Introduction:
management of HIV infection. Three groups of ARV drugs have been tried, tested and found successful in interrupting viral replication. Strict adherence, the use of combination of three drugs leads to sustained viral suppression for several years. Though, antiretroviral therapy (ART) does not cure HIV/AIDS, but effective antiretroviral regimens inhibit the efficient replication of the HIV virus, and reduce viremia to undetectable levels. This leads to slowing of disease progression and fewer opportunistic infections and helps people lead more productive lives, with perceptibly reduced stigma and discrimination. The HAART has led to a significant reduction in mortality and morbidity associated with the disease. However, a curative therapy / effective vaccination still elude the mankind.
The first drug effective against HIV, Zidovudine (AZT, ZDV) was approved as early as 1986. However, till early nineties, only Zidovudine (ZDV) & Didanosine (ddl) were available and were used as monotherapy. By the year 1995, results from several studies had demonstrated that use of two nucleoside analogue combined together (dual therapy) was quite effective in delaying the disease progression, showed impressive clinical improvements and increase in CD4 counts. The scenario changed dramatically in 1996 with the introduction of ‘Protease Inhibitors’ (Pls), which were very potent drugs and reduced the viral load by 10 – 100 times. As a result of effective triple combination therapy, hospitalisation rates of HIV infected individuals reduced dramatically, patients returned to work and opportunistic infections were reduced significantly. The drugs were no doubt quite efficacious but were associated with problems of significant toxicities, adherence to large number of pills (20 – 30 per day) and high costs.
Presently, we have 21 anti-retroviral agents approved by US FDA, of which 15 are currently available in India. The efficacy of drugs is well documented, options available are several and large numbers of patients are on ARV therapy. However, the management of HIV is becoming increasingly complex as problems of long term toxicities; drug-drug interaction and drug resistance are emerging. There are issues about wide availability of monitoring facilities like viral load, drug resistance testing, and second line ARV drugs.
Goals of Antiretroviral Therapy:
The currently available ARV drugs cannot eradicate the HIV infection from human body. The primary goals of antiretroviral therapy are maximal and durable reduction in plasma viral levels, restoration of immunological functions aimed at prolongation of life and improvement in quality of life. The reduction in viral load also leads to reduction in risk of sexual transmission. Besides, ARV drugs can also be used to reduce the risk of transmission of HIV from an infected mother to her child (MTCT), transmission after an accidental needle stick injury to a Health Care Worker from an infected person and in cases of sexual assault and rape etc.
ART INITIATIVE IN INDIA
There are an estimated 2.31 million people living with HIV/AIDS in India. As per estimates, at any given time approximately 10-15% of the total numbers of people with HIV infection are expected to be in need of ART. This means that nearly 3-4 lakh patients will need ART presently. Till now the high costs and complicated treatment regimens were the major barriers in introducing free ART under “Care & Support” component of the National AIDS Control Programme. With advent of newer ARV drugs with lesser side effects and lowered costs, it was considered appropriate to introduce provisioning free ART through public sector health facilities in a phased manner. To begin with, provision of ART was launched in eight government hospitals in six high prevalence states, i.e., Andhra Pradesh, Karnataka, Maharashtra, Tamil Nadu, Manipur and Nagaland and NCT of Delhi. Currently there are 228 centres providing ART.
Objectives & Targets:
The Objective of ART programme is to provide long-term ARV therapy to eligible HIV+ persons. Specific targets under NACP-III are:
- To provide free ART to 300,000 adult and 40,000 children by 2012 through 250 ART centres and 650 Link ART centres
- To achieve and maintain a high level (>95%) of drug adherence and minimize the number of patients lost to follow up (<5%) for effective control
- To increase life span so that 50% of patients on ARV are alive 3 years after starting ARV
Principles of Antiretroviral Therapy
A continuous high level of replication of HIV takes place in the body right from the early stages of infection. At least 1010 viral particles are produced and destroyed each day. The HIV destroys CD4 Cells, while body produces more CD4 cells. This balance is maintained for some years after which the rate of CD4 destruction becomes more than that of CD4 production. This progressive immune system damage results in susceptibility to different opportunistic infections (OI), malignancies, neurological diseases, wasting and, ultimately, death.
Regular measurements of CD4 cell count and plasma HIV RNA levels (if possible) are necessary to determine the risk of disease progression in HIV infected patients and to determine when to initiate or modify ART regimens. The viral load levels indicate the magnitude of HIV replication while CD4 counts indicate the extent of HIV induced immune damage. The antiretroviral drugs act on various stages of replication of HIV in the body and interrupt the process of viral replication. Commonly used agents, target the virus mainly by inhibiting the enzymes reverse transcriptase (RT Inhibitors), and protease (Protease Inhibitors). The newer group of drugs include Fusion Inhibitors, integrase inhibitors, CCR5 antagonist and second generation NRTIs.
PRACTICE GUIDELINES
The ART treatment guidelines approved by National AIDS Control Organization in May 2007 (modified in April 2009) are summarized below and are available at www.nacoonline.org.
As a principal, a combination of at least three agents from different classes of ARV drugs is the regimen of choice as this gives maximal achievable suppression of HIV replication over a prolonged period of time.
ART has to be initiated as and when the patient becomes eligible according to the technical guidelines. However, before starting the ART, it is of utmost importance to ensure that the patient is well prepared for the therapy. The preparedness includes that the patients has adequate understanding of the disease, is aware of the treatment regimens, importance of adherence to therapy and is willing to take the treatment. The adequate preparedness of the patient is critical in ensuring a high level of adherence to ART.
It is also important to have reliable laboratory services for investigations such as complete blood count and bio-chemistry, access to CD4 count and viral load facilities (if possible). One has to ensure reliable, affordable and uninterrupted access to quality antiretroviral drugs, and drugs to treat opportunistic infections and other related illness.
Prior to starting therapy, it is essential to have a detailed clinical evaluation, so as to assess the present stage of HIV infection, presence of any Opportunistic Infection (Present or Past) and identifying co-existing medical conditions. The patient should have a detailed physical examination and should undergo investigations like complete blood count, chest X-Ray, renal and liver function, lipid levels, VDRL, Hepatitis B & C serology, pregnancy testing and urine for routine and microscopic examination and CD4 counts.
Major issues concerning ART for an individual are:
- When to start treatment?
- Which and how many agents to use? Choice of optimal regimen?
- How to monitor the therapy?
- How long to give therapy?
- When to change therapy and to what?
- Drug interactions involving antiretroviral therapy.
When to start treatment?
The guidelines on ART are issued and periodically updated by National AIDS Control Organisation in India (May 2007 modified April 2009). The NACO guidelines on initiating therapy are based on clinical staging and CD4 count (see table below).
Table 1: NACO guidelines on initiation of ART
WHO Clinical Stage | CD4 count (cells/mm3 ) |
I. | Treat if CD4 count< 250 (If between 251-300, repeat CD4 count after 4 weeks) |
II. | |
III. | Treat if CD4 count < 350 |
IV. | Treat irrespective of CD4 count |
Specific Situations
a. Pulmonary TB & HIV- start ART after 2 wks of initiation of ATT for all patients with CD4 < 350 cells/mm3. ( as soon as patient is stabilized) (for patients with CD4 more than 350, defer ART.) b. Extra Pulmonary TB & HIV- start ART after 2 wks of initiation of ATT in all patients irrespective of CD4 count. ( as soon as patient is stabilized) (Special attention to monitor hepatotoxicity) Currently the guide line mentions that if CD4 > 350, the pt needs to be re assessed for CD4 and clinical stage at completion of ATT.
a. WHO stage I & II start ART at CD4 < 250 cells/mm3. (If between 251-300, repeat CD4 after 4 weeks) b. WHO stage III start ART at CD4 < 350 cells/mm3 (with strict monitor of adverse affects of nevirapine) c. WHO stage IV, start ART irrespective of CD4 Count. | |
What to start with?
It is recommended that all patients should be started with a three drug combination from two different classes, namely NRTI and NNRTI as follows:
The ART regimen approved for use by NACO are as below
National ART Regimen | Regimen | Indications | Availability |
Regimen I | Zidovudine + Lamivudine + Nevirapine | “Preferred regimen” | First Line regimens available at all ART centers |
Regimen I (a) | Stavudine* + Lamivudine + Nevirapine | For patients with Hb < 8 gm/dl | |
Regimen II | Zidovudine + Lamivudine + Efavirenz | Preferred for patients on anti-tuberculosis treatment and Hb> 8gm/dl | |
Regimen II (a) | Stavudine* + Lamivudine + Efavirenz | For patients on anti-tuberculosis treatment and Hb < 8 gm/dl | |
Regimen III | Tenofovir+ Lamivudine + Nevirapine | For patients not tolerating ZDV or d4T on a NVP-based regimen | Alternate first line ART to be made available at 10 Centers of Excellence |
Regimen III (a) | Tenofovir + Lamivudine + Efavirenz | For patients not tolerating ZDV or d4T on a EFV-based regimen | |
Regimen IV | Zidovudine + Lamivudine + Lopinavir/Ritonavir | For patients not tolerating both NVP and EFV, and Hb > 8gm/dl | |
Regimen IV (a) | Stavudine + Lamivudine + Lopinavir/Ritonavir | For patients not tolerating both NVP and EFV and Hb < 8 gm/dl | |
Regimen V | Tenofovir + Lamivudine + Lopinavir/Ritonavir + Zidovudine | “Preferred regimen” | Second line ART ART to be made available at 10 Centers of Excellence |
Regimen V(a) | Tenofovir + Lamivudine+ Lopinavir/Ritonavir | For patients with anemia < 8 gm/dl |
Follow up of patients on ART:
The patients on ART must be followed every month for clinical evaluation, adherence counselling and toxicity. All patients must undergo a regular CD4 count every six month. Hb% of all patients on AZT should be mentioned every month in initial six months.
Adherence to ART:
The adherence to ART is one of the most crucial determinants of success of ART on long term basis. The adherence of 95% or more is crucial for patients to achieve desirable suppression of viral replication.
Drug Interactions
Potential drug-drug interactions should be taken into consideration while selecting an antiretroviral regimen and review of drug interaction potential should be undertaken when any new drug is to be added to an existing antiretroviral combination. The list of drugs that may have significant interactions with PIs and/or NNRTIs is extensive and continuously expanding. Some examples of these drugs include medications that are commonly prescribed for HIV patients for other conditions, such as rifamycins (rifampicin), lipid-lowering agents (statins), benzodiazepines, calcium channel blockers, immunosuppressants (such as cyclosporine, and tacrolimus), neuroleptics, sildenafil, ergotamine, azole antifungals, macrolides, oral contraceptive and methadone.
No immune-modulators or ayurvedic preparations be used with ARVs as they may cause drug interaction with ARVs leading to their decreased bioavailability. The patients should be cautioned against going to quacks who often claim to have ‘cure’ for HIV/AIDS.
Changing Therapy (Substitution or Switching)
The reasons for changing an antiretroviral therapy regimen include
1. Drug adverse effects,
2. Inconvenient regimens such as dosing/number of pills that may compromise adherence,
3. Treatment failure, ( Clinical/immunological or virological)
4. Occurrence of active tuberculosis and
5. Pregnancy.
The decision to change regimen should be based on clinical history and physical examination; routine and relevant laboratory investigations, and changes in CD4 count. An assessment of adherence to medications should be made and remaining treatment options considered. Potential of initial viral resistance, drug interaction and diet also need to be considered.
In a patient who experiences adverse effects or is intolerant to an otherwise successful regimen, “substitution” of the offending drug is reasonable. An example would be adverse effects of Zidovudine that can be replaced by Stavudine or skin reaction to nevirapine that should be substituted by efavirenz. For serious adverse effects, such as Abacavir hypersensitivity reactions and nevirapine related hepatic failure, rechallenge should not be attempted as this may lead to toxicity and death.
Change due to treatment failure
Clinical failure is defined as occurrence or re-occurrence of HIV related events (after at least six months on an antiretroviral regimen), excluding immune reconstitution syndrome. Immunologic failure can be defined as fall of CD4 count to pre therapy baseline or below, 50% fall from the on treatment peak value or persistent CD4 below 100cell/cmm. Virological failure can be defined as viral load of more than 10,000 copies/ml.
Identifying Failure:- Clinical, Immunological and Virological Failures
Clinical failurei | New or recurrent WHO stage 4 condition, after at least 6 months of ARTii,iii |
Immunological failure4 | · Fall of CD4 count to pre-therapy baseline (or below) · 50% fall from the on-treatment peak value (if known) · Persistent CD4 levels below 100 cells/mmiii,v |
Virological Failure | Plasma viral load >10,000 copies/mLvi |
The entire regimen should be “switched” from a first to a second line combination regimen in the case of treatment failure. A single drug should not be added or changed to a failing regimen. The new second-line regimen will need to use drugs, which retain activity against the patient’s virus strain and ideally include at least three new drugs, in order to increase the likelihood of treatment success. The table below is the second line regimens one could consider in adolescent and adults for each of the first-line regimens identified. NACO recommends the following second line drugs in the program.
TDF/3TC + LPV/r + ZDV is the standard regimen for all patients provided second line ART unless there is contraindication to ZDV such as hypersensitivity or anaemia from previous first line therapy use. In cases where the patient is anaemic and has prior history of intolerance to ZDV eg ZDV-related anaemia, the NACO regimen is TDF+3TC +LPV/r (without the ZDV).
ARV drugs for 2nd line | Dosage | Dosing schedule |
TDF + 3TC | Fixed dose combination of TDF 300 mg + 3TC 300 mg Once daily | 1 – 0 – 0 (one tablet in the morning) |
LPV/r | Heat stable co-formulation of LPV 200mg + Ritonavir 50 mg Two tablets Twice daily | 2 – 0 – 2 (2 tablets in the morning and 2 tabs in the evening) |
ZDV | Zidovudine 300 mg Twice daily | 1 – 0 – 1 (one tab in the morning and one tab in the evening) |
ART and Tuberculosis
Due to a high prevalence of tuberculosis (TB) among HIV-infected individuals, many patients who are candidates for ART will have active TB. In addition, patients already receiving ART may develop clinical TB. Effective treatment and control of TB is a central priority when developing treatment strategies for co-infected patients. The management of HIV and TB co-infection is complicated because some antiretroviral agents produce unacceptable drug interactions with anti-tubercular agents and/or can increase toxicity of TB treatment. Tuberculosis treatment following the DOTS strategy should be initiated promptly in diagnosed cases of TB. The two major issues in the clinical management of patients with HIV and TB are when to start ART and which regimen to use. Initiation of ART for TB patients has been described in Table 1.
Patients already receiving ART when they develop TB should adjust the regimen to be compatible with TB treatment (EFV based). Following completion of anti-tubercular therapy, the ART regimen can be continued or changed depending upon the clinical and immunologic status of the patient and affordability of drugs (EFV being more expensive than NVP). However, the National guidelines for India (NACO) recommend that the regimen should be changed from EFV to NVP once ATT is completed, and in such instances, NVP should be started as twice daily doses and not as once daily dose for 14 days
Progress in ART programme:
As of July 2010, nearly 9.5 lakh patients have been registered at ART centres and 3,35,625 clinically eligible patients are alive and receiving free ART in Govt. & intersectoral health sector. Year wise number of centres set up, states covered and patients seeking treatment are given below:
Period | ART Centres | States Covered | Patients on ART |
April 2004 | 8 | 7 | Nil |
April 2005 | 25 | 13 | 6845 |
April 2006 | 54 | 21 | 29746 |
April 2007 | 107 | 31 | 70276 |
April 2008 | 174 | 31 | 141163 |
February 2009 | 197 | 31 | 215625 |
July 2010 | 282 | 31 | 335625 |
All ART Centres are provided with a CD 4 machine or linked to another centre with CD4 machine. The kits for CD4 tests are provided centrally as commodity assistance. A Computer along with printer and internet facility is provided to ARV treatment Unit along with M&E tools. All centres are supplied ARV drugs by NACO through UNOPS. Average cost of generic first line ARV drugs per patient works out to be Rs. 5,500/- per year. Each ART centre is provided with funds of Rs. 12–14 lakh for salary of additional manpower and operational costs as per guidelines under NACP III.
National Pediatric HIV/AIDS Initiative
NACO launched National Paediatric AIDS Initiative on 30th November, 2006 in order to provide comprehensive Care & Support (including ART) to children infected and affected by HIV/AIDS. For this initiative NACO, along with the Indian Academy of Paediatrics (IAP), UNICEF, WHO and Clinton Foundation, has developed guidelines for paediatric ART including diagnosis in children. The various activities under this initiative include establishment of seven Regional Paediatric Centres, free CD4 monitoring, free DNA PCR test for children up to 18 months, paediatric ARV formulations for children, diagnosis, treatment of opportunistic infections and micro nutrient supplementation. The initiative also includes training of paediatricians and counsellors, establishing laboratory diagnosis, introducing Dried Blood Spot system to transport dried blood samples. Care and Support for CLHA (Children Living with HIV/AIDS) orphans and vulnerable children forms an integral part of NACP III. The paediatric formulations of ARVs are now available in all ART centres. These centres have registered 65474 HIV infected children. Till 2006, there were 1800 children on ART which has now increased to more than 20,000 children. Under NACP III (2007-12), the target is to provide treatment to 40,000 children.
Centres of Excellence
Following ten Centres of Excellence have been set up in the country to provide state of art services for PLHAs, and function as knowledge hubs, resource centres and undertake training and operational research in HIV/AIDS:
- Government Gandhi General Hospital , Hyderabad Andhra Pradesh
- Post Graduate Institute of Medical Education & Research (PGIMER) , Chandigarh
- Maulana Azad Medical College (MAMC), New Delhi
- Bairamji Jijibhai Medical College (BJMC), Ahmedabad, Gujarat
- Bowring and Lady Curzon Hospital, Bangalore, Karnataka
- Sir J.J. Hospital, Mumbai , Maharashtra
- Regional Sciences of Medical Sciences (RIMS), Imphal, Manipur
- Calcutta School of Tropical Medicine (STM), Kolkata, West Bengal
- Banaras Hindu University Institute of Medical Sciences, Varanasi
- Government Hospital of Thoracic Medicine (GHTM), Tambaram , Chennai
In addition, following 7 Regional Paediatric ART Centres have been established for comprehensive paediatric care, training and research including facilities for early infant diagnosis. :
1. Indira Gandhi Institute of Child Health – Bangalore
2. Institute of Child Health – Chennai
3. Sion Hospital – Mumbai
4. Jawaharlal Nehru Hospital – Imphal
5. Kolkata Medical College, Kolkata
6. Kalawati Saran Children’s Hospital, Delhi
7. Gandhi Hospital, Hyderabad
Second-line ART
In untreated persons the HIV multiplies very rapidly (upto 10 billion new viruses every day) and during this multiplication some ‘errors’ (mutation) occurs which make the virus resistant to commonly used ARV drugs(so called ‘first line drugs’). Since the rate of multiplication is very high, drug resistance cannot be totally eliminated. However, it can be minimized by good access to high quality simple ART regimen, uninterrupted drug supply and high levels of drug adherence. As we scale up our national ART programme, there is bound to be some degree of resistance to HIV drugs and these patients will require second line ARV drugs. In order to estimate the number of patients requiring second line drugs, we have to know the magnitude of drug resistance in the country.
The second line ART was rolled out under the National ART Programme on 1st January 2008 on a pilot basis initially at JJ Hospital, Mumbai and GHTM, Tambaram. The access to second line ART has now been expanded to all the 10 Centres of Excellence which have the necessary expertise and laboratory facilities required for initiating and monitoring second line ART.
Eligibility criteria for enrolment into second line treatment under NACP-III are:
1. Free treatment and free viral load testing for all PLHA below poverty line, widows and children.
2. Patients under treatment in Government ART centres continuously for at least two years, irrespective of income status.
State AIDS Clinical Expert Panel (SACEP) have been set up at 10 Centres of Excellence to review suspected treatment failure cases referred from ART centres providing first line ART. Each COE will have defined ART centres linked to it and patients from these centres only will be reviewed by a particular COE
.
Link ART centre
The concept of the link ART centres was developed taking into consideration the large distances PHLAs had to cover to reach ART centres. These link ART centres are being developed at ICTC or CCC, whereby, stabilised patients will get their drugs within their easy reach will have to travel to main ART centre once in six months only. A total of 434 Link ART are functional presently.
Community Care Centres
In order to improve the quality of counselling and also reduce the inconvenience caused to PLHAs while being investigated at ART centres, all ART centres will be linked to a Community Care Centre, whereby, patients can be admitted during the period of investigation and adherence counselling can be reinforced. Presently a total of 287 CCCs are operational and it is planned to have a total of 350 CCC across the country, by 2012. Each CCC will be linked to the closest ART Centre.
Conclusion:
Antiretroviral therapy is quite effective in suppressing viral replication, delaying the progression of disease and has changed the management of HIV disease dramatically, yet issues of adherence, toxicity, emerging resistance and cost of second line drugs dominate the scenario. The HIV care is still very complex and is rapidly evolving. The future options include new group of drugs, better strategies but the correct usage of these agents, their timings of initiation and proper monitoring is of utmost importance if we want these drugs to remain effective. The therapy is no doubt panacea for those already infected, but HIV prevention messages and probably AIDS vaccines are the keys to halting the progression of the epidemic of this dreaded disease.
Key Messages
· No monotherapy or dual therapy is recommended.
· Do not start ART in a patient who is not motivated enough to follow such treatment for indefinite period.
· Do not start ART without providing adequate information about how and when to take the drugs, potential side effects and interactions with other drugs, when to stop the drugs, etc.
· For successful outcomes of ART it is very essential that patient is counselled adequately on every visit about maintaining more than 95% adherence throughout the period of treatment.
· Always start with rational first line treatment with proper monitoring of adherence and toxicity, avoid unnecessary supplementary drugs without much proven efficacy. Initiate second line only after ruling out OI, checking adherence to first line and documenting first line failure.
· Always keep in mind patient’s other needs such as sufficient nutritional support, adequate home care etc.
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