HIVreport.de. Pharmaceuticals in Prevention. aidshilfe.de

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1 HIVreport.de Pharmaceuticals in Prevention 3 Treatment as prevention 4 HPTN 052: ART protects sexual partners 9 Test-and-treat 11 Pre-exposition prophylaxis aidshilfe.de

2 Issue No. 05/ /09/2011 Dear Readers, The 1996 World AIDS Conference in Vancouver was all about pharmaceuticals in therapy. The efficacy of the triple combination therapy was impressively demonstrated. 15 years later, at the IAS Conference in Rome, pharmaceuticals were again the focus of attention in prevention. The results of a large-scale interventional study with the identification code HPTN 052 conclusively verify the reduction of infectiousness through therapy. Hence, the viral load method, which has so far been internationally disputed, is considered to be verified at the highest level of evidence. But do the methods defined for individual partners under specific conditions also apply to all? Can HIV-negative people be effectively protected against infections at the population level by regular screening and immediate treatment of HIV-positive people? Can the epidemic be brought to a standstill this way? These questions were subject to intense and heated debate in Rome. Hard facts have so far not been available, but are expected to be delivered in the next few years. The subject of pharmaceuticals in prevention is far from being concluded by treating HIVpositive persons. New data on pre-exposition prophylaxis (PrEP) was presented in Rome and more is to follow in the next 2 years. We have summarised this development in this report. Enjoy reading! PHARMACEUTICALS IN PREVENTION TREATMENT AS PREVENTION... 3 Viral load method... 2 Viral load method... 4 HPTN 052: Early ART protects sexual partners... 4 Sexually transmitted infections (STIs) and the viral load method... 5 Conclusion for prevention... 7 Test-and-treat... 9 Improvement of test-and-treat empirical evidence Criticism of test-and-treat PRE-EXPOSITION PROPHYLAXIS (PREP) Current state of research Comments on the PrEP studies PrEP research pipeline What questions are still open? Bottom line REFERENCES IMPRINT. FEHLER! TEXTMARKE NICHT DEFINIERT. Best regards, Armin Schafberger, Steffen Taubert 2

3 Treatment as prevention Antiretroviral therapy (ART) minimises the infectiousness of HIV-positive persons. Its efficacy has so far been proved in observational and cohort studies: The number of infections of sexual partners has dropped. Further evidence is now provided by the HPTN 052 study: The probability of infection for sexual partners is reduced by at least 96%. The HIV therapy is thus considered a highly effective prevention method. At individual prevention level, the results so far have led to the statement of the Swiss National AIDS Commission (EKAF) in 2008 and the Position paper of Deutsche AIDS-Hilfe e.v. (DAH German AIDS Service Organisation) in Under certain strictly defined conditions, the successful treatment of the HIV-positive partner provides sufficient protection for the HIV-negative partner. The German AIDS Society (DAIG) followed suit by publishing a similar, however, more carefully formulated position paper, which was substantially endorsed by the German Association of Practicing Physicians (DAGNÄ). The central objective was to reduce the fear of infections and reduce discrimination. As far as we know, no other country (except for Switzerland and Germany) has so far formulated similar messages at this individual level. The EKAF and the DAH were partly exposed to substantial criticism, particularly because of the fact that the messages were only verified by observational and cohort studies, but no by interventional studies and that the study design was inconsistent (Attia 2009). Since July 2011, the study design has been modified. The results of the HPTN 052 study were presented at the congress of the International AIDS Society in Rome (Cohen 2011 a-c). Cohen compared the effect of early ART on HIV transmission with the therapy being started at a later point, as recommended in the guideline. Bottom line: Early ART of the positive partner almost completely protects the negative partner against infections. Hence, the viral load method (at individual level) is considered to be verified at the highest level of evidence (see p. 4). At international congresses and in expert literature, however, therapy as prevention is predominantly discussed at the second, public health level. At this level, the question is whether the epidemic can be stopped by proactive testing of the entire population as well as immediate treatment (test-and-treat). However, the feasibility has so far not been investigated in an interventional study, but only in model calculations and observational studies. We report about this on p. 9. HIV therapy protects against HIV-Therapie schützt vor Infektionen infections Therapie als Prävention Therapy as prevention Prävention Prevention auf at individueller individual level Ebene (diskordante (discordant sexual Sexualpartner) partners) Viruslastmethode Viral load method Prävention Prevention auf at public Public health Health level Ebene Test Treat Test-and-treat 3

4 Viral load method HPTN 052: Early ART protects sexual partners Antiretroviral therapy reduces the risk of infection for the sexual partners in the study by at least 96%. In the group of HIV-positive subjects treated at an early point, only one infection occurred and this infection occurred shortly after starting the ART the viral load was probably not yet below the detection limit (Cohen 2011 a-c). HIVreport 5/2011 Pharmaceuticals in Prevention 1. Probability of infection reduced by more than 96% when starting treatment at an early stage The end point of the study was the infection of the HIV-negative steady partner. In the group receiving early treatment, four infections occurred. According to the genome analysis of the viruses, three of these infections were attributable to third partners and only one infection to the steady partner receiving ART. 1,763 serodiscordant couples were observed for In the group receiving late treatment, 35 infections an average period of 1.7 years. 54% of the participants came from Africa; the rest came from Bra- steady partner. occurred, 27 of which were attributable to the zil, India, Thailand and the USA. Half of the HIVpositive participants were men, 97% of them het- For calculating the efficacy of ART, only infections attributable to the steady partner are decisive. The erosexual. The couples had to have lived in a ratio of 1:27 yields a 96% reduction of the transmission probability in early ART compared to late steady relationship for more than three months and had to be sexually active. The helper cell ART. count in the positive partner had to be between helper cells/µl of blood serum. After the study had been published, four more infections became evident 886 in the late therapy arm, Therapie Immediate sofort therapy couples of which one infection could definitely be attributed to the steady 1,763 couples partner. In the three other cases, the genetic CD couples Therapie Late therapy später analysis of the virus yielded no clear result or CD4 CD4<250 oder or symptoms Symptome or oder AIDS AIDS was not yet finished. The positive partners of one group received immediate ART (early therapy), the other group was treated according to the guideline, i.e. as from a helper cell count of 250/µl. As usual with all prevention studies, the partners received regular advice 886 on safer sex. Therapie Immediate sofort therapy couples Bottom line: In a followup analysis of the study, the reduction of the transmission risk turned out to be even somewhat higher than 96%. From partner: couples Therapie Late therapy später 4 From partner:

5 2. Additional benefit of early treatment less clear in positive partners The clinical endpoints of the study were the occurrence of pulmonary tuberculosis, serious bacterial infections, other serious diseases or death. In the early therapy group, 40 such incidents occurred, in the late therapy group 65. However, this difference is attributed to the reduced number of pulmonary tuberculosis cases in the early therapy group (3 vs. 17). Some commentators of the study regard the reduced number of serious diseases in ART as evidence of the benefit of early treatment. In our opinion, this rationale cannot be transferred to Germany, since in this country pulmonary tuberculosis is a rather rare disease (thus requiring no prevention by ART). In the study, pulmonary tuberculosis almost exclusively occurred in India. In the early therapy group, the number of deaths was somewhat lower (10 vs. 13). This difference was statistically insignificant; furthermore, some of the deaths are not associated with an HIV infection (Cohen 2011 b). The results of HPTN 052 are therefore not suitable to prove the benefit of early treatment (as opposed to treatment according to the guideline) for asymptomatic HIV-positives in Europe. In this respect, the results of the ongoing interventional study (START) should be awaited. Comments on the HPTN052 study o o The only infection in the early therapy group occurred just a few weeks after starting the ART. On day 85 (i.e. less than three months after starting the ART), the previously negative female partner had a positive test result. The infection thus must have occurred during a period where the viral load was probably not yet below the detection limit. In the early therapy group, there were three infections with other partners and only one with the steady HIV-positive partner receiving ART. Having sex with supposedly negative partners was thus more risky than with the steady partner receiving therapy. o The early and late treatments were compared with each other irrespective of the ultimate viral load. Example: Three months after starting the study, the viral load was below the detection limit in 89% of the participants in the early therapy group compared to 9% in the late therapy group. o The detection limit for the viral load was 400 virus copies/ml (in Germany approx /ml). o The following STIs were examined and treated at the beginning of the study and subsequently at an interval of three months: hepatitis B, syphilis, gonorrhoea, chlamydial infections as well as only in women trichomonads and bacterial vaginosis. Sexually transmitted infections (STIs) and the viral load method Sexually transmitted infections increase the risk of HIV transmission to the sexual partner by two- to fivefold, which has been proved in numerous studies (Fleming 1999). However, these studies were conducted in HIV-positive persons receiving no ART. Whether the presence of an STI also increases the probability of HIV transmission in HIVpositive persons receiving effective ART (or their partners) was not investigated in previous studies. For this reason, the EKAF statement and the DAH position paper consider the absence of STIs in both partners to be an absolute prerequisite for applying the viral load method (=ART sufficient as the sole prevention method). This requirement has led to the feasibility of the viral load method being doubted by many critics, since the absence of STIs is only guaranteed under absolute monogamy and absolute monogamy is usually more theory than reality. HPTN 052 and another study (Kelley 2011) now provide further insights into the significance of STIs and the management of these diseases in discordant patients and/or HIV-positive patients receiving ART. sch 5

6 the most when having sex with untreated HIVpositive persons. Treatment was initiated upon HPTN 052 and STIs positive STI results. The research group around Cohen conducted STI screenings and treated STIs at an interval of three months. It should be noted that no screening was conducted for herpes infections, although herpes, as an ulcerous STI, is counted among the infections where the risk of HIV transmission increases Early therapy Late therapy (n=886) (n=876) Start Follow-up Start Follow-up 1-5 % 0-3 % 1-5 % 0-3 % STI Sexual activity Use of condoms thereof: thereof: HIV-pos Hepatitis B 5% Hepatitis B 5% Syphilis 3% Syphilis 4% Gonorrhoea 1% Gonorrhoea 1% Chlamydia 2% Chlamydia 2% Partner 1-3 % 0-2 % 1-2 % 0-4 % HIV-pos 72 % % 74 % % Partner 72 % % 73 % % HIV-pos 94 % % 92 % % Partner 92 % % 92 % % Table 1: STIs; Sexual activity and use of condoms by the participants at the beginning of the study and in the follow-up examinations (every 3 months). The prevalence of trichomonads (3-5%) and bacterial vaginosis (10-17%) investigated only in women at the beginning of the study are not shown in the table (Cohen 2011 b and c) Kelley study: Correlation between viral load in blood and in the rectum The studies that have led to the Swiss/EKAF statement in 2008 almost exclusively refer to heterosexual couples. EKAF critics have repeatedly pointed out that the recommendations cannot be automatically transferred to MSM, since there is only few data on anal intercourse. The HPTN 052 study included hardly any homosexual couples either. A U.S. study (Kelley, 2011) has now revealed that usually there is a correlation between low viral load in blood and low viral load in the rectum and that the viral load does not seem to increase, even in the presence of an STI, in patients receiving effective ART unlike in those not receiving ART. The research group around Colleen Kelley collected rectal smears from 80 HIV-positive MSM over a period of two years. All MSM were participants of the U.S. SUN cohort ongoing since The researchers examined 91 samples from 80 MSM for HIV, gonococci and chlamydia. In doing so, they found a close correlation between the viral load in blood and the viral load in the rectum. Only in 9% of all study participants with a low viral load in the blood serum (less than 1000/µl) was it possible to identify HIV in the rectum. By contrast, this figure was 87% in men with a viral load of more than 1000/µl in the blood serum. 6

7 Most notably, the researchers found no correlation between the presence of a bacterial STI and an increased viral load in the rectum. They, too, seemed to find their results quite remarkable and referred to a meta-analysis (Johnson 2008) which proved on the basis of 39 studies that there indeed was a connection between genital STIs and an increased genital viral load. However, the investigations refer to HIV-positive persons with a high viral load, usually not receiving therapy. These results are opposed by a study (Sadiq 2002) examining HIV-positive men receiving ART with and without urethritis. In those with effective treatment and a stable, low HIV viral load, the otherwise harmful effect of STIs was minimised to genital viral load. The results of Kelley can also be interpreted that way this time, not in the urethra but for the first time in the rectum. Limitations The authors limited the study s evidential value, since the HPV-RNA measurements had been conducted retrospectively on the basis of frozen samples taken and stored under suboptimal conditions. Prior to the HIV-RNA measurement, the researchers had to go to great lengths to remove interfering substances and cell material (it was an intestinal smear). The samples were nevertheless partly contaminated with HIV-DNA from cells. The attempt to examine the samples for herpes (HSV) failed technically, so it was not possible to establish a correlation between HSV infections and HIV viral load. It is unclear whether the measuring method applied is sufficiently reliable to measure the rectal viral load. Another limitation resulted from the researchers being only able to measure free viruses as RNA. Since HIV can also be transmitted via cell-cell contact, it would have also been desirable to examine proviral DNA in immune cells, which migrate into the mucosa when an STI is present. Despite all limitations, the researchers around Kelley regard their study as reliable enough to prove that the viral load in blood is a good method of measuring the viral load in the rectum and that 7 bacterial STIs at a low viral load do not significantly increase the HIV concentration in the rectal secretion. Therefore, they recommend using ART to reduce the number of HIV transmissions in MSM in the USA. tau Conclusion for prevention The above-presented studies once again substantiate the great significance of antiretroviral therapy in preventing HIV transmission. Regarding the reduction of infectiousness, the results of the HPTN 052 study are overwhelming. Effective ART reduces HIV transmission just as well as regular condom use. A prevention method reducing the probability of transmission by (more than) 96% must be integrated into prevention, because if a prevention method exceeds the threshold of 95%, it reaches and/or exceeds the safety limit of condoms, thus reaching safer sex quality. There is no exact data on the protective effect of condoms because there is no interventional study investigating the use of condoms (and, for ethical reasons, it was not possible to conduct an interventional study either; otherwise, one group would have to be denied safer sex). Based on the results of cohort studies, it is generally assumed that the proficient and regular use of condoms reduces the risk of HIV transmission by approx. 95% (e.g. Wilson 2009). Residual risks are posed by incorrect use (also under influence of alcohol), material defects and so-called minor risks during sexual intercourse which are not covered by condoms or where condoms are usually not used (oral intercourse, contact of blood or sperm with genital mucosa). A cohort analysis (Weller 2006) in heterosexual subjects yielded a protective effect of 80%. A higher protective effect (95%) is generally assumed for MSM (and also for heterosexual people proficient in using condoms). There is no cohort analysis on the safety of condoms in MSM. o The viral load method is no substitute for condoms, since where neither the partner s sero-

8 o status nor a possible ART is known, e.g. in the case of anonymous occasional contacts, condoms constitute a more effective protection method. Furthermore, condoms provide additional protection against other STIs. In cases where it is not about protection against other STIs, however, the viral load method is advantageous because it provides protection against minor risks (oral intercourse), in addition to protecting against major risks (anal/vaginal intercourse). If the need of protection is extremely high, the two methods can also be combined. tau Viral load method: Harmonisation of position papers In Germany alone, there have so far been three slightly different position papers dealing with the viral load method. Following the results of the HPTN 052 study, it should be possible for those involved in prevention, therapy and HIV research (DAIG - German AIDS Society, DAGNÄ - German Association of Practicing Physicians Treating HIV- Infected Patients, DAH - German AIDS Service Organisation, RKI Robert Koch Institute) to reach a common statement including specific recommendations for preventing STIs. This could contribute to physicians and advisory centres being able to provide uniform advice on a scientific basis. This has so far not been the case. Moreover, a harmonised position paper would shed more light on the career opportunities of people affected by HIV (e.g. for HIV-positive surgeons) as well as on questions about HIV transmission under penal law. sch Rome, Roman Forum and Coliseum: Will the viral load method now become a fixed pillar in prevention? Photo: sch Rome, Via Giulia: Can the limitations of the viral load method be eased? Photo: sch 8

9 Test-and-treat Testing as many people as possible, ideally all, for HIV as often as possible and starting treatment as quickly as possible if the result is positive: This is probably how the test-andtreat strategy, which has been intensely discussed at international congresses since 2008, can be described best. In addition to the goal to provide timely treatment to all HIVpositive people, the advocates of this strategy are hoping to be able to prevent a great deal of new HIV infections by reducing the viral load of the patients. However, there have so far only been model calculations and observational studies. It has yet to be proved whether or not the test-and-treat strategy works. An interventional study in South Africa is now supposed to prove its efficacy. Following the Swiss statement, there have been a great number of publications dealing with the benefits and optimum application of ART to counteract the epidemic. A WHO study group was the first to start (Granich 2008). Assuming that ART reduces infectiousness by 99%, it was calculated in a mathematical model that an annual voluntary testing of all South Africans above the age of 15 would virtually completely stop the number of new infections, and the prevalence of HIV infections in South Africa would drop below 1% after 50 years. Further model calculations, other study groups and numerous contributions at congresses followed. Problem 1: Test-and-treat does not reach all The great effect of ART on infectiousness is undisputed; however, it is still unclear whether the strategy of proactive testing and treatment on a voluntary basis is feasible at the population level and how effective it would be, since the model calculations exhibit too many uncertainty factors, because not all people... o are reached with the test offering o consent to the tests o pick up their test results o are able or willing to start treatment o reach a viral load below the detection limit during therapy o continue the treatment in the long term Problem 2: Infections attributed to an acute HIV infection One of the most significant uncertainty factors is, however, the number of infections attributed to an acute infection phase of the sexual partner: An annual HIV test is predominantly suitable to detect chronic infections; recognising acute infections requires either shorter test intervals or different methods. Using the example of Malawi, a study group (Powers 2011) investigated this issue. The researchers calculated that more than 38% of all HIV infections in Malawi are attributed to sexual partners suffering from an acute infection. They expressed criticism concerning the study by the WHO study group (Granich 2008), which calculated that it would be possible to eradicate HIV infections at the population level in South Africa, arguing that the South African eradication model neglected the significance of acute infections. There are also estimates for industrial countries suggesting that 25-49% of all infections can be attributed to sexual intercourse with persons suffering from an acute infection (Brenner 2007, Pao 2005, Yerly 2001, Lewis 2008). Test-and-treat: Should we take this path or not? sch 9

10 Improvement of test-and-treat empirical evidence Test-and-treat strategies have so far only been based on mathematical models and observational studies and are even disputed in this form. In order to improve the empirical evidence, an interventional study starting in 2011 will now be conducted, which is expected to provide insights into the feasibility and efficacy of a test-and-treat strategy around 2015 (ANRS 2010). The French ANRS research centre and the Africa Centre of Kwazulu-Natal University collaborate in the study project with the identification code TasP The scientific advisory board is chaired by Prof. Bernhard Hirschel, co-author of the EKAFstatement. The test-and-treat strategy in this project is structured in such a way that all adults in some regions of the Hlabisa sub-district Umkhanyakude in KwaZulu-Natal are tested once a year and are immediately treated once the result is positive. In other regions, diagnosis and consultation will continue to be provided according to the VCT (Voluntary Counselling and Testing) principle just like before. The treatment in these control regions is performed according to the WHO guideline, i.e. no later than upon reaching a CD4 cell count of 350µl but not immediately following the test. The primary goal is to compare the regions (test-and-treat regions vs. VCT regions) in 2015 to find out whether the test-and-treat strategy can lead to a considerable reduction in the number of new HIV infections. The secondary goal is to ascertain whether the test-and-treat strategy is more or less effective for HIV-positive patients than the previous standard regimen in terms of compliance, side effects and diseases. Criticism of test-and-treat o Test-and-treat strategies require unrestricted access to diagnostic and therapeutic measures, which is still far from being a reality in many regions in the world. Nine million people are in urgent need of life-saving antiretroviral therapy in the next few years for HIVreport 5/2011 Pharmaceuticals in Prevention o o o o a medical, rather than a preventive, indication (Cates 2011). However, the funding of the HIV therapy by Global Fund and other organisations is stagnating. If test-and-treat was currently implemented in developing countries, HIV-positive people with a preventive indication would receive early treatment, whereas those who do not receive therapy despite a medical indication would be left out. We would have to ask ourselves whether the right people receive treatment! People exposed to high risk of HIV infections belong to the most stigmatised groups especially in countries of high prevalence. Without any anti-discrimination strategies, this access barrier to tests and treatment will most likely see hardly any change. However, it is to be feared that conventional prevention (information, advice, anti-discrimination) will be cut back in favour of medical test-and-treat strategies. In test-and-treat, individuals are treated for the benefit of the society without the benefits of immediate treatment for individuals being currently proved an ethically questionable approach. In a test-and-treat situation, the moral pressure may make it difficult for individual people to plead ignorance or non-treatment. The mental pressure that may develop in such a setting conflicts with elementary individual rights. The same applies to a test-and-treat setting as to medication-based prevention methods such as PEP or PREP: The Achilles heel (Mayer 2011) is compliance! Hence, all new methods have the same weak spot as the old prevention methods. Armin Schafberger and Steffen Taubert 10

11 Pre-exposition prophylaxis (PrEP) The studies published in the last few months substantiating that the proactive application of pharmaceuticals (PrEP) can considerably reduce the risk of HIV transmission met with a huge media response. However, the protective effect clearly fell behind the expectations. Is the establishment of PrEP as a new arrow in the quiver of prevention nevertheless justified? These are the first positive study results with a microbicide although research has been ongoing in this field for 20 years. Since the research pipeline only includes microbicides containing antiretroviral drugs, the microbicides are from now on classified as vaginal (and in the future also rectal) PrEP. The results of the iprex study (Grant 2010) were published in November Using Truvada for PrEP in MSM, a protective effect of 44% was achieved compared to placebo. The iprex study will now be continued as an open-label study. Those MSM who have so far been taking a placebo are now also offered the active substance Truvada. Hence, all current study participants are aware that from now on they actually receive Truvada. Rome, in front of the Basilica of St. Peter in Chains: We take two souvenirs home from the IAS Conference in July 2011: New insights into the viral load method (HPTN 052) and into PREP Current state of research The results of the five interventional phase-iib and III studies investigating and vaginally applied microbicides are now available. Last year, HIVreport comprehensively reported on the CAPRISA microbicide study (vaginal PrEP in women) and the iprex study (PrEP in MSM) (HIVreport 3/2010, HIVreport 5/2010). At the World AIDS Conference in Vienna in July 2010, the researcher couple Salim & Quarraisha Abdool Karim presented the results of the Caprisa study (Abdool Karim 2010): the vaginal application of tenofovir (Viread ) as gel both before and after vaginal intercourse. In the study arm with tenofovir gel, 39% less infections occurred than in the study arm with a placebo gel. 11 The investigations concern the compliance and the protective effect under these conditions and aim to find out whether the knowledge of the PrEP study results changes the risk-taking behaviour (referred to as risk compensation). The results of the Fem-PrEP study were disappointing. On 18 April 2011, Family Health International (FHI) announced that it will stop a PrEP study with Truvada (Family Health International 2011). An interim evaluation had shown that the number of infections were equal in the group of women taking Truvada and in the control group taking a placebo. According to their statements, 95% of the women adhered to the PrEP regimen. It is also unclear why many women became pregnant despite double contraception (hormonal plus condoms). The reasons for the failure are not known yet; at present, as of the end of September 2011, the data of a final examination is still not available.

12 Study Study population Place of study Substances Protective effect Caprisa Heterosexual women iprex 2499 Fem-Prep TDF2 Partners PrEP VOICE (MTN 003) MSM 1951 heterosexual women 1200 young heterosexual women and men 4758 heterosexual couples 5000 heterosexual women South Africa predominantly Peru, Brazil, South Africa, Thailand, USA Kenya, South Africa, Tanzania, Zimbabwe Botswana Kenya, Uganda South Africa, Uganda, Zimbabwe Table 1 Phase-III or IIIB interventional studies (safety, efficacy) Truvada : Combination of Viread (tenofovir) and Emtriva (emtricitabine) Viread : Individual substance (tenofovir) vaginal PrEP (microbicide) Viread gel intermittent Truvada Truvada Truvada Truvada Viread Truvada Viread vaginal PrEP (microbicide) Viread gel intermittent 39 % 44 % 0 % (no effect) 63% 73 % 62 % Study still ongoing (see table on p ) 0% stopped 0% stopped The results of the TDF2 and the Partners PrEP studies were presented at the conference of the International AIDS Society in Rome in July For the first time, it was possible to attain a protective effect in heterosexual persons through PrEP: The TDF2 study (Thigpen 2011) investigated the HIV drug Truvada applied as PrEP in young heterosexual women and men aged between years. The study revealed a protective effect of 63% for Truvada-PrEP, compared to the placebo. This study will now be continued as open-label study (all participants are offered Truvada ) for an additional 12 months. The Partners PrEP study (Baeten 2011) investigated discordant couples where the HIV-positive 12 partner had not yet received antiretroviral therapy i.e. had not yet been treated. Three groups of equal size were formed. HIV-negative partners in the first group were given a daily dose of Viread (Tenofovir), those in the second group Truvada (tenofovir and emtricitabine) and those in the third group a placebo. This study also had a high pregnancy rate of 10.3 per 100 women years, with no statistically significant difference between the groups taking placebo (9.9) Viread (12.1) and Truvada (8.9). 47 HIV infections occurred in the placebo group, 18 in the Viread group and 13 in the Truvada group. This yields a protective effect of 62% for Viread-PrEP and 73% for Truvada-PrEP. From the statistical perspective, there is no significant

13 difference between the protective effect of Truvada and that of Viread (p=0.18). Hence, these results do not indicate that Truvada is the more effective PrEP. The efficacy in men and women is statistically similar as well. The PrEP study will now be continued as an open-label study; the placebo group will be offered active PrEP and those participants who become infected with HIV will continue to be examined (development of resistances, viral load). Just like in all prevention studies, detailed advice was given on safer sex and condoms were made available. Comments on the PrEP studies PrEP is only effective in highly compliant patients A central problem of all these studies was compliance. Although the studies involved monthly consultations on compliance and the ration of pills given was checked at the end of the month, blood and hair analyses in e.g. the iprex study revealed that the tablets had only been taken in insufficient amounts. The VOICE study was the first to investigate oral PrEP with a microbicide. The with Viread was, however, prematurely stopped in September 2011 because of lack of efficacy, followed by the study arm with vaginal Viread in November 2011 for the same reason. At first sight, the poor results of Viread as microbicide conflict with the results of the Caprisa study (protective effect 39%); however, the 95% confidence interval of the Caprisa study ranged from a protective effect of 6% to 60%, since the number of participants was relatively low. After the Caprisa results had been published, it was therefore demanded that the result be verified within the scope of a larger study. The VOICE study did not verify the result. The study arms with oral Truvada and oral placebo will be continued; this is why HIVreport lists the VOICE study under still ongoing studies (cf. p ). Data evaluations do not take account of reallife conditions Sub-groups with better compliance attained a higher protective effect (in the iprex study up to more than 90%) than the overall study group. These sub-group analyses are often mistakenly referred to in public debates as the actual protective effect. Prevention studies just like the market authorisation study for pharmaceuticals take account of intent-to-treat evaluations, rather than as-treated analyses. The latter may provide interesting additional information, but in the end the deciding factor is whether the administration of a drug was intended rather than if it was actually taken. Intent-to treat also takes persons into account who did not take their medication under real-life conditions. If these study participants were not taken into account in data evaluations, every study investigating e.g. condoms would achieve a protective effect of 100%. After all, people have reasons for not being willing or able to take a drug or apply a prevention method, and these barriers have to be considered in the assessment of a specific method. A recurrent topic: Long-term prophylaxis All four studies investigating were conducted using the same drug (Truvada or Viread ) as long-term prophylaxis (once a day over several months and years). Another study with the same drug and dosage schedule will be concluded in 2012 (see Table 3). 13

14 Intermittent PrEP: Short-term PrEP, e.g. at the weekend, would be more attractive to users. Two studies investigating intermittent PrEP are currently being planned (see Table 4), but these are phase-i and II studies. These studies provide no insights into the efficacy of intermittent PrEP. Studies investigating intermittent PrEP, monthly injections as well as PrEP with the entry inhibitor Maraviroc are still in a very early stage of development, i.e. the planning and implementation of the subsequent efficacy studies will still take several years (see Table 4). The monthly PrEP injection: The substance TMC278-LA (long acting rilpivirine) is currently being tested as a monthly PrEP injection in early stages of clinical development (see Table 4). Rilpivirine is a new NNRTI, which has so far only been approved in the USA and is expected to be approved in Europe as from late The development of a monthly injection is expected to increase compliance. PrEP research pipeline 2013 will be an exciting year for PrEP because this is when the results of the open-label studies are expected (see Table 2). They will provide answers as to whether the knowledge of actually taking PrEP (and not a placebo) increases compliance and whether the knowledge of the initial research results changes the risk-taking behaviour of PrEP users. Rome, Tiber: Not all PrEP studies reach the finishing line. Some studies or study arms (e.g. of the VOICE study) have to be stopped prematurely. The largest study (VOICE), which attempted to compare with a microbicide, will also end in 2012 (see Table 3). This project has, however, failed. A study arm of the with Viread was stopped in September 2011 due to missing efficacy, followed by the 2 study arms with vaginal Viread (due to missing efficacy) and vaginal placebo in November Only 2 study arms with oral Truvada and oral placebo are still ongoing. sch 14

15 Overview of PrEP research pipeline from Armin Schafberger HIVreport 5/2011 Pharmaceuticals in Prevention Study Study population Place of study Substances Result expected in iprex OLE MSM of the iprex study predominantly Peru, Brazil, South Africa, Thailand, USA Truvada 2013 TDF2 Partners PrEP Young heterosexual women and men Botswana Truvada Heterosexual couples Kenya, Uganda Viread or Truvada 2012 / 2013? 2012 / 2013? Table 2 Open-label studies (compliance, efficacy, risk compensation): The completed phase-iii studies will be continued as open-label studies. All study groups now receive the active substance, nobody receives placebo. Study Study population Place of study Substances Result expected in CDC i.v. drug users Thailand Truvada early 2012 VOICE (MTN 003) 5000 heterosexual women South Africa, Uganda, Zimbabwe Table 3 Phase-III or IIIb interventional studies (safety, efficacy) : Viread 1 or Truvada or vaginal PrEP (microbicide) Viread gel intermittent 2012 Study Study population Place of study Substances Stage TMC 278-LA 66 men and women Great Britain Monthly injection (i.m.) Rilpivirine Result 2012 Ipergay 300 MSM as a preliminary study France : Truvada intermittent Start autumn 2011 HPTN women and 180 MSM South Africa, Thailand : Truvada intermittent planned HPTN MSM USA : Maraviroc, Emtriva, Truvada planned IAVI E heterosexual men and women Uganda : Truvada intermittent? Table 4 Interventional studies investigating acceptance, compliance, safety and feasibility Notes on the tables: The expected results indicated are estimations. Under certain circumstances, studies can be opened earlier. The postponement of the data analysis to a later point is also possible. Phase-I and II studies provide no insights into the efficacy of PrEP; these are preparatory studies for larger efficacy studies (phase-iib and III). The tables were compiled based on the information provided by AVAC, as of September 2011, URL: as well as the IAS Conference in Rome, July 2011 and ANRS ( 1 VOICE study: Because of inefficacy, the PrEP study arm with oral Viread was stopped on 28 September 2011, followed by the discontinuation of the substudy with Viread as microbicide on 28 November

16 What questions are still open? Some questions can hardly be answered on the basis of studies but only during the application of PrEP. Will a black market develop for Truvada? The majority of PrEP studies were conducted using Truvada, a pharmaceutical that is also frequently prescribed for HIV treatment. The pharmacy sales price for this drug currently amounts to 840 per month in Germany. Transferring the drug from therapy to prevention is thinkable. Furthermore, Truvada is already being offered for sale on the Internet from abroad (HIVreport 5/2010). How beneficial is PrEP for Central Europe? Which population groups in Germany would benefit from PrEP? So far, there has been no social scientific research on this but this would be necessary. In this respect, many people think of the group of MSM. However, the incidence of HIV in MSM is so low in Germany (<1%) that more than 200 men would have to be treated for one year to prevent an infection, even when there is a high protective effect (HIVreport 5/2010). Social scientific research would first have to identify MSM who are exposed to an extremely high risk and would benefit from PrEP. What are the long-term side effects? Long-term side effects and long-term compliance are also unclear. The data obtained from studies running for approx years provide no reliable insights into the health effects of long-term medication-based treatment on the HIV-positive patient receiving treatment, or whether HIVnegative persons are put to the acid test as frequently as HIV-positive patients taking Truvada. Does PrEP change the risk-taking and/or protective behaviour during sexual intercourse? There has so far been no data on whether the application of PrEP outside studies (if the client is sure that he is not receiving a placebo) increases the risk-taking behaviour, thus partly eliminating the method s protective effect. There is also no data available on whether condoms (for protection against STIs) are accepted to a relevant extent in such a setting. Would fixed-term PrEP not be more reasonable than virtually lifelong PrEP? There is no social scientific data available on whether fixed-term PrEP (e.g. during annual holiday) can be a reasonable contribution to prevention by increasing the willingness to safer sex in the aftermath. Such fixed-term PrEP is not being investigated in the ongoing efficacy studies either. May resistances yet develop when applying PrEP over years? During studies, resistance development is virtually excluded through intensive monitoring and monthly HIV tests. The question is to what extent resistances can develop during therapy-free periods and at longer test intervals under real-life conditions limiting the subsequently required antiretroviral therapy. Do statutory health insurance funds bear the costs? Off-label use (on private prescription) is possible in both the USA and Germany. PrEP can thus be prescribed without additional market authorisation for Truvada. To physicians, however, off-label use also involves special diligence. If off-label use yields no success i.e. the client becomes infected legal disputes cannot be excluded (HIVreport 5/2010). sch 16

17 Bottom line In general, PrEP is primarily rated according to its protective effect. Whether the protective effect achieved in studies can also be attained in practice is doubtful because the level of consultation and monitoring in studies cannot be implemented in real life. Further questions (risk compensation, black market, development of resistances) can only be answered later on during practical application. At present, we consider the implementation of PrEP in practice to be too early and its protective effect too low. The initiation of social scientific research on PrEP would be reasonable. In order to avoid incorrect application, the development of preliminary recommendations for PrEP in Germany would be worth considering. In January 2011, the CDC issued preliminary recommendations for PrEP in MSM (Smith 2011, German summary in the HIVreport 1/2011) sch/tau References Abdool Karim Q., Abdool Karim S.S. et al.: Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women July 2010 ANRS: Press Release. What would be the impact of universal Test and Treat on the HIV pandemic? Paris, 29 November 2010 Attia S, Egger M, Müller M, Zwahlen M, Low N.: Sexual transmission of HIV according to viral load and ART Systematic review and meta analysis. AIDS 2009 Baeten J, Celum C for the Partners PrEP Study Team: Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention among Heterosexual African Men and Women: The Partners PrEP Study. IAS Konferenz, Juli 2011, Rom Brenner BG, Roger M, Routy JP et al: High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 2007; 195: Cates W: HPTN052 and the future of HIV treatment and prevention. The Lancet, Vol. 378, July 16, 2011 Cohen MS, Chen YC, McCauley M, Gamble T, Hosseinipour MC et al. (a): Prevention of HIV-1 Infection with Early Antiretroviral Therapy. NEJM Cohen MS, Chen YQ, McCauley M et al. (b): Supplementary Appendix. Prevention of HIV-1 Infection with Early Antiretroviral Therapy. NEJM 2011 Cohen MS (c): HPTN 052. IAS Konferenz, Juli 2011, Rom Family Health International: FHI to Initiate Orderly Closure of FEM-PrEP. 18. April 2011 Fleming DR et al.: From epidemiological synergy to public health policy and practice. The contribution of other STD to sexual transmission of HIV. Review. Sex Transm Inf 1999;75:3 17 Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG: Universal voluntary testing with immediate ART as a strategy for elimination of HIV transmission: a mathematic model. The Lancet 2008 Grant R.M. et al. (for the iprex Study Team): Preexposure Chemoprophylaxis for HIV Prevention in Men who have Sex with Men. NEJM, Nov. 23, 2010 HIVreport 3/2010 zu Mikrobiziden. Deutsche AIDS-Hilfe, Berlin, 2010 HIVreport 5/2010 zur iprex-studie. Deutsche AIDS-Hilfe, Berlin, 2010 HIVreport 1/2011 zu den vorläufigen Empfehlungen der CDC zur PrEP. Deutsche AIDS-Hilfe, Berlin, 2011 Johnson LF, Lewis DA: The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex Transm Dis Nov;35(11): Kelley CF, Haaland RE, Patel P, et al: HIV-1 RNA rectal shedding is reduced in men with low plasma HIV-1 RNA viral loads and is not enhanced by sexually transmitted bacterial infections of the rectum. JID 2011:204 (1 September), Lewis F, Hughes GJ, Rambaut A, Pozniak A, Leigh Brown AJ: Episodic sexual transmission of HIV revealed by molecular phylodynamics. PLoS Med 2008: 5: e50 Mayer KH: Antiretrovirals for HIV prevention: translating promise into praxis. The Lancet, Vol. 378, July 16, 2011 Pao D, Fisher M, Hue S et al: Transmission of HIV during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS 2005; 19: Powers KA, Ghani AC, Miller WC, Hoffman IF, Pettifor AE, Kamanga G, Martinson FEA, Cohen MS: The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study. The Lancet, Vol. 378, July 16, 2011

18 Sadiq ST, Taylor S, Kaye S, Bennet J et al: The effects of antiretroviral therapy on HIV-1 RNA loads in seminal plasma in HIV-positive patients with and without urethritis. AIDS 2002, 16: Smith et al: Interim Guidance: Preexposure Prophylaxis for the Prevention of HIV Infection in Men Who Have Sex with Men. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC. Morbidity and Mortality Weekly Report. January 28, 2011 / 60(03); Thigpen MC, Kebaabetswe PM, Smith DK et al for the TDF2-Study-Team: Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active adults in Botswana: results from the TDF2 study. IAS Konferenz, Juli 2011, Rom Weller SC, Davis-Beaty K: Condom effectiveness in reducing heterosexual HIV transmission (Review). Cochrane Database of Systematic Reviews 2002/2006, Issue 1. Art. No.: CD DOI: / CD HIVreport 5/2011 Pharmaceuticals in Prevention Imprint Publisher Deutsche AIDS-Hilfe e.v., Wilhelmstr Berlin Tel: (030) Fax: (030) Responsible in the sense of the German "Pressegesetz" (law on publishing/news): Steffen Taubert (tau) Armin Schafberger (sch) Texts Armin Schafberger, Physician, MPH Steffen Taubert, Qualified Psychologist German-English Translation: Macfarlane International Business Services GmbH & Co. KG Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JK: Relation between HIV viral load and infectiousness A model based analysis Lancet 2008; 372: Yerly S, Vora S, Rizzardi P et al: Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001; 15: Order new and download older sues: Donations account of Deutsche AIDS-Hilfe e.v Account no Berliner Sparkasse Sort code Notice The procedures, medication, constituents and generic drugs are communicated regardless of the existing patent situation. Protected product names (trademarks) are not always marked as such; however, this must not give rise to the assumption that the designations used are non-proprietary names. Deutsche AIDS-Hilfe accepts no liability for the correctness of the information provided as well as for any damage caused by possible errors. We recommend that our readers refer to the manufacturers summary of product characteristics and package inserts. The translation of this issue was made possible by the support of 18