Achieving viral suppression with HIV multi-drug resistance: peg-interferon and valaciclovir as part of rescue therapy

1 December 2015. Related: Conference reports, Antiretrovirals, Treatment strategies, Drug resistance, EACS 15 Barcelona 2015.

Simon Collins, HIV i-Base

An important case was presented at EACS as a poster, where highly individualised care achieved sustained viral suppression for a person with extensive resistance to antiretroviral therapy (ART).

This success was due both to very careful management that minimised the risk of drug resistance and the strategic use of novel drugs that are often overlooked for their antiretroviral potential.

The lead author was Dr Markus Bickel from Goethe University Frankfurt who reported on a case of a 26 year old man who was diagnosed HIV positive when a child (age 4) and who, despite complex sequences of different combinations since the age of 6, was unable to get undetectable viral load.

By 2009, he had extensive drug resistance to five ARV classes having used all approved HIV drugs including tipranavir, T-20 and raltegravir. Viral load was >160,000 copies/mL and risk of clinical progression was severe with a CD4 count of 10 copies/mL.

From May 2009 to April 2013, he received a dual-boosted-PI “holding strategy” using darunavir/atazanavir/ritonavir to limit further drug resistance. Despite the lack of a CD4 recovery and viral load that at it’s highest points fluctuated between 3 to 5 million copies/mL this person was lucky to remain clinically stable.

In April 2013, due to serious opportunistic infections (meningitis and MAC), he switched to a six-drug combination of AZT, tenofovir DF, FTC, darunavir/r, maraviroc and dolutegravir. Although this multi-drug combination reduced viral load by one log from about 3 million copies/mL to 330,00 copies/mL, in June 2013, T-20 and dolutegravir were discontinued in order to hold on to these drugs for future options – resistance being a likely outcome in someone with such high viraemia.

In October 2013, due to severe herpes encephalitis, aciclovir and later valaciclovir, were added to his ART, and which steadily reduced viral load to 60,000 copies/mL by March 2014.

In March 2014, dolutegravir and T-20 were added back to his combination, reducing viral load to 5,000 copies. Adding pegylated interferon and increasing the darunavir/r dose (to 1000/100 mg twice-daily) led to continued viral decline, dropping to below 50 copies/mL by August 2014.

From November 2014 to June 2015, his treatment was steadily simplified, dropping AZT, FTC, tenofovir DF and T-20 while maintaining viral load at <20 copies/mL

Once his viral load was suppressed, his CD4 count steadily increased to the point where OI prophylaxis drugs were also stopped and by June 2015 his CD4 count was around 500 copies/mL.

Comment

Two recent studies have reported direct antiretroviral impact of aciclovir and valaciclovir, independent of HSV activity. [2, 3]

In the encouraging and impressive case reported by Bickel et al, finding a way to overcome multidrug HIV resistance was dependent on a several stages.

• Firstly finding a combination with sufficient antiretroviral pressure – or potency – to drive viral load to <50 copies/mL in blood. This cut-off seems sufficient to limit the greatest risk for the development of additional new mutations, including to any drugs in the new combination to which someone is still fully sensitive.
• Maintaining this drug combination (likely to include more rather than fewer drugs) for several months (minimum 3 to 6 months) in order to reduce viral load in lymph and other compartments.
• Steadily reviewing treatment to discontinue drugs that are least likely to be contributing to continued antiviral pressure, in order to improve tolerability.

This case was also important for the prompt decision to discontinue drugs that were likely to be vulnerable to developing resistance in the presence of high viral load, in order to reserve these for later use.

Luckily, the availability of five classes of antiretroviral drugs has dramatically reduced the number of people with extensive drug resistance. The development of new medications is desperately needed as life-saving treatment for people who are in this situation. Two promising pipeline compounds include the attachment inhibitor (BMS-663068) and maturation inhibitor (BMS-955176), both in development by BMS. [4]

Many people with multi drug resistance are likely to also have complex HIV histories, perhaps involving decades of ART.

i-Base publishes a community guide to treating drug resistance. [5]

The online version has always included the option to use other drugs with anti-HIV activity but that are only used in difficult cases because of a poorer tolerability profile compared to widely recommended drugs. [6]

References:

Unless stated otherwise, all references are to the programme and abstracts of the 15th European AIDS Conference (EACS), 21-24 October 2015, Barcelona, Spain.

1. Bickel M et al. Successful interferon-based salvage therapy in a panresistant HIV+ adolescent. 15th EACS 2015, Barcelona. Poster abstract PE 8/86.
2. Vanpouille C et al. Valacyclovir decreases plasma HIV-1 RNA in HSV-2 seronegative individuals: a randomized placebo-controlled crossover trial. Clin Infect Dis. (2015) doi: 10.1093/cid/civ172. (3 March 2015).
   http://cid.oxfordjournals.org/content/early/2015/03/03/cid.civ172.abstract
3. Saracino M et al. 2013. High-dose valacyclovir decreases plasma HIV-1 RNA more than standard-dose acyclovir in persons coinfected with HIV-1 and HSV-2: a randomized crossover trial. J Acquir Immune Defic Syndr. 2013 Jun 1;63(2):201-8. doi: 10.1097/QAI.0b013e3182928eea. doi:63(2):201-8.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738066
   https://www.fredhutch.org/en/news/spotlight/imports/restricting-hiv-1-replication-with-high-dose-valacyclovir.html
4. Collins S. Pipeline ARVs at IAS 2015: doravirine, BMS-955176 and BMS-663068. HTB September/October 2015.
   https://i-base.info/htb/28799
5. 5.HIV i-Base. Guide to Changing Treatment: what to do if your viral load rebounds. (14th edition, February 2015).
   https://i-base.info/guides/changing
6. Ibid. Chapter: Non-ARV drugs. (February 2015).
   https://i-base.info/guides/changing/non-arv-drugs