ARV-based microbicides: second-generation efficacy trials

‘Second-generation’ microbicide candidates are entering large-scale effectiveness trials at a time when the field of new prevention technologies (NPTs) has widened. More pre-exposure prophylaxis (PrEP) efficacy trials are now underway or planned than microbicide trials. Also underway are trials of new HIV-vaccine candidates and ‘test and treat’, a prevention strategy involving the early initiation of anti-retroviral therapy in HIV-positive individuals to reduce the risk of onward transmission to their HIV-negative partners. 

This new generation of microbicide candidates incorporates antiretroviral (ARV) drugs and hold the promise of being far more potent than the first-generation products. As researcher Robin Shattock observed in a 2008 interview: “These are as different from the first generation as chalk from cheese.”1

At least 13 different, ARV-based, microbicidal compounds, in more than 20 studies, have demonstrated efficacy in blocking HIV infection in monkeys. These range from drugs as familiar as tenofovir to ones as exotic as nucleocapsid protein inhibitors and broadly neutralising antibodies. This section will describe those which are currently in effectiveness trials. To provide a clear picture of what is required in these trials, however, it is first necessary to review some of the key challenges inherent in testing candidates in this category.



Pharmacokinetics, pharmacodynamics and the challenge of resistance

One major challenge for any microbicide trial is ensuring that the topically applied drug reaches its target location in a functional state and in the concentration needed. Orally administered drugs like PrEP reach their destination via the blood stream. But microbicides are applied to mucous membranes and work from the outside in. To be effective, enough of the active drug in a microbicide must get across the vaginal or rectal mucosa and into the underlying cells to equip them to resist HIV, if exposed to it. Simultaneously, however, it is vital that no more drug than necessary be absorbed, since high rates of absorption could facilitate the emergence of drug-resistant virus if the person using the microbicide is HIV-positive (a ‘real-life’ possibility if a product is used inconsistently by someone who is not being tested for HIV frequently).

Pharmacokinetics (PK) is the study of how a drug behaves in the body over time, including how, when and where it is absorbed, distributed, changed and then excreted. In the case of microbicide trials, pharmacodynamics (PD) assesses a drug’s activity at its intended site, and measures how long it remains active.

PK and PD testing of animal tissue is also routinely done in preclinical trials to assess the speed and degree of drug absorption in dosed animals, how their cells have responded to it, and whether the drug appears to have caused any difference in their vulnerability to infection following viral challenges. But, as the first-generation microbicide trials have shown, animal data are not always predictive of how drugs will work in humans. As a result, increasingly sophisticated approaches are being developed to meet the challenge of obtaining human PD and PK data accurately and ethically.

Computed tomography (CT scan), magnetic resonance imaging (MRI) and tissue sampling can be used to track radio-labelled hydroxyethyl cellulose (HEC) (used here as a microbicide surrogate) and synthetic semen as they travel up the digestive tract after rectal insertion.2 Their images show that these substances travel as much as 60 cm up the colon. This approach to collecting PK data has been adapted to assess vaginal distribution as well.

Experimentation with human-tissue explants is also providing new techniques for gathering PK and PD data. Human tissue to create these explants is obtained after surgery (hysterectomy, for example) or by biopsy. This tissue is dissected into small blocks and maintained on gel-foam rafts in a medium that keeps the cells alive. If the tissue explants are shown to be susceptible to ex vivo HIV infection (become HIV infected when exposed to virus), they can be used to test the impact of candidate microbicides in preventing such infection. Human-tissue explants, especially from sexually exposed mucosa, such as vaginal or rectal lining, allow for direct observation of HIV infectivity and factors affecting it. 

In one study, for example, explants from participants who had applied UC-781 (an ARV-based gel) rectally showed far fewer infections after ex vivo exposure to HIV than those from participants who applied the placebo gel.3 3

These new methods of collecting PK and PD data are indicative of what researcher Robin Shattock has referred to as the “exquisite technology being brought to bear” on the task of deciding which second-generations candidates should advance into large effectiveness trials. Such innovative research methods will also be required to detect, track and manage the possible emergence of drug resistance among trial participants who are using ARV-based microbicide candidates.

Resistance is the ability of viruses, parasites or bacteria to multiply in the presence of a drug that would normally kill or deactivate them. At present, the likelihood that ARV-based microbicide use might lead to the emergence of drug-resistant HIV is unknown. Also unknown are the chances of an ARV-based microbicide failing to provide protection when challenged by a strain of HIV that is resistant to the ARV used in the product.

Although drug-resistant virus is transmitted more rarely than wild-type, an estimated 5 to 15% of all new HIV infections in areas where ARVs are widely used involve the transmission of drug-resistant virus from one person to another.4 Experts have acknowledged that epidemiological ‘train wrecks’ could occur if ARVs used for both prevention and treatment (such as tenofovir and Truvada, both drugs being tested in PrEP and microbicide trials) are rolled out simultaneously and badly. This could result in a rapid rise in the prevalence and transmission of virus that is resistant to these drugs which would lead, in turn, to first-line treatment regimens being ineffective (especially disastrous in low-income countries where few second-line treatments are available) and a rise in mortality.5 

The question of whether ARV-based microbicide users could develop resistant virus if they seroconvert simply by continuing to use the product is difficult to study before the product is widely available. The emergence of resistance among trial participants is relatively unlikely because participants are tested for HIV very regularly and discontinue their use of the trial product if they test HIV-positive. This means that their exposure to the ARV in the microbicide will likely stop before resistance has a chance to develop (which requires a few weeks to a month on average, in the case of tenofovir). But this does not really tell us much about the likelihood of resistance developing with prolonged use of the product after seroconversion. This is why ARV-based microbicides will likely only be available by prescription and following a recent, negative HIV test.

Emergence of resistant virus may be much less likely to follow microbicide use than the use of ARVs for treatment or as oral PrEP. This is because the amount of drug absorbed into the blood after topical application is generally far less than that after oral dosing. When absorption rates are low, the risk of resistance is small. Moreover, the amount of active drug in a microbicide to start with is also far less than the amount in an oral dose. One tablet of maraviroc (an ARV used for treatment), for example, contains enough drug to make 16 to 20 doses of the candidate microbicide containing maraviroc. Nevertheless, it is a risk that must be thoroughly investigated before non-prescription access to ARV-based microbicides can be considered.

Another response to the risk of resistance is the ongoing quest to identify ARVs which, while not unsuitable for therapeutic use, may be better suited to topical prevention. Dapivirine (also called TMC 120), for example, was abandoned as a treatment drug because of its poor systemic absorption, but is being actively pursued as a candidate microbicide. Development of such alternatives can minimise the risk of ‘train wreck’ scenarios by making it more possible to rely on some drugs for prevention and others for treatment, with minimal overlap.

CAPRISA trial: the first microbicide proven to be effective

While 75 new microbicide candidates are currently in the preclinical and clinical pipeline at this time,6 only three late-stage effectiveness studies of second-generation candidates are now underway or completed. The first two contain tenofovir and Truvada, both nucleoside reverse transcriptase inhibitors (NRTI) drugs. Truvada is a combination of tenofovir and FTC, also called emtricitabine. Topical application of these drugs has shown significant protective effect in monkeys and a range of human safety studies have been successfully completed.

On 20 July 2010, the results of a phase 2B effectiveness trial called CAPRISA 004 were announced with great fanfare. The trial product, a 1% tenofovir gel, became the first microbicide proven conclusively to be both safe and effective – thus demonstrating that a topically applied product can, in fact, reduce an individual’s risk of HIV infection. Conducted by the Centre for AIDS Programme of Research in South Africa (CAPRISA), CAPRISA 004 is notable for historic and scientific reasons. It not only provided ‘proof of concept’, but was also the first microbicide trial to be led by South African scientists and co-funded by the South African government.

CAPRISA 004 enrolled 889 women at two trial sites: one in Durban, South Africa; and one in Vulindlela, a rural community in KwaZulu Natal where the HIV-prevalence rate peaks at 51% among women between the ages of 23 to 24.7 Ninety-five per cent of enrolled participants completed the trial. Participants were randomly assigned to one of two trial arms. Half of the participants used the 1% tenofovir gel and half used an inert placebo gel.

Recognizing that low levels of adherence to the assigned pattern of gel use had been a key stumbling block in previous microbicide trials, CAPRISA researchers developed an unusual protocol called BAT 24, an acronym for the instruction to use a dose Before sex, a dose After sex, and not more than Two applications within 24 hours. Participants were instructed to apply the gel within the twelve hours before sex and again within the twelve hours after having sex – but never more than twice during a 24-hour period, regardless of how often they had sex.

This regimen was developed after in-depth consultations with both international experts and the South African communities involved. It was modelled on the proven protective strategy of nevirapine administration to prevent vertical (mother-to-child) HIV transmission, in which a single dose is given at onset of labour to provide pre-exposure drug to the baby and a second post-exposure dose is given to the baby within 72 hours of birth to boost his or her nevaripine level. Because it avoids daily dosing, BAT 24 has the advantage of reducing unnecessarily frequent exposure to an ARV (thus reducing the risk of side effects and possible emergence of resistant virus). It was designed to maximize adherence and, hence, the potential for protection, especially among women with migrant partners who have sex infrequently.8 

Intensive counselling was also used during the trial. Counsellors worked with women who reported adherence difficulties to develop ‘adherence-support prescriptions’ that contained personalised suggestions and strategies designed to assist them in their individual situations.

The trial results showed that the tenofovir gel prevented four out of ten HIV infections overall. Among participants using the tenofovir gel, 38 new HIV infections occurred; there were 60 among those using the placebo. This result, however, reflects the collective impact of the product among both those who adhered to the trial protocol (applying the product as instructed each time they had sex) and those whose adherence was less than perfect.

A sub-study showed that, among women who used the gel on more than 80% of occasions, efficacy was 54%. Even among the women who used the gel less than half the time, however, 28% fewer infections occurred than were experienced among women in the placebo group.

As expected, adherence to the study protocol also changed over time.  At the end of the study’s first year, 50% fewer infections had occurred among participants using tenofovir. But, as adherence rates declined during the remaining 18 months of the study, this effectiveness rate also declined, which led to the 39% effectiveness rate for the trial overall.9

The gel also reduced the risk of infection with the genital herpes virus, HSV-2, by 51%. In other words, among the trial entrants who did not already have HSV-2, those using the tenofovir 1% gel were half as likely to acquire herpes as women using the placebo.9

CAPRISA 004 included this assessment of herpes infection because tenofovir has a similar molecular structure to drugs used on herpes viruses, such as cidofovir. This additional result is particularly good news because a number of ecological studies have shown that having herpes at least doubles an individual’s chance of acquiring HIV. Surprisingly, randomised controlled studies using anti-herpes drugs to prevent people acquiring or transmitting HIV have produced disappointing results. 

It is important to note that the CAPRISA 004 data showed only that the gel prevented herpes and prevented HIV infection. The trial provided no evidence that preventing infection by one virus caused fewer infections by the other. On the other hand, the researchers noted, the trial was not powered to detect such synergistic effects, so the lack of such evidence does not rule out the possibility that a synergy may exist.10

While rejoicing in this breakthrough, researchers and policymakers concurred that the product is unlikely to become publicly available within the next three to four years, at least. Data from other studies validating the protective effect of tenofovir 1% gel will be required by regulatory authorities such as the South African Medicines Control Council, which may well be the first such body to consider approving the product for national distribution.

Other second-generation trials

As noted above, the results of the CAPRISA trial need to be confirmed by other studies. Fortunately, the VOICE study is already comparing the preventive efficacy of tenofovir gel to that of tenofovir and Truvada pills.  

The trial will enrol approximately 5000 southern African women and randomly assign them to one of five study groups, with three groups taking oral tablets (either tenofovir, Truvada, or oral placebo) and two groups using a gel (tenofovir gel or placebo gel). Participants take their assigned intervention daily, making VOICE the first microbicide trial to explore the feasibility of non-coital product use (when doses are taken on a pre-set schedule that is unrelated to the timing or frequency of sex). If the VOICE trial results, expected in 2011, also show that the gel has a protective effect, these confirmatory data would likely speed up efforts to bring it to market. 

The third of the current wave of efficacy trials is IPM 009, the International Partnership for Microbicides’ first effectiveness trial. Scheduled to start in 2011 and produce results in 2015,11 this trial will test the effectiveness of dapivirine (also called TMC 120), a non-nucleoside reverse transcriptase inhibitor (NNRTI) added to two microbicide formulations. In addition to the standard gel formulation, the drug is also being loaded into a vaginal ring similar to those already in use to deliver contraceptive drugs (such as the NuvaRing) or therapeutic hormones (such as ESTRING or Femring) into a woman's body.  

 IPM’s flexible silicon ring contains 25 mg dapivirine and is designed to stay in place for 28 days. Once in place, the ring delivers a fairly constant level of drug into the vagina throughout the 28-day period, with a small initial burst at insertion and a slight decrease in drug level at the end of the 28-day period.12 PK studies show that the drug distributes itself evenly throughout the vagina when delivered in this fashion. The concept of an inconspicuous, sustained-release device that provides consistent protection over time has been shown to be more acceptable to many women than are products applied daily or before each sex act. For more on alternative delivery options, see Formulation and drug-delivery options.

As of July 2010, five other microbicide candidates have entered clinical trials to gather safety, acceptability and (in the case of maraviroc) baseline PK and PD data. The remaining 70 are still in laboratory trials. Together, these candidates represent a wealth of creative thinking and determined effort. As the Alliance for Microbicide Development points out, however, they are not enough. On average, they note, of about “10,000 compounds entering preclinical testing, only 5 make it to human testing, and only one of those is approved for distribution…. This means that screening programs and efforts to acquire more candidate compounds from the pharmaceutical industry for development as microbicides should be awarded high priority.”6


Candidates in early clinical testing


As indicated above, in vitro and ex vivo (explant) testing of UC-781 explored its impact on colorectal, vaginal and cervical tissue. Like dapivirine, UC-781 is an NNRTI rejected as an orally administered drug to treat HIV because of its poor systemic absorption.13 In 2005, researchers in St George’s, University of London, used in vitro and cervical-tissue explants to show that UC-781 could inhibit direct infection with HIV and prevent dissemination of virus by migratory cells.14Subsequent research explored the extent to which tenofovir, UC-781 and dapivirine, testedalone and in combination, could inhibit HIV infection in colorectal explant models. These data not only advanced consideration of UC-781, but also shed new light on the potential drug concentrations requiredto prevent rectal transmission of HIV.15

Phase 1 rectal-safety trials were conducted on UC-781 with satisfactory results, as well as an acceptability trial enrolling 26 men and ten women who applied the gel rectally for seven consecutive days. These participants were randomised into three arms and used 0.1% UC-781 gel, 0.25% UC-781 gel, or a placebo. The results indicated that the UC-781 gel is highly acceptable, although participants recommended some modifications to the applicator used in the trial.16

The Microbicide Trials Network is now planning a Phase 2 trial (called MTN-010) to assess the safety of extended daily use of UC-781 gel. The trial will enrol 150 women who will insert either a 0.25% UC-781 gel or a placebo gel vaginally every day for approximately 24 weeks. The start date of this study has not yet been announced.


SPL7013 (the active ingredient in a product called VivaGel), belongs to a relatively new class of compounds called dendrimers (dentritic polymers) that are created in the lab using nanotechnology. Chemical and Engineering News described dendrimers as: “treelike macromolecules with branching tendrils that reach out from a central core.”17 Since the 1970s, scientists have been designing and building dendrimers to serve specific scientific, engineering and medical purposes. The surface of the active dendrimer in VivaGel is designed to bind to the HIV or HSV-2 (herpes simplex virus). Thus, it blocks HIV’s ability to attach to its target cells.

The Microbicide Trials Network conducted a safety and acceptability study (MTN 004) in which VivaGel was tested by 61 women between the ages of 18 and 24 in the mainland US and Puerto Rico. Specifically, the study looked at safety, adherence, acceptability and effect on vaginal microflora (bacteria and other microorganisms that are important to the health of the vagina). Participants were randomly assigned to one of three treatment groups: one receiving VivaGel; one receiving a VivaGel placebo (formulated in the same way, but without the active ingredient), and one receiving a placebo gel. Participants applied the gel twice daily for 14 consecutive days.

None of the women experienced serious side effects but women in the VivaGel group had significantly more side effects than those in the HEC placebo group. Interestingly, the level of adherence to product use reported by women using VivaGel (77%) was lower than that reported by the other two groups (95% adherence in the VivaGel placebo and 94 % in the HEC placebo group). Acceptability differences were also noticeable. Only 35% of participants in the VivaGel group said they would be likely to use the product again in the future versus 48% in the VivaGel placebo group and 61% in the HEC placebo group. This study was initiated in 2007 and the data reported by MTN in 2010.

Also in 2010, StarPharma (developers of VivaGel) reported data on VivaGel’s potential potency. Their researchers collected cervicovaginal samples (CVS) from trial participants before and after dosing with VivaGel, and then challenged the samples (in a saline dilution) with HIV and HSV-2 (herpes simplex virus) in cell-culture assays. The twelve participants provided the test samples by inserting and removing Softcup diaphragms. Baseline samples were collected before drug administration. Women were then asked to apply a 3% VivaGel dose and collect a second sample via Softcup at an assigned time (times ranged from 10 minutes to 24 hours after application). The results of this CVS testing suggest that potent antiviral activity against both HIV and HSV-2 was maintained for at least three hours post dose. This activity was maintained in the presence of seminal plasma. StarPharma describes this trial as having been conducted “in a clinical setting” although the viral challenge, obviously, did not occur in vivo.18

In light of the MTN 004 acceptability data mentioned above, MTN co-principal investigator Dr Ian McGowan said that: “it may be necessary to consider reformulating VivaGel before moving to Phase 2 studies.”19


In October 2009, the US Food and Drug Administration (FDA) recommended marketing approval for maraviroc (known as Selzentry in the USA, Celsentri elsewhere), the first of a new class of entry inhibitors that blocks the CCR5 receptor. Individuals infected with HIV that is not CCR5-tropic, however, do not experience a viral-load reduction when treated with maraviroc. This, together with its twice-daily dosing requirement, puts the drug at some disadvantage in the first-line drug market. 

Two presentations at the 2010 Conference on Retroviruses and Opportunistic Infections (CROI) reported data from preclinical and clinical investigations of maraviroc as a possible microbicide candidate. In one, rhesus macaque monkeys were dosed with maraviroc vaginally and then challenged with a high dose of SHIV that featured CCR5 receptors.20 SHIV (Simian Human Immunodeficiency Virus) is an artificial virus generated for research purposes. Although very similar to HIV, SHIV is able to infect and cause AIDS-like disease in monkeys. Four out of the five maraviroc-dosed macaques were protected from infection by the drug.

The same test protocol was repeated using an SHIV variant with the CXCR4 co-receptor. As expected, maraviroc offered no protection against this variant, but neither was any change observed in the viral loads of the infected monkeys. This helped to allay concerns that using a CCR5 inhibitor microbicide might facilitate infections of particularly aggressive X4-using viruses.

The second study reported data on the maraviroc concentrations in the semen and rectal tissue of male volunteers after oral dosing. Twelve HIV-negative male volunteers took an eight-day course of maraviroc dosed at the treatment level (300mg twice daily). Researchers tested their blood and semen drug levels regularly and took rectal-biopsy specimens. The maraviroc levels in participants’ semen were found to be somewhat lower than in their blood plasma21 - a surprising finding given that previous studies had shown levels in vaginal fluid to be 3.3 times higher than in blood plasma. Drug levels in the participants’ rectal-tissue biopsies were much higher than in their blood, suggesting that maraviroc might be a promising rectal microbicide candidate.

At Microbicides 2010, additional in vitro and ex vivo explant data were presented that support the view of maraviroc as a potential microbicide, including evidence of the drug being more active in colorectal tissue explants than in cervicovaginal tissue.22 Data from another trial indicate that its effectiveness may be heightened when administered in combination with other ARVs (such as reverse transcriptase inhibitors) that work in different stages of the viral lifecycle.23

IPM has developed an intravaginal ring loaded with a dapivirine-maraviroc combination24 that, according to preclinical results, releases the drug at a high and consistent level over 30 days.  Clinical testing is expected to follow.

Preclinical pipeline

Six existing classes of ARVs are now being tested as microbicides (assuming we categorise entry inhibitors, attachment inhibitors and CCR5 inhibitors together in one class). In the clinical pipeline, two NRTIs (tenofovir and Truvada) are in large-scale effectiveness trials, one attachment inhibitor (VivaGel) has been through a Phase I trial; two NNRTIs (dapivirine and UC-781) are scheduled to go into phase-1 safety trials and one CCR5 inhibitor (maraviroc) has undergone some very early clinical studies collecting baseline PK and PD data. In the preclinical pipeline, three more classes of drugs are now being explored to assess their microbicidal potential.

Integrase inhibitors block a step after HIV entry - the integration of HIV’s genetic information into the DNA of a host cell. They have also been shown to suppress virus that is resistant to some other ARVs, such as NRTIs.

L-870812, for example, is an integrase inhibitor first identified as a candidate ARV during the development of raltegravir (the first integrase inhibitor to be licensed for ARV treatment). Investigators from the US Centers for Disease Control found that L-870812’s ability to protect monkeys from HIV infection after vaginal exposure was similar to that of other classes of ARVs. Two of the three drug-treated macaques involved in this trial were protected while the third seroconverted.25

Of particular interest was the fact that the one seroconverter did not develop drug-resistant virus, even after being dosed with the L-870812 gel for an additional 15 weeks after seroconversion. Resistance is a real concern given that people may unknowingly continue to use ARV-based microbicides after seroconversion. So, a drug that does not appear to be associated with the development of resistant virus after seroconversion is noteworthy.

Researchers at St George’s, University of London, and Princeton University are also developing fusion inhibitors as microbicides. The St George’s team have taken a pre-existing fusion-inhibitor molecule called C34 (an HIV treatment candidate initially developed by Merck) and attached it to a cholesterol ‘tail’ that greatly enhances its ability to bind to HIV’s gp41 entry protein and stop it from entering cells.

The resulting compound, called L'644, appears to have exceptional potency as a microbicide.  In vitro data show that it works at sub-nanomolar concentrations (less than one-in-a-billion-solution), demonstrates superior potency to the existing fusion inhibitors T20 and T1249, and significantly inhibits HIV infection of rectal explants, even when applied an hour after viral challenge.26

Protease inhibitors (PIs) have previously not been considered as microbicide candidates because they act at the post-integration stage of HIV’s life cycle and therefore, in theory, might not be able to prevent an infection. They could, however, inhibit the second stage of infection, when HIV in mucosal cells is ‘amplified’ and locally-infected lymphocytes travel to the lymph nodes, where they seed a systemic infection.

The St George’s team also evaluated multiple PIs - saquinavir, lopinavir, ritonavir and darunavir - as potential microbicides and found that darunavir was the most potent by an order of magnitude.[ref27

Dendritic cells are thought to be the first cells in the genital tract to be infected by HIV. When darunavir was combined with dapivirine (an NNRTI) in the London lab, the latter drug’s efficacy in preventing dendritic cell infection rose by 82% and darunavir’s by 44%. The team is now planning to take this PI/NNRTI combination forward into animal studies.

Candidate combinations

One-third (23) of the 70 candidates now in the preclinical pipeline have multiple mechanisms of action. The Alliance for Microbicide development notes that, “[d]espite a still unclear regulatory pathway and other complexities, combination approaches are seen as offering a potential for synergy, reduced drug resistance, and multiple targeting that is compelling, and the existence of new funding opportunities for combination microbicides supports that perception.”6

The Alliance report goes on to note that: “combinations of judiciously-selected ARV-based components…. could:

  • Act synergistically, resulting in greater efficacy, lower toxicity, and either greater antimicrobial specificity or a broader spectrum of activity.

  • Reduce risk of drug resistance, since the chance of HIV strains emerging with resistance mutations to two agents is smaller than the chance of developing resistance to a single agent.

  • Address challenges posed by entry inhibitors that favour a single co-receptor, since combinations could permit simultaneous blockade of more than one transmission pathway, thus increasing efficacy.

  • Target different steps in the HIV life cycle and provide protection against other STIs known to facilitate HIV infection.

  • Possibly reduce viral shedding in those unaware of their HIV status.6

We are not only seeing a growing number of ARV-based, cross-class combinations proposed and tested (some examples of which are cited above) but also candidates being formulated that combine ARV-based and non-ARV-based components. Advocacy for this latter area of work is being led by the Public Health Institute, the California Microbicides Initiative and other entities specifically interested in accelerating development of, and access to, multi-purpose prevention tools - those capable of preventing HIV, other STIs and/or unplanned pregnancies.

Along those lines, the Population Council is developing a water-based combination gel that contains carrageenan (the active ingredient in Carraguard), an NNRTI called MIV-150, and zinc acetate (a broad-spectrum antiviral agent).  Preclinical studies show that this product, called PC-1005, blocks HIV and HSV-2 in vitro, as well as blocking SHIV infection in macaques for up to 24 hours. The Population Council plans to launch a Phase I clinical trial of PC-1005, once the optimised formulation is developed.28

Researchers working at St George’s and Albert Einstein College of Medicine (Bronx, New York) are exploring the possible utility of PPCM, a compound that results from the reaction between D,L-mandelic acid and sulfuric acid. PPMC has been shown to be non-cytotoxic and to have activity against HIV and HSV in vitro. In gel form, it prevents herpes infection in mice.  Combining PPCM with either UC-781 or tenofovir increases its in vitro activity against HIV.29 Thus, its developers speculate that, as part of a combination microbicide, it could contribute protection against both HIV and HSV.

Formulation and drug-delivery options

Advances in drug formulation and delivery technology have dramatically expanded the formats in which effective, acceptable microbicides might be developed. The first-generation microbicides all took gel form because this is the easiest formulation to make and women generally like its lubricating qualities. The disadvantages of gels, however, include the fact that they are sometimes perceived as messy, they are expensive to ship (because they are heavier and bulkier than tablets, rings or films) and they are coitally-dependent.

Some people prefer coitally-dependent products (that can be set aside during times when they are not sexually active) and others prefer coitally-independent products (that do not require application before each sex act). Ultimately, both options must be available. But, given that poor adherence likely compromised the results of many (if not all) of the first-generation trials, it is immediately evident that more acceptable, convenient, portable formulations are clearly needed.

Among the new alternatives now in development are slow-releasing vaginal rings, thin films and tablets. The films and tablets can to be applied without an applicator and dissolve inside the body.

The International Partnership for Microbicides (IPM) clearly believes time-released, coitally-independent products are the way ahead, because they are now devoting substantial resources to developing vaginal rings that sit on or near the cervix and slowly deliver antiretroviral drugs over a period of a month (for example, trials of a dapivirine ring). As noted above, such rings are already marketed as the bearers of contraceptives and hormone therapies.

Another alternative to gel is a vaginal tablet that dissolves quickly, turns into a thick gel-like mass and delivers sustained levels of ARV. IPM’s tablet is ‘bioadhesive’ – meaning that the gel adheres to the mucous membrane, concentrating the drug at the surfaces where it is needed and providing a consistent level of drug delivery over an eight- to twelve-hour period.

Being ARV-based, this method does not require the resulting gel to form a physical barrier, as did some of the first-generation products. Given the drug’s potency, a smaller volume of gel is needed, reducing the risk of messiness sometimes reported with first-generation products.

In terms of rectal microbicide development, researcher Robin Shattock has speculated that thicker tablet/gel formulations could be developed that would enable the drug to adhere to the colorectal mucosa for long periods, though there would have to be careful studies to assess the safety of this concept.30

One of IPM’s dissolving tablets, about the size of an almond, has been developed containing dapivirine. Designed for vaginal use, it dissolves in less than three minutes and delivers

therapeutic levels of the drug for at least twelve hours after insertion. IPM report that they are also developing a version containing a tenofovir/ UC781 combination. They anticipate that this formulation could be adapted for rectal use without difficulty.31

Other US researchers have developed a film delivery format that is smaller than a stick of gum and as thin as a sheet of paper. The film, itself, is made of a polyvinyl alcohol polymer, a water-soluble synthetic plastic used in multiple consumer and biomedical products, including contraceptive films, contact-lens solutions and mouthwash strips.

ImQuest BioSciences, the film’s manufacturer, have impregnated the film with a microbicide candidate called IQP-0528 which acts both as an NNRTI and as an entry inhibitor. They report that the resulting product is not cytotoxic, has no negative effect on normal vaginal flora, and is inexpensive to produce. Acceptability studies are the next step for this product.32

IPM is also supporting development of two quick-dissolving films, one loaded with a maraviroc/tenofovir combination and the other with a maraviroc/dapivirine combination.33

Finally, the possibility of using microbicides as a condom coating has generated renewed interest. Condom manufacturers began to add a nonoxynol-9 coating to condoms in the 1980s, as a feature that might enhance their HIV-prevention capabilities. After evidence was released indicating that N-9 was actually even more damaging to rectal than to vaginal mucosa, the Global Campaign for Microbicides initiated a public call for the removal of N-9 from all lubricants and condoms, on the grounds that rectal use of such products during anal sex could exacerbate HIV risk if the condom broke or slipped.34 While SSL Laboratories (makers of Durex) and some other condom manufacturers complied with this request, two major companies did not. N-9-coated condoms remain on the market, despite the fact that the N-9 coating provides no demonstrable benefit, either for contraception or HIV prevention, and may increase HIV risk, especially among those who use them rectally. The idea of adding a safe microbicidal layer of protection to the physical layer provided by a condom, however, remains a viable delivery option. In 2007, StarPharma announced that they had signed an agreement with SSL Laboratories to develop VivaGel-coated condoms (presumably to be manufactured after VivaGel is proven both safe and effective).35

PATH (Program for Appropriate Technology in Health) and CONRAD are collaborating on development of a novel female condom with UC781. To facilitate easy insertion, the body of the PATH women’s condom is gathered into a dissolving capsule that is roughly the size and shape of a tampon. Once inserted, the capsule film dissolves and helps the condom adhere to the vaginal lining.  The developers have added UC-781 to the capsule film for additional protection and are now optimizing the modification to ensure uniformity of drug distribution and long-term stability.36


  1. Cairns G A Slippery Hope Positive Nation, issue 138, 2008
  2. Hendrix CW, Fuchs EJ, Macura KJ et al. Quantitative imaging and sigmoidoscopy to assess distribution of rectal microbicide surrogates. Clin Pharmacol Ther. Jan 83(1):97-105, 2008
  3. Anton P, Adler A, Khanukhova E et al. A Phase 1 Rectal Safety and Acceptability Study of UC781 Microbicide Gel. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract Y-147, 2009
  4. Deeks SG Transmitted Minority Drug-Resistant HIV Variants: A New Epidemic? PLoS Med 5(7); e164, 2008
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  9. Abdool Karim S Overview of the CAPRISA 004 results. Panel presentation at Using Antiretrovirals to Prevent HIV: Implications of the outcome of the CAPRISA 004 tenofovir-gel microbicide trial, Eighteenth International AIDS Conference, Vienna, 2010
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  19. Microbicides Trials Network Phase I study finds candidate microbicide VivaGel generally well tolerated but women less willing to use it. 2010 International Microbicides Conference, Pittsburgh, press release, 25 May 2010
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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.