The distinctive feature of the human immunodeficiency virus (HIV) epidemic in Sub-Saharan Africa is the burden on women, in particular young women of reproductive age. Consequently, most late-phase effectiveness microbicide clinical trials are conducted in sub-Saharan Africa where fertility rates are high. Because late-phase clinical trials are conducted over prolonged periods of time, women participating in these trials may fall pregnant during the trial. Their unborn babies may be exposed to a drug whose teratogenic potential is unknown if the investigational drug is not withdrawn. High pregnancy rates in such trials may compromise statistical integrity, as women will be withdrawn from the study drug for the duration of the pregnancy. It is therefore imperative for microbicide trials to implement effective contraceptive and pregnancy management programmes that maintain low pregnancy rates and the safety of unborn babies while not compromising the conduct and statistical integrity of the trial.
Introduction
A distinctive feature of the human immunodeficiency virus (HIV) epidemic in the 21st century is its increasing burden in women, particularly young women. Women now account for about one-half of all people living with HIV, and for more than 60% of new infections in Africa, where heterosexual transmission is the primary driver of the epidemic. Africa is the only region where this occurs, with young women in the reproductive age group bearing the brunt of the epidemic. This is also the region where fertility rates are high as a result of cultural norms and expectations, and where socio-cultural gender dynamics prevail in sexual relationships. This affects a woman’s ability to make independent decisions about her sexual and reproductive health, often negatively.
Barrier contraceptive methods are an effective HIV and pregnancy prevention strategy; however, many women in Africa are unable to negotiate successfully their use with male partners, often for socio-cultural reasons. Therefore, a method that women can initiate or control is urgently required. As a result of the shortfall of barrier contraceptive methods to protect women against HIV acquisition, a topical virucide that could block HIV transmission by the vaginal route was suggested as an alternative strategy in 1990. Since then, three generations of various intravaginally administered microbicides, with varying mechanisms of actions, have been tested. To date, one antiretroviral-based and 12 non-antiretroviral-based microbicide effectiveness trials among women have taken place to assess their effect on the prevention of HIV infection, with varying success rates ( Table 1 ). The 14 th trial implemented in 2009 is currently ongoing, and its results are anticipated early in 2013. The most recent to be implemented is the South African study, FACTS 001, with an anticipated completion date in 2013.
| Microbicide trial | Study product | Study Phase | Number enrolled (N) | Number included in analysis (N) | Age (years) | Study population | Study duration | Study sites |
|---|---|---|---|---|---|---|---|---|
| Surfactants | ||||||||
| Kenya N-9 Sponge Trial | N-9 | III | 138 | 116 a | – | Female sex worker | 1987–1990 | Kenya |
| FHI N-9 Film Trial | N-9 | III | 1292 | 1170 a | 18–45 | Female sex worker | 1994– 1996 | Cameroon |
| Low-dose N-9 gel Trial | N-9 | III | 278 | 262 a | 18–48 | Female sex worker | 1996– 1998 | Kenya |
| UNAIDS COL-1492 Trial | N-9 | II/III | 892 | 765 a | over 18 b | Female sex worker | 1996–2000 | Benin, Côte d’Ivoire, South Africa, Thailand |
| FHI Savvy Trial/Ghana | C31G | III | 2142 | 2038 a | 18–35 | Sexually active | 2004–2005 | Ghana |
| FHI Savvy Trial/Nigeria | C31G | III | 2153 | 2082 a | 18–35 | Sexually active | 2004–2006 | Nigeria |
| Buffers and blockers | ||||||||
| CONRAD Cellulose Sulfate Trial c ,17 | Cellulose sulfate | III | 1147 | 1122 a | over 18 | Sexually active | 2005–2007 | Benin, India, South Africa, Uganda |
| FHI CS Trial | Cellulose sulfate | III | 1644 | 1506 a | 18–35 | Sexually active | 2004–2007 | Nigeria |
| Population Council Carraguard Trial | Carraguard ® | III | 6202 | 6005 d | over 16 | Sexually active | 2004–2007 | South Africa |
| MDP 301 (0.5% & 2% PRO 2000) | PRO 2000 ® | III | 9385 | 8859 a | over 18 e | Sexually active | 2005–2008 | South Africa, Tanzania, Uganda and Zambia |
| HPTN 035 0.5% PRO 2000 and Buffergel ® Trial | PRO 2000 ® and Buffergel ® | II/IIb | 3087 | 3050 a | over 18 | Sexually active | 2005–2009 | Malawi, South Africa, Zambia, Zimbabwe, USA |
| Antiretroviral drugs | ||||||||
| CAPRISA 004 Tenofovir gel Trial | Tenofovir | II/IIb | 1085 | 889 f | 18–40 | Sexually active | 2007–2010 | South Africa |
| MTN 003 VOICE Trial | Tenofovir | IIb | Ongoing | Ongoing | 18–45 | Sexually active | 2009– Present | South Africa, Uganda, Zimbabwe |
| FACTS 001 Trial | Tenofovir | III | Ongoing | Ongoing | 18–30 | Sexually active | 2011–Present | South Africa |
a Sample size based on a subset of the intent-to-treat population for whom at least one post-enrollment HIV evaluation is available.
b In South Africa the age was 16 years or older.
c Data from the two sites in India (Chennai, Bangalore) were not included in this analysis because only two pregnancies were observed in those sites and because of the high prevalence of surgical sterilisation. See Halpern et al (2011).
d Individuals were excluded from the analysis if they did not have at least one post-enrolment HIV evaluation, if they had window period seroconversion, or if they only returned unused applicators.
e In Tanzania and Uganda, the age was 16 years or older.
f Individuals were excluded from the analysis if they they did not have at least one post-enrolment HIV evaluation, were co-enrolled in another microbicide trial, were in a microbicide trial less than 12 months ago, or had window period seroconversion.
One of the greatest challenges in conducting these trials has been the associated high pregnancy rates. In clinical trials of experimental drugs where teratogenic effects on the fetus are not fully understood, participants who become pregnant during the trial may be taken off the product for safety reasons. Microbicides are relatively new developmental drugs whose pharmacokinetics and pharmacodynamics are not completely understood. They act locally, however, and their systemic absorption is either minimal and transient or unlikely, and trans-placental fetal exposure via systemic circulation is therefore likely to be insignificant. Taking pregnant women off the study drug may be a prudent cautionary option, as no specific guidelines are available for their inclusion in late-phase clinical trials. In microbicide trials, high pregnancy rates with discontinued product use have implications for the design, conduct and generalisability of the results, including the loss of power and effect size of the study outcome in an intention-to-treat analysis.
To address the challenges of high pregnancy rates and potential adverse pregnancy-related outcomes, various trials have implemented different strategies with varying levels of success. Although some trials reported pregnancy rates as high as 64 per 100 person years with time off product loss as high as 151 per 100 person years, recently completed trials have achieved pregnancy rates as low as four per 100 person years with negligible time off product lost. In this publication, strategies used by previously completed trials to enhance contraceptive use and reduce pregnancy rates while maintaining the safety of the fetus are reviewed. The successes and failures based on the respective strategies as measured by contraceptive uptake and pregnancy rates are compared. On the basis of these outcomes, strategies that may be selected for future use in these trials are recommended, and gaps in current knowledge are identified.
Contraceptive use management
Need for a contraceptive programme
Of the estimated 208 million pregnancies that occurred in 2008, about 86 million were unintended, of which 33 million resulted in unplanned births, 41 million in abortions, and the remaining 11 million in spontaneous miscarriages. Although some unintended pregnancies occur in women on a contraceptive method as a result of method failure with either typical or perfect use, others occur in women who are not on a contraceptive method at all. Outside of research, almost one-half of unintended pregnancies occur in women not on any contraceptive method. The Guttmatcher researchers reported that, in 2001, almost one-half of the 6.4 million pregnancies in the USA were unintended and, in 52% of these, no contraceptive method was used during the month of conception. It is essential, therefore, to prevent or reduce unintended pregnancies and minimise the sequalae on the efficiency of trial conduct and statistical integrity. An intensive contraceptive programme has to be implemented in any microbicide trial.
Besides the mismatch in pregnancy intentions and contraceptive use behaviour, women may not be on a contraceptive method for other reasons, including poor access and availability owing to high cost and unavailable or limited family planning services. It is important that microbicide trials endorse strategies that make contraceptives widely accessible and available, but also accentuate contraceptive uptake and use. Researchers conducting microbicide trials should promote the use of highly effective and reliable contraceptives throughout the study period in order to keep rates of unplanned and unwanted pregnancies to a minimum. Strategies from screening and enrolment through to follow up and exit visits have been used by various microbicide studies with varying degrees of success ( Table 2 ).
| Microbicide trial | Screening | Enrolment | Follow up | Provision | Exit | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Contraception Use | Eligible method prespecified | Not using contraception (%) | Oral contraceptive pills (%) | Injectables (%) | Condom/barrier (%) | Other (%) | Frequency of visits | Assessment of method frequency | On-site provision | Free | Methods other than condoms | Not using contraception (%) | ||
| Surfactants | ||||||||||||||
| Kenya N-9 Sponge Trial | No | No | – | 25 | – | – | – | Monthly | Exit | No | – | – | – | |
| FHI N-9 Film Trial | No | No | 87 a | – | 5 a , b | – | – | 8 a | Monthly | – | No | – | – | – |
| Low-dose N-9 gel Trial | No | No | 49 | 14 | 15 | 11 | 7 | Monthly | – | No | – | – | – | |
| UNAIDS COL-1492 Trial | No | No | – | – | – | – | – | Monthly | – | No | – | – | – | |
| FHI Savvy Trial/Ghana , d | No | No | 39 a | 12 a | 2 a | 47 a | 0.6 a | Monthly | – | No | – | Family planning counselling c | – | |
| FHI Savvy Trial/Nigeria , d | No | No | 8 a | 15 a | 1 a | 75 a | 1 a | Monthly | – | No | – | Family planning counselling c | – | |
| Buffers and blockers | ||||||||||||||
| CONRAD Cellulose Sulfate Trial , d | No | No | 13 a | 8 a | 24 a | 47 a | 9 a | Monthly | – | Yes e | Yes | OCPs, Injectables | – | |
| FHI CS Trial , d | No | No | 27 a | 16 a | 1 a | 55 a | 0.3 a | Monthly | – | No | – | Family planning counselling c | – | |
| Population Council Carraguard Trial , f | No | No | 23 | 8 | 42 | 18 | 14 | Quarterly | Quarterly | Yes e | Yes | OCPs, injectables | 20 | |
| MDP 301 (0.5% and 2% PRO 2000®) | No | No | – | – | 56 g | – | – | – | Monthly | – | Yes | Yes | OCPs, injectables, IUD h | – |
| HPTN 035 0.5% PRO 2000 ® and Buffergel ® Trial , i | No | No | – | 20 | 48 | – | – | Monthly | Quarterly | Yes e | Yes | OCPs, injectables | – | |
| Antiretroviral drugs | ||||||||||||||
| CAPRISA 004 Tenofovir gel Trial | Yes | Yes j | 0 | 16 | 82 | 29 | 2 | Monthly | Monthly | Yes | Yes | OCPs, injectables, IUD, h tubal ligation h | 5 | |
| MTN 003 VOICE Trial | Yes | Yes j | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing | Monthly | Monthly | Yes | Yes | Contraception Services k | Ongoing | |
| FACTS 001 Trial | Yes | Yes j | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing | Monthly | Quarterly | Yes | Yes | OCPs, injectables, IUD, h sterilisation, h implants h | Ongoing | |
a Percentages were calculated using the primary-analysis population.
b 5% was reported for ‘hormonal’ contraception, which included OCPs and injectables.
c Family planning counselling was provided with referral to services if requested.
d Data were supplemented with information from Halpern et al. (2011).
e Trials began with contraception not always provided on site and then changed to on-site management.
f Data were supplemented with information from Friedland (2009).
g 56% of the population was considered to have ‘effective contraception’, which included sterilisation, IUD, or use of injected, implanted or oral contraception.
h Referred to family planning clinics.
i Data were supplemented with information from Abdool Karim (2007).
j Effective contraception for enrollment includes non-barrier methods such as hormonal (oral, injectable), IUD, and sterilisation.
k Study staff will provide contraceptive counselling to enrolled participants as needed throughout participation and will facilitate access to contraceptive services through direct service delivery.
Eligibility criteria
Early trials implemented before 2007 studying the first two generations of non anti-retroviral-based microbicides (i.e. the surfactants and polymers), did not specify contraceptive use as an eligibility criterion for trial participation ( Table 2 ). Perhaps that was understandable given that some of the earlier microbicide agents such, as nonoxynol 9, a spermicide, and cellulose sulphate, an entry inhibitor, also possessed a primary underlying contraceptive effect. Pregnancy rates were not high in the nonoxynol 9 trials, and were found to be comparable to those of cellulose sulphate (CS) as established in a (CS) non-comparative trial. In addition, this was in the early days of microbicide trials before the scale of the effect of high pregnancy rates could be appreciated. A first meeting of experts to discuss pregnancy-related challenges in microbicide trials was convened in 2005. This was a culmination of lessons learned from ongoing trials in the field, with pregnancy rates as high as 64 and 37 per 100 person years overall in the Savvy/Ghana and Savvy/Nigeria trials, respectively and 76 per 100 person years in one of the Ghana sites. In the meeting, a recommendation to specify contraceptive-related eligibility criteria among others was made. Subsequent discussions by experts in the field occurred at the 2006 microbicide conference in Cape Town, and again at the pregnancy and contraception in microbicide clinical development meeting in 2009.
Microbicide trials implemented after this era, such as CAPRISA 004 implemented in 2007, MTN 003 implemented in 2009, and FACTS 001 implemented in 2011, specified contraceptive-related eligibility criteria, including enrolment of women on a pre-specified eligible type of contraceptive method. To date, CAPRISA 004 is the only published study that included contraceptive use as an eligibility criteria and enrolled women with documented evidence of contraceptive use ( Table 2 ). These women were counselled. If they voluntarily opted for contraceptive use at screening, they were commenced on a contraceptive method. Consequently, it is the only study with 100% contraceptive uptake at baseline.
Recent studies on microbicides have used various specifications to define an eligible method of contraception, ranging from reliable to effective to non-barrier methods. The definition of an “effective” method was based on the conventional typical use rates characterised by a pregnancy risk of 3% or less in the first year of use. Additionally, in the context of these trials, other attributes to consider would be a method that is less user dependant, less likely to be used inconsistently, and with less provider training requirements. The CAPRISA 004 trial had inclusion criteria for non-barrier methods of contraception. This strategy was based on the high probability of inconsistent use of barrier methods which could result in higher pregnancy rates. Barrier methods, however, were promoted and supplied widely, but were promoted as part of risk-reduction counselling to reduce the acquisition and transmission of sexually transmitted infections, HIV and other reproductive infections. This strategy was included in the comprehensive contraceptive curriculum used and implemented by the CAPRISA 004 trial, which achieved around 80% uptake of long-acting injectable contraceptive methods during the trial.
Some concerns have been raised with pre-specifying contraceptive eligibility criteria. One concern is that it may compromise enrolment targets. This was not evident in CAPRISA 004, 10 however. Of the total number of 2160 women screened, only 26 out of 1075 women did not fulfil the criteria of trial entry of not being on an eligible contraceptive method. Another ethical concern with pre-specifying contraceptive-related eligibility criteria is that it might be misinterpreted as mandating a certain contraceptive method among women who are interested in participating in a trial but who would prefer to use a non-eligible method. To date, no consensus on this has been achieved. Unless there is evidence to the contrary, this strategy is recommended for implementation in clinical trials, as it ensures enrolment of women less likely to default taking contraceptive methods.
On-site provision of free contraceptives
Accessibility and availability of contraceptive facilities and methods are not always optimal in countries in which these trials are conducted. It might be problematic to therefore prescribe contraceptive practices within a study when the pre-specified methods are neither accessible nor available, or they are not provided as per the local national contraceptive programmes. It is therefore in the best interest of the trial sites to provide eligible methods as well as ongoing care and counselling that are necessary with such a service. Providing family planning services within clinical trials, however, poses extra burdens on the trial resources and infrastructure. This is a specialised service necessitating staff training to provide and switch methods when indicated, manage complications, and to maintain a constant supply. Implementation of this service has proven to be a necessary and rewarding trade-off, as direct temporal effects have been seen in lowering pregnancy rates after implementation of on-site contraceptive provision.
Studies or sites within studies that have introduced on-site provision of contraceptives from the beginning or sometime during the study have achieved either the lowest or drastic declines in their pregnancy rates after implementation of this strategy. The latter was seen with some sites of the Population Council’s Carraguard, HPTN 035 and MDP 301 trials. The Population Council’s South Africa sites observed declines in pregnancy rates after revising their contraceptive strategy to include on-site provision after high-incident pregnancies between 2004 and 2005.
At the Medical University of Southern Africa, the incidence decreased from 60 in 2005 to 23 per 100 person years in 2006. At the Medical Research council and University of Cape Town, a decrease in rates from 51 and 43 in 2005 to 32 and 14 per 100 person years in 2006, respectively, were clearly evident. Similarly, the pregnancy rates in the Microbicide Development Programme 301’s Zambia site decreased stepwise from 23% to 18,6% to 12,9% after implementation of contraceptive provision, family planning checklists and training of staff on counselling. All these studies, however, emphasised one thing in common; the implementation of free on-site provision combined with training of staff and ongoing counselling of participants were together effective in increasing contraceptive uptake and reducing pregnancy rates.
Ongoing counselling by trained staff within clinical trials
Counselling by trained clinical trial staff is an important part of offering contraceptive services, as it affords an opportunity to assess compliance, manage complications and adverse events, and guide method switching. This is important, as it has previously been reported that ineffective contraceptive use, rather than non-use, contributes to unintended pregnancy. In high-income countries, it has been reported that most women undergo legal termination of pregnancy as a result of contraceptive failure, whereas only a small proportion are caused by non-use of contraception. In Eastern European and South Asian countries, as many as two-thirds of abortions are due to contraceptive failure, and one-third are due to unmet needs for contraception.
In CAPRISA 004, method switching and the oral contraceptive pill use were significantly associated with high pregnancy incidence. Because of ongoing monitoring of contraceptive usage at monthly counselling sessions, the need for additional counselling to participants on oral contraceptives owing to the high number of pregnancies that resulted because of inconsistent use was identified. Once implemented, these measures improved adherence to contraception as uptake remained high, and kept pregnancy rates reasonably low, with only 5% of the women not on a documented contraceptive method at study exit ( Table 2 ). In the Population Council’s Carraguard trial, only 20% were not on a contraceptive method after modification of the contraceptive guidelines to provide support to women. In the MDP Zambia site, pregnancy rates dropped from 23 to 12.9% within 16 months after implementing counselling coupled with on-site provision. This indicates that developing a contraceptive curriculum that is tailor made to suit the needs of the participants is effective in keeping contraceptive uptake and use high in a clinical trial.
Investigators from CAPRISA 004, Microbicide Development Programme 301, HIV Prevention Trials Network 035, and Population Council concluded that the targeted contraceptive curriculum significantly enhanced contraceptive uptake and use, and recommended therefore that future microbicide trials should factor the implementation of these comprehensive curriculums in their protocol development and budgets.
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