Drug resistance rises when ART regimes aren’t properly followed, often because patients can’t cope with the strong side-effects of medications.

Why new ART drugs with less side effects are crucial for Indias fight against HIVImage for representation
Delve Health Thursday, September 13, 2018 - 09:39

In 2017, India’s National Aids Control Organisation (NACO) updated its guidelines for anti-retroviral therapy (ART), requiring that every person testing positive for HIV be put on ART, irrespective of their CD4 count. But if this test and treat scale-up has to align with NACO’s wider goals of preventing the transmission of HIV and ending AIDS as an epidemic by 2030, a change in the drug of choice is a major need of the hour, say experts. 

No less an authority than the WHO released updated guidelines earlier this year supporting the idea of a change in the ART drug regimen, particularly to combinations based on Dolutegravir (DTG) as a first option in India. Though a dedicated follower of WHO guidelines, India is two years behind on WHO recommendations in this regard, framing its own guidelines for ART treatment. This is because of the specific local conditions, epidemic characteristics and, most importantly, the affordability of a public health system servicing a massive population. In India, there are an estimated 2.1 million people living with HIV, of whom 50% are availing of ART.

Regimens, side-effects and resistance

Drug resistance occurs when HIV replication is not fully suppressed. This is usually because of non-adherence to ART. Resistant viruses can spread and affect the efficacy of antiretroviral (ARV) treatment. The transmission of ARV-resistant strains is of increasing concern in countries where ART is widely used. The most important factors affecting the progression of HIV in resource-constrained countries like India are a failure to access care and discontinuation of, or non-adherence to, ART. 

It is in response to this need that the government of India started the national programme of free anti-retroviral therapy, and has been distributing ARV drugs free of cost since the year 2004. With drug resistance setting in, on an average between eight to ten years after initiation of ART, a significant number of patients are now lining up for second-line drugs. 

Experts acknowledge that there are reasons for the development of resistance even in ideal conditions. Due to the need for lifelong therapy, HIV’s prodigious replication rate, and error-prone reverse transcriptase varying amounts of drug resistance are common in individuals undergoing treatment. “It is now well known that even with good adherence levels, resistance occurs. HIV drug resistance evolves naturally due to the selective pressure from drugs or from the immune system,” admits NACO’s ART manual. Given this limitation, effective treatment requires that the clinical goals of HIV treatment are achieved optimally through consistent high-level adherence to HAART (Highly Active Antiretroviral Treatment), and sustained suppression of the viral load.

Resistance can be contained, and its occurrence can be reduced or prevented, through an appropriate and careful choice of treatment, intense support to ensure adherence, monitoring for resistance, and by reinforcing positive prevention through condom use. Nationally, there is a need to define drug resistance qualitatively and quantitatively, through surveillance and monitoring conducted in accordance with international standards. Such studies have already been initiated by NACO and WHO.

Preventing the emergence of HIV drug resistance (HIV DR) has been accorded a high priority, and is a crucial component of the National ART Programme, say senior medical officers at the Government Hospital for Thoracic Medicine, a centre of excellence for HIV care, treatment, and training in Chennai.

What is DTG and why is it advisable? 

New drugs like Dolutegravir (DTG) score over current regimens in having tolerable side effects and a rapid suppression of viral load, facilitating better adherence levels. They are, therefore, less likely to lead to drug resistance. This is why DTG has been recommended by the WHO over the currently administered Efavirenze-based drugs, which have significant side effects, including serious mental health problems due to neuro toxicity, liver problems, and severe rashes.

Antiretroviral therapy refers to the use of pharmacologic agents that have specific inhibitory effects on HIV replication. Antiretroviral agents belong to six distinct classes of drugs: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PI), Fusion inhibitors, and CRR 5 Co-receptor and Integrase Inhibitors. Each of these classes of drugs inhibits HIV replication at different stages in the HIV life cycle and blocks its entry at different levels. 

Of the six classes of antiretroviral (ARV) drugs,NACO prescribes a combination of NNRTIs, NRTIs and Protease Inhibitors. The combination is decided based on the patient’s clinical stage, CD4 countand viral load. The PI class of drugs is reserved for second-line treatment in the event of resistance to first-line of drugs.

DTG is an Integrase Inhibitor. It blocks the virus from growing and infecting more cells.On the other hand, Efavirenz is an NNRTI which attaches to and blocks an HIV enzyme called reverse transcriptase. This prevents HIV from multiplying, and can reduce the amount of HIV in the body.

DTG is not entirely free of side-effects, and the WHO has recommended against it being given to pregnant women or those intending to bear children. However, it performs much better as compared to EFV-based combinations.  

The use of DTG in the USA and Europe has substantially reduced the number of people who fail first‐line treatment and are therefore lost to care or forced to switch to second‐line ART. Despite their success, the cost of DTG-based combinations stands as the main obstacle in the way of their immediate introduction in India by NACO. 

DTG cost-effective over time?

However, research into cost effectiveness suggests that the costs of DTG-based ART may even out over time.

Using a mathematical simulation model of how HIV responds to different treatments, a studypublished in the Journal of the International AIDS Society examined the clinical and economic impact DTG could have on India’s HIV response in comparison to Efavirenz (EFV). The findings indicate that using DTG as the first option for HIV treatment would be cost‐effective, and potentially cost‐saving, for India’s public health system.

The study found that DTG has the potential to avert 13,000 new HIV infections over five years, which is equivalent to a 20% decrease in HIV incidence. This will result in a savings of 800,000 USD in projected care costs.This is important as, with increasing coverage of treatment and decreasing AIDS-related mortality, a significant number of people are likely to require first-line and second-line ART treatment in the coming years. The study also factored in the increased cost of ART for longer periods

Taking all factors into account, care costs for the number of people initiating treatment on EFV were estimated to be 139 million USD at two years, and 590 million USD at five years. In comparison, the care costs for DTG at two years were found to be 137 million USD, and care was found to be cost-neutral at five years, at 590 million USD. The model identified certain cost increases linked to DTG over longer periods. However, these reflect the fact that more people are likely to live longer when on DTG, incurring greater lifetime care costs.

Despite attempts to contact them, the Technical Resource Group (TRG) of NACO, which decides on choice of drugs and frames treatment guidelines, has not clarified whether or when it is likely to change the primary ART drug to one with lesser side effects in compliance with the WHO’s guidelines, or what potential road blocks stood in the way.

Time for a better drug, say doctors

A senior Medical Officer at the Centre for Thoracic Medicine at the Tambaram Sanatorioum, speaking on condition of anatomy, says that better alternatives in ART drug regimens are available, but are not adopted because of the weightage NACO’s TRG gives to costs. Currently, effective counselling, committed follow-ups of patients and regular monitoring of CD4 and viral loads are used to keep more people in the loop and hence ensure adherence.

However, those involved in clinical research and clinicians who treat the HIV-infected on a daily basis feel that it is high time a better drug is introduced, based on the WHO’s latest guidelines.

Dr N Kumarasamy is the Chief Medical Officer at YRG Care, the medical centre in Chennai founded by the late Dr Suniti Solomon, who diagnosed the first case of HIV infection in India in 1986. He argues that there should be no delays in adopting DRT-based combinations. “As regards the cost factor, as far as I know, pharma companies have offered a generic Dolutegravir drug at a price almost equal to that of the present drugs. This cost neutrality must be seen as a boon,” he says. 

A clinician and researcher, Dr Kumarasamyis an expert panel member for the WHO ARV treatment guidelines committee, and has published more than 275 manuscripts in peer reviewed medical journals. “A better ARV drug with less side effects is needed to reduce drug resistance and to increase adherence. The goal here should be a better quality of life for patients. While the decision should be primarily patient-centric, the goal of averting transmission is better achieved through intensive and sustained awareness, and better pre- and post-prophylaxis regimens,” he says.

While Dr Kumarasamy is wholeheartedly in support of DTG-based combinations, others acknowledge that the high costs are an important factor to consider. Dr K Madhavan, a noted clinician in Coimbatore, known for his free/low cost treatments for people living with HIV says, "DTG is certainly a more advanced drug and patients are much better off with it. But I give it only to those who can afford the cost, which may come to around Rs 3,000 per month. It does address all issues concerning serious side effects, and reduces non-adherence. However, the government may consider the costs too high for introducing it on a mass scale under free treatment programmes. But, as there are only two suppliers in the market, one can expect that competition among them could bring down cost.” 

Dr Madhavan says that the use of DTG as a first-line treatment does come with a risk, but one that is worth it. “Given HIV's character to mutate and replicate quickly, going for advanced drugs as the first option will limit further lines of defence for patients. But the benefits outweigh the limitations and the gamble is worth it," he asserts. 

The debate over the choice of ART drugs is crucial for patients, since NACO has initiated a fixed-dose single-pill regimen in the last year, based on the thinking that the convenience of a single pill will enhance ART adherence levels. The single pill is a combination of Tenofavir, Lamivudine and Efavirenze. However, the two-drug regimen, which includes a combination of Zidovudine+Lamivudine and Nivaprine,is yet to be phased out completely. Tenofavir, Lamivudine and Zidovudine belong to the NRTI class of drugs, while Efavirenze and Nivaprine are NNRTIs.

While the single-pill regimen may have been introduced as a convenient alternative, however, ART users say that the impact of side effects under the new regimen is too high. Rajamahendiran, President of the Dharmapuri Network of Positive People, says that those who are initiated into ART under the single-pill regimen find the accompanying side-effects too strong to cope with, which leads many to discontinue with the treatment. “The single pill is better tolerated by those already on a two-pill regimen. If a better drug option is available, it would be advisable to provide it for both long time and new users,” he says.


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