TRANSMITTED BY UNGAURDED SEX
Association of Physicians of India
Guidelines for use of Antiretroviral therapy in adults (API-ART Guidelines) 2005-2006
Endorsed by the
AIDS SOCIETY OF INDIA
Guidelines Development Committee
Chairpersons
SB Gupta, *Central Railway Headquarters Hospital, Mumbai.
SN Pujari, **Ruby Hall Clinic, Pune and University of South Florida, Tampa, USA.
Co-Chairs
SR Joshi, ***Lilavati Hospital, Mumbai.
AK Patel, +Infectious Diseases Clinic, Ahmedabad.
International Experts :
David Cooper, University of New South Wales, Sydney, Australia.
Jeffrey P Nadler, University of South Florida, Tampa, USA.
Writing Committee
Chairpersons
Co-Chairs
Raman Gangakhedkar, National AIDS Research Institute, Pune;
N Kumarasamy, YRG Care, Chennai
Panel Members
Subhasish Guha, School of Tropical Medicine, Calcutta;
Janak Maniar, Jaslok Hospital, Mumbai;
Bharat Rewari, Senior Physician, Dr RML Hospital, New Delhi;
Avina Sarna, Population Council, New Delhi;
K Satish, Wockhardt Hospital, Bangalore;
Jehangir Sorabjee, Bombay Hospital, Mumbai;
Soumya Swaminathan, Tuberculosis Research Center, Chennai;
Jaideep Gogtay, Cipla Ltd. Mumbai
Ajay Wanchu, PGIMER, Chandigarh;
Panel members (AIDS Society of India)
Ishwar Gilada, Unison Medicare and Research Center, Mumbai;
Suniti Solomon, YRG Care, Chennai and President AIDS Society of India
EXECUTIVE SUMMARY
With rational use of antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection has been in transformed into a chronic manageable illness like diabetes and hypertension. This guidelines provide information on state of art, evidence based approach for use of ART in Indian context.
When to initiate ART?
Antiretroviral therapy is indicated for all symptomatic HIV infected persons regardless of CD4 counts and Plasma Viral load (PVL) levels. In asymptomatic patients, ART should be offered when the CD4 counts <200/mm3 and should be considered in patients with CD4 counts between 200-250/mm3. Therapy is not recommended for patients with CD4 count more than 350/mm3. Involvement of patient in all treatment decisions and assessing readiness is critical before initiating ART.
What to start with?
A non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen is recommended for antiretroviral naïve patients. The choice between nevirpaine and efavirenz is based on differences in adverse events profiles; cost and availability of convenient fixed dose combinations and need for concomitant use of rifampicin. A backbone of 2-nucleoside reverse transcriptase inhibitors (NRTI's) is combined with the NNRTI. Various combinations and ART strategies not to be used in clinical practice has been enlisted.
How to follow up?
Recommendations have been made for baseline evaluation and monitoring of patients on ART. These include guidelines on laboratory and clinical evaluation. A plasma viral load at 6 months after initiation of first-line ART is strongly recommended. Yearly estimation of lipid profile has been recommended.
How to identify and manage ART failure?
The guidelines recognize the issue of identifying ART failure late if only CD4 counts are used for monitoring. In the absence of resistance testing various second line regimens have been enlisted. A boosted protease-inhibitor based regimen is recommended in this situation to be combined with 2-NRTIs.
Special situations
Recommendations have been made for use of ART in HIV-TB, HIV-HBV, and HIV-HCV co-infected patients. In patients with active TB and a CD4 count < 200/mm3, initiation of ART is recommended as soon as the anti-TB treatment is tolerated. Efavirenz is the only ARV drug, which can be safely used with rifampicin. In pregnancy use of single dose nevirpaine for reducing risk of mother to child transmission of HIV is not recommended, because of the risk of development of resistance. For post exposure prophylaxis taking ART treatment history of the source patient is crucial in designing an effective regimen.
INTRODUCTION
Antiretroviral therapy (ART) has dramatically reduced morbidity and mortality rates in advanced human immunodeficiency virus (HIV) disease in both the developed and developing world.1-3 Generic manufacturers of antiretrovirals(ARVs)have made ART more affordable and accessible. In order to provide optimal quality care, physicians need to have knowledge about ART including indications for its use, which drugs to choose and how to choose them, complications of therapy and managing special situations like HIV and tuberculosis(TB), HIV and pregnancy. Of
the twenty-one antiretrovirals approved by US FDA, currently fourteen are available in India(Zidovudine (ZDV), Stavudine (d4T),Lamivudine (3TC),Didanosine (ddI), Zalcitabine (ddC),Abacavir(ABC),Tenofovir(TDF), (Nucleotide RTI),Nevirapine (NVP), Efavirenz (EFV),Nelfinavir (NFV), Lopinavir (LPV/r),Saquinavir (SQV), Indinavir(IDV), Ritonavir (RTV)). Rational use of ART is critical for prevention of drug resistant HIV epidemic in India in future.
The objectives of these guidelines are:
· To develop evidence-based, state-of-the- art guidelines for use of ART in India
· To develop guidelines which are simple to implement in clinical practice
· To balance science with feasibility to provide quality care to HIV infected persons
The guidelines are designed to assist physicians in extending care to HIV infected individuals and establish a standard of clinical practice across India. HIV medicine is a rapidly changing speciality necessitating periodic updating. Most issues relating to use of ART in the Indian context will be addressed by the guidelines andupdated every three months on the Web. The Web Version is available on www.japi.org These guidelines will be reviewed on an annual basis.
WHEN TO INITIATE ART?
With currently available therapeutic options, eradication of HIV cannot be achieved [4]. However, with the advent of potent antiretroviral therapy, HIV infection has now been transformed into a chronic, manageable illness.
The goals of ART are:
1. To ensure maximal and durable suppression of the virus
2. To reconstitute and preserve immunologic quantity and function
3. To improve quality of life
4. To reduce morbidity and mortality due to HIV infection
Additionally, antiretroviral drugs can be used to reduce transmission of HIV in various situations, e.g. transmission of HIV from infected mother-to-child (MTCT), after occupational post-exposure prophylaxis (PEP) and non-occupational exposures. Theoretically a reduction in plasma viral load is likely to lead to reduction in the risk of sexual transmission of HIV.
Since use of ART is life-long, and associated with long-term adverse events, not all patients diagnosed with HIV infection need to be started on treatment. The decision to initiate ART is made after weighing the risk of progression to AIDS and other important determinants such as the incidence of short and long-term adverse events, commitment to high levels of adherence, development of resistance to ARVs and affordability and patient's readiness for therapy. An algorithm summarizing when to initiate ART is illustrated in Fig. 1.
Antiretroviral treatment is indicated for all patients who are symptomatic with an AIDS defining illness, irrespective of CD4counts or viral load levels. Patients with AIDS have higher rates of mortality unless treated with ART.5,6 In addition patients with non-AIDS defining illness like recurrent oral candidiasis, oral hairy leukoplakia may have a risk of rapid progression, and therapy is indicated in these patients if CD4 count is <350/mm3.7,8
Adequate control of opportunistic infections (OIs) with appropriate antimicrobial therapy and stabilizing patients is crucial before initiating ART. This helps reduce risk of development of IRIS, reduces pill burden, prevents additive toxicities and makes it easier to identify the offending drug in case of overlapping toxicities. Finally, certain AIDS defining illness like cryptosporidiosis, progressive multifocal leucoencephalopathy(PML) may be most effectively treated with ART induced immunereconstitution.9,10
There is a limited HIV natural history data from India, especially the risk of progression to AIDS at various CD4 counts and viral load levels. A retrospective analysis demonstrated that Indian HIV infected patients with CD4 counts <200/mm3 were 19 times more likely to die than were those with CD4 counts>350/mm3.11 Since the risk of developing OIs is significant whenCD4 counts drop to less than 200/mm3, therapy is indicated for these patients.5 At the same time it should be
remembered that
HIV infected patient
History and Physical examination
AIDS defining No Symptoms
Illness/some
Non-AIDS
Defining
CD4 Counts
Stabilize OIs
CD4 counts
CD4 <200 CD4 200 - 350 CD4 >350
CD4 200-250 CD4 250-350
Confirm 4 WKS Monitor
PVL>1, 00,000
HCV/HIVAN
Recommend HAART Defer
________________________________
*AIDS Defining illness **Non AIDS defining illness
Esophageal candidiasis Idiopathic thrombo-
Invasive cervical cancer cytopenic purpura
Extrapulmonary cryptococcosis Oropharyngeal candidiasis
Chornic instestinal Oral hairy leucopalkia
Cryptosporidiosis Moderate or severe cervical
Cytomegalovirus disease dysplasa
HIV related encephalopathy Papular Pruritic dermatitis Chronic herpetic ulcer>1 Month
Isospora diarrhea>1 Month
Lymphoma-immunoblastic,Burkitt's and primary CNS
MAC
Extrapulmonary TB
Pneumocystis jiroveci pneumonia
Recurrent bacterial pneumonia
Progressive multifocal leucoencephalopathy
Cerebral toxoplasmosis
Adapted from 1993 revised CDC classification system for HIV infection and 2005 interim WHO clinical staging of HIV/AIDS
Fig. 1: Algorithm for When to initiate ART.
ART is effective even in patients with advanced immunosuppression (CD4<50/mm3) and should be offered.12,13However, the risk for development of IRIS is higher at this stage and should be closely monitored for.
Therapy may not be offered to asymptomatic patients with CD4 counts >350/mm3. The risk of progression to AIDS in these patients is very low.14 Initiating ART at this stage would mean longer exposure to the drugs resulting in increased costs, potential for development of short and long term adverse events and development of drug resistance in cases of sub-optimal adherence. For example the risk of developing fatal hepatitis due to nevirapine is higher at this stage.
Initiation of ART in asymptomatic patients whose CD4 count ranges between 200-350/mm3 is debatable. Observational studies have demonstrated a significant decline in mortality and morbidity when ART is initiated in this range rather than waiting until CD4counts drop to below 200/mm3.14,15 Treatment can be considered in patients with CD4 count <250/mm3, especially if this value is confirmed with a repeat estimation 2-4 weeks apart. This is based on the rationale that this cut off is close to the 200/mm3 range and would also be the upper bound of the 30% physiologic variation in the CD4 counts.
Between CD4 250-350 mm3, therapy is considered for patients with one or more of the following criteria:
1. A rapidly declining CD4 count- more than 100 cells/year.
CD4 counts should be monitored every 3-6 months to
Identify this.
2. A plasma viral load >100,000 copies/ml (5 logs).
3. Patient choice and readiness
4. Other clinical situations like non-Hodgkin's lymphoma (or
other malignancies), patients with hepatitis C co-infection
who plan to take anti HCV treatment,where immunosupressants /immunomodulators are used, or with HIV associated nephropathy (HIVAN).16,17
Other surrogate markers like the total lymphocyte count (TLC)have been recommended for initiation of ART by some guidelines. However, the
sensitivity and specificity of TLC are not sufficiently high to replace CD4 counts.18 Additionally, the use of TLC in monitoring response to treatment is unproven. Hence TLC is not recommended as a marker for decisions about initiation of ART.
The role of ART in primary HIV infection is controversial. Till further data is available treatment of primary HIV infection with ART is not recommended in routine clinical practice and should be restricted to clinical trial settings only.
Apart from the biological indications for therapy, assessing patient readiness prior to ART initiation is crucial for long-termsuccess.19 The following points should be discussed with the patient prior to initiation:
1.Treatment is life-long, since viral eradication is not achievable.
2.Treatment is expensive.
3.High levels of adherence are needed.
4.Awareness of short and long term adverse events.
5.Awareness of drug-drug interactions.
It is also recommended that patient be provided some time to think. Therapy should never be initiated on the first visit and patients should be encouraged to involve at least one family member in making the decision.
BASELINE EVALUATION
A standard clinical and laboratory evaluation is recommended prior to initiation of ART. It is intended to establish the baseline status for future comparison, individualizing ART according to patient's clinical status and preferences, and ruling out active OIs.
History
Points to be elicited in history taking:
1. HIV specific symptoms- present and past
2. Genital ulcers and other sexually transmitted diseases
3. Personal history- smoking, alcohol, drugs
4. Past history of any coronary artery disease
5. High risk behavior- partner's HIV sero-status if known
6. Women- gynecological history, past pregnancies,contraception
7. Family history of coronary disease, hypertension,
diabetes and hyperlipidemia
8. Treatment history: any past or current use of ARVs (useful
for designing ART regimen), sexual partners ARV use, ARV use
during pregnancy and use of any alternative (e.g.herbal)
preparations.
Physical examination
A routine physical examination is essential prior to initiating ART. Following evaluation is recommended:
1. Body weight, height, Body Mass Index
2. Temperature/Lymph-node
3. Dermatological/Oral cavity: oral candidiasis, oral
hairy leukoplakia
4. Genital/Pelvic (women)
5. Systemic examination
6. Fundus examination
Laboratory evaluation
The purpose of baseline laboratory evaluation is to stage HIV disease, rule out concomitant infections and determine baseline safety parameters. The following tests are recommended:
Essential
1. Confirm HIV infection : A pre-requisite prior to ART
initiation, it also is needed to rule out HIV-2 infection.
Non-nucleoside reverse transcriptase inhibitor's (NNRTIs)
haveno activity against HIV-2.20
2. Specific investigations to rule out OIs
3. CD4 counts : Estimated by flow-cytometry. Alternative
low cost technologies are becoming available, however
further evidence is needed to recommend its routine use in
clinicalpractice.21
4. CBC : Baseline Hemoglobin and WBC counts are needed
to monitor hematological toxicity on Zidovudine (ZDV).
5. LFTs : Necessary to find evidence of hepatitis,
particularly when NVP use is contemplated.
6. Urine routine: To evaluate proteinuria and sugar
(necessitate estimation of blood glucose)
7. Creatinine : Dose of some nucleoside reverse transcriptase
Inhibitors (NRTIs) has to be adjusted according to creatinine clearance.
8. HBsAg : To rule out concomitant hepatitis B infection, this
can influence choice of ARV regimen. Additionally, abrupt
stopping of anti-HBV drugs like lamivudine and tenofovir is
not recommended in patients with chronic hepatitis B co-
infection since it may result in hepatitis B flare.22
9. Chest X-ray : To rule out TB or other pulmonary infection
10. VDRL/TPHA
11. Pap smear : Helps in earlier diagnosis of cervical
intraepithelial neoplasia (CIN)
Optional:
1. Fasting lipid profile : May be recommended in patients with
established coronary disease risk factors or if
stavudine, efavirenz, protease inhibitor (PI) use is
contemplated.
2. Plasma viral load (PVL) : A baseline PVL may not be
necessary. With optimum adherence and a potent
regimen, undetectable levels at 6 months after ART initiation
should be achieved.23
3. Pregnancy test : EFV is contraindicated in pregnancy and most
ARVs are in FDA category B/C.
4. Anti-HCV : The prevalence of HCV is low in HIV infected
patients except, such as in northeastern states of India
where injection drug use is a risk factor. It is also
recommended inHIV infected hemophiliacs and thalassaemics.
CAUTIONS WITH INTERPRETATION OF CD4 COUNTS AND PVL
" Standard methods
CD4 counts: Flow cytometry
PVL: Amplicor 1.5 , Branched DNA assay
" The laboratory should have quality assurance program
" Inter-current illnesses may influence the CD4 counts and PVL values.
" Some evidence to suggest that CD4 counts in normal north Indians is significantly lower than the western population [24].
" Physiologic variations
o CD4 counts:
" 30% changes especially at higher CD4 counts
" Diurnal variations: A practice to draw blood for CD4 counts around same time during follow up is necessary.
o PVL: 0.3-0.5 log (2-3 fold change)
" Specimen processing
CD4 counts: within 18-24 hours of specimen withdrawal, ideally as soon as possible [25].
PVL: plasma separated within half an hour of specimen withdrawal
" PVL: Currently validated for HIV-1, not for HIV-2
WHAT TO START?
Currently, antiretroviral agents of four classes are approved by US FDA for use in HIV infected patients (Table 1). These four classes include the nucleoside and nucleotide reverse transcriptase inhibitors (NRTI/NtRTI),non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and entry inhibitors.
The terminology "highly active antiretroviral therapy" (HAART) refers to use of combinations of three antiretroviral agents for treatment of HIV infection. To date, most clinical experience with use of HAART in treatment-naïve individuals has been based on three types of combination regimens: NNRTI-based (1 NNRTI + 2 NRTI), PI-based (1-2 PI + 2 NRTI), and triple NRTI-based regimens. Most experience in India is with NNRTI based regimens.
Table 1: Antiretrovirals approved for use
NRTI NRTI PI Entry inbhitor
Zidovudine Nevirapine Saquinavir Enfuvirtide
(ZDV) (NVP) (SQV) (T-20)
Stavudine Efavirenz Indinavir
(d4T) (EFV) (IDV)
Lamivudine Delavairidine* Ritonavir
(3TC) (DLV) (RTV)
Didanosine Nelfinavir
(ddI) (NFV)
Zalcitabine* Lopinavir
(ddC) (LPC/r)
Abacavir Atazanavir
(ABC) (ATV)
Emtricitabine* Amprenavir*
(FTC) (APV)
Tenofovir Fos-amprenavir*
(TDF) (FPV)
(Nucleotide RTI) Tipranavir
(TPV)*
*Drugs not available in India
Initial Regimen for ART-naïve HIV-1 Infected Patients in India
Regimen selection should be individualized, taking into consideration a number of factors including: co-morbidity or
conditions such as tuberculosis, liver disease, depression or mental
illness, cardiovascular disease, adherence potential; cost of
treatment and affordability, dosing convenience including pill
burden, dosing frequency, storage requirement, and food and fluid considerations; potential adverse events; gender; and pregnancy potential.
An NNRTI based regimen is recommended as first line therapy
for most ART-naïve HIV infected patients. Recommended regimen for initial therapy in treatment naïve patients are depicted in Table 2.
NNRTI- based regimens are potent and have shown comparable efficacy to unboosted PI based regimens and are superior to 3 NRTI based regimens.29-31 NNRTI-based regimens have the advantage of lower pill burden and are cheaper compared
Table 2: Recommended NNRTI-Based Reimens for India
(1-NNRTI + 2-NRTIs)
2NRTI and NNRTI
Preferred
Zidovudine + Lamivudine Nevirapine
Or Or
Tenofovir + Lamivudine Efavirenz
Alternative
Stavudine* + Lamivudine
Or
Abacavir + Lamivudine
Or
Didanosine + Lamivudine
*Stavudine is considered as an alternative ARV because it is associated with a high incidence of adverse events including peripheral neuropathy, pancereatitis, hyperlactatemia and lipodystrophy and dyslipidemia that may not be reversible on treatment discontinuation.26-28
to most of the PI-based regimens. Use of NNRTI-based regimens as initial therapy can preserve the PIs for later use, reduce or delay patient exposure to some of the adverse events more commonly associated with PIs.
The major disadvantage of currently available NNRTIs is their
low genetic barrier for development of resistance. These agents only require a single mutation to confer resistance (mutations at codons 103, 181, 106, see section on treatment failure), and cross-resistance often develops across the entire class.32 As a result, patients who fail this initial regimen may lose the utility of other NNRTIs and/or may transmit NNRTI-resistant virus to others.
The major short-term adverse event associated with efavirenz is CNS disturbances. Usually these are self-limiting and wane off within two to four weeks and do not warrant discontinuation ofefavirenz.33 Patient should be forewarned about these before initiating treatment. Efavirenz should be avoided during pregnancy (especially during the first trimester) or in women who are planning to conceive or women who are not using effective and consistent contraception, as it is associated with neural tube defects in the baby.
Nevirapine may be used as an alternative to efavirenz for the initial NNRTI-based regimen in adult females with pre-treatmentCD4+ T cell counts <250 cells/mm3 or adult males with pre-treatment CD4+ T cell counts <400 cells/mm3. 34 Symptomatic, sometimes serious or life-threatening hepatic events were observed with higher frequency in women with pre-treatment CD4+ T cell counts >250/mm3 and men with pre-treatment CD4+ T cell counts>400/mm3.35 Nevirapine should be used with caution in patients already having background liver disease like hepatitis B and C co-infected patients. When starting nevirapine, a 14-day lead-in period at a dose of 200mg once daily should be prescribed before increasing to the maintenance dose of 200mg twice daily.
Efavirenz is the only NNRTI, which can be concomitantly used with
rifampicin. An efavirenz-based regimen is recommended in HIV infected
patients receiving rifampicin based antituberculous therapy (see section on drug-drug interactions and HIV and TB).
A large randomized controlled trial has shown similar efficacy between nevirapine and efavirenz based first line regimens, although there were differences in safety profile.36 Hence the choice between using NVP and EFV is based on toxicity concerns.37
Patients Intolerant to NNRTI
Patients who develop severe adverse events to nevirapine and Efavirenz should be treated with ritonavir boosted protease inhibitors (IDV/r, SQV/r, LPV/r) combined with 2NRTIs.Nelfinavir as a sole PI along with 2NRTI may be used in case of lack of storage facility for ritonavir or if patients can't afford a ritonavir boosted PI or while providing treatment during pregnancy.
Selection of Dual Nucleoside "Backbone" as Part of InitialCombination Therapy
Six nucleoside/nucleotide HIV-1 reverse transcriptase inhibitors (NRTI's)are currently available in India. Lamivudineis a common second agent in these combinations because of its tolerability. Though lamivudine has a low genetic barrier to resistance (a single mutation M184V/I causes high levelresistance), this mutation renders the virus less fit and delays development of thymidine-associated mutations (TAMs) which are responsible for ZDV and d4T resistance.38
The choice of another NRTI to be combined with lamivudine depends on cost, adverse event profiles and availability of fixed dose combinations, which potentially improves adherence. Another important issue would be the sequencing potential and availability of other NRTI's to be used in future regimens. Randomized controlled trials have shown no difference in the potency between zidovudine + lamivudine and stavudine + lamivudine along with a PI.39,40 However, stavudine is significantlyassociated with long-term adverse events and is recommended only as an alternative in patients who cannot be initiated on ZDV(due to anemia) and cannot afford tenofovir. A combination of Zidovudine + lamivudine is recommended NRTI backbone for majority of the patients.
Another strategy may be to start with stavudine + lamivudine backbone (in patients who are anemic) and then switch to zidovudine + lamivudine at 12-24 weeks, when hemoglobin improves. However, no randomized controlled trials have been undertaken to assess this strategy.
Tenofovir is an NtRTI with once daily convenience and a good safety profile. When combined with lamivudine it has shown comparable efficacy with other NRTI backbones.41 However, there is very limited data on the use of tenofovir in the developing world. Other non-thymidine based backbones using ABC and ddI have the advantage of not being associated with long-term adverse events like lipodystrophy and dyslipidemia.42,43 When NVP based regimens are contemplated, consideration should be given to using fixed dose combinations (FDCs) of ZDV+ 3TC +NVP and d4T + 3TC + NVP which improves adherence due to low pill burden. It also reduces prescription errors and in a large observational cohort from India has shown effectiveness and tolerability.44
Though boosted protease inhibitors based regimens are extremely potent as first line therapy, they are only recommended in patients who can't tolerate both NVP and EFV. Boosted PI based regimens are costly, complex, with high pill burden, associated with long term adverse events like dyslipidemia and diabetes. The advantage for boosted PI based regimens is their high genetic barrier to resistance and patients failing these regimens usually do not have PI resistant mutations.
Antiretroviral Regimens Not Recommended
Some antiretroviral regimens or components are not recommended for HIV-1 infected patients due to sub-optimal antiviral potency, unacceptable toxicity, or pharmacological concerns. These are summarized below:
1. Monotherapy and dual nucleoside therapy: These regimens are
not recommended because they have not demonstrated potent and sustained antiviral activity.45
2. Tenofovir + ddI + NNRTI is not recommended as an initial
regimen due to reports of early virological and immunological
failure.46
3. 3-NRTI regimen of abacavir + tenofovir + lamivudine and
didanosine + tenofovir + lamivudine should be avoided due to
high rates of virological failure.47 These combinations should
not be used as a 3-NRTI regimen in any patient.
4. Didanosine + stavudine: The combined use of didanosine and
stavudine as a 2-NRTI backbone can result in a high incidence
of toxicities, particularly peripheral neuropathy,
pancreatitis, and lactic acidosis. In general, a combination
containing didanosine and stavudine should be avoided unless
other 2-NRTI combinations have failed or have caused
unacceptable toxicities, and where potential benefits outweigh
the risks of toxicities.48
4. Stavudine + zidovudine: Combination regimens containing these
two NRTIs should be avoided due to the demonstration of
antagonism in vitro and in vivo
6. Unboosted PIs should be avoided if possible due to poor
bioavailability and higher pill burden.
7. Do not alter dosages or schedules of ARV drugs.
8. Efavirenz should be avoided in pregnancy or in women who plan
pregnancy.
9. Nevirpaine should be avoided in women with CD4count>250/mm3
and in men with CD4 count>400/mm3.
Antiretroviral strategies, which are not recommended
1. Induction-maintenance: Initiation of three drug ART and then
reducing it to a combination of two ARV drugs is not
recommended
2. Sequential adding of drugs: A third drug, especially
NNRTI should not be added to an on-going two drug regimen, as it can lead to rapid selection of resistance.
3. Structured treatment interruptions: Any form of treatment
interruptions is not recommended in clinical practice unless a
patient develops severe adverse events
FOLLOW UP AFTER INITIATING ART
Table 3 depicts the recommended follow up scheme after initiating ART.
Frequent follow up during the initial months is necessary to diagnose and efficiently manage acute adverse events, work with the patient on adherence issues, and diagnose clinical conditions like IRIS. Once a patient is on an effective and stable regimen at 6 months,
quarterly follow up is recommended.
Table 3: Recommended follow up scheme after initiation of ART
2Wks 1 Mo 2 Mo 3 Mo 6 Mo Every3 Mo Every6 Mo
Clinical and Adherence Yes Yes Yes Yes Yes Yes Yes
CD4 counts No No No No Yes No Yes
PVL No No No No Yes No Yes
(200 Yes Yes
Toxo <200 TMP-SMX1 DS qd >200 Yes Yes
MAC <50 Azithromycin >100 Yes Yes
1 gm/q wkly
CMV Not indicated Secondary: >100 NA Yes
Valganciclovir
Cryptococcosis Secondary: >100 NA Yes
Not indicated Fluconazole
Candidiasis Secondary: >100 NA Yes
Not indicated
Fluconazole
instructions e.g. empty stomach. Adherence rate is calculatedaccording the following formula:
Adherence rate =number of pills expected to be taken
- number of pills missed x 100
----------------------------------------------------
Number of pills expected to be taken
During the era of unboosted PIs an adherence rate of more than 95% was recommended for successful ART outcome.53However, with use of more potent drugs (e.g. boosted PIs) in regimens, this cut off of 90% may be slightly reduced. Additionally, the longer half-life of NNRTIs may actually prevent development of resistance because of continued exposure to the drug even after missing the dose. There is evidence to suggest that at least for an intermediate level of adherence (adherence rate 76%-99%), NNRTI based regimens may be more forgiving than PI based regimens.55 Nevertheless, physicians should encourage patients to achieve high rates of adherence to ART and work towards achieving the same.
Measuring adherence in clinical practice is difficult. Self-report is the easiest and cheapest method of assessing the same, they may be quite reliable.56 Pill counts and other objective markers of adherence measurement like MEMS caps are rarely possible in clinical set ups. Patients should be asked whether they have misseddoses over the last 4-7 days and over the last follow up period, rather than asking whether they have been taking drugs regularly. If a patient accepts missing doses then the reasons for doing the same should be explored and tried to address. Indirect markers of good adherence are keeping appointments and getting prescription refills. Another marker of adherence on a thymidine-based regimen (ZDV or d4T) is evidence of macrocytosis on a hemogram, although it is not uniformly seen in all patients.
The physician should use various strategies to achieve good adherence. One of the most important aspects is to develop a trusting relationship and rapport with the patient. Some of the strategies to achieve adherence are the following:
" Careful screening before starting: It is very important to screen for patient readiness before initiating ART. Cost is a major barrier to adherence in India and financial status of the patient should be assessed prior to prescribing ART.57 Itmay be worthwhile not to initiate therapy at the first visitand give some time for the patient to think.
" Emphasize adherence before starting: Explaining the patient that a high level of adherence is needed, and that the treatment is lifelong is crucial. Patient's comprehension must be ascertained.
" Demonstrate how to take drugs (e.g. NVP): Many patients make mistakes during the initial lead-in dose phase of nevirapine, as it can be quite confusing. Demonstrating how to take the regimen and ensure that the patient has understood the same may be by asking him/her to repeat what has been explained.
" Using fixed dose combinations pills: Using fixed dose combination of ARV drugs reduces the pill burden, potentially improving adherence. Additionally, using these combinations is associated with fewer prescription errors, and ensures that the patient takes all drugs in a regimen.
" Advice patients to buy monthly packs: Patients are more likely to take drugs regularly if they buy monthly packs. Buying loose pills on an as needed basis has a higher risk of missing doses.
" Follow up before supplies exhaust: One of the common reasons for missing doses is following up after the drug supplies are over. Patients should be encouraged to follow up 3-4 days before their drug stocks are exhausted.
" Remind every time during follow up: During follow up apart from assessing adherence the importance of achieving good adherence should be re-emphasized.
" Using once daily regimens/user-friendly regimens: There is evidence to suggest that adherence rates are higher if patients are prescribed once daily or twice daily drugs as compared to thrice per day or higher frequencies.
" Anticipate and treat adverse events efficiently: Patients miss doses when they develop adverse events, which can be quite distressing. It is essential to inform patients about anticipated ARV adverse events, identify them early when they do occur and manage them efficiently. This is particularly important with the CNS side effects of efavirenz or with GI intolerance of PIs, which wane on their own after 2-4 weeks, and patients should be told not to discontinue the drug without informing the physician. Patients should be encouraged to contact the physician before contemplating any reduction of doses or changing of their ARV drugs due to any reasons.
" Reward the patient with positive feedback on
_ Declining viral load
_ Improving CD4 counts
" Patients should be advised not to miss doses at work and to pack medications with them when they travel.
" Involvement of spouse, a family member in treatment education and adherence issues only after the patient consents for the same.
" Patients should have access to physicians or other members of the care team so that any problem can be sorted out without interfering with adherence.
" Studies have documented numerous predictors of poor adherence, depression being one of the most important. Identifying and managing depression is essential for successful ART outcome.58
Table 5: Use of ritonavir in PI boosting [59]
Main PI Non-Boosted Dose Boosted bid Boosted qd
dose RTV/PI dose RTV/PI
Indinavir 800 mg q8h, 100/800 mg N/A
empty stomach without food
restrictions
400/800 mg,
200/800 mg
Saquinavir 1200 mg tid 100/1000 mg 100/200 mg
400/400 mg
Lopinavir N/A 100/400 mg 200/800 mg
Nelfinavir 750 mg tid or Not boosted Not boosted
1250 mg bid
_______________________________________________________________________
DRUG-DRUG INTERACTIONS
Knowledge of interactions between ARVs and other commonly used concomitant medicines in HIV infection is essential. The NNRTIs and the PIs are metabolized by the cytochrome P-4503A4 group of enzymes in the liver and this enzyme is either induced or inhibited by other drugs. This can either decrease or increase the levels of NNRTIs or PIs with resulting decrease in blood levels and development of toxicity respectively.
Use of ritonavir for boosting levels of concomitantly administered PI is the most common example of positive use of drug-drug interaction. Ritonavir used in low dose is a potent inhibitor of cytochrome P450 3A4 enzyme systems. When administered with other PIs, which are metabolized through this pathway, increased blood levels of the co-administered PIs are achieved. This helps reduce the dose and modify schedules of the concomitant PI. Table 5 summarizes the recommended doses of ritonavir boosted PIs.
Drugs like rifampicin are potent inducers of the cytochrome enzyme systems. Concomitant administration of NNRTIs and PIs with rifampicin can lead to reduction of blood levels of the former and development of resistance and failure of ART. Table 6summarizes commonly used drugs and their interactions with ARVs in clinical practice.
The use of alternative medicines including herbals is very common amongst patients in India. St Johns Wort has been documented to reduce PI levels when administeredconcomitantly.60 Until more data is available concomitant use of alternative therapy including herbals is strongly discouraged.
Table 6: Common Drug-drug interactions with ARVs
ARV Drug Problem Drug Consequence Recommended Action
Nevirapine Rifampicin Reduce NVP levels Use efavirenz
(NVP)/PIs Non-rifa based
ATT?
Nevirapine Fluconazole Increase NVP Monitor ALT
levels-hepatitis closely
NNRTIs Citalopram Alter citalopram/ Fluoxetine
Sertraline sertraline levels Doxepin
NNRTIs Phenytoin Reduce NNRTI levels Close Monitoring
Carbamazepine Reduce anticonvulsant Gabapentin
Phenobarbitol levels Valproate with
Valproate EFV
PIs/Efavirenz Midazolam Increase Lorazepam
Triazolam benzodiazepine levels Temazepam
PIs Simvastatin Increase statin Pravastatin
Lovastatin levels increased Fluvastatin
Toxicity Atorvastatin
( with caution)
PIs/NNRTIs Oral Contraceptives Increase or decrease Use indinavir
Levels according to Avoid OCPs and
The agent Recommend
Alternative
Contraception
Methods
Before prescribing any concomitant medication in a patient on ART, the physician needs to keep possible drug interactions at the back of mind. Checking for the same can be done at the website:
www.hiv-druginteractions.com.
Drug schedules and relationship with food intake should also be strictly followed since this helps in maintaining optimum drug levels. For example, ddI should always be administered on an empty stomach and nelfinavir should be taken with food. In addition a difference of more than 1-2 hours around the dosing time should be avoided as much as possible.
ARV ADVERSE EVENTS
ARV drugs may be associated with acute and long-term adverse events (AEs). Recognizing and managing these are essential because they may compromise adherence or some times necessitate switching of drugs, which may result in exhausting treatment options. Additionally, many of the concomitant drugs used for treating OIs are also associated with overlapping toxicities, making it difficult to identify the true offending agent. Patients should also be educated about these so that they are recognized early since many long term AEs may not reverse or may take years to improve.
The etiology of long term NRTI AEs involves cellular mitochondria. By inhibiting mitochondrial DNA polymerase enzyme gamma, NRTIs can induce reduction in respiratory chainfunction.61 Most of the long term AEs like lactic acidemia, pancreatitis, peripheral neuropathy, lipoatrophy and hepatitis may be caused in this way.
Table 7 and 8 summarize the common acute and long term adverse events associated with use of ARV agents.
Table 7: Acute adverse events of ARV drugs
Adverse event Offending Clinical Prevention Management
agents Presentation
GI disturbance ZDV,ddI Neusea,Vomiting Taking with Mostly self
NVP Diarrhea or after limiting
ALL PIs Abdominal food Symptomatic
distress treatment
Rash NVP Diffuse maculo- Always use Mild-modera
ABC popular with/ NVP in lead te rash:
EFV without pruritus in dose antihistam-
Severe reaction: Do not ine severe
With fever and double NVP rash:
Hepatitis or dose when Distcontinue*
Mucus membrane rash present and never re-
Involvement(SJS) Do not use challenge
Prophylactic
Steroids/ant-
histamines
CNS symptoms EFV Drowsiness, Educate Self limiting
abnormal patient take resolve in
dreams, impaired 2-3 hrs 2-4 weeks
concentration before slee-
ping Take on
empty stomach
Hepatitis NVP Nausea, anorexia Monitoring ALT Symptomatic
ALL PIs vomiting /AST. Avoid :discontinue
EFV Sometimes NVP in women permanently
jaundice with CD4>250 Asymptomatic:
& men with CD4 ALT>5 times
400 Careful discontinue
use of NVP in
HBV/HCV
co-infected
patients
Hypersent- ABC Fever, rash Higher incidence Discontinue
Itivity malaise,worsens with od dose and never
reaction (HSR) with continutation rechallenge
of ABC
*While discontinuing NNRTIs, the long half life has to be taken into account to avoid functional monotherpy and development of resistance.
Normally the NRTI backbone is continued for at least 1 week after NNRTI discontinuation, or briefly a PI based regimen may be prescribed for the patient.
Table 8: Long term toxicities of ARV drugs
Adverse event Offending Clinical Prevention Management
agents Presentation
Anemia ZDV Fatigue, Avoid in Discontinue
leucopenia breathlessness anemic and never re-
palpitations patients and challenge.
In patients Transfusion or
With advanced growth factors
disease. fore severe
Monitor Hb anemia
levels as
recommended
Peripheral d4T,ddI Numbness and pain Identify Early switching
Neuropathy in lower limbs early symptomatics
because some like gabapentin
times carbamazepine
irreversible
Avoid using d4T
/ddI entirely
Avoid using with
pre-existing
neuropathy
Lactic d4T,ddI Nausea, vomiting Identify early Discontinuation
academia28 ZDV abdominal distress No specific
fatigue progressing treatment
to breathlessness for acidosis
when acidosis , riboflavin
develops and thiamine
High lactate levels can be tried
Pancreatitis d4T, ddI Abdominal pain, Avoid in Discontinue
nausea and vomiting patients with Medical
High amylase/lipase h/o management of
levels pancreatitis pancreatitis
Lipoatrophy d4T, ZDV Fat loss in face Avoid d4T as Discontinue
Lipohype- PIs extremities, far as possible offending rtorphy 26,27 buttocks Increase Identify early agent. No
visceral fat in because can be specific
abdomen irreversible treatment
available
Dyslipidemia26 d4T Increase in total Avoid these Life style
EFV and LDL cholesterol drugs when Modification
ALL and triglycerides possible. Lipid lowering
boosted Identify early agents switching
PIs by measuring to less offending
(except ATV) fasting lipids agents
as recommended
in follow up
Hyperglycemia d4T Polyuria, Polydipsia Avoid offending Change offending
PIs polyphagia, increased agents monitor agents Life style
fasting glucose sugar modification Drugs
: OHAs, insulin
Note : Discontinuing the offending agent would also mean substituting
With an alternative drug to ensure efficacy of the regimen
IMMUNE RECONSITUTION INFLAMMATORY SYNDROME (IRIS)
Antiretroviral therapy partially restores immune defects caused by chronic HIV infection. This typically includes restoration of protective pathogen-specific immune responses. This has resulted in a sharp decline in the incidence of opportunistic infections in HIV patients.62 However, suppression of HIV viraemia by ART is accompanied by atypical OI manifestations or other inflammatory diseases in some patients. In these situations restoration of an immune response following HAART is immunopathological rather than protective. These conditions are therefore labeled as immune restoration inflammatory syndrome(IRIS). IRIS is defined as occurrence or worsening of clinical and/or laboratory parameters despite a favorable outcome in HIV surrogate markers (CD4 counts and PVL).63 These immune responses can be elicited against infective or non-infective agents. The temporal association between commencement of HAART (or change from a previously failing regimen) and the development of an unusual clinical phenomenon often provides a strong clue to the diagnosis of IRIS.
The following points help in diagnosis of IRIS
1. Temporal association between starting HAART regimen and
Subsequent development of clinical phenomena (the majority within 3 months).
2. Unusual clinical manifestations in patients responding to
HAART. This includes
a. Unexpected localized disease, e.g. lymph nodes (new or
enlargement &/or suppuration of lymph nodes), liver,
spleen.
b. Exaggerated inflammatory reaction, e.g. severe fever,
with exclusion of other causes
c. Painful lesions
d. Atypical inflammatory response in affected tissues,
e.g. granulomas, suppuration, necrosis
e. Perivascular lymphocytic inflammatory cell infiltrate
f. Progression of organ dysfunction or enlargement of pre-
existing lesions
g. Development or enlargement of cerebral spaceoccupying
lesions after treatment for cerebral cryptococcosis or
toxoplasmosis
h. Progressive pneumonitis or the development of organizing
pneumonia after treatment for pulmonary MTB or PCP
i. New onset or worsening of uveitis / vitritis after there solution of CMV retinitis
j. Fever and cytopenia after treatment for disseminated MAC
3. Unexpected clinical course.
4. Exclusion of alternative explanations-e.g., drug
hypersensitivity reactions, drug resistance, non-compliance
with treatment for the opportunistic infection.
5. Evidence of preceding immune restoration-e.g., a rise in blood
CD4 lymphocyte count; restoration of cutaneous hypersensitivity
to mycobacterial antigens (PPD); increased in-vitro T-cell
proliferative responses to PPD.
6. Histopathological or cytological appearances of unexpectedly
florid cell-mediated immune response within tissue samples.
7. Decline of plasma viral load by > 1 log (> 10 fold) from
baseline value.64
Table 9: Types of IRIS
Pathogen Manifestation Characteristic
MTB Clinical: High fever, Common during first 8
lymphadenoPathy, Cough, dyspnoea, weeks. Caseating,
appearance of new effusion granuloma, reactive
(commonly pleural and pericardial changes; AFB smear &
effusion occasionally), culture usually negative;
hepatosplenomegaly, ascites, often associated with
oedema, epididymorchitis, abscess CD4 rise and PPD conversion.
inflammatory bowel perforation
psoas abscess etc.
Radiological: worsening pulmonary
ifiltrate or consolidation, intra
-abdominal lymphadenopathy, deve-
lopment or enlagement of cerebral
space occupying lesions.
MAC Lymphadenitis, abscess (skin, Common during first 12
endobronchial, abdomen) lung weeks. Localized;
infiltrate, CNS. focal granulomatous
lymphadenitis. Blood
cluture often negative;
MAC may be isolated
from lymph node culture
M.leprae Cutaneous lesions BT
Cryptococcus Meningitis, palsy, lymphadenitis Variable occurrence
abscess, cavitary pneumonia. from 1 week to 8 months.
CSF pleocytosis, raised
protein, India ink &
culture- ve but Ag.+ve
in low titer
Pneumocystis Pneumonitis Severe hypoxia, ARDS
Hep B/Hep C Hepatitis Biopsy often characteristic
of viral hepatitis;
variable response of
Hepatitis B&C
Virologic markers
VZV Herpes zoster Few lesions; usally
late
CMV Retinitis, virtritis, cystoid Inactive CMV retinitis
macular edema, immune recovery in affected eye in
uveitis, CNS, pancreas,lung case of IRU
colon, skin
JCV PML Contract enchancing
inflammatory cellular
infiltration lesion on
MRI. On biopsy
perivascular
inflammatory cellular
infiltration
HIV Demyelinating leucoencephalopathy
HPV Inflammed warts molluscum Large numbers,
increase in size of
existing lesions
Pravovirus Encephalitis Focal
B19
Risk factors for IRIS
Identified risk factors for infectious IRIS are
1. An active or sub-clinical infection by opportunistic
pathogens.
3. The antigens of non-viable micro-organisms (e.g. Cryptococci
and CMV) are all possible targets for an immunopathological
response.
4. Cd4 T count below 50 / mm3 prior to initiation of HAART is a
major risk factor for IRIS.65
4. Being ART naïve is an important risk factor for development
of IRIS.64
5. Starting ART in close proximity to the diagnosis & initiation
of treatment for an OI.64
Table 9 depicts various types of IRIS seen in clinical practice.
Non-infectious IRIS includes GBS, autoimmune thyroiditis and sarcoidosis. The differential diagnosis for IRIS includes active OI, ARV drug failure, ARV drug toxicity or failure of anti-microbial
therapy if patient is already on the same. Culturing the microorganism in body fluids may provide a clue for an active OI, which would warrant antimicrobial therapy.
Treatment of IRIS
There are no standard guidelines for treatment of IRIS. There is very limited information on the effectiveness of various interventions to manage IRIS, with lack of evidence from randomized clinical trials. Most cases will resolve without any additional treatment. Milder forms of IRIS resolve with continuing anti-infective therapy and HAART. In the majority of cases, HAART can be safely continued without need for interruption. In general, most clinicians prefer to continue ART if CD4 count is<100/µL or if IRIS manifests months after initiation of HAART.
On the other hand, discontinuation of ART should be considered if inflammatory responses are considered life-threatening (e.g.
intracranial IRIS leading to encephalitis, cerebritis, perilesional
cerebral edema, pulmonary IRIS with ARDS etc), unresponsive
to steroids, or if the involved pathogens are no amenable to specific antimicrobials (e.g. parvovirus B 19, polyomavirus JC causing PML) or if ART toxicity is the main differential diagnosis(e.g. hepatitis).
Nonsteroidal anti-inflammatory drugs (NSAIDs) are also helpful in
controlling inflammation and fever associated withIRIS.63 However, in
severe IRIS a short course of oral prednisoloneis required to alleviate
symptoms. The dose and duration required is very variable and should be
judged clinically. Severe disease will require at least 1-2 mg/kg of
prednisolone. Thalidomide has also been tried effectively in some patients.
SPECIAL SITUATIONS
HIV and TB
Tuberculosis (TB) is one of the commonest OI and is a leading
cause of death amongst HIV infected patient in developing countries. Management of HIV and TB co-infection is complicated because of drug-drug interactions, overlapping toxicities, additional pill burden, and problems relating to adherence and development of IRIS.66
Treatment of Tuberculosis
All HIV/TB patients should be treated with standard 4 drug anti-TB combinations as per TB treatment guidelines. Once weekly and twice weekly intermittent therapy should be avoided; especially in patients with advanced HIV infections.67 Duration of anti-TB treatment in HIV is not well defined, but drug susceptible TB not involving the CNS should be treated with a 6month regimen.68-70 In patients with slow response (cultures positive at 2 months) treatment should be prolonged for a total of 9months. Tuberculosis involving the CNS should be treated for 1year.
Two important questions need to be answered while managing
concomitant HIV and TB infections
When should ART be started?
CD4 cell count is important in deciding when to start ART in
HIV/TB co-infected patients.
1. HIV/TB with CD4 cells > 200/mm3: ART is delayed till the
completion of TB treatment. The indications for ART
initiation are the same as mentioned above.
2. Patients with CD4 cells < 200/mm3: Delaying ART can result
in HIV related morbidity and even mortality due to risk
of occurrence of other OIs. In such situations ART should be
initiated as soon as anti-TB medicines are tolerated and
patient has shown clinical improvement. One should
closely monitor for development of IRIS in patients initiating
ART with baseline CD4<50/mm3.
Which combination antiretroviral regimen should be used?
There are limited options available for antiretroviral treatment
in HIV/TB co-infected patients. Rifampicin, a critical component of antituberculous therapy interacts with PIs and NNRTIs and reduces exposure of PIs by 75-95% and NNRTIs nevirapine by31% & efavirenz up to 20%.71-74 Sub-optimal exposure to these drugs may lead to development of drug resistance.
Unfortunately, of all available PIs and NNRTIs, rifampicin may be used only with full dose ritonavir or with efavirenz.75Though some experts recommend increasing the dose of EFV to800 mg when using with rifampicin, studies in developing countries have documented good efficacy with a dose of 600mg.75,76
Ritonavir boosted saquinavir should not be used with rifampicin due to significant elevation (up to 20 x upper limit ofnormal) of serum
transaminases in a Phase I study evaluating the pharmacokinetic interaction of this drug combination in healthy volunteers.77
Therapeutic strategies for concomitant use of ART and ATT include:
1. Using Efavirenz + 2NRTIs : Efavirenz based HAART when used at standard dosages in HIV/TB patient-receiving rifampicin has demonstrated good clinical, immunological& virological outcome.75,78 Although EFV is more expensive than NVP, it should be used at least until the duration of TB therapy. After the completion of ATT, patients may be switched back to
NVP based regimen in order to make the regimen less expensive.
However, before the NNRTI switch it is necessary to document
good virologic control of the EFV based regimen (PVL<400
copies/ml). The hepatic induction effect of rifampicin
continues for up to 2 weeks after discontinuation. The switch
from EFV to NVP should bemade after 2 weeks of ATT completion.
A lead in dose is not necessary when NVP is switched for EFV.
An additional concern is the risk of severe hepatitis in
patients who are switched from EFV to NVP at higher CD4
DRUG(S) OF CH