

 

   V.        
What
are the Next Steps?

Before
determining whether the effectiveness of a monthly dapivirine ring is
sustainable or not, longer study periods
are required. According to the most up-to-date news, this concern has been put
into practice already. Currently, two open-label extension studies have already
been underway to prolong previous studies. The open-label extension trial for Baeten et al.’s study is called HOPE (MTN 025-OLE). Another is DREAM (IPM OLE),
which is the the Ring Study (IPM 027)
extension.23 In these extension studies, former trial participants
were given dapivirine ring for an additional year. During this stage, additional
data can be collected to address the remaining concerns and can help clarify the discussion on
whether resultant benefits of the ring discussed in the report declined or not.
More data is also needed in explaining the reason for low effectiveness in the
adolescent group to answer questions like “Is it the result of biological
difference, non-effective medication or low adherence?”.

This
study left doubts about the variations of effective treatment among age groups,
especially the youngest group. This warrants further investigation on the
impact of age on the efficacy of dapivirine vaginal rings. At the current stage,
several studies focussing on adolescent girls are also being conducted. One
study, MTN-034/IPM 045, enrolled 300 healthy adolescent women aged 16 to 21. 24.
In this Phase 2a, multi-site, randomized, open-label study, the same vaginal
ring containing 25 mg of dapivirine as used by Baeten et al. is given to
participants. Such a study, using the same medication, is expected to give
comparable results and to better illustrate the effect of the dapivirine
vaginal ring on African young girls. Important challenges in adherence remain.
A closer examination of adherence can include more accurate detection
approaches, a higher frequency of clinic visits and a combination of objective
and subjective reporting to measure medication usage consistency.

In the real world, policymaking and
implementation is key to reducing HIV infections in African women. Access to
ARV medications such as the dapivirine ring is expending today, but slowly. The
current implementation status in Africa also varies among countries. PrEPWATCH
illustrated PrEP’s implementation status by country files. In Nigeria, even
though the political framework of “National Guidelines for HIV Prevention Treatment and Care” was established, drug
registration status has been delayed. The status for the TDF/FTC drug is
awaiting approval for use as a preventative and is not yet registered as of the
end of 2017.25 The same “non-registration status” can also
be found in other African countries, including the Congo and Ethiopia.25
Therefore, another important next step is to ensure the implement of policies
in practice. From a public health perspective, such a situation implies that
success in trials is not the same as success in reality. There remains a long
way to go between the development of medication and its actual public benefits.