The human
immunodeficiency virus (HIV) is the virus that causes AIDS and is one of the most
critical human health and development challenges of our time. According to
UNAIDS, by the end of 2016, there were about 36.7 million people around the
world living with HIV/AIDS1. Of these, 2.1 million were children
(<15 years old), most of whom live in sub-Saharan Africa and became infected
by their HIV-positive mothers during pregnancy, childbirth, or breastfeeding. Of
the people living with HIV, the majority are in low- and middle-income
countries, mostly in sub-Saharan Africa, where women largely bear the burden of
the epidemic1.
Across the world today, there is a high HIV incidence
among women. Women make up more than half of the people infected with HIV in
sub-Saharan Africa, and young women in particular are at least twice as likely
to acquire HIV as young men across the region1. Women are often
disproportionately affected and are at a greater risk of contracting HIV
compared to men, mainly due to biological, gender inequity, economic, and
social reasons.
If left
untreated, HIV can advance to AIDS within two to fifteen years. While treated
HIV is considered a chronic illness, AIDS is the cause of death for 1.2 million
people worldwide each year, making it the second-leading cause of death by
infection, behind tuberculosis1. There is no cure for HIV, however, antiretroviral
medications used as prophylaxis have been proven as effective treatment that
can control the virus and make it less likely to transmit to others. Even
though condoms are still the most effective way to prevent transmission, oral pre-exposure
prophylaxis (PrEP) daily pills are also available. This medication does not
work if not taken correctly and requires regular follow-up with a health care
provider. However, these current prevention options are not enough to significantly
lower the rate of new HIV infections.
Finding
an effective HIV prevention option for women in sub-Saharan Africa has been
challenging. Previous clinical trials of tenofovir-based prophylaxis investigating
medicines and vaginal gels as HIV-1 prevention options for African women found
no reduction in HIV-1 due to the low adherence to prescribed
antiretroviral-containing pills and vaginal gels6,7. Therefore, longer-acting
drug delivery methods, such as antiretroviral-containing vaginal rings, may simplify
use and may help protect people from infection, particularly in sub-Saharan
Africa where men often refuse to wear condoms during intercourse.
A
monthly antiretroviral-containing vaginal ring is a new alternative method to protect
healthy HIV negative women from HIV infection during intercourse and has been
shown to safely help reduce the risk of transmission. The flexible ring is
worn inside the vagina, up against the neck of the cervix, where it slowly
releases the microbicides in small quantities into the walls of the vagina. Therefore,
it offers protection right at the location where infection could occur during intercourse.
The first
efficacy trial of a vaginal ring for HIV prevention, the Ring Study, was
conducted across six sites in South Africa and one site in Uganda2. This
clinical trial studied the effectiveness of a vaginal ring that provides
sustained release of dapivirine, an antiretroviral drug. It enrolled 1959 healthy, sexually active women, aged 18 to 45 years, and
randomised them in 2:1 ratio to
receive self-inserted vaginal rings containing 25 mg dapivirine or placebo. During
follow up, HIV incidence rate was 4.1 per 100 person-years in the dapivirine
group compared to 6.1 in the placebo group, a 31% relative reduction with dapivirine. Incidence of HIV-1 infection was
significantly lower in the dapivirine versus the placebo group (hazard ratio,
0.69; p=0.04)2. In addition,
the
reduction in HIV-1 acquisition was 37% in women older than 21 but only 15% in
younger women.
Along
with the Ring Study, a closely similar efficacy and safety study of the
dapivirine ring—ASPIRE—ran from 2012 to 20153. The objective of this
trial was to determine effectiveness and safety of dapivirine (25 mg)
administered in a silicone elastomer vaginal matrix ring in preventing HIV-1
infection. This was a phase 3, multi-centred, randomized, double-blind,
placebo-controlled trial of a monthly vaginal ring containing dapivirine, a
non-nucleoside HIV-1 reverse-transcriptase inhibitor3. Dapivirine provides
protection against HIV for about a month by slowly releasing chemicals that
keep the virus from making copies of itself. Researchers included healthy,
sexually active, and non-pregnant HIV-1 uninfected women between ages of 18 and
45 years in Malawi, South Africa, Uganda, and Zimbabwe. The primary outcome was
new HIV infection, and the intervention treatment was a vaginal ring containing
the non-nucleoside reverse transcriptase inhibitor, dapivirine.
In
this study, 2629 women were enrolled and followed across fifteen sites in four
countries: Malawi (10%), South Africa (54%), Uganda (10%), & Zimbabwe
(26%). Median age was 26 years (IQR 22-31), less than half (41%) were married,
nearly all (>99%) reported a primary sex partner, 17% reported more than one
partner in the prior 3 months, and nearly half did not use a condom with their
last sex act3.
About
half of the participants (1313) had a ring with dapivirine, while the other
half (1316) had a placebo ring using randomisation of 1:1 ratio to the
dapivirine ring or placebo. All participants
received a comprehensive package of HIV-1 prevention services, which included regular
HIV testing, counselling, treatment for sexually-transmitted infections, and
condoms. Every four weeks, participants took the ring out and replaced it with
another unless they were found to be pregnant. Follow up time was for a minimum
of one year. Of all participants, 2614 (99.4%) women completed at least one
follow up visit. Overall, participants attended 91% of expected follow up
visits (97% after accounting for early withdrawals from the study)3.
A total of 4280 person years of follow up were accrued, with median follow up
of 1.6 years and maximum of 2.6 years.
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A
total of 168 HIV-1 infections occurred, 71 in the dapivirine group and 97 in
the placebo group. HIV-1 incidence rate was 3.3 per 100 person-year in dapivirine
group compared to 4.5 in placebo group, a 27% relative reduction (95% CI 1-46%,
p = 0.046)3. There was no difference in antiviral resistance between
those who developed HIV-1 and those who did not. Good adherence to treatment
was measured by plasma dapivirine concentrations and remaining dapivirine
levels in returned rings. When researchers excluded data from two sites where
women were not returning for their monthly visits or were not using the ring
consistently, they found that the ring reduced the risk of HIV infection by 37%
(95% CI 12-56%, p=0.007)3. Lastly, safety was a co-primary
endpoint. No statistically significant differences in frequency of safety
endpoints between treatment and placebo groups were found.
In
subgroup analyses by country, education, marital status, STIs at baseline,
number of sexual partners, and partner knowledge of study participation, no
differences were found in HIV-1 protection. However, HIV-1 protection differed
significantly by age, with women ?25 years showing significant HIV-1 protection
(61%; 95% CI 32-77%, p=0.02), while those <25 years of age had no statistically
significant reduction in HIV-1 incidence with the ring (10%; 95% CI -41-43%; p=0.02)3.
This indicates that the ring was less effective in younger women.
Age
and HIV-1 protection effectiveness were explored in additional age-stratified
categories. The dapivirine group had 56% (95% CI 31-71%, p<0.001) efficacy
among women older than 21 but offered no protection in those younger than 21. The
first measure used to assess adherence was through quarterly-collected plasma
samples; levels >95 pg/mL, indicating at least 8 hours of continuous use,
defined adherence. Residual drug in returned, used rings was also measured
after the first year of study; levels <23.5 mg (=1.5 mg released, indicating
at least some use during the month) defined adherence3. According to
blood samples taken, the difference in effectiveness between the two age
subgroups could be explained by poor adherence among the younger women, given
by the higher levels of dapivirine in blood among women 21 years or younger. Women
ages 25 and older used the ring more consistently, and thus, had lower levels
of dapivirine.
Overall,
this clinical trial determined that a monthly vaginal ring containing
dapivirine reduced the incidence of HIV-1 infection among African women, with
increased efficacy in subgroups parallel to increased adherence and more
consistent ring use. Risk was reduced by ~1/3 overall and by more than half
among those aged ?22. These are some of the first results to demonstrate HIV-1
protection by a sustained release approach for delivery of an antiretroviral
for HIV-1 prevention.
HIV-1
protection was greater in subgroups with evidence of better adherence to ring
use. Therefore, a strong relationship between adherence and HIV protection is
to be expected in future studies of HIV prophylaxis. No conclusive results on
the lack of efficacy are shown among young women, and the reasons are not
completely understood. It may be a combination of more-frequent sexual activity,
poorer adherence, and increased likelihood of genital inflammation.
Findings
of this clinical trial are together an important step in improving effectiveness
of novel antiretroviral delivery methods, such as medicated vaginal rings for
HIV prophylaxis. Even so, there are several limitations that should be noted.
There may be issues with the use of vaginal rings. We have
no complete knowledge that women developing HIV-1 in the drug group was due to nonadherence
or to nonvaginal exposures. Women who used the vaginal rings for HIV-1
prevention may acquire HIV through nonvaginal exposures and then conclude that
the products were ineffective. This clinical trial does show that vaginal rings
do reduce HIV acquisition in some women, but perhaps only in people with only
vaginal exposure. The dapivirine vaginal ring is unlikely to provide
substantial protection from HIV-1 in nonvaginal HIV-1 exposures such as anal
sex. However, vaginal sex is responsible for most new infections in African
women. Nevertheless, among individual women, the risk of HIV-1 associated with
anal, intravenous, and other exposures may be particularly important.
It
might have been possible that some women knew they were inserting the rings
with dapivirine. In the study, these rings were self-inserted, so there might also
not have been any level of standardization in the way rings were inserted and
removed across all sites. The participants may have inserted and removed rings
in different ways, and rings may have been removed at time of intercourse. This
lack of standardization may have affected the outcomes found. Measure of adherence
conducted by researchers may have affected the study blinding as measuring
adherence was their way of excluding two sites from the final analysis. Furthermore,
psycho-social features that would relate to use and acceptability of rings may
be one of the reasons for the low adherence seen among younger women. This
psycho-social aspect of vaginal ring use could be further investigated. Low adherence
among young women is also seen in contraception settings4, so potential
research could also focus on a setting in which there is proven effectiveness and
demonstration of safety and evaluating if adherence might differ than what was
seen in the ASPIRE study.
This
particular study was multi-centred, and any results found may conflict with
generalisability as the testing of these rings was conducted on women across multiple
different countries in one geographical region. The findings of this may not be
applicable to other women populations.
Open label
extension studies are the next step forward, and these studies can also provide
answers to questions, such as how women will use the ring when they know that
it actually provides protection. Open-label extension studies of vaginal rings
may guide best practices on identifying and counselling persons who practice
anal sex or inject drugs. Once licensed and approved for public use, the dapivirine
ring could address a central gap in HIV prevention strategies, and fill the need
for a discrete tool that women can use to take charge of their own health and
protect themselves from HIV infection. Further pharmacokinetic analyses may also help define
whether there is a threshold use of dapivirine for protection against HIV-1,
analogous to investigations that have followed the initial clinical trials of
tenofovir-based prophylaxis. Notably, in tenofovir studies, adherence was
greater in open-label evaluations following placebo-controlled trials.
