Executive summary – HIV
14 July 2016. Related: Pipeline report.
The antiretroviral pipeline
In their chapter on Antiretroviral Treatment in this year’s Pipeline Report , Tim Horn and Simon Collins provide a sweeping overview of developments in the past twenty years to put those of the past year into context.
The first decade after the advent of effective combination antiretroviral treatment (ART) was marked by improving safety, tolerability, and ease of administration among ART regimens. This was accompanied by growing awareness of the side effects of the earlier regimens, concerns about the evolution of acquired drug resistance, and outstanding questions about when to start ART and whether structured treatment interruptions (STIs) were safe. Subsequent research culminating in the Strategic Management of ART (SMART) study showed definitively that STIs had serious risks due to a host of inflammatory complications of untreated HIV – including cardiovascular, liver, and kidney disease – which had previously been seen as side effects of ART .
In the meantime, with when-to-start guidelines swinging back to later initiation of ART, the International AIDS Conference in Durban in 2000 provided the impetus for an enormous, unprecedented global effort to combat a chronic, incurable infectious disease with life-long ART. This effort encompassed the launch of affordable generic combination ART ; the establishment of a number of new institutions such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM) , the President’s Emergency Plan for AIDS Relief (PEPFAR) , and new initiatives such as the WHO ‘3×5′ strategy , the U.S. Food and Drug Administration (FDA) program for tentative approval for generic ART combinations for use in developing countries, the tax-funded UNITAID, and others. Over the subsequent 16 years, more than 17 million people have been able to use ART; AIDS death rates dropped; and there are emerging signs that HIV incidence rates are going down at least in some parts of the world.
After SMART, it became imperative to define with a randomized controlled trial whether the benefits of immediate HIV treatment outweighed any risk, partly enabled by easier to use ART, which increasingly came in the form of fixed-dose combinations (FDCs) and single-tablet regimens (STRs). Thus the U.S. NIH and other partners launched the START study  and France’s ANRS launched TEMPRANO . Both studies, released in 2015, showed that immediate ART led to better clinical outcomes. Several other studies, including HPTN 052  and early results from the PARTNER study  demonstrated that virologic suppression dramatically reduced the risk of HIV transmission, and that perhaps this effectively is zero. These advances set the stage for the WHO’s revised 2015 “treat all” guidelines,” which mean that in the coming years we must continue treating the 17 million people already on ART  and add to them the 20 million who are not yet receiving it, while simultaneously scaling up ART-based prevention such as PrEP. Together, if scaled up rapidly, these converging approaches hold out the promise of bringing down new HIV infection rates to very low levels, while enabling people with HIV to live long and healthy lives.
Activists, providers, and program managers are concerned that prevalent austerity policies worldwide – coupled with the Global Fund’s narrowing focus which excludes most middle-income countries where millions of people living with HIV, TB, or malaria live  will make it harder to secure and sustain the resources required to achieve the promise of these gains, and at the same time the shrinking number of innovator companies in the ART discovery and development space leads to fears that too few players will diminish the fruitfulness of the pipeline while possibly creating unacceptably high prices through limited voluntary licenses which will diminish access for those whose countries cannot pay for their treatment – as is already occurring with direct-acting antivirals (DAAs) in the global hepatitis C virus (HCV) pandemic.
Advancing in the clinical development pipeline this year are a number of new drugs, combinations, and formulations such as long-acting injectable ART, and new strategies such as reduced drug ART using dolutegravir – either alone or with lamivudine (3TC). It’s too soon yet to assess whether this approach will prove as durable as initial studies suggest and whether it will work in the diverse settings in developing countries where it has the potential to both increase quality of life (with reduced side effects) and save considerable resources.
Reviewed elsewhere in this year’s pipeline are other approaches to optimize ART using lower doses, e.g., of efavirenz at 400mg, or combinations with lower molecular weight, that would reduce the cost of the active pharmaceutical ingredient (API); particularly attractive are combinations of dolutegravir with TAF and 3TC; see Polly Clayden’s Fit for Purpose: Antiretroviral Treatment Optimization.
To validate a new first-line regimen with dolutegravir, additional studies are already underway to get more data for use in women, during pregnancy, and in TB coinfection.
The 2016 ART chapter summarizes the status of twelve drugs and combination therapies in clinical development – seven in phase III, four in phase II, and two in phase I (see Table 1: Summary of Pipeline Compounds in 2016).
Fit for purpose: antiretroviral treatment optimisation
Polly Clayden leads us on a brisk, bracing walk through the changing landscape of ART optimization in her 2016 “Fit for purpose: antiretroviral treatment optimisation” chapter. 
“Since the 2015 Pipeline Report global antiretroviral treatment (ART) guidelines have moved to recommending “treat all” HIV positive people. With this recommendation comes the massive task of starting and keeping everyone with HIV on ART. ART optimization is one of many critical steps to universal access to HIV treatment that is: safe, effective, tolerable, durable, simple and affordable. Antiretrovirals can sometimes be optimized by dose reduction. [14, 15] Reducing an approved dose of a drug might be possible, because when new ones are developed, the highest tolerated doses in phase II are usually selected for phase III and approval. In some cases lower doses might have equivalent efficacy and better tolerability – as has been shown with efavirenz (EFV).  But since discussions on treatment optimization began the field has evolved and newer, better, and lower dose antiretrovirals have been approved. [17, 18] With a couple of exceptions, treatment optimization has shifted away from making older drugs more efficient. Speeding up the introduction of generic versions of newer drugs – in appropriate regimens and formulations – into low-and middle-income countries (LMIC) – is now the main focus of ART optimization. 
“Experts now agree on a short list of antiretrovirals that have shown superior or non-inferior efficacy compared to existing recommended ones. These drugs offer improved durability and tolerability, higher bioavailability, lower pill burden, and the potential for fewer side effects. [20, 21] The antiretrovirals are: dolutegravir (DTG), tenofovir alafenamide (TAF), efavirenz (EFV) 400 mg, and darunavir/ritonavir (DRV/r).” 
As Clayden points out, the 2015 WHO guidelines now include dolutegravir and efavirenz 400mg; generic formulations of dolutegravir are on the way; and the FDA has begun to approve TAF-containing regimens to replace those with tenofovir disoproxil fumarate (TDF). WHO second-line recommended alternative regimens now “include ritonavir-boosted darunavir (DRV/r) or raltegravir (RAL) as alternatives to boosted lopinavir (LPV/r).” 
New generic formulations of dolutegravir (DTG), DTG/TDF/3TC, efavirenz 400mg/TDF/3TC, and DRV/r will ]come on-line in the next year; see Table 3: New generic antiretrovirals available 2016/2017 for adults. “By the end of 2025 the introduction of TAF, EFV 400 mg, and DTG into ART programs in LMIC could mean savings up to a whopping US $3 billion” – please see Table 5: Table 5: Market share and cumulative savings 2025. 
Clayden reviews studies investigating dolutegravir or efavirenz at 400mg as global first-line ART anchor drugs (see Table 6: New first-line regimen studies), first-line pregnancy studies (see Table 7: First-line pregnancy studies), reviews the urgent case of first-line ART in combination with tuberculosis co-treatment (see Table 8: First-line HIV/TB co-treatment studies), and considers the potential use of darunavir/r/dolutegravir in second-line therapy (see Table 9: Low dose DRV/r studies).
This chapter provides a long view of what to expect in the coming decade and how research can provide answers which will make it easier to treat all of the world’s 37 million HIV-infected persons.
The paediatric antiretroviral pipeline
In the paediatric antiretroviral pipeline  Polly Clayden shows us that developing “new antiretroviral drugs and appropriate formulations for children continues to be far too slow;” and that 40% of children on ART are on suboptimal regimens. Among noteworthy steps forward are the inclusion in the new WHO guidelines of integrase inhibitors, efavirenz 400mg and dolutegravir as alternatives for adolescents, raltegravir as recommended second-line for children, and dolutegravir and darunavir/ritonavir for third-line , and FDA approval of dolutegravir tablets for children aged 6 to 12 . New solid lopinavir/ritonavir pellets are now approved for infants and young children [54, 55], but apparently don’t taste very good . Priority formulations identified back in 2013 remain lacking, including AZT or abacavir (ABC) plus 3TC and lopinavir/r and ABC with 3TC and efavirenz . Additional priority formulations from 2014 remain unavailable.  Clayden reviews ongoing and planned trials to address gaps in treatment options for newborns [see Table 3: Newborn treatment options (or lack of options to date): including ongoing and planned IMPAACT trials), children, and adolescents. The current pediatric ARV pipeline is shown in Table 4: The pediatric antiretroviral pipeline.
Preventive Technologies: Antiretroviral and Vaccine Development
Tim Horn and Richard Jefferys present an overview of developments in their “Preventive Technologies: Antiretroviral and Vaccine Development” chapter .
The current paradigm is shifting not only to universal immediate ART among those living with HIV, but to intensified biomedical prevention efforts focusing on pre- and post-exposure prophylaxis (PrEP, PEP), as well as increased use of other prevention modalities such as harm reduction, syringe exchange, opiate substitution therapy, and voluntary male medical circumcision. As Horn and Jefferys write, [this] “fierce commitment to primary biomedical prevention… isn’t simply rhetoric, but rather a public health mandate that is supported by a growing body of epidemiological and other scientific data. [24, 25, 26, 27]
In the U.S., where tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) were first approved for use as PrEP in mid-2012, just 4% of the estimated 1.2 million U.S. residents who might benefit from its use are or have used it. [28, 29] To make a public health impact, however, PrEP will have to be scaled up to reach almost half of high-risk MSM, as well as at least 10% of people who inject drugs and among high-risk heterosexual persons, who may not even realize they are at risk for contracting HIV. 
In the U.S., failure to expand Medicaid in states where HIV is infecting the most people today – such as young MSM of color, particularly in the South, creates often-insuperable obstacles for those who need PrEP the most. Elsewhere, PrEP has only been approved in a handful of countries and, even where it is approved and subsidized, high levels of provider stigma or ignorance plus lack of HIV prevention education among at-risk individuals impedes its successful uptake at the requisite scale.  Other potential PrEP approaches now under study include oral maraviroc (MVC) or TAF instead of TDF, but these are in early stages still.
Long-acting (LA) injectable ART such as cabotegravir, if shown safe and effective, could potentially be used as PrEP.
A variety of genital gels, rings, tablets, and films are also being investigated for potential preventive therapy indications in both women and men. There is also tremendous interest in multi-purpose biomedical prevention technologies, notably ring and other extended-release delivery systems that can provide broad-spectrum protection against multiple viral infections—HIV, herpes simplex virus 2 (HSV-2), and human papillomavirus (HPV)—as well hormonal contraception.
NIH is launching large-scale efficacy trials to see whether infusions of broadly-neutralizing HIV antibodies such as VRC01 can be used as a durable HIV prevention intervention; but – as with treatment – it’s possible that combinations of antibodies will be more effective both in protecting from infection and in preventing the rapid emergence of resistance among those exposed. [34, 35]
The long-awaited successor study to RV144, the only HIV vaccine trial that has shown even a marginal level of statistically-significant protection, is finally close to being launched. . “The trial, HIV Vaccine Trials Network (HVTN) 702, is designed to try and duplicate or improve on the 31.2% reduction in risk of HIV acquisition that was observed in RV144, a large-scale evaluation of a prime-boost vaccine regimen that was conducted in Thailand.  HVTN 702 will take place in South Africa and, if all goes according to plan, results are anticipated by 2020.” 
In the vaccine field, a whopping 52 candidate vaccines are in various stages of clinical trials, as well as three studies of passive immunization with the NIH’s VRC01 and one antibody gene transfer study; see Table 4: HIV vaccines, passive immunization, and antibody gene transfer pipeline. The contrast with the TB vaccine field – with only 14 candidates in clinical trials (see Table 1: TB Vaccines in Development, in Mike Frick’s TB Prevention Pipeline chapter – is stark, though both fields face analogous challenges trying to develop protective immunity against tough and complex intracellular pathogens.
Research toward a cure and immune-based and gene therapies
Once again, Richard Jefferys effortlessly guides us through the challenging landscape of “Research Toward a Cure and Immune-Based and Gene Therapies” .
HIV cure research is now acknowledged as a central goal of U.S. NIH-funded AIDS research [40, 41] Meanwhile, it is expected that the currently-underway renewal of the Martin Delaney Cure Collaboratories may result in the funding of five or six consortia compared with the current three. amfAR has established a new Institute for HIV Cure Research at U.C. San Francisco. 
In Durban the International AIDS Society expects to release an updated global scientific strategy towards an HIV-1 cure. 
Currently ongoing and planned cure-related clinical trials are not expected to lead directly to a cure, but rather to define pathways which when further developed and possibly combined may lead to sterilizing or functional cure. The only possible exception to this would be if researchers were able to replicate the one documented case of a cure for HIV-1 in a human being, the case of Timothy Brown. This approach would involve giving stem-cell or bone marrow transplants from a CCR5-delta32 homozygous mutant immune system to an HIV-infected person whose cancer therapy requires such a transplant. [44, 45]
According to Jefferys, “at least six individuals have since been reported who underwent similar procedures, but all of them died due to either the underlying cancers or complications from the transplantation procedure.  One new case was described in a poster at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI), and the preliminary signs appear encouraging: the cancer is in remission and HIV cannot be detected by multiple techniques.  However ART had not yet been interrupted at the time of the presentation, so it is too early to know if this may represent a second example of an HIV cure.”
Research on putative immune-based therapies for HIV infection seems to be in decline, aside from a few studies such as one of pitavastatin to reduce cardiovascular disease incidence among people on ART. 
However there is still a clinical need for therapies for people who in spite of successful virologic suppression on ART fail to reconstitute their immune systems to healthy and safe levels. Late initiation of ART – simultaneous with the diagnosis of AIDS, as is the case with 23.6% of newly-diagnosed HIV in the U.S. as recently as 2013)  – greatly increases the risk of becoming an immunologic non-responder (INR). Jefferys states that “TAG is currently collaborating with other activists to explore whether candidate treatments for INRs might be considered orphan drugs, a U.S. Food and Drug Administration (FDA) designation intended to spur the development of treatments for disorders that are relatively rare.” 
The 2016 immune-based therapy pipeline (see table 2) includes fifteen agents with a broad variety of putative therapeutic mechanisms; all are languishing or at best moving forward slowly in phase I or II studies.
2016 HIV pipeline recommendations
Antiretroviral Therapy Recommendations
- “With some major pharmaceutical manufacturers retreating from the ARV research and development space, the industry partners that remain should strengthen their resolve to meet the ARV safety, efficacy, acceptability, and affordability challenges that remain in low-, middle-, and high-income countries.
- Manufacturers must commit to the drug prices required to achieve cost-contained HIV care and service delivery in high-income countries.
- Manufacturers must also commit to meet the treatment access needs in middle-income countries, which will be home to 70% of people living with HIV before the end of this decade and are facing both funding losses from donor agencies as well as crippling intellectual property rules that will block access to affordable generics.
- Manufacturers developing new oral drugs are strongly encouraged to follow the emerging trend of evaluating coformulations with historically potent and safe generic ARVs, notably TDF and 3TC. However, these fixed-dose combinations must be priced accordingly.
- The development of new drugs for treatment of cross-class-resistant HIV should remain a priority. It is very encouraging to see progress in this area. For drugs with limited indications, including those without clear marketing potential for treatment-naive individuals, the Orphan Drug Designation program should be explored and engaged.
- Manufacturers should continue to closely collaborate with, and invest heavily in, evidence-based research, implementation science, policy advocacy, and service delivery aimed at improving HIV diagnosis and clinical care engagement rates. Their efforts should aim to maximize virologic suppression rates required to improve disease-free mortality and prevent ongoing transmission of the virus.” 
Antiretroviral Treatment Optimization Recommendations
- “Upgrade the new first-line regimen. Sufficient evidence to change WHO guidelines to recommend DTG and TAF as part of the preferred first-line regimen (replacing EFV and TDF) needs to be generated in order to convince generic manufacturers to invest in new production for the new regimens. A recommendation from WHO is the strongest signal to generic manufacturers to take the risk and produce new FDCs. Such WHO recommendations will require results from the studies discussed here.
- Originators donate drugs to strategy studies for LMIC. Originator manufacturers must take responsibility and supply prioritized antiretrovirals to key investigator-led studies (as well as the supporting substudies) to generate data to support their use in LMIC. And not after several years of deliberation. The lack of information on use of new regimens in pregnancy and with TB treatment – that is critical to treating populations in LMIC – will continue to be a barrier to their universal recommendation however impressive the results from the phase III trials are.
- Countries get ready to switch. Countries with high volume ART programs such as South Africa, Kenya, and Uganda, need their guideline committees briefed as results are generated (even before they are publically released), so that they can make new recommendations, hopefully before final WHO decisions.
- Donors must support switch to new drugs and regimens. Donors can play a huge part in changing standard of care in countries. UNITAID bought large volumes of TDF and helped to bring down the price and speed up the switch from d4T – so called market dynamics.
- Timely approval. Regulatory agencies in LMIC, such as the South African Medicines Control Council, need to register new originator and generic formulations, as swiftly as possible. Ideally this should happen before new WHO and national recommendations.
- Generic companies need time to plan for high volume manufacture. Generic manufacturers need to be briefed on when data from key studies are expected to be released, guideline changes, and tender timing in countries, so that they can start planning to compete to supply the newly recommended regimens.
- Pre-empt possible chaos. Before introducing new drugs, issues such as stockpiling (and stock outs) need to be discussed and planned, so that hitches with switching from old to new regimens are kept to a minimum.
- Second-line needs more consideration. Although there is consensus on the likely best optimized first-line regimen, second-line is not quite there yet and requires more discussion and research and development to ensure best regimens and formulations.” 
Pediatric Antiretroviral Recommendations
- Speed up development. The gap needs to be narrowed between approval of new drugs for adults, children, and neonates. An evidence base to support not always taking a de-escalated age band approach when studying new drugs is needed. Optimize use of pharmacokinetic data and modelling.
- Speed up approval. Harmonization of regulatory requirements (including age categories and weight bands) between stringent authorities, WHO prequalification, and national authorities is needed to help speed up approval.
- Implement WHO recommendations. As simpler formulations identified to implement the guidelines become available (most topically LPV/r pellets), countries must ensure that they are swiftly approved and distributed, with appropriate training for health workers.
- Coordinate Procurement. Guidance on optimal formulations needs to be easily available to countries and updated as better ones become available. Companies need to be informed of the priority formulations. Plans need to be in place to phase out suboptimal formulations and phase in new ones. Donors need to ensure the availability of low volume products in a diminishing market.
Preventive Technologies: Antiretroviral and Vaccine Recommendations
- Consider “how to incorporate PrEP into background standard-of-care options in vaccine and prevention-based immunotherapy clinical trials. In HVTN 702, for example, South African study participants will receive referrals to local programs where they may obtain TDF/FTC, as opposed to active provision of PrEP as a component of prevention services (e.g., free condoms and lubricant, counseling, and access to STI testing and treatment). This is similar to the standard-of-care approach being employed in the VRC01 AMP Study (HVTN 704/HPTN 085), although in that case US participants have access to a specific referral program that allows their primary care provider to offer TDF/FTC PrEP free of charge. It has been argued that TDF/FTC should be offered through these trials themselves.82 This is, however, a difficult issue to wrestle with, as active provision of PrEP may substantially increase the person-years of followup required—and, with it, the study’s population size and expense—to reach the statistically sound number of seroconversion events needed for efficacy analyses. Indeed, the local Institutional Review Boards and both local and global Community Advisory Boards responsible for reviewing and approving both HVTN 702 and the AMP Study appear to have found the practice of referring participants to external sources of PrEP to be acceptable, at least at the current time.”
- Promote “registrational trial methodologies that are necessarily rigorous in their design, yet feasible for the sponsors of new biomedical prevention candidates—a large number of which are not-for-profit programs that are dependent on finite public and philanthropic support. A major factor influencing study designs is the ethical principle of beneficence, which requires the abandonment of placebo comparisons and the inclusion of proven interventions, such as oral TDF/FTC, in control groups. Regulatory agencies, however, still want proof that an experimental PrEP regimen is more effective than placebo. This in turn requires reliable background incidence estimates, which have repeatedly proven to be difficult to come by in PrEP clinical trials. Also required are many person-years of follow up—and, by extension, extremely large, long, and expensive clinical trials—to yield the number of seroconversions necessary for standard non-inferiority comparisons, particularly with a highly efficacious regimen such as TDF/FTC.”
- “Close attention to these issues, particularly as an increasing number of products enter phase II and III stages of development, is critical. A stringent, but amenable, regulatory climate is necessary to ensure the availability of necessary safety, efficacy, and acceptability data, without being prohibitively costly and ultimately deterring critical investments by product sponsors, particularly those heavily dependent on limited public and philanthropic funding.” 
Research Toward A Cure and Immune-Based and Gene Therapies Recommendations
- Continue to increase funding for cure-related research.
- Promote dialogue between regulators, researchers, funders and community stakeholders on trial design issues, with a particular view to smoothing the pathway toward the evaluation of combination approaches
- Support efforts to develop novel means to make potentially complex interventions such as gene therapy more convenient, accessible and affordable.
- Improve communication on concepts of HIV remission, and be clear that the maintenance of low viral load in the absence of ART may not necessarily be equivalent to suppression of HIV by ART in terms of long-term health outcomes.
- Broaden community education efforts on HIV cure research and promote and facilitate participation of diverse populations in clinical trials.
- Invest in webcasting for all cure-related scientific conferences in order to facilitate greater global sharing of information.
- Be vigilant for any evidence that interventions could benefit immunologic non-responders (INRs) even if they fail in the cure research context, and conduct studies in this population when appropriate.
- Convene a scientific workshop (or workshops) on drug development and trial design for the INR population.
- Develop a research agenda to resolve outstanding uncertainties on the value of probiotics as an adjunctive therapy for individuals on ART.
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