When the going gets tough: Resistance to ART

The antiretroviral therapy (ART) has undisputed benefits for people living with HIV. When people living with HIV (PLHIV) become resistant to drugs used in ART, treatment options that they can fall back upon to stay alive and healthy, reduce. This was a major point of academic discussion at the recently concluded Chennai ART Symposium (CART 2011).

CART 2011 was organized in Chennai, India (8-9 January 2011) by Y.R. Gaitonde Centre for AIDS Research and Education (YRG CARE), in collaboration with Centre for AIDS Research (CFAR), Brown University, National Institute of Health (NIH), University of California (San Diego), Karolinska Institute, and HIV Medicine Association of India (HIVMAI).

The ART inhibits the replication of HIV, decreases viral load (indirectly increases CD4 cell count leading to decreased opportunistic infections - OIs), ART treatment is lifelong and should be used upon designated healthcare providers’ approval only.

There are at least two key goals of ART. First is virological goal, which is to decrease viral load (number of HIV in any body fluid, usually blood), thus slowing HIV infection progression; and second is to ensure that as a consequence of good treatment, the person is able to live a good quality normal life.

But these good benefits of ART are delivered as long as ART regimen works. If a PLHIV becomes resistant to drugs used in ART regimen, then these advantages are severely nipped unless desired change takes place in their treatment and care (which does include second-line or third-line ART as required).

“We may define ART resistance differently but causes are same” said Dr Constance A Benson, Professor of Medicine, University of California, San Diego, USA, while referring to the different definitions of treatment failure from lead health agencies like the World Health Organization (WHO), National AIDS Control Organization (NACO – Government of India’s apex agency to respond to HIV/AIDS in India), and United States Department of Health and Human Services (DHHS).

Dr Benson listed some of the common causes that lead to ART resistance which included poor adherence, social or behavioural factors, ART regimen toxicities, ART tolerance issues, incorrect drug doses in ART regimen, host genetics, poor absorption of drugs used in ART regimen, ART drug pharmacokinetics, ART drug interactions, transmitted ART drug resistance, among others.

All of the above listed causes that could brew ART resistance lead to insufficient drug levels, due to which HIV viral replication takes place, and which eventually results in resistant HIV virus.

Elaborating on the different definitions of treatment failure by WHO, NACO and DHHS, Dr Benson said that NACO defines first-line ART treatment failure by monitoring ART clinically and with CD4 counts. NACO indicator of clinical failure is new or recurrent WHO stage-IV condition after at least 6 months of ART. NACO indicators to assess immunologic failure is the decline of CD4 cells to pre-treatment levels or lower than that level before the person was put on ART, or 50% decrease from on-treatment peak of CD4, or persistent CD4 count below 100 cells/ ul.  NACO indicator for virologic failure is a viral load more than 10,000 copies/ml (WHO criteria is viral load more than 5,000 copies/ml).

However WHO indicators for first-line ART failure include a persistent viral load which is above 5,000 copies/ml. According to the WHO, where viral load is not available, immunologic criteria come into the play. WHO recommends use of viral load monitoring at every six months interval (where routinely available) to detect viral replication and to confirm treatment failure.

The US Department of Health and Human Services (DHHS) recommends monitoring ART with plasma HIV RNA levels. The DHHS indicators for virologic failure are two consecutive viral loads which are more than 400/l after 24 weeks of ART or more than 50 copies/ml after 48 weeks of ART.

One may wonder what should a national AIDS programme do if a person living with HIV becomes resistant to first-line ART. The NACO suggests the following strategies to respond to first-line ART resistance:
1. Counsel PLHIV and support adherence to ART
2. Opportunistic infections (OI) prophylaxis or treatment of OIs (like tuberculosis - TB) as appropriate
3. Laboratory testing to confirm ART failure

NACO recommends those PLHIV who are likely to be failing first-line ART treatment, to go for State AIDS Clinical Experts Panel (SACEP) evaluation for second-line ART. SACEP is a major concern among PLHIVs – and in a different meeting held in November 2009 in New Delhi, this correspondent was narrated a range of issues PLHIV people face while dealing with SACEP.

Before bringing the concerns of PLHIVs regarding SACEP, let us see who prescribes second-line ART in India. The second-line ART is provided by SACEP which consists of two or more expert physicians (one nodal officer, and others to be nominated by NACO and not from the same ART centre), one joint director (care, support and treatment - CST) of State AIDS Control Society (NACO’s representative agency at the state-level in India), NACO regional coordinator (CST) of the concerned state, a paediatrician, among others.

The representative of PLHIV networks at the above-mentioned New Delhi meeting (November 2009) demanded greater transparency in functioning of SACEP. They insisted on time-bound decisions whether to initiate second-line ART or not. Some activists wondered why cannot ART nodal officers decide if second-line ART is needed for medical reasons. In some Indian states SACEP didn’t even include HIV physicians.

So in India SACEP gives the green light whether to put a person on second-line ART or not and its evaluation is based on viral load. In USA, instead of SACEP, after genotypic resistance testing for first-line ART failure, the results of which are obtained while on failing regimen or within four weeks of stopping, a review is done of any previous resistance tests to identify ‘archived’ resistance mutations, said Dr Benson.

Dr Benson reminded us of the goal to move to second-line ART for those who are facing treatment failure with first-line ART regimens which are to re-establish maximal virologic suppression, HIV-1 RNA less than 50 copies/ml (as per DHHS guidelines) and to improve survival and reduce HIV associated illnesses (as per WHO and NACO guidelines).

Dr Benson recommended that national AIDS programmes should develop policies for third-line ART considering funding, sustainability and provision of equitable access to available ART regimens. She suggested that the third-line ART regimens should include new drugs likely to have anti-HIV activity such as integrase inhibitors and second-generation ARTs.

A very long way to treatment – surely lies ahead before we can realize the universal access to HIV prevention, treatment, care and support services for those in need.

Bobby Ramakant - CNS 

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