these drugs brought about a major breakthrough in the treatment of HIV infection. ... down AIDS related mortality levels and improved quality of life. HAART served ... adverse drug reaction (ADR) reported by them was rash due to Nevirapine.
Editorial
Antiretroviral Therapy: Toxicity and Adherence Milind Y Nadkar*, Smrati Bajpai** ‘The highest attainable standard of health is one of the fundamental rights of every human being, without distinction of race, religion, political belief, economic or social conditions’, this is what the constitution of WHO states. In the perspective of HIV/AIDS this statement is very tricky.
adverse effects. Compliance to ART is one of the major areas of concern in management of HIV/AIDS patients especially in view that it is a lifelong treatment. HIV virus is a highly mutation prone virus, there is increasing evidence that resistant strains are being transmitted in North America and Europe as a result of the difficulty in completely suppressing viral replication. This scenario can develop in any area where adequate attention is not given to the factors leading to development of resistant strains. HAART for its effectiveness requires high level of adherence, to the tune of ninety-five per cent. Adherence thus plays a critical role in the effectiveness of HIV treatment.6 Nevertheless, the complexity of regimens and frequent side effects make HAART difficult to take, and many HIV-infected persons fail to adhere.
HIV/AIDS has great physical, emotional and psychosocial implications. Growing socioeconomic burden of the disease in India led to the inception of National AIDS Control Organization (NACO) in the year 1986 and subsequently in the formation of National AIDS Programme in the year 1987. The programme initially started with education, testing and prevention activities so as to bring awareness about this disease in the community and prevent the spread. Today, India has the third highest HIV burden in the world with an estimated 2.5 million people living with HIV in 2006 with an adult HIV prevalence of approximately 0.36%.1
The vast research in the field of antiretroviral drugs in the last decade has led to emergence of multiple drugs in the market which have tried to achieve the aim of effective viral suppression with minimal adverse effects and minimal pill burden, so as to increase patient adherence. The regimens provided under the free ART programme of India include drugs which are effective; however there are better drug regimens available in the market with much lower incidence of side effects.
UNAIDS and WHO launched the “3 by 5” initiative in the year 2003 with the aim to ensure treatment for 3 million people living with HIV/AIDS in low- and middle-income countries by the end of 2005.2 In accordance with this on World AIDS Day - 2003, the Government of India announced a strong policy commitment to provide free antiretroviral therapy (ART) to 100,000 people with HIV/AIDS starting 1 st April 2004. 3 This was started with ART being provided firstly in the government hospitals of six high prevalence states namely Andhra Pradesh, Karnataka, Maharashtra, Manipur, Nagaland and Tamil Nadu.
It must be stressed that majority of patients are able to tolerate HAART well, even over years. The monitoring of treatment toxicity by an HIV clinician is recommended in at least threemonthly intervals, even in asymptomatic patients, and more often at the beginning of a new HAART, when it should be weekly or fortnightly. Standard evaluations include a thorough history (including drug allergies and other side effects), physical examination and measurement of vital signs and body weight. Routine investigations include a full blood count, liver, pancreas and renal function tests, electrolytes as well as fasting cholesterol, triglycerides and glucose levels. At the same time the patient should be counseled in detail about potential side effects, in order to be able to recognize them and to consult physician in time.
ART became the keystone of the National AIDS Programme, these drugs brought about a major breakthrough in the treatment of HIV infection. After they became available HIV-AIDS no more sounded like a death sentence to the patient, it rather transformed into a manageable ailment. The advent of such highly active antiretroviral therapy (HAART) sharply brought down AIDS related mortality levels and improved quality of life. HAART served two goals simultaneously, restoration of health in HIV infected patient and retarded the spread of HIV. The latter was significant from public health point of view. Before the availability of antiretroviral therapy, median survival after diagnosis of AIDS was 12 to 18 months. This has changed dramatically since the advent of highly active antiretroviral therapy (HAART).4
The article by Sivadasan et al7 in this issue of JAPI highlights some of these inadequacies of present free ART regimens. Their study clearly shows that adverse effects of the various drugs of the HAART regimen are one of the major reasons for treatment change.
NACO supplies fixed drug combination of zidovudine, lamivudine, stavudine (nucleoside reverse -transcriptase inhibitors, NRTI), nevirapine and efavirenz (non-nucleoside reverse transcriptase inhibitor, NNRTI) in free ART programme. These drugs are provided through a chain of ART centres distributed in the country. Currently there are 197 ART centres in India.5
There are very few available Indian data on the aspect of ART toxicity, although with the long term international experience it is a known fact that there are both short term and long term adverse effects to ART. A study by Sharma et al 8 from Gujarat has observed 71% incidence of side effects in their patients who were on HAART, although their study included all ADRs irrespective to the fact whether the treatment required any change of therapy or lead to noncompliance in patient. The commonest adverse drug reaction (ADR) reported by them was rash due to Nevirapine. Other ADRs in their study were peripheral neuropathy (PN) in 22.2% and anemia in twenty per cent. Another study from South
H A A R T p re s e nt l y i s a l i fe l o n g t h e ra py. I t i nvo l ve s administration of a group of drugs with the aim of maximal viral suppression for the longest period of time and with minimal * Professor, **Assistant professor, Department of Medicine, Seth GS Medical College and KEM Hospital, Parel, Mumbai-400 012
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India by Kumarasamy et al9 reported a 15.2% incidence of rash, 9% incidence of PN, 5.4% anemia and 3.5% hepatitis.
will improve compliance thereby decreasing the incidence of drug resistance. Protease inhibitors (PIs), the other class of ART as a part of second-line regimen, in free ART programme also need consideration when NNRTI use is not possible.
Nucleoside reverse transcriptase inhibitor (NRTIs) class of drugs form an important part of the ART regimen, these drugs due to their mitochondrial toxicity cause most of their adverse effects like myopathy, lactic acidosis, lipodystrophy etc. Lactic acidosis/hyperlactatemia is a serious side effect most commonly caused by stavudine in the ART regimen available in the free ART schedule. Lactic acidosis though is a side effect which develops late in patients on HAART, it is difficult to diagnose early because of the nonspecific symptoms thus leading to patients presenting late with symptoms of severe acidosis. It thus needs to be observed in all patients on NRTI class of drugs more so with stavudine. This potentially fatal complication has been reported from India as well by studies of Patel et al10 from Ahmedabad and Sundaram et al11 from Chennai. Although their incidence is not as high as has been observed in the study by Sivadasan et al7 who reported lactic acidosis as the major ADR in their cohort with an incidence of 8.7% and also the onset of this ADR in there cohort is quite early. Further studies on larger population with correlation of other factors would be able to give better insight about this ADR in Indian scenario.
There is always a balancing act for the treating physician when he starts patient on HAART. The initial regimen should be the best possible so as to be able to effectively suppress the virus and prevent the development of resistance to the drugs thus making the regimen effective for the longest period of time and simultaneously regimen should be free from side effect and be affordable. This balance needs to be relooked at in the present free ART programme. The modification of present ART programme would lead to an educated, updated and efficacious implementation of free ART services, which would also lead to long term success of this programme.
References
Apart from the acute toxicities, HAART can lead to delayed toxicity in the form of morphologic and metabolic complications like lipodystrophy, dyslipidemia, osteonecrosis, and oeteopenia as well. Pujari et al 12 have highlighted these chronic ADRs of HAART in a study on patients from Western India. Patient cohort in study by Sivadasan had very advanced disease with very low median CD4 counts; this also seems to be the reason for the large degree of ADRs observed. They state the shortcomings of the drugs in the free ART programme as low genetic barrier of resistance, but we would also like to put forward that the other currently available options are not totally free of ADRs. Also, cost factor in free ART programmes need to be addressed.
1.
HIV-AIDS epidemiological Surveillance and Estimation report for the year 2005, Indian National AIDS Control Organization (NACO), April 2006.
2.
The “3 by 5” Target; Newsletter: Department of HIV/AIDS, World Health Organization; August/December 2005; Available from Website: www.who.int/hiv,www.who.int/3by5
3.
Expanding access to HIVAIDS treatment; mission report India; 8-12 December 2003; WHO: Publication of Regional Office of South East Asia, New Delhi.
4.
Kumarasamy N, Solomon S, Chaguturu SK, et al. The changing natural history of HIV disease: Before and after the introduction of generic antiretroviral therapy in Southern India. Clinical Infectious Diseases 2005; 41:1525–8.
5.
National AIDS Control Organization. List of ARTC as of Jan 09. Available from: http://www.nacoonline.org
6.
Skolnik PR. HIV therapy- What do we know, and when do we know it? N Engl J Med 2003; 349:2351.
7.
Sivadasan A, Abraham OC , Rupali P, et al. High rates of regimen change due to drug toxicity among a cohort of south Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment. J Assoc Physicians India 2009;57:15-19.
8.
Sharma A, Vora R, Modi M, Sharma A, Marfatia Y. Adverse effects of antiretroviral treatment. Indian J Dermatol Venerol Leprol 2008; 74:234.
9.
Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum of adverse events after generic HAART in Southern Indian HIVinfected patients. AIDS Patient Care STDs 2008, 22:337-344.
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Therapeutics of HIV patient is further complexed because of the other adjunctive medications which most of these patients are prescribed when suffering from other conditions such as tuberculosis, fungal infections, Pneumocystis carinii pneumonia (PCP), lymphoma etc. One has to consider drug-drug interactions between ART and drugs given to treat concomitant illnesses. This leads to further increase in incidence of side effects of ART and decrease in compliance. Clinical dilemmas of noting the exact culprit drug producing toxicity may be intriguing, e.g. acute dermatological toxicity of nevirapine is at times difficult to differentiate from TMP-SMX.
10. Patel AK, Patel K, Patel J. Lactic acidosis in HIV-I infected patients receiving antiretroviral therapy. J Assoc Physicians India 2004; 52:666-69. 11. Sundaram M, Srinivas CN, Shankar EM, et al. Co-factors for abnormal lactate levels among persons with HIV disease at a tertiary HIV care setting in South India. Food Chem Toxicol 2008; 46:2823-5.
Most of the drugs which are available and approved for the use in HAART have some or the other adverse effect, thus treatment of HIV infection has become a complicated balancing act between the benefits of durable HIV suppression and the risks of drug toxicity. One thus should have the knowledge of drugs having more modest and nonfatal adverse effect profile. The newer additions in the NRTI class like Tenofovir and Abacavir offer some such options. Introduction of these drugs
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12. Pujari SN, Dravid A, Naik E, et al. Lipodystrophy and dyslipidemia among patients taking first-line, World Health Organization recommended highly active antiretroviral therapy regimens in Western India. 2005; 39:199-202.
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