Before the 1996 “protease moment” (i.e. the breakthrough arrival of effective triple combination therapies) HIV treatment was marked by ineffective treatment resulting in drug failure and drug resistance. Combination therapy marked a new era, a veritable turning point.
Throughout the late 90’s and into the new Millennium of the year 2000 triple combination drugs were coming into longer-term use and observation of their effects – the good and bad. First generation nukes like AZT, ddC and ddI were still in use at that time as the “backbone” of treatment, combined with the new class Protease Inhibitors (PIs)…or Non-Nukes as an alternative which arose closely after that in 1997
Although we now had a more robust treatment strategy in combination therapy, we were still left with but 3 classes of drugs to work with that offered up many tolerability issues and ‘archived resistance’ from the previous single class strategy.
At that time “salvage therapy” was a common treatment strategy term – finding drugs from what was available that durably suppressed HIV without attendant side effects and ongoing development of resistance. Drugs trials were (and still are, but to a somewhat lesser degree) considered not to show their true benefit until longer-term use in the real world (outside of trials), but tolerability (side effects management) of the first generation drugs brought out some limitations – the worst of which was lipoatrophy and lipodystrophy (a syndrome of fat re-distribution, metabolic and lipid [blood fat] changes).
New, more robust and more tolerable drugs were still needed, and lesser pills amounts, less often. The research pipeline grew in this needed direction, such that the next (2nd) generation drugs of this period were highly sought after (even among new PIs which were beginning to show some troublesome side effects).
Special Access Schemes (SAS) arrangements were imperative for people who needed faster access to new drugs before they could be fully licenced and approved (albeit under late stage trial development).
Fortunately that era has now past and there is little need for universal SAS programs like the past. The reason? – a fully expanded pipeline of new drugs had come about with highly improved tolerability and superior efficacy, was the order the new treatment millennium, and new drugs were being delivered that fit this bill…Towards the mid 2000’s and onwards newer drugs were delivering on this promise, but they were still less than optimal so cautious research but eventual changes in treatment strategies occurred. One thing was for certain, treatment failure was no longer common; the newer generation drugs worked durably over many years, even though side effects were (and still are, although to a changed degree or impetus) a principle concern.
In absence of a cure for HIV it was initially thought we could ‘treat our way out of HIV’ – this strategy was eventually considered futile due to HIV ‘seeding’ of the viral reservoirs (where ARV treatment could not reach).
Earlier and later drugs were studied as to how well they could penetrate the central nervous system, and there is a strata table for these, but viral reservoirs (hiding places) cannot be purged of virus – as was shown in a recent cure strategy study that didn’t work as was hoped in this regard.
Despite HIV cure research continuing intensively among world scientific researchers (the Utopian goal!), until a breakthrough happens we are still at a place where HIV treatment is required lifelong, but encouragingly so 3rd generation drugs are now with us!
Most encouraging is that we now have 2 new classes of antiviral treatment since the original 3 classes (i.e. Nukes, Non-Nukes and PIs) – namely Entry/Attachment Inhibitors (which emerged first), but now Integrase (strand transfer) Inhibitors (INSTI) have arisen.
Current research is looking intensely upon which combinations are best to be used together, as most new entrant 3rd generation treatments now mostly demonstrate only matched efficacy (non-inferiority) over existing treatments, rather than superior efficacy like was so sorely needed in the past.
Given there seems to be few other viral replication steps identified that could potentiate further classes of drugs, then perhaps the most exciting real-time development occurring in current research is long-acting formulations of these latest generation of treatments. This new treatment concept strategy is raising a very real and exciting possibility that HIV treatment could soon be as in-frequent as once-a-month as opposed to once-daily and twice-daily treatment as it presently stands.
New long-acting molecules of Dolutegravir (a brand-new Integrase Inhibitor) and Rilprivine (a recent new Non-Nuke) are under study currently showing great promise. Furthermore, despite the current persistence in the treatment guidelines of using “backbone” nukes like tenofovir (Viread – also contained in Truvada) as the cornerstone of HIV treatment strategies, newer research is looking at “nuke-sparring regimens” in order to avoid side effects from that class as a whole, although the evidence is not convincingly better than nuke-containing regimens, yet.
At the same time, from within the nuke drug class, the specific kidney function concerns of tenofovir use are also being addressed in new research looking for a lowered dose formulation of that drug – a new formula called TAF (Tenofovir Alafenamide): http://aidsinfo.nih.gov/drugs/514/tenofovir-alafenamide/0/patient Meantime, ritonavir boosting of existing drugs seems to be on the gradual out, predicted to be replaced (eventually) with a new booster drug called Cobicistat – which is now available co-formulated in the most recent combined single tablet drug – Stribild – but expected to be given singularly to boost other new drugs as well.
All up it has been a long journey thus far, with more work to go, and hopefully new strategies if not further new improved treatments, on the road to an HIV cure. There is great hope once again. The following timeline will hopefully give some perspective of where we have come from since 2000 (and the Protease moment shortly before then) to where we are now.
Australia’s HIV Treatment Timeline 2000-2014
2000: Efavirenz (EFV) – Non-Nuke Class: changed dose to once daily towards mid 2000’s.
2000: Abacavir (ABC) – Nuke Class: changed to once daily option in 2009.
2001: Trizivir (AZT/ABC/3TC) – Nuke Class: single pill containing 3 nuke drugs, taken twice daily. Not used now since triple nuke (single class) treatment strategy was a failure compared to using multi-class combination treatment.
2001: Didanosine ddI (Videx EC) – Nuke Class: Changed formula of Videx – The first once-daily treatment!
2002: Kaletra (LPV/rtv) – PI Class: soft capsule twice daily dosing. 2006 change to tablet (ME- Meltrex) formulation.
2002: Amprenavir – Nuke Class: 2004/2005 change to fos-Amprenavir formulation.
2002: Tenofovir (TDF) – Nuke Class: the second once daily treatment.
2004: Atazanavir – PI Class: once daily.
2004: Fuzeon (T20) – Entry Inhibitor Class: Injectable twice daily (the last of the ‘salvage’ era, rarely in use now).
2005: Kivexa (ABC/3TC) – Nuke Class: once daily.
2005: Emtricitabine (FTC) – Nuke Class: once daily.
2006: Truvada (TDF/FTC) – Nuke Class: once daily.
2007: Tipranavir (TPV) – PI Class: twice daily.
2007: Darunavir (DRV) – PI Class: change to once daily 800mg dose Dec 2013.
2008: Raltegravir (RAL) – INSTI Class: twice daily.
2009: Etravirine (ETV) – Non-Nuke Class: twice daily.
2010: Atripla (TDF/FTC/EFV) – Nuke + Non-Nuke Class: once daily. The 2nd available triple combination drug (the 1st being Trizivir triple nuke single pill), but the 1st true multi-class combination single tablet regimen (STR).
2010: Maraviroc (MVC) – Entry Inhibitor Class: the first pill based attachment inhibitor. Twice daily.
2012: Nevirapine XR (once daily) – Non-Nuke Class: new once daily formula.
2012: Rilpivirine (RPV) – Non-Nuke Class: once daily.
2012: Eviplera (TDF/FTC/RPV) – Nuke + Non-Nuke Class: once daily. The 2nd true “STR” (single tablet regimen).
2014: Dolutegravir (DTG) – INSTI – the 2nd Integrase Inhibitor, but the first once daily Integrase Inhibitor.
2014: Stribild (TDF/FTC/ELV/COBI) –the first STR to contain an Integrase Inhibitor [ELV – Elvitegravir] and the 1st pill to use boosted Cobicistat (COBI). Neither Elvitegravir nor Cobicistat are available in Australia as separate pills as yet.
…..With no new drugs expected in 2014, our eye is firmly upon 2015 with some expected extensions of what has been reviewed here…I think we’re OK for now, in that anyone with HIV can expect to gain good benefit from this lineage of treatment availabilities, with no one left without.
Always discuss treatment with your doctor, and sometimes discuss it with your peers for ‘real world’ perspective. QPP is also here to answer any treatment-related questions you may have and to provide you with information for discussion with your doctor. We hope this perspective…well…provides some more perspective! Yours in Health. Peter, QPP.