By Gus Cairns
Two studies of the use of oral pre-exposure prophylaxis (PrEP) in heterosexual people show that oral PrEP will protect women against HIV.
The 6th International AIDS Society Conference in Rome heard the additional data from two trials of pre-exposure prophylaxis in heterosexuals yesterday. First results from these trials, the Partners PrEP trial and the TDF2 trial, were announced on Wednesday, 13 July. This was when the placebo arm of the Partners trial was closed well in advance of the planned ending date as it was realised that there were many more infections in this arm than in people taking antiretroviral PrEP.
The new data on PrEP in men and women were keenly anticipated because another study of PrEP in women, FEM-PrEP, had closed recently after finding zero efficacy for Truvada, and it had been theorised that oral PrEP might not work for women because drug concentrations in the genital tract were too low.
The results of the TDF2 trial were planned to be announced at the IAS conference, but in the event were released at the same time as the Partners PrEP results, while a special session was convened at the conference to include more data from both studies.
The Partners study compared tenofovir and tenofovir/FTC (Truvada) versus placebo as PrEP in serodiscordant couples (one person HIV-positive, one negative) in Kenya and Uganda, while the TDF2 study compared Truvada versus placebo in heterosexual men and women in Botswana.
In brief, the Partners study found that tenofovir had an efficacy of 62% in preventing HIV infection and Truvada an efficacy of 73%; there was no statistical difference between the efficacy of Truvada and tenofovir. In the TDF2 study, Truvada had an efficacy of 63%, but was 78% efficacious in patients who had last received study drugs less than a month ago and who therefore had pills available.
Efficacy in men and women
In the Partners PrEP study, the HIV-negative partner was female in 38% of the 4758 couples. There was no difference in efficacy of either tenofovir or Truvada between men and women. The efficacy of tenofovir was 68% in women and 58% in men versus placebo; the efficacy of Truvada was 62% in women and 83% in men. None of the differences between men and women, or between tenofovir and Truvada, was statistically significant.
Unadjusted figures in the TDF2 study at first suggested there might be some difference in efficacy between men and women. It is important to note that this study was not ‘powered’ to demonstrate efficacy; this means that – due to there being fewer infections than expected – even a statistically significant positive result is based on too few cases for it to be regarded as a truly convincing efficacy result. Nonetheless, the headline finding of 63% efficacy against placebo was statistically significant.
In this study, 45% of the 1200 participants were women. The efficacy of Truvada in men was 80% (two HIV infections in men on Truvada versus ten on placebo) and this was statistically significant. The efficacy in women was 49% (seven infections on Truvada versus 14 on placebo), and this lost statistical significance.
However when only participants who had refilled their pills at the clinic in the last 30 days were counted, there were three infections in women on Truvada versus 13 on placebo. This was an efficacy of 75.5%, which was statistically significant (p=0.021). In men in this group there was one infection on Truvada versus six on placebo (82% efficacy), which was actually not statistically significant, due to the small numbers.
Other data - Partners study
Because the Partners study has only recently closed its placebo arm, a limited amount of other findings were announced. Placebo-arm recipients will be offered tenofovir or Truvada. Recipients already taking active drug will remain blinded (will not know whether they are on tenofovir or Truvada) to see if outcomes remain similar.
Presenter Jared Baeten of the University of Washington said that adherence had been excellent throughout, with approximately 97% adherence in all arms, and strong correlation between self-reported adherence and pill count. Baeten speculated that adherence might tend to be higher in couples, especially ones who received adherence and sexual risk counselling together, as they would tend to look after each other. Although 27% of the couples reported unprotected sex in the previous month at baseline, this declined throughout the study to about 10% at month 30.
Initial safety data raised no concerns with similar rates of adverse events and laboratory abnormalities. There were 17 cases of raised creatinine (indicative of kidney malfunction) on tenofovir and 20 on Truvada versus twelve on placebo – not a significant difference.
There was a slightly raised incidence of nausea in the first month in patients on tenofovir or Truvada (6.3 and 5.9%) versus placebo (4.5%) but no difference after the first month.
Other data - TDF2
Adherence in the TDF2 study was somewhat lower; by pill count it was about 84%, which makes the efficacy measures reported even more impressive. There was no difference in reported adherence between seroconverters and others in the Truvada group, though it was slightly higher (93%) in the placebo group.There were no differences observed in sexual behaviour: 14% in all arms reported having had more than one sexual partner in the previous month and 81% reported consistent condom use.
There was a statistically significant difference in nausea between Truvada recipients (19%) and placebo (7%) and also in vomiting (11.5 and 7%) and dizziness (15 versus 10.5%), though presenter Michael Thigpen did not specify whether these were concentrated into the first month. There was no difference in the rate of serious adverse events (approximately 9% in all arms).
Forthcoming analyses will include efficacy among participants with varying levels of self-reported adherence, drug level testing for efficacy and adherence, changes in bone mineral density and trends in risk behaviour over time. All participants will now take open-label Truvada if they want to.
Acute infections and resistance
Amongst the most important data presented were those concerning acute infection. In Partners PrEP, twelve participants who had tested HIV-negative at screening were found to have acute HIV infection.
In TDF2, there was one case of a participant who started taking Truvada while having acute HIV infection, and developed multi-drug-resistant HIV. S/he tested positive for the K65R tenofovir resistance mutation and the M184V FTC mutation; s/he also had a broad-spectrum NNRTI mutation A62V, which suggests that the virus contracted was not wild-type. This individual is currently undetectable on AZT, 3TC and boosted lopinavir.
One seroconverter in the placebo arm was also found to have HIV with low levels of the K65R mutation. This is a reminder that one of the most problematic aspects of PrEP is the need to exclude patients who are in the process of seroconverting to HIV from taking it, and also that it does not protect against drug-resistant virus.
References
Baeten J Antiretroviral Pre-Exposure Prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0106, 2011.
Thigpen M et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract WELBC01.
A completed series of investigations into the iPrEx study of tenofovir/FTC(Truvada) as pre-exposure prophylaxis (PrEP) has found that the drug was 92% efficacious in preventing HIV infection amongst those who had detectable drug levels, though only 42% efficacious overall.
An expanded number of drug-level tests show that only 44% of those who did not become infected with HIV had drug detectable in their blood and/or cells, suggesting that overall adherence in the study was even lower than thought. This suggests that adherence will be the factor that may limit the effectiveness of this strategy in curbing HIV in many populations, and that it may need to be offered only to people highly motivated to take it.
Efficacy
The iPrEx study reported its initial findings in November 2010. It found at this point that the overall efficacy of the drug in preventing HIV was 44%, in other words that nine HIV infections our of 20 that would otherwise have happened were prevented.
Updated findings, presented at the International AIDS Society conference (IAS 2011) in Rome by the trial’s lead investigator Robert Grant, show that the finally-calculated overall efficacy was 42%. There were 131 HIV infections during the study, 83 in the placebo arm of the 2499-member trial and 48 in the Truvada arm. The 95% confidence interval was 18% to 60%, meaning that the ‘true’ efficacy, allowing for chance, had a 95% chance of lying within these figures. The probability that the finding was a chance one was 0.002, meaning there was only a one in 500 chance that the efficacy observed was purely due to chance.
Efficacy was notably higher in some groups than others. It was 83% in circumcised men and 36% in uncircumcised men. There were relatively few circumcised men in the study, so this could have been a random finding, but this mysterious interaction between circumcision and other prevention methods, which has also been seen in the STEP vaccine trial, needs further investigation.
Efficacy was 52% in those with secondary education or above and only 14% in those with only primary education. It was also, rather discouragingly, only 28% in men aged younger than 25. It is not news that young people find adherence a problem, but given that PrEP might have its highest potential effectiveness if given to young people at their peak of HIV risk, more studies are needed to see if it is feasible as a prevention measure in youth. It was also completely ineffective (efficacy minus 3%) in the small number (1% of the study population) of transgendered people taking it.
None of these differences are statistically significant, but one significant difference was that PrEP was 52% efficacious in men who reported unprotected anal intercourse as the passive partner, and worse than ineffective in men who did not report it. This may indicate that adherence was highest in those who knew they were at highest risk.
Adherence and drug levels
In the initial findings, one unexpected one was that while very few men who caught HIV had detectable drug levels in their blood, the same was true of over half of the men who did not catch HIV, indicating low adherence.
This analysis was only conducted in 34 people who caught HIV and 42 who did not in the original findings. An expanded substudy (Anderson) tested drug levels in all 48 men who caught HIV, each matched with three controls (144 in total) of similar age and background who did not catch HIV.
This found that only 10% of those who caught HIV had detectable drug levels in either cells or blood plasma. However it also found that only 44% of those who did not catch HIV had detectable drug in their system either. This may indicate that overall adherence was even lower than thought.
The absence of detectable drug in cells also indicates that most men did not take the drug on an on/off basis: either they did consistently or they didn’t at all. In the 10% of men who caught HIV who did have detectable drug, levels were half of those seen in controls; these people may be amongst the minority who took it now and then. Overall, the HIV acquisition rate in people with detectable drug in their system was 87% lower than in those where drug was undetectable.
Another substudy (Liu 1) measured drug levels in hair, and indicator of whether people had ever taken the drug. Drug was detected in 90% of subjects form US and South African sites, who may be more used to randomised drug trials, and only 55% of subjects from the South American and Thai sites.
Risk compensation
Only a minority of people thought they know whether they were taking drug or placebo; 63% didn’t hazard a guess and 6% weren’t asked. Amongst those who thought they knew, 9% thought they were on placebo and 22% thought they were on Truvada – indicating that hope springs eternal, perhaps. They were wrong about their guess exactly half of the time, indicating that the trial remained truly ‘blinded’.
During the trial, the proportion of men reporting unprotected receptive anal intercourse declined from 58% at baseline to about 25%. It was non-significantly higher (about 30%) in men who thought they were on Truvada, providing very little evidence of behaviour change. Only an open-label study, however, where all subjects know they are taking PrEP, will show if it causes people to change their risk behaviour.
Acute HIV infection and resistance
One concern is whether many people taking PrEP will do so when they already been infected with HIV, but not yet developed antibodies. Because during acute infection viral levels are very high, this provides an ideal environment for the development of drug resistance, and in fact ten men out of the 131 infected during the study in fact had acute HIV infection (virus detectable but not antibodies) at the time they started PrEP. Two of those men appear to have developed resistance as a result of taking PrEP.
This means that one in 250 men in the study had acute HIV at baseline. During the study, however, only one in 1666 subjects actually came down with acute HIV infection while taking Truvada, and no one developed resistance.
Depression, adherence and behaviour
Depression has been associated with poor adherence in treatment studies. A substudy (Liu 2) of depression showed that drug levels in hair in people reporting high depression scores were somewhat lower than in other people (70% with detectable drug versus 81%), but this was not statistically significant.
Depressed people were somewhat more likely to have had unprotected receptive anal intercourse in the past three months (29% versus 24%) but had nearly twice the number of partners (an average of 0.8 in three months versus 0.45).
References
Grant R et al. Completed observation of the randomized placebo-controlled phase of iPrEx: daily oral FTC/TDF pre-exposure HIV prophylaxis among men and trans women who have sex with men. Sixth IAS Conference, Rome, abstract WELBC04, 2011.
View abstract WELBC04 on the conference website. You can download Robert Grant's presentation from the session webpage.
Anderson PL et al. Expanded case-control analysis of drug detection in the global iPrEx trial. Sixth IAS Conference, Rome, abstract MOLBPE034, 2011.
Liu A et al (1). Hair as a biological marker of daily oral pre-exposure prophylaxis (PrEP) adherence and tenofovir/emtricitabine (TFV/FTC) exposure in the Global iPrEx Study. Sixth IAS Conference, Rome, abstract MOLBPE037, 2011.
Liu A et al (2). Depression among men who have sex with men (MSM) at risk for HIV infection in the Global iPrEx study. Sixth IAS Conference, Rome, abstract TULBPE024, 2011.
By Keith Alcorn
Antiretroviral prevention methods are not in competition, and policy makers and providers need to start to thinking about how antiretrovirals, pre-exposure prophylaxis and microbicides will be provided as part of a combination prevention package – and who will benefit most from each method, delegates heard at a satellite meeting on the opening day of the Sixth International AIDS Society Conference in Rome.
“You don’t want to have the family planning clinic here, the pills clinic here, the injections clinic here, and the microbicides clinic over here,“ said Dr Stephen Becker of the Bill and Melinda Gates Foundation.
Delegates were discussing the rapidly changing landscape of HIV prevention methods that use antiretroviral drugs. One year ago, at the International AIDS Conference in Vienna, the world heard the results of the CAPRISA study, which showed that a microbicide gel containing tenofovir halved the risk of HIV infection in women who used the vaginal gel consistently.
Since then results from four studies have added to the array of prevention methods that exploit antiretroviral drugs to prevent transmission or acquisition of HIV infection:
The first tenofovir-containing microbicide could receive regulatory approval by the end of 2013, subject to positive results from a confirmatory trial now taking place in South Africa. That study is testing exactly the same dosing regimen as that used in the CAPRISA study, the so-called BAT 24 dosing schedule: one dose Before, one After, and no more than Two doses in 24 hours.
A second CAPRISA study (008) is testing the roll-out of tenofovir gel through family planning clinics in KwaZulu-Natal, comparing the monthly testing and follow-up schedule used in the original CAPRISA study with a three-monthly schedule, in order to examine the feasibility and acceptability of providing a microbicide through existing health services that target sexually active women.
Although the South African government has already begun investing in the scale-up of production facilities to manufacture the gel, the extent of demand for the microbicide is still unclear. Studies of women’s’ attitudes towards the microbicide will be needed to gauge demand, but a lot of work will also be needed to develop demand – and to make sure that women understand how they could benefit from using the microbicide.
“We need to reach out to women who don’t perceive themselves to be at risk, and we should be getting communities to rally round to be early adopters of tenofovir gel,” said Samu Dube of the Global Campaign for MIcrobicides.
“We need to get the product to the places where women are: the family planning clinics, the immunisation centres, antenatal clinics. We also need to target the school health system.”
However, work will also be needed to convince the providers of those services that they have a role to play in expanding women’s opportunities to protect themselves from HIV infection.
“Providers can be major gatekeepers – their attitudes and how they present it to women will be critical. We saw very negative attitudes from the providers towards the female condom. Ideally they should use [the microbicide] themselves at least once,” said Catherine Hankins of UNAIDS.
Provider and donor preferences for particular prevention methods could also overshadow the need to think about prevention technologies as a spectrum of methods that will suit different people at different times.
“Is treatment always the best option [as the prevention measure] in the serodiscordant couple? If the index partner can’t or won’t take pills, or if the HIV-negative partner is having concurrent partners, they might need PrEP or a microbicide,” said Professor Myron Cohen of the University of North Carolina, lead investigator on the HPTN 052 study.
He also pointed to the estimated volume of transmission that takes place during the early weeks after infection. In the region of Malawi in which the HPTN 052 study recruited participants, his team calculated that around 30% of HIV infections came from undiagnosed people who had been infected less than six months previously.
In these circumstances, he pointed out, a microbicide or PrEP would still have an important role to play, even if counselling, testing, early diagnosis and treatment could be maximised.
Indeed, defining the niches of different antiretroviral-based prevention methods will depend on up to date information about local epidemics and behavioural patterns, applied through mathematical modelling to generate options for policy makers, what Willard Cates of Family Health International called “the science of prioritisation, to make scarce resources go further to maximise impact”.
“Modellers have their hands full at the moment, and that’s for good reason. That information needs to go out now [in order to help with prioritisation],” said Peter Cherutich of the Kenyan Ministry of Health.
“It’s very important not to pit prevention technologies against each other,” said Renée Ridzon of the Bill and Melinda Gates Foundation.
However, microbicides may have unique introductory challenges, said David Stanton of USAID, whose agency is strongly committed to supporting microbicide scale-up in sub-Saharan Africa. The tenofovir microbicide will have to clear the hurdles of confirmatory trials, as well as differences in regulatory requirements between countries before it can even be distributed. The South African Medicines Control Agency has not yet given a clear opinion on what data it will require for registration, leaving the danger that further studies could be needed to achieve registration in South Africa.
There is also the challenge of ensuring that the gel is manufactured to a consistently high standard, so that contains the right quantity of tenofovir in each dose, and the challenge of organising an efficient distribution system.
WHO and UNAIDS are working with CONRAD and the South African Ministry of Science and Technology, two of the sponsors of the satellite meeting, to plan for introduction of tenofovir gel, and WHO will develop guidance on use of the microbicide so that it can be released as soon as the first regulatory approval is granted.
Global Campaign for Microbicides, the third sponsor of the meeting, is working to raise awareness of the choices around prevention technologies, both for policy makers and communities, and to build community awareness and demand for the tenofovir microbicide.
But perhaps the biggest challenge for introduction will be the accessibility of the microbicide gel for a group at particularly high risk of infection in southern Africa – young women and girls. Dr. Sengiziwe Sibeko, a women’s health practitioner in KwaZulu-Natal, said that sexually active adolescent girls represented an important group who could benefit from prevention counselling that included discussion of the microbicide gel.
But, said Dr Stephen Becker, “the idea of doing sex education in schools and distributing products for HIV prevention is not a straightforward path and will take a great deal of pushing.”
Nevertheless, it highlights one of the key discussions about niches for prevention products that will need to take place: as well as thinking about the characteristics of populations most likely to benefit, a clear strategy will also be needed for overcoming the social, legal and health system barriers that could prevent maximum impact of microbicides.
While circumcising male adolescents is easy and socially acceptable, social and legal constraints on the sexuality of women will continue to undermine the central promise of microbicides – a prevention tool to empower women – unless confronted head-on.
By Gus Cairns
Two consecutive sessions at the sixth International AIDS Society conference in Rome yesterday were devoted, now we have convincing scientific data on the benefits of treatment as prevention and PrEP, to putting these new prevention methods into practice.
“We have moved from ‘What if?’ to ‘What now?’” was the comment of Mitchell Warren, Executive Director of the AIDS Vaccine Advocacy Coalition (AVAC), on what else we need to know, what barriers need to be addressed , and what resources might be required, to maximise the promise of antiretroviral-based prevention.
Anthony Fauci, Director of the US National Institute of Allergies and Infectious Diseases (NIAID), said: “We now have a solid scientific foundation to say that even in the absence of a vaccine we have the capacity to end the epidemic. I can’t go to the US President and say: 'We can cure HIV.’ But I can say ‘Ending the epidemic is scientifically doable’.”
Earlier, however, Nancy Padian from the Office of the US Global AIDS Coordinator had outlined formidable challenges still to be answered if antiretroviral treatment could bring about this goal.
She said that questions still needing answers include whether antiretroviral drugs (ARVs) really are a durable and reliable means of viral load suppression over a period of years and whether increasing the proportion of people on treatment would lead to increased levels of resistance. The biggest practical question, however, was whether treatment as prevention would work in situations where a high proportion of transmissions came from people with acute, recent HIV infections.
The biggest barriers to treatment as prevention, however, are stigma and lack of resources. Implementing ARV-based prevention would not only be expensive in terms of drugs; it would require added human resources and increased training and task-shifting for prevention counsellors so they can deal with biomedical data. There would also be added costs in terms of tests and monitoring.
The other big barrier will be the stigma of being tested, she said, particularly for at-risk populations in societies where injecting drug use, male-male sex, or sex work were criminalised and stigmatised. Treatment as prevention would require people not simply to test and then go to more supportive community organisations for prevention advice; it required a much closer relationship with medical personnel who might be prejudiced or feared to be so.
Mitchell Warren issued a call to action to implement the new strategies, but his presentation was tempered by realism. “We have evidence, we have data, and we now need to make decisions,” he said.
Firstly, he said, we need "smart combinations" of prevention interventions tailored to different people and populations. “It can be seen as frustrating to have all these tools (he counted 13 different ones for which there is now evidence) and not know what to choose or how to pay for them,” he said, “but it’s a better kind of frustration than in 2004” (at the time of the closing of the first PrEP study in Cambodia).
Given that, even now, only 8 to 9% of people who need them have ready access to condoms or clean needles, only 11% of gay men have access to behaviour-change programmes, and only a third of HIV-positive mothers have access to ARVs to prevent transmission to their baby, making ARVs more widely available as prevention or PrEP would be a big challenge.
Using ARVs for prevention would continue to be a behavioural issue, he added, in terms of people coming forward for testing and, crucially, for adherence.
One important consideration was to match the prevention intervention to the person. PrEP, for instance, had been criticised as a ‘niche intervention’, but niche interventions were important for specific groups of people and could be extremely effective; an example from another context was injectable contraceptives.
Lastly, of course, money and resource allocation would be a huge issue. “Scientific data do not change the world – programmes and policies backed by civil society, donors, implementers and governments do,” he said.
In this context, Tim Farley of the World Health Organization, presenting a comprehensive review of the licensing processes needed for ARV-based prevention methods in the USA, Europe and Africa, remarked on the extreme range of prices paid for tenofovir and Truvada in different contexts, from $35.82 as the US list price (almost always discounted) for one Truvada tablet, to $0.87 as the ‘no profit’ price paid to the developers Gilead in low-income countries and the even lower $0.28 for a generic equivalent. He noted, however, that Gilead was already licensing generic companies to produce tenofovir and Truvada at lower prices.
Helen Rees, University of Witwatersrand in South Africa, said that the new data from the treatment-as-prevention and PrEP studies had come along just as she was involved in writing the country’s new National Plan for HIV. She said that the new prevention choices offered could feel bewildering. “Do we put more people on treatment, circumcise all men or buy millions of condoms?” she asked. As an initial step, the country had extended its CD4 criteria to 350 cells/mm3 in line with WHO guidelines and had decided that, with still only 45% of those who need it on treatment, that treatment access remained South Africa’s biggest priority.
She added, however, that the data from serodiscordant-couple studies did not necessarily provide the kind of data needed on the likely effectiveness of treatment as prevention, or of PrEP. “South Africa is a country of female-dominated households and a low level of marriage,” she said, “and serodiscordant couples are hard to identify: men still won’t come forward.” It had been decided that HIV-negative women wishing to conceive who were or might be having sex with HIV-positive men were a logical first population who might need PrEP, but setting up PrEP as a service was a much bigger step than expanding existing HIV treatment, as it involved a new type of service that didn’t yet exist.
Myron Cohen, principal investigator of the HPTN 052 study, said that if the world did not pay for ARVs now it would do so later, in terms of an indefinitely increasing number of people needing HIV treatment. He said that his study’s findings did not imply a huge expansion of treatment to groups not previously entitled to it; for the study’s purposes, it had needed to offer ARVs to people with relatively high CD4 counts but the reduction in infectiousness should apply to people with CD4 counts below 350 cells/mm3 too, and should serve as a further incentive to get ARVs to the two-thirds of people with CD4 counts below this figure who were not yet on treatment.
Above all, moving from the data provided by scientific studies to the business of trying to make HIV prevention work in the real world was an exercise in dealing in uncertainty. Microbicide researcher Ian McGowan of the University of Pittsburgh commented that: “In an ideal world, we’d treat all the HIV-positive people and the negative ones would use condoms. But people may not go on treatment, may fail treatment, and may fail to use condoms. The world has never been black and white, and the debate about moving from treatment, to treatment-as-prevention, to PrEP is the kind of debate we have been having on access to medications for HIV ever since we’ve had them.”
By Roger Pebody
We now know that starting antiretroviral therapy early, pre-exposure prophylaxis (PrEP) and vaginal microbicides can all have an impact on HIV transmission, Victor de Gruttola told a satellite session at the International AIDS Society conference in Rome on Sunday. But researchers now need to do more than establish efficacy, he said.
Studies need to identify the mechanisms by which interventions do and do not work in different communities. They need to get to understand the characteristics of sexual networks, sexual behaviour and local epidemiology that influence their effectiveness. And they need to compare the impact of providing a stand-alone intervention with that of combined packages of interventions.
Other speakers at the satellite, which had been organised by AVAC and the European AIDS Treatment Group, emphasised the importance of implementation research – identifying barriers to the implementation of prevention interventions and developing strategies to overcome them.
Both Victor de Gruttola from the Harvard School of Public Health and Timothy Hallett from Imperial College London suggested there is no single best intervention – or even best package of interventions, but that this will depend on the characteristics of different communities and epidemics.
For different settings, researchers need to identify the combination of prevention interventions which could keep the spread of HIV under control. They also need to establish the breadth of programme coverage that is required.
Timothy Hallett presented some results from a basic mathematical model which aimed to identify the impact and cost of providing antiretroviral therapy to 80% of people at a number of different CD4 counts, PrEP to varying proportions of young people, PrEP to most people of all ages, or a combination thereof.
For each level of spending, Hallett identified the programme that would have the greatest impact – at the lowest levels of spending identified, this would be antiretroviral therapy alone. Should there be budget available to fund more than making therapy available for all with diagnosed HIV, policy makers should then provide PrEP for young people, and then for people of all ages.
But the model’s results change if baseline assumptions shift. If the costs of PrEP are actually lower than Hallett estimated (because drug prices come down), or if it turns out to be more expensive to get people diagnosed early and on to treatment (because testing promotion has less impact than anticipated or because new health services need to be provided), strategies with a greater reliance on PrEP would start to make more sense.
And the modelling studies need to consider other issues. Interventions – and combinations of interventions – will have different levels of effectiveness in different places, depending on a vast range of local factors which researchers are only beginning to get to grips with.
For example, Victor de Gruttola mentioned assortativity: the tendency for people who have many sexual partners to choose partners with the same characteristic. When this is the case, interventions will have less impact than when there is less assortativity.
Other important local factors are the number of transmissions that are due to people who are themselves recently infected, the proportion of people with HIV who are diagnosed and linked to care and the proportion of HIV-negative people who can be provided with an intervention.
Timothy Hallett noted that, although we know from the HPTN 052 trial that early initiation of treatment can reduce transmission to stable partners by 96%, this does not mean that changing treatment guidelines will bring about a 96% reduction in new infections.
Far too many people are diagnosed late for this to be possible. While early treatment strategies rely on early diagnosis, Sheena McCormack of the UK's Medical Research Council said that frequent HIV screening is not always an acceptable intervention.
New modelling work suggests that, even to achieve a 60% reduction in new infections through early treatment, testing would have to be so frequent that 60% are diagnosed within a year of infection, 90% of diagnosed people would have to be treated, 87% would need to be virally suppressed within six months of starting therapy, with only a 1% drop-out rate from treatment programmes.
Just minor modifications in these highly optimistic assumptions can wipe out the predicted impact. On the other hand, a combination of interventions would be more resilient in real-life conditions.
Should there not be the resources to make treatment available for everyone who needs it, its impact could be increased by prioritising its provision to people at higher risk of passing their infection on.
Sheena McCormack argued that the next prevention trials need to show that it is feasible to deliver interventions in a service setting, rather than with a great number of extra resources or with excessive demands placed on participants. Requirements for clinic visits, HIV tests and laboratory monitoring should be cut back, while users should be advised that PrEP may only be used around the time of sex, rather than on a daily basis. These measures will reduce the cost of interventions and increase their acceptability to users, she said.
She pointed out that a key question for a pilot PrEP study in the UK is whether a significant number of gay men are actually interested in taking it.
More acceptable interventions are more likely to be used consistently, and Sheena McCormack said that adherence is key to all the interventions discussed: “It’s all about behaviour,” she said. This applies as much to condom users as it does to people using a microbicide, PrEP or antiretroviral treatment.
