It has never been more urgent to prevent new HIV infections. The rollout of antiretroviral therapy (ART) globally has been more successful than we could have imagined but, in 2008, the estimated number of new HIV infections was 2.5 times higher than the increase in the number of people on antiretroviral drugs, underscoring the need for substantially greater success in preventing new HIV infections . The falling mortality from AIDS due to implementation of ART is not only increasing HIV prevalence globally but also increasing the numbers of individuals living with HIV requiring lifelong therapy . In the absence of novel strategies to prevent these new infections, the provision of long-term therapy and care will become logistically and economically unsustainable .
All 20th century experience suggests that a vaccine is the optimal public health tool to control pandemic infectious disease. Yet, not only is there no licensed vaccine against HIV infection, but there are also no candidates currently in phase III trial [3,4]. Following the failure of the vaginal microbicide, PRO 2000 in December 2009 , there is no other microbicide in phase III trial . Although behavioural interventions have been shown to have some impact on HIV transmission [7–9], the lack of sustainability of such strategies [10,11] makes it difficult for them alone to confer substantial effects at a population level. In addition, multiple randomized clinical trials (RCTs) [12–15] investigating treatment of cofactors known to enhance HIV transmission such as herpes simplex virus 2 (HSV-2) and sexually transmitted infections (STIs) have had disappointing results when tested as an HIV prevention strategy in RCTs. So, with the exception of the ancient technologies of male condoms and male circumcision, all we are left with to prevent new HIV infections are the antiretroviral drugs themselves . Fortunately, there are compelling data to suggest that ART can prevent the transmission of HIV at an individual level [17–21]. Antiretroviral drugs are used routinely in the clinic for occupational postexposure prophylaxis (PEP) in healthcare workers  and in maternal HIV infection to prevent transmission to the child . As will be shown below, there are several recent findings from ecological studies [13,24,25] supporting the universal test and treat (UTT) approach as prevention against HIV transmission at a population level. Indeed, one mathematical model of the impact of enhanced HIV testing and universal treatment of all testing HIV positive suggests that it might be possible to eliminate HIV infection through ART over time, without the need for a vaccine [26,27].
The antimicrobial era, which effectively began in 1942, has revealed the enormous potency of antibiotics and later antiviral drugs to alter the natural history of infection within an individual, in addition to the significant impact on infectious disease morbidity and mortality. However, the impact of the use of these antimicrobial drugs to prevent infection is much less clear. For example, although the use of isoniazid antimicrobial prophylaxis against Mycobacterium tuberculosis transmission has been demonstrated to be efficacious in preventing infection at an individual level [28–30], studies [31,32] reported that the potential effectiveness at a population level maybe compromised by poor compliance to treatment in healthy immunocompetent individuals. Adherence to isoniazid prophylaxis appears to be most effective in the first 6 months of dosing in the setting of familial exposure or other high-risk exposure and least effective in general populations .
There is only one example to date of the ability of an antibiotic to actually eliminate an infectious disease at a continental level without the use of a vaccine. The endemic treponematoses, known colloquially as Yaws in Africa, Pinta in South America or Bejel around the Mediterranean, were contagious, nonvenereal cutaneous infections caused by Treponema pallidum sub species pertenue . From 1952 to 1964, WHO and United Nations Children's Fund led a worldwide campaign to control and ultimately eradicate Yaws and the other endemic treponematoses in 46 countries by case finding and immediate treatment with depot benzathine penicillin. By 1964, reported cases of treponemal infections had fallen from 50m to 2.5m (95% reduction), and elimination of the disease was reported in the Mediterranean, India and South America. The successful elimination of these infections was related to their exquisite sensitivity to penicillin without significant emergence of resistance, the use of a single long-acting depot benzithine injection to ensure compliance, relatively stable populations allowing population-level treatment campaigns without re-infection, and most critically of course, committed political will and sufficient funding. Indeed, global eradication of the endemic treponematoses might have been achieved by penicillin alone in the 1970s if vertical control programmes had been continued . Instead, the initiative was moved into general public health programmes, which were too weak to sustain control, and Yaws has reemerged in Sub-Saharan Africa . However unusual these treponemal infections may have been biologically, the successful control of this infection does at least support the concept of the control of an infectious disease at a regional level without a vaccine, through antimicrobial action only.
There are now 26 licensed antiretroviral drugs for HIV infection that could be used for prevention of infection either singly or in combinations. All are currently dosed daily, generally orally, although one long-acting antiretroviral drug is being developed which may ultimately allow 12 weekly dosing intervals . What, realistically, are the prospects of using these drugs to prevent HIV infection at the level of the individual, and at a population level within current healthcare systems, funding and capacity constraints? Which strategy offers the best prospect for success and how could the best approach be assessed? Should the focus be on preexposure prophylaxis (PrEP) and PEP to protect the uninfected individuals or on a UTT approach focusing treatment and resources on the HIV infected? One critical issue when assessing the feasible and safe use of PEP and PrEP in humans is the HIV status of the individual exposed to a potential HIV risk. Use of less than triple ART in an HIV-infected individual will confer viral drug resistance. In the absence of knowledge of HIV status, the potential danger of exposing an infected individual to suboptimal ART, which could potentially compromise their responses to later therapy, could outweigh the reduced risks of HIV acquisition.
When addressing the different approaches to prevention, it is important to differentiate between HIV acquisition, which refers to an HIV uninfected individual's risk of becoming infected, and transmission, which refers to an HIV-infected individual's risk of infecting an HIV-uninfected individual. The risk of sexual acquisition of HIV by an uninfected individual reflects a composite of sexual behaviour , male circumcision status in heterosexual men , STI coinfection  and, in particular, genital ulcer disease , naturally occurring genetic  and immunological barriers  to acquisition as well as the characteristics of the exposing virus [44,45]. Sexual transmission of HIV reflects the quantification and characteristics of the virus in the infected host, in particular, the level of viral shedding from the genital tract, sexual behaviour in terms of nature of sexual practices as well as disease stage [46,47] and STI coinfections .
Animal models of antiretroviral therapy for prevention of infection
The role of animal models in the development of HIV prevention technologies remains controversial. This is not because there is conflict over the need for a challenge model; after all, no human vaccine has ever been developed without an animal challenge model. However, the relationship between the results from animal challenge models and those from human phase III trials for both HIV vaccines and microbicides do not engender confidence that the correct animal model and/or challenge virus yet exists. Immunization with the Merck (Whitehouse Station, New Jersey, USA) adenovirus type 5 Gag construct repeatedly led to attenuated simian immunodeficiency virus (SIV) infection in the macaque model but not in human infection in the STEP trial [3,4]. Moreover, the ALVAC–glycoprotein 120 prime boost was not preventive against simian/human immunodeficiency virus (SHIV) challenge in the macaque, but has produced significant protection in a human phase III trial in Thailand, the RV144 study . The microbicide PRO 2000 was reproducibly highly effective in preventing infection in macaque SHIV vaginal challenge experiments, but failed in a human phase III trial . These results suggest either that the biology of SIV infection in the macaque is not equivalent to the biology of HIV in humans or that the mechanisms of mucosal transmission and/or immunity in humans is biologically different from macaques or both .
Whatever the ultimate explanation for the discrepancies between macaques and man, and given the caveats over the significance of current macaque models, it is still important to review the use of ART in animal challenge models. The macaque SIV model is the only model other than large, long and costly human clinical trials, which can compare ART strategies for prevention of transmission, and so must in the broadest sense inform research strategy on HIV prevention. It is important to bear in mind that not all antiretroviral drugs are active against SIV; in brief, all of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are active against SIV but not the non-NRTIs (NNRTIs) or the protease inhibitors. For this reason, most macaque challenge experiments have been conducted using SIV with mono-NRTI or combination NRTIs.
SHIVs, chimaeric viruses comprising the SIV backbone engineered to express a single HIV gene, have generally been made with HIV-env for vaccine experiments, but HIV-pol SHIVs also exist which could allow NNRTIs and protease inhibitors to be studied in future; HIV-env SHIVs can be used for examining the C–C chemokine receptor type 5 (CCR5) inhibitors such as maraviroc.
For logistical reasons, macaque challenge studies tend to use no more than four or six animals per arm; clearly, this small sample size does not approach the levels of statistical confidence required for a human clinical trial . However, it is generally possible to ensure 100% transmission in the control arm, and so reproducibility of results in the active arms gives confidence. When the control arm is less than 100% infected, the results tend to be considerably less interpretable.
Results of macaque challenge studies
Garcia-Lerma et al.  showed that tenofovir–disoproxil–fumarate (TDF) daily given subcutaneously prevented SIV infection in all macaques when given 48 h before, or 4 or 24 h after inoculation; all controls became infected. TDF blocked SIV given intravenously, if given within 24 h of challenge, and if continued for 28 days . TDF was not effective if started 48–72 h postexposure or if used for only 3–10 days, rather than 28 days . TDF blocked vaginal challenge if given within 36 h for 28 days; three out of four macaques were protected if TDF was started within 72 h . These results suggested that PEP was effective in the SIV/macaque model, but had to be initiated within 24 h of exposure and that the ART needed to be continued for 28 days. These data have informed clinical guidelines internationally, wherein no RCT of PEP has ever been undertaken and none is now possible.
More recently, macaque studies have looked at the efficacy of daily ART as PrEP. Oral daily TDF was used with weekly low-dose intrarectal SHIV challenge (once a week for 14 weeks), wherein three out of four became infected . When daily oral TDF was studied against single high-dose intrarectal SHIV challenge in macaques, two out of five were infected . Intrarectal TDF gel was effective against single high-dose intrarectal SHIV challenge in macaques, six out of nine animals receiving 1% gel were protected .
These results suggested that NRTI monotherapy could be partially but not fully effective as PrEP, and led to experiments with dual NRTI therapy, generally TDF plus emtricitabine (FTC), the combination used clinically as a single combination pill called Truvada (Gilead Sciences, Inc., Foster City, California, USA). Once daily oral TDF/FTC protected four out of six animals after 14 low-dose rectal challenges and two out of six exhibited delayed infection, a 7.8-fold total risk reduction compared with controls [60,61]. Once daily TDF/FTC subcutaneously protected six out of six animals after 14 challenges; however, this study required TDF levels 3–4× higher than could be achieved through oral dosing in humans .
These data suggest that PrEP, through single daily dosing, can be protective against SIV transmission but a reproducibly high level of protection may require the use of two drugs such as TDF/FTC (Truvada). In the macaque, the most consistent protection against HIV acquisition was seen with higher doses of TDF than can achieved through oral dosing in humans, and there are still no published data on oral PrEP and vaginal challenge in the macaque model. It should be borne in mind that the protection seen with Truvada in the SIV/macaque low-dose repeated mucosal challenge model, which presumably is closest to the human situation, is generally partial , and that the phamacokinetics of the NRTI drugs may not be identical in macaque and man.
Prevention of HIV acquisition in humans
Lessons learned from the uses of ART for HIV-positive individuals need to be taken into account when planning the use of ART for the prevention of HIV acquisition. NRTI monotherapy in previously untreated HIV-positive individuals inexorably leads to the emergence of antiretroviral resistance over, on average, a 6-month period. Use of two NRTIs delays but does not prevent the emergence of resistance, , whereas a combination of three drugs generally leads to persistent suppression of viraemia, which can be maintained indefinitely (theoretically) without breakthrough or resistance emerging.
The use of antiretroviral therapy in HIV-uninfected individuals either before or after sexual exposure to HIV
When assessing the use of ART for PrEP in humans, extrapolation from primate data is often difficult. In primates, the dose of challenging viral inoculum is known and is set at a level known to successfully infect. In humans, the use of PrEP is to prevent against a hypothetical risk of HIV acquisition as the nature of exposure and challenge dose of virus is unknown and the composite risk of HIV acquisition for that individual remains uncertain.
Optimizing an ART regimen following sexual HIV exposure when the risk is more real, provided the HIV status of the exposing partner is known, maybe very different from a recommended PrEP regimen. The viral load of the infected partner is the key determinant to predict the risk of onward HIV transmission , and the presence of drug-resistant viral variants within the ‘donor’ HIV-infected partner will predict which ART agents will be most efficacious to prevent acquisition of infection. For the majority of exposed individuals wherein the HIV status of the exposing partner is unknown, a risk assessment is undertaken based on the background population HIV prevalence and the timing and reported sexual practices employed .
Occupational exposure postexposure prophylaxis
In 1997, the Centers for Diseases Control (USA) reported the results of a case–control study  of HIV seroconversion in healthcare workers after percutaneous exposure; there was an 81% reduction in HIV infection in those who had taken zidovudine antiretroviral monotherapy after exposure compared with those without any ART. There has been no RCT of PEP for occupational exposure, and none will ever now be undertaken, although the macaque data described above support the use of ART within 24 h of exposure and continued for 28 days . Triple ART is used in order to minimize the risk of induction of resistance in the event of HIV seroconversion after exposure, and PEP is now widely used by healthcare workers after occupational exposure. However, although the uptake of PEP for occupational exposure is high, the reporting of side effects is considerably more frequent among PEP users than matched HIV-infected individuals, and many fail to complete a full 28-day course of PEP  Interestingly, the reported toxicity and frequency of early cessation of ART for PEP in HIV-negative individuals greatly exceeds the reported toxicity for ART in HIV infection, which may reflect the differential impact of anxiety underlying the exposure and uncertainty over outcomes.
Nonoccupational postexposure prophylaxis
In 1998, Pinkerton et al.  raised the issue of the use of PEP among men who have sex with men (MSM) to prevent HIV infection after high-risk behaviour and likely sexual exposure to HIV infection, now known as nonoccupational PEP (N-PEP). Schechter  studied the feasibility of the zidovudine/lamivudine combination (Combivir; GlaxoSmithKline plc, London, UK) in 202 gay men in Rio de Janeiro, Brazil. Volunteers were given a 4-day supply of Combivir with instructions to use immediately after a high-risk sexual exposure and to report to the clinic within 4 days; if the exposure was deemed high-risk at clinic, the volunteer was given a full 28-day course of the same combination. Out of the 202, N-PEP was initiated 110 times by 73 volunteers; the full 28-day course was completed in 91.1% of episodes. There were 11 HIV seroconversions, 10 in those who did not take N-PEP and one despite taking a full course of N-PEP, but when subsequent analysis demonstrated partial resistance (M184V indicating resistance to lamivudine) of the infecting virus . However, this was not a randomized trial and the different outcomes may have reflected differing behaviours and hence different risks of exposure rather than a direct N-PEP effect. In observational, nonrandomized studies [69,70] of zidovudine/lamivudine in 480 sequential initially seronegative cases of heterosexual rape in South Africa, there was one seroconversion, and that occurred in a individual who did not initiate N-PEP until 96 h after exposure.
There have been no RCTs of N-PEP for nonoccupational exposure to HIV to date, although guidelines for use have been produced . Any such study would need to be very large to be adequately powered, and the ethics of a no-treatment arm for an intervention, which is currently standard of care for occupational HIV exposure, would be extremely challenging. It is most unlikely that an RCT of N-PEP could now ever be conducted.
The current guidelines recommend the use of triple ART as nonoccupational N-PEP for high-risk groups such as MSM . Although the use of three drugs adds enhanced risk of toxicity and hence lower adherence, the regime reduces the risk of infection in the face of PEP because of transmitted viral resistance. N-PEP appears to work, at least in nonrandomized observational studies, but the greatest hurdle is the low adherence to the full course of 28 days therapy . As noted in Table 1, N-PEP requires patients to have repeated HIV tests, hold a starter pack of 4–5 days therapy and self-prescribe after an exposure, be willing to attend for a full prescription at day 4, must be motivated, well educated (at least about sexual health) and with access to a sophisticated healthcare system. In addition, the clinical studies of nonoccupational PEP to date have been restricted to targeted populations with a high level of knowledge and commitment to N-PEP such as MSM. For these reasons, it may be implausible that N-PEP could be considered as a safe population-level control strategy against HIV transmission; although as a targeted approach to key core high-risk populations, it may be highly effective and potentially cost-efficient [67,72]. There are concerns that the availability of N-PEP may enhance sexual disinhibition and limit the overall effectiveness of such an intervention at a population level, although this remains controversial [73,74].
Usually, triple ART for 28 days is recommended for PEP in an HIV-uninfected individual after high-risk HIV exposure to ensure that should prophylaxis fail and HIV infection become established, there will be only a negligible risk of antiretroviral resistance developing. The potential availability of a triple ART regime for all exposed uninfected individuals is globally unaffordable. This is further compounded by the need to know the HIV status of all individuals prescribed PEP prior to initiating a short course of triple therapy. In the context of the Strategies for Management of Anti-Retroviral Therapy (SMART) study , the cessation of ART initiated in chronically HIV-infected individuals conferred a significantly higher morbidity and mortality compared with individuals remaining on continuous therapy. Cessation of a 28-day course of ART in an undiagnosed HIV-infected individual could potentially trigger an increased cardiovascular risk concomitant with a viral load rebound.
PrEP refers to the use of ART for those individuals known to be HIV uninfected prior to exposure to virus. The macaque data and the success of ART in preventing mother-to-child transmission of HIV suggest strongly that PrEP could be effective at preventing HIV transmission.
There are certain situations and core high-risk groups such as MSM, commercial sex workers and injecting drug users (IDUs) who would benefit from PrEP. For couples in HIV serodiscordant relationships wishing to conceive, PrEP offers an option for conception without the risk of HIV transmission and such a strategy may be a highly effective and potentially cost-efficient use of therapy. However, the necessity to know the HIV status as discussed above for the use of PEP similarly applies, particularly when the majority of PrEP guidelines and trials employ mono or dual therapy. One key challenge with the widespread introduction of PrEP as a prevention strategy is the use of scarce resources to provide ART for uninfected individuals when there is limitation on access to ART as therapy to prevent mortality and morbidity among HIV-infected individuals in need of treatment.
Which and how many drugs are needed for preexposure prophylaxis?
Table 2 shows the status of the current 11 phase II and III RCTs of ART as PrEP. Four of the trials use TDF alone, generally as a daily dose, and the remainders use either TDF/FTC (Truvada) as a single daily dose or in one case as a topical (vaginal) TDF gel in a coitally dependent manner.
More recent pilot studies are investigating the use of the CCR5 inhibitor maraviroc  and the safety of a novel depot injectable NNRTI inhibitor . Clearly, the more drugs, which are used in healthy, HIV-negative individuals, the greater the cost, the greater the risk of toxicity and hence the poorer the adherence. In addition, global introduction of these antiretroviral agents as first-line regimens  will increase the population levels of viral resistance to these drugs, limiting their potency for use as PrEP and therapy simultaneously.
Within the context of tightly controlled and supervised PrEP clinical trials with regular HIV testing at 12-week intervals, the risk of antiretroviral resistance emerging will always be low, assuming that all individuals are truly HIV-negative prior to enrolment. Outside of a clinical trial, use of TDF monotherapy PrEP will require repeated HIV testing before and during PrEP use, to a far greater extent than has ever been achieved to date, to ensure that inadvertent monotherapy in HIV infection does not induce antiretroviral resistance and limit future ART options.
First, as demonstrated by Brun-Vezinet et al. , continued use of mono or dual ART in the face of primary or established HIV infection will inevitably lead to the induction of antiretroviral resistance. The development of resistance will act as a detriment to the long-term management of the HIV-infected patients. So, individuals requiring PrEP will need to take an HIV test before starting PrEP, and will need regular HIV testing at a minimum of 6-monthly intervals to ensure that they are not inadvertently taking PreP when already infected. Ideally, repeated HIV tests at 12-weekly intervals would lead to greater confidence that HIV infection would be found promptly. If found to be HIV infected, individuals would need to switch immediately to fully suppressive triple ART. Should HIV testing be extended from 6 monthly to annually, the risk of inadvertent use in infected individuals will increase. This 6-monthly frequency of HIV testing has not yet been achieved routinely in high-risk populations outside of a clinical trial. In the real world, even in well educated high-risk populations with open access to free HIV testing, such as gay men in London, over 30% of the HIV-infected individuals remain unaware of their HIV status and have never been tested for HIV .
ART remains a prescription medicine with significant toxicities, both short-term and medium-term, with long-term toxicities still to be fully determined. ART is not currently an over-the-counter medicine. Individuals taking PrEP will need to be prescribed these drugs, adding to the medicalization of healthy individuals. For example, long-term use of TDF is associated with risk of renal tubular dysfunction [80–82]. Although this may be an acceptable risk in HIV-positive individuals who have a life-threatening disease and in whom some degree of toxicity monitoring is indicated, the impact of these toxicities in HIV-negative populations are unlikely to be so well tolerated as with the PEP example given above , and monitoring them maybe unfeasible.
As the same drugs will be used for PrEP, in the same doses and fixed drug combinations (Truvada and Combivir), as for treatment of established HIV infection, there will exist the potential for considerable confusion; confusion as to the number of drugs required for PrEP as compared with established infection, and confusion over the goal of ART, when the same drugs could be taken within a single household for different reasons. Furthermore, both TDF and FTC have activity against hepatitis B virus (HBV) infection. As both HIV and HBV may be vertically and sexually transmitted, coinfection with both viruses may occur; the potential inadvertent treatment of HBV by intermittent use of PrEP on coincident chronic HBV infection has not yet been studied, but could potentially risk the development of HBV drug resistance.
Although the number of subjects with HIV infection who require ART is large , it is discrete and whilst challenging to weak healthcare systems, can be achieved even though still reliant on full external funding . The number of individuals who might be eligible for PrEP is clearly larger than the number of HIV-positive individuals. The need to medicalize those without HIV infection through prescribing, HIV testing and toxicity monitoring will add considerably to the pressure on already stretched healthcare systems.
Finally, there is a risk that reliance on PrEP will lead to migration away from the use of condoms or safe sexual behaviour, with an overall negative effect on HIV incidence at a population level . This risk may become clearer after the current PrEP clinical trials have reported.
Universal test and treat
N-PEP and PrEP both posit the use of ART in healthy HIV-uninfected individuals to prevent infection. The UTT concept proposes a new direction for HIV prevention research through targeting the HIV-infected and infectious rather than the uninfected population [21,26].
The amount of HIV virus present in the blood and genital secretions is the single most important determining factor for onward viral transmission [63,85,86]. The seminal Rakai study  of HIV transmission in discordant couples showed a highly significant association between transmission and higher viral load in the donor HIV-positive partner. In this study, sexual transmission did not occur in individuals with a plasma viral load of less than 1000 copies/ml. Similarly, transmission of HIV from mother to child is associated with the level of viraemia in the mother, and transmission is not observed if maternal viraemia is lower than 1000 copies/ml [87,88]. Successful ART reduces plasma viral load to very low levels (<50 copies/ml); levels at which HIV transmission events are extremely rare [63,85,86,88], although not zero [13,89,90]. HIV viral load and hence infectiousness is especially high at the two extreme stages of infection: in acute infection prior to the emergence of an immune response [91,92] and at end-stage disease when the CD4 cell count is reduced below 200 cells/ml . However, the much longer asymptomatic stage, despite its relatively lower viral load, still contributes significantly to onward viral transmission because of the long duration of infectiousness [46,47,94]. In the African setting, it is hypothesized that no one disease stage is primarily responsible for onward transmission . In most African communities, uptake of HIV testing is poor and for those with known HIV status, access to ART is, at best, limited to those with advanced disease [96–98]; this leaves large numbers of unidentified and untreated individuals at risk of transmitting HIV-1 to their sexual partners and offspring .
It has been hypothesized that enhanced identification of HIV-infected individuals followed by immediate access to ART, irrespective of CD4 cells count or disease stage, will reduce infectiousness at a population level, thereby reducing HIV incidence [99,100]. Current mathematical models predict hypothetical elimination of the HIV epidemic with such an approach, if universal annual voluntary HIV counselling and testing and immediate ART for all who test HIV positive were to be achieved . However, the model requires more than 90% of HIV-infected individuals in a population to be identified, and to agree to take lifelong ART. The assumptions underlying this model have provoked much debate, although similar models by other groups [101–103] have concurred on the potential population impact of this strategy.
The key controversy of such models is the assumption that to be successful, the UTT approach would firstly need to enhance the identification of HIV-infected individuals in the population through widespread uptake of ‘universal’ HIV testing. Uptake of HIV testing is complicated by HIV stigmatization, and there are concerns that delivery of ‘universal’ uptake of testing threatens individual human rights and may potentially confer marginalization of vulnerable groups who fail to test or decline therapy. Second, the intervention will need to assure stakeholders and funders that treatment of HIV-infected individuals at higher CD4 cell counts (>500 cells/ml) than is current standard of care in most countries, in order to additionally reduce infectiousness, is rational, feasible and not harmful. Fortunately, international guidelines are increasingly recognizing the safety of ART and the value of early therapy , and the WHO recommendations on CD4 cells count for initiation of ART have recently been increased from 200 to 350 cells/ml [23,78]. Furthermore, recent controversial US Department of Health and Human Services guidelines recommend ART initiation at CD4 cell counts between 500 and 350 cells/ml  and hence a switch to unrestricted use of ART in all individuals testing HIV positive is decreasingly radical.
The detection of a high proportion of the HIV-positive population in order to assure a sufficient population level reduction in viral load remains challenging. In practice, a detection rate of more than 90% of HIV-positive individuals outside of clinical trial settings has not yet been reported, which is one of the reasons that widespread ART in well resourced countries has not yet led to a reduction in HIV incidence [106,107]. Such a level of detection may not be possible without a strong public health commitment and an assault on stigma. However, even if less than 90% identification of HIV-positive individuals is achieved, if associated with a high uptake of ART and high adherence, this may still lead to a larger impact on HIV incidence than any previously tested HIV prevention strategy [26,103]. Encouraging data from recent ecological studies investigating the impact of increased HIV testing and wider coverage of ART show reduced population level HIV incidence in MSM in San Francisco  as well as among IDUs in British Columbia . Findings from an African multicentred study  of HIV serodiscordant couples showed that phylogenetically confirmed sexual transmissions between HIV serodiscordant couples were only identified from HIV-infected partners not on therapy.
In addition to the potential public health impact of the UTT approach, a large individual benefit could be anticipated [16,108]. Although current recommendations support the initiation of ART once total CD4 cells count has fallen to below 200–350 cells/ml, the average CD4 cells count for those initiating ART in an African setting has been estimated at 90 cells/ml . As ART becomes more affordable, less toxic with lower pill burdens, it becomes increasingly reasonable and safer to start ART earlier. In addition, the rate of active tuberculosis (TB) is greatly increased in HIV-positive individuals even with higher CD4 cell counts , and before they are usually eligible for ART, and this would be reduced by earlier ART [99,100]. An additional public health benefit of UTT approach would be the universal antiretroviral treatment of all HIV-infected women, which could potentially eliminate mother-to-child transmission as well as overcoming the issue of transmission through breast-feeding.
Of course, there are real concerns that increased availability of ART could increase risk-taking [109–112], thereby negating the population-level impact of starting ART early, if accompanied by poor adherence, which may also lead to increasing prevalence of drug resistance and limit future treatment options . In the absence of RCT data to support earlier ART, the field remains in equipoise as to the real outcome of such a UTT approach. The optimal time to start ART remains an unanswered question when the individual mortality and morbidity outcomes have to balance the cost, sustainability, capacity, drug-related toxicity and risks of developing resistance. To date, no RCT powered to address the effectiveness and cost-effectiveness of the UTT approach has commenced. The Preventing Sexual Transmission of HIV with Anti-HIV Drugs (START) trial which will compare the effects of starting treatment with a CD4 cells count above 500 cell/ml versus waiting until the CD4 cells count is below 350 cell/ml is not due to report for the next 5–7 years. The HPTN 052 study is a phase III, two-arm, multisite, randomized trial whose primary objective is to compare the rates of HIV infection among partners of HIV-infected participants receiving either ART upon enrolment plus HIV primary care, or HIV primary care without initiation of ART until the participant has two consecutive CD4+ cell counts within or below the range of 200–250 cells/ml or develops an AIDS-defining illness. The study will also address the acceptability of treatment for prevention in the context of stable HIV serodiscordant relationships. The Partners in Prevention HSV/HIV Transmission Study, which investigates the risks of HIV transmission from individuals with suppressed viraemia in HIV serodiscordant relationships, reported a 92% reduction of HIV transmission between long-term, HIV-serodiscordant heterosexual couples in Africa if the HIV-positive partner is on ART . Finally, the Partners of people on ART: a New Evaluation of the Risks (PARTNERS) study will investigate the factors associated with condom use in HIV discordant partnership to estimate the rate of HIV transmission. Therefore, a study investigating the feasibility, acceptability and deliverability of a UTT approach is now needed. Several groups have developed initial trial protocols from which to test such a strategy: PopART (Uganda), TasP (Treatment as Prevention, South Africa), TLC+ (Testing and Linkage to Care PLUS, USA) and TnT (Test and Treat, USA), Ecological studies continue in San Francisco, British Columbia and Malawi (MP3).
Postexposure prophylaxis, preexposure prophylaxis or universal test and treat?
The fundamental thesis of the UTT approach to the control of HIV transmission through ART is the enhanced identification of HIV-infected individuals followed by universal treatment. The greatest possible proportion of HIV-positive individuals within a population needs to be identified through greatly enhanced testing, and these individuals will need to overcome stigma, accept ART at any stage of infection and remain on therapy indefinitely. Although this approach requires more extensive HIV testing than ever yet achieved, once identified as HIV infected, no further individual HIV testing is required. The process of enhancing HIV testing will identify a greater proportion of the HIV-infected population, many of whom currently are undiagnosed and include many with dangerously low CD4 cell counts. TB control and overall mortality from HIV will undoubtedly be improved as a consequence. UTT supports the current medical model of HIV diagnosis and prescription of ART. The toxicity of ART remains acceptable within the context of a life-threatening disease. There is little ambiguity about UTT; ART drugs are used only in HIV-positive individuals, only for treatment, with reduction in transmission a secondary effect. The UTT approach would need to be continued for a generation to reduce transmission; too early cessation, as with the control of Yaws, will lead to loss of initial control.
The challenge of PrEP at a population level is, we believe, even greater than for UTT. Greatly enhanced HIV testing will be required, but individuals taking PrEP will need repeated HIV testing to avoid inadequate therapy if they have become HIV infected. Healthcare structures will need to be re-directed to HIV-negative individuals in order to deal with prescribing and monitoring ART, to the potential detriment of care for HIV-positive individuals. There is the potential for therapeutic confusion as the same drugs are used, but differently, for treatment as for prevention, and this could lead to undertreatment of HIV-positive individuals with mono or dual therapy. We believe that widespread uptake of PrEP would require that the drugs were available over-the-counter rather than by prescription, and this could lead to immense risk of resistance developing, further affecting detrimentally the therapy of the HIV-infected individuals. The practical lessons from PEP suggest that tolerability for antiretroviral drugs is lower in HIV-uninfected individuals, and poor adherence over time has always been the principal obstacle to successful long-term chemoprophylaxis, such has been the case for isoniazid use to prevent TB.
Where equipoise exists, clinical research should provide the evidence to direct public health policy. The clinical trials of PrEP are advanced, and the appropriately designed UTT trials need to be initiated as soon as possible, so that the effectiveness and consequences of the differing prevention strategies can be directly compared. This is now an urgent issue for global health.
Conflicts of interest: None.
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