Impact of a massive earthquake on adherence to antiretroviral therapy, mental health, and treatment failure among people living with HIV in Nepal

Introduction The April 2015 Nepal earthquake resulted in more than 8,700 deaths and 22,000 casualties including damage to health facilities. The impact of this situation on chronic conditions such as human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) may become a long-lasting public health threat. Therefore, the objectives of this study were i) to assess the association of antiretroviral therapy (ART) adherence with mental health problems, and social behaviors, ii) to examine factors affecting treatment failure, and iii) to investigate changes in ART adherence and post-traumatic stress disorder (PTSD) among people living with HIV 6 and 12 months after the disaster. Methods Study was conducted 6 months after the earthquake in 2015 with a sample size of 305 earthquake victims with HIV and followed after 12 months of the earthquake. A logistic regression analysis was used to examine relationships, while a paired t-test analysis was conducted to assess changes in adherence to ART and PTSD level at 6 months and 12 months after earthquake. Results In the earthquake, 5.2% of the participants lost their family member. Approximately 44% of participants had earthquake-PTSD symptoms and 50% experienced HIV stigma. PTSD and HIV status disclosure were significantly associated with adherence to ART, while HIV stigma and religion were associated with treatment failure. PTSD and adherence levels to ART were significantly improved over the 6-month period. Conclusion Awareness programs for general public to eliminate HIV stigma; promote psychosocial counseling to earthquake victims living with HIV in order to reduce PTSD will contribute to maintaining optimal ART adherence and to prevent treatment failure.


Foreword
HIV/AIDS remains a very important social and public health problem in the South Asian region. Over the years the National Center for AIDS and STD Control has done much to curb the spread of the virus through the introduction of prevention, treatment, care and support programs. Introduction of highly active antiretroviral therapy to eligible PLHIV since 2004 and establishment of prevention of mother-to-child transmission of HIV infection programs are some of these initiatives which have contributed a lot in saving lives of PLHIV. The national response to HIV/AIDS is guided by "HIV and STI Policy" 2010 and "National HIV/AIDS Strategy 2011-2016," which uses the principles of universal access.
Nepal with adult (15-49 years) HIV prevalence of 0.33% and approximately 55,626 people estimated living with HIV, our HIV caseload is hardly modest. While preventive efforts to bring down prevalence levels are ongoing, the importance of treatment, care and support of those that have already been infected cannot be over emphasized. The government of Nepal has made an effort to rapidly scale up antiretroviral therapy, so that treatment may be readily accessible to those in needs. Antiretroviral therapy is available today at 35 ART centers in the country and we intend to rapidly scale-up the number of such centers in the near future.
These guidelines are part of the ongoing effort to rapidly scale-up antiretroviral therapy (ART) throughout the country. A lot of effort has gone into the preparation of these guidelines. We have been able to incorporate the latest guidance from WHO on Antiretroviral therapy and PMTCT including lessons learnt from our own in country experience with ART over the last 8 years, when the first edition of the guidelines came out.
These guidelines are meant for use by doctors, nurses and paramedics who are actively involved in care of the patients. I would like to acknowledge the Technical Working Group for the incessant effort they have put in bringing out these guidelines. I would also like to thank our partner organizations-the WHO, UNDP, and FHI 360 as well as all the other individuals and organizations for their time and effort in bringing out these guidelines. A special thank you goes to Dr Hemant Ojha, Dr. Sushil Shakya, Dr. Sashi Sharma, Dr. Prem Khadga, Dr. Lisa Stevens, and Dr. Atul Dahal who were instrumental in ensuring the guidelines capture the latest development and experiences in regards to HIV treatment and care.
I am sure this revised guideline will enable doctors and nurses to deliver a high standard of HIV treatment and care services, which will improve the quality of life for people living with HIV/AIDS in Nepal.

I. Background
The first case of AIDS was reported in 1981 in the USA. Since then, AIDS has become the most devastating and threatening disease of humans. More than 60 million people have been infected and about 34 million people are estimated to be currently living with HIV, among whom one-third are between 15 and 24 years of age. Initially, the epidemic was concentrated in the African continent. But it continues to spread in Asia, particularly in South Asia. In South and South East Asia, there are approximately 4 million people living with HIV. In Nepal, the first case of HIV was diagnosed in 1988.
The major mode of transmission in Nepal is heterosexual. The available data show that there is a high prevalence of HIV in high-risk groups such as injecting drug users and female sex workers. Currently, it is estimated that there are approximately 50,200 people living with HIV (PLHIV) in Nepal, with an estimated 4,906 deaths in 2010.
In 1986, antiretroviral therapy was initially introduced in other countries with the first drug Zidovudine (ZDV). Over the next few years, other antiretroviral drugs (NRTIs, NNRTIs and Pls) were introduced. Initially, mono and dual therapies were used but the problem of resistance emerged. At present, 3 or more ARV drugs are recommended worldwide for the treatment of people with HIV infection. Since the use of combination therapy, this disease has been transformed into a chronic condition. Although the use of antiretroviral therapy is not the final answer to HIV prevention and care programs, treatment and prevention have been proven to be inextricably linked. ART dramatically decreases the chance of transmitting the virus both sexually and from mother-tochild. The delivery of effective care and antiretroviral treatment for people living with HIV in the poorest countries is considered an urgent priority and is now an integral part of HIV transmission prevention programs. Initially, antiretroviral therapy was very expensive and so, unaffordable in most developing countries. As drugs are increasingly affordable, the development of guidelines on the appropriate and rational use of ART has become relevant in developing countries.
These current guidelines are intended basically for use by medical practitioners who prescribe ARV therapy to the people infected with HIV. Guidelines for the treatment and management of HIV infection have been produced in a number of countries of Europe, USA, Australia, India, Thailand, etc. and by WHO. While these guidelines attempt to represent the current state of knowledge, it is inevitable that as HIV is a rapidly evolving medical field new information will change therapeutic choices and preferences. This should be kept in mind while using these guidelines.

II. Principles of Antiretroviral Therapy
Goals of Antiretroviral Therapy Preconditions for Starting Antiretroviral Therapy The following specific facilities and services are desirable before starting Antiretroviral Therapy Availability of HIV testing and counseling (HTC) services along with follow-up counseling services.
Medical services capable of managing common HIV-related infections including opportunistic infections (OIs) and sexually transmitted infections (STIs).
Routine laboratory services, preferably with access to CD4 lymphocyte count and PCR facility for viral load count. Lack of viral load testing and even CD4 testing should not preclude initiation of ART.
Access to antiretroviral drugs and other drugs to treat OIs and other associated diseases.

III. Indications for Antiretroviral Therapy
Recommendations for initiating antiretroviral therapy in adults and adolescents with documented HIV infection are given in the box below.
If CD4 Testing Available: It is recommended to document baseline CD4 counts and to offer ART to patients with: Note: In co-infection with other diseases, treatment of tuberculosis and some other opportunistic infections the priority is usually to start OI treatment before antiretroviral therapy. However, recent evidence suggests that ART should be started early in the setting of acute AIDS-related OIs, if there are no major contraindications to doing so. Waiting to complete OI treatment before initiating ART appears to be associated with a higher risk of AIDS-related disease progression and/or death without any significant benefit in terms of safety or virological response.
All people living with HIV (PLHIV) with TB should start TB treatment first and then begin ART as soon as possible, but not more than 8 weeks after ATT.
Note: Pregnant and breastfeeding postpartum women should start ART Those eligible for ART as above should begin life-long therapy as soon as possible.
Those not yet eligible should start triple ARVs as short term prevention from the 14 th week of pregnancy onwards and continue until 1 week after cessation of breastfeeding. See Nepal PMTCT Guidelines for details. c. Some additional specific conditions can also be included in regional classifications (such as penicilliosis in Asia).

IV. Antiretroviral Drugs and Their Actions
Categories of Approved Antiretroviral Drugs Include The Following:  "Class side effect": All nucleoside analogs have been associated with lactic acidosis and hepatic steatosis. Efavirenz is contraindicated in the first trimester of pregnancy. "Class side effect": All PIs can produce increased bleeding in hemophilia, GI intolerance, altered taste, increased liver function test and bone disorder, and all have been associated with metabolic abnormalities, such as hyperglycemia, insulin resistance, and increase in triglycerides, cholesterol and body fat distribution (lipodystrophy).

Recommendations
Discontinue ART. Give supportive treatment with laboratory monitoring. Resume ART with an NRTI with low pancreatic toxicity risk such as AZT or TDF.
Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered.
In very mild cases, symptomatic care. EFV rash often stops spontaneously after 3-5 days without need to change ARVs. If moderate rash, non-progressing and without mucosal involvement or systemic signs, consider a single NNRTI substitution (i.e. from NVP to EFV). In moderate and severe cases, discontinue ART and give supportive treatment. After resolution, resume ART with LPV/r based regimen or triple NRTI if no other choice.
Consider replacing the suspected PI by drugs with less risk of metabolic toxicity. Adequate diet, physical exercise and antilipaemic drugs should be considered.
Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered.
If severe (Hg <7 g% and/or ANC <750 cells/mm 3 ), replace by an ARV with minimal or no bone marrow toxicity (e.g. TDF) and consider blood transfusion.

Recommendations
If ALT is at more than five times baseline, discontinue ART and monitor. After resolution, restart ART and replace the drug most likely associated with the condition (e.g. EFV replaces NVP).
Generally asymptomatic but can cause scleral icterus (without ALT elevations). Replace ATV with other PI.
Discontinue ABC and do not restart. Symptomatic treatment. Re-exposure may lead to a severe and potentially lifethreatening reaction.
Discontinue ART and give supportive treatment. After clinical resolution, resume ART with TDF.
Early replacement of the suspected ARV drug (e.g. d4T replaced with TDF or ZDV).
Usually self-limited, without the need to discontinue ART. If intolerable to patient, replace with NVP or LPV/r. Single substitution recommended without stopping ART. Regimen potency, tolerability and adverse effect profile Possible drug interactions and potential for alternate treatment options in the event that the initial drug regimen fails.

Consider substitution with AZT
Antiretroviral therapy with dual drug regimen is not recommended except for in some cases of post exposure prophylaxis of HIV.
The combination of a either an NNRTI or a protease inhibitor with 2 NRTIs is potent and causes durable suppression of viral replication. Combination of ritonavir with another PI results in a boosting effect by increasing plasma concentration of these drugs, thereby reducing their doses frequency and pill burden. Currently, several regimens with acceptable antiviral potency are available. These regimes are composed of three or four drugs. Two NsRTIs generally form the backbone of most combinations (see box below).  Didanosine and Stavudine should not be used together due to high risk of toxicity.
Didanosine and Tenofovir should not be used to together due to poor efficacy and side effects. Some patients will have started Stavudine + Lamivudine (d4T/3TC) in the past, this should no longer be used as a first line regimen for new patients as it is "phased-out" of Nepal due to high risk of toxicity of stavudine. Only during 2 nd and 3 rd trimester. EFV should not be given to women in the first trimester of pregnancy or women of childbearing potential, unless effective contraception can be assured Only during 2 nd and 3 rd trimester. EFV should not be given to women in the first trimester of pregnancy or women of childbearing potential, unless effective contraception can be assured

Major Potential
The common recommended regimens are further given in table 5. If patient is on ART containing stavudine (d4T), they should be changed from stavudine to either zidovudine or tenofovir.
New patients should not be started on stavudine (d4T) containing regimens. a See Section (Tuberculosis and Antiretroviral Therapy). b See Section (Antiretroviral Therapy in Pregnancy and breast feeding).

What to Use for Confirmed HIV 2 Cases
For HIV-2 infections, the triple NRTI or PI based regimens should be used because of inherent resistance of HIV 2 to NNRTI drugs. PI based regimen is the preferred option. WHO has recommended that Stavudine (d4T) be "phased out" due to unacceptable rates of toxicity.
Patients started or switched to Stavudine (d4T) for anemia, can switch to Zidovudine after 6-12 months of stable Hb above threshold, to avoid d4T toxicities. If unable to tolerate ZDV, switch to Tenofovir.
Abacavir can be used in the place of Tenofovir.

NATIONAL ANTIRETROVIRAL THERAPY GUIDELINES Some Other Considerations for NRTIs:
Do not combine "d-drugs" (ddI, d4T).
Do not give single d-drugs with pre-existing neuropathy.
Do not combine 3TC and FTC.
Do not combine ddI and TDF.
The Choice between Nevirapine (NVP) and Efavirenz (EFV): NVP and EFV are both potent NNRTIs.
The major toxicities associated with EFV are central nervous system (CNS) related, metabolic toxicity, teratogenicity and rash. The CNS symptoms typically abate within the first month of therapy.
NVP has higher incidence of rash, which may be severe and life threatening. NVP has also a higher risk of hepatotoxicity.
Thus for most patients ZDV/3TC/NVP will be preferred as a first line ART. In patients with Hb less than 7gm% the regimen of choice should be TDF/3TC/ NVP. In a female patient who is in the first trimester of pregnancy or likely to be pregnant, EFV should be avoided. In a patient with a certain side effects, an alternative drug should be used.

Triple NRTI-based First-line Regimens
Triple NRTI-based first-line regimens such as ZDV+3TC+ABC or ZDV+3TC+TDF can be recommended in specific circumstances where both NNRTIs are contraindicated or not tolerated. Other triple NRTI combinations should not be used. Triple NRTIs have the advantage that they still preserve the PI and NNRTI class for second-line ART. These regimens can be used in the following circumstances: Intolerance or resistance to NNRTIs; Psychiatric disorders; Women starting ART with CD4 >250, since great risk of NVP toxicity.
Pre-existing liver disease-an increase of the ALT level by more than 3-5 fold and established cirrhosis; Coinfection with HBV or HCV; HIV-2 infection due to intrinsic resistance to NNRTI class; and Cotreatment of TB in women of child-bearing age and where adequate contraception cannot be guaranteed, and when NVP and boosted PIs cannot be used.
ZDV+3TC+ABC has short-term inferior virological efficacy at least in patients with high initial viral loads, but comparative immunological efficacy to ZDV+3TC+EFV regimen (CD4 recovery). ZDV+3TC+TDF is now also recommended by WHO. Triple NRTI regimens may be used especially in the management of tuberculosis and HIV co-infection; management of hepatitis C and HIV co-infection; and management of hepatitis B and HIV co-infection. Other triple NRTI-based regimens, such as ZDV+TDF+ABC or TDF+3TC+ddI have unacceptably high virological failure rates and high incidence of the K65R mutation and should not be used.

PI Based Regimen in First Line
Boosted PIs are usually reserved for second-line ART. They can exceptionally be used as part of first-line ART in combination with two NRTIs when triple NRTI regimen is not available or deemed inappropriate and when there are contraindications to NNRTIs (i.e. neither EFV nor NVP can be prescribed) including: Psychiatric disorders; An increase of the ALT level by more than 3-5 fold; Cirrhosis; Pregnancy with CD4 count of 250-350 cells/mm 3 , particularly in the 1st trimester of pregnancy (as EFV is contraindicated); HIV-2 infection due to intrinsic resistance to NNRTI class A baby under two years of age with previous exposure to PMTCT NNRTIs.
A woman starting ART within 12 months of receiving PMTCT single-dose NVP without an NRTI tail; If a first-line ART regimen containing a PI fails, there are very limited options for subsequent regimens within the public sector in Nepal. In general therefore, it is recommended that PIs be reserved for second-line ART. For a patient who is not responding to treatment, a viral load test will be requested whenever feasible.
Where available, obtain viral load to confirm treatment failure.
If resources allow, obtain viral load every 6 months to detect viral replication.
Additional pediatric recommendation: Babies under 12 months starting NVP-based ART after NNRTI exposure through maternal or infant PMTCT prophylaxis, should have viral load checked 6 months after start, if possible.
Pregnant women at near term (36 weeks gestation) who are on ART and considering an elective caesarian section, should be offered viral load testing if possible.
Women starting NNRTI based ART after PMTCT exposure to sd-NVP or triple ARV with EFV and no ZDV/3TC tail, should have viral load testing 6 months after start, if possible.
A Persistent Viral Load >5,000 Confirms Failure.

Adherence
A high degree of adherence to ARV drugs is necessary for optimal virological suppression. Studies indicate that >95% of the doses should be taken for optimal suppression. Lesser degree of adherence is more often associated with virological failure. Adherence should be assured before initiation of antiretroviral therapy. The patient should fully understand the importance of adherence to antiretroviral therapy. Adherence counseling and patient education should be done at every follow-up visit.

Promoting Adherence: Issues to Consider
Health care personnel should be supportive and non-judgmental Simplified treatment regimen e.g. once or twice a day dosing, less number of pills with minimal side effects.
The motivation of the individual to begin and continue therapy The individual's understanding of the importance of adherence and its relationship to drug resistance The impact of therapy on the individual's lifestyle and psychological well being Education of patient's family and friends.
The provision of memory aids (such as pill boxes, bleepers, medication record cards, mobile phone messages), to establish and maintain a pill taking routine Treatment of any underlying mental health problems

Management of side effects
The potential risks and benefits of therapy, in the short and long term.
The provision of written information to provide support outside the clinic setting, covering the regimen, potential side effects and the consequences of low adherence.

Advice to Patients for Missed ARV Doses:
When you notice that you missed a dose, take your pill right away.

For The NEXT DOSE
If the next planned pill-taking time is four hours away or less, DO NOT take your next dose. Instead wait four hours and then take your next dose. After this follow your regular dosing schedule.
Do not take two doses at one time.
If is it already time for the next dose, just take that dose and carry on with the treatment schedule.

NATIONAL ANTIRETROVIRAL THERAPY GUIDELINES
Adherence Performance Chart for Nepal  Toxicity and Failure of Antiretroviral Therapy Appearance of HIV related opportunistic infections may mean failure of the antiretroviral regimen. Detailed history taking and physical examination should be done at least every 3 months. At the time of follow-up visits, monitoring should be done for CBC, serum ALT, serum creatinine, blood glucose and serum lipids depending on the drug regimen and possible drug adverse effects. Whenever feasible, CD4 count should be performed at least every 6 months. In patients with optimal antiretroviral therapy CD4 counts increase by >100 cells/mm 3 in the first 6-12 months in ARV naive, adherent patient with drug susceptible virus. Immunologic failure is indicated by a fall in CD4 counts higher than 50% from the peak value or a return to, or below, the pre-therapy baseline, or by persistent CD4 <100 cells/mm 3 . Viral load is available on a limited basis in Nepal. Ideally, viral load will be checked starting at 6 months after ART initiation and rechecked every 6 months (at least once a year). In addition, it should be checked after a history of non-adherence and at the time of suspected clinical or immunologic failure to confirm the presence or absence of virologic failure.

VII. Changing Antiretroviral Drugs
The usual reasons for changing antiretroviral drug regimen include: Drug adverse effects Inconvenient regimens (dosing and number of pills that may compromise adherence). Treatment failure Occurrence of active tuberculosis and pregnancy. Concomitant illness (i.e. Hepatitis B) The general principle is that single-drug substitution because of toxicity should involve drugs belonging to the same ARV class. If toxicity is related to an identifiable drug in a regimen, the offending drug can be replaced with one that does not have the same side-effects (e.g. substitution of AZT or TDF for d4T in cases of neuropathy, TDF for AZT where anemia occurs, or NVP for EFV for CNS toxicity or in first trimester of pregnancy). Given the limited number of ARV drug options available in Nepal, drug substitutions should generally be limited to situations where toxicity is moderate to severe (grade 3) or life-threatening (grade 4). In a patient who experiences adverse effects, substitution of the offending drug is reasonable. In case of abacavir hypersensitivity reactions and nevirapine related hepatic failure or severe hypersensitivity, rechallenge should not be attempted as this may lead to toxicity and death.

Antiretroviral Treatment Failure and When to Switch Therapy
The decision on when to switch from first-line to second-line therapy is critical. If the decision is made too early the months or years of potential further survival benefit from many remaining first-line ARVs is lost; if it is made too late, the effectiveness of second-line therapy may be compromised and the patient is put at additional and appreciable risk of death. The time of switching is dictated by treatment failure, and this can be measured in three ways: clinically, by disease progression and WHO staging; immunologically, using trends in CD4 counts over time, and virologically, by measuring HIV viral loads (plasma HIV-1 RNA levels). Definitions of clinical and CD4-related treatment failure are given below. Nepal will continue to heavily rely on clinical and CD4 count criteria, in order to define treatment failure. It has been recognized that, treatment failure is recognized later solely on the basis of clinical and/or CD4 criteria, thus providing a greater opportunity for drug resistance mutations to evolve before regimen change. This can compromise the use of alternative regimen through drug class cross-resistance. Therefore, viral load will be used when possible to assist with diagnosis of treatment failure (see below). It is not likely that drug resistance testing will become a routine part of clinical care in Nepal in the foreseeable future and so is not considered in these recommendations. In all cases, adherence counseling is indicated and clinical judgment should be included in decision-making.

Treatment Failure
Three types of treatment failures (clinical, immunologic and virologic) have been identified.

NATIONAL ANTIRETROVIRAL THERAPY GUIDELINES
Clinical Disease Progression as an Indicator of Failure: Clinical disease progression with development of an opportunistic infection or malignancy when the drugs have been given sufficient time to induce a protective degree of immune restoration is a strong indicator of treatment failure. It should not be concluded, on the basis of clinical criteria, that an ARV regimen is failing until there has been a reasonable trial of first-line therapy lasting at least six to twelve months, adherence has been assessed and optimized, intercurrent opportunistic infections have been treated and resolved, and IRIS has been excluded. IRIS can be seen within the first several weeks after the institution of therapy, if a sub-clinical infection is present at baseline. It is also possible that this immunological reconstitution may lead to the development of atypical presentations of some opportunistic infections.
In IRIS, changing the antiretroviral regimen is not indicated. The development of a new or recurrent WHO stage 3 or 4 condition on treatment (but after the first six months of ART) is considered functional evidence of HIV disease progression. TB can occur at any CD4 level and does not necessarily indicate ART failure. The response to TB therapy should be used to evaluate the need to switch ART. with pulmonary TB and some extrapulmonary TB diagnoses (e.g. simple lymph node TB or patients with uncomplicated pleural disease), where a good response to TB therapy is frequently seen, the decision to switch ART can be postponed and monitoring can be increased. This also applies if severe and/or recurrent bacterial infections or oesophageal candidiasis respond well to therapy.
Immunologic Failure: The CD4 cell count remains the strongest predictor of HIV-related complications, even after the initiation of therapy. The baseline pretreatment value is informative: lower CD4 counts are associated with smaller and slower improvements in count. Patients starting with low CD4 counts may demonstrate slow recovery, but persistent levels below 100 cells/mm 3 represent significant risk for HIV disease progression. It should be noted that intercurrent infections can result in transient CD4 count decreases. As a general principle, intercurrent infections should be managed, time should be allowed for recovery and the CD4 cell count should be measured before ART is switched. If resources permit, a second CD4 cell count should be obtained to confirm immunological failure.
Definitions of immunological failure are: (1) CD4 count below 100 cells/mm 3 after six months of therapy; (2) a return to, or a fall below, the pre-therapy CD4 baseline after six months of therapy; or (3) a 50% decline from the ontreatment peak CD4 value. The CD4 cell count can also be used to determine when not to switch therapy, e.g. in a patient with a new clinical stage 3 event for whom switching is being considered or in a patient who is asymptomatic and under routine follow-up.
Plasma Viral Load as an Indicator of Treatment Failure: Viral load testing, when available is a sensitive and informative way to identify treatment failure. When treatment failure is defined on the basis of clinical and/or CD4 criteria the diagnosis may be made later than when viral load is being monitored. The viral load threshold triggering a switch in ART is defined as persistent viral load >5,000 after 6 months on ART. An undetectable viral load mandates that ART should not, in general, be switched irrespective of the CD4 cell count or the clinical stage.
All clients being considered for second-line therapy will have their case reviewed by certified National HIV experts. Both decisions of when to change therapy and what regimen to change to should be made in consultation with experts. When ZDV or d4T was used in the first line, the best possible second-line regimen is TDF/3TC. The issues of drug hypersensitivity with ABC remain as does the fact that high-level ZDV/3TC co-resistance confers diminished susceptibility to ABC. TDF often retains activity against nucleoside-resistant viral strains. It is attractive because it is administered once daily. TDF should not be used in combination with ddI due to decreased virologic efficacy and increased toxicity. Recycling 3TC is now recommended to prolong the common 3TC mutation which makes the virus "less fit" as one of the best options for second-line therapy.
Because of the diminished potential of almost any second-line nucleoside component, a ritonavir-boosted PI (bPI) component, i.e. lopinavir (LPV/r) or atazanavir (ATV/r), is preferred. Of these, currently, only LPV/r is available in a heat-stable form, which does not require refrigeration, although ATV/r heat stable version is under development.
For treatment failure with a first-line PI-based regimen, the choice of an alternative regimen depends on the reason for the initial choice of a PI-based, rather than an NNRTI-based, regimen. If the reason was suspected NNRTI resistance or HIV-2 infection the choice of the alternative regimen is not straight forward. In these situations the options depend on the constraints imposed by the circumstances of individual patients, the capabilities of individual managements to test for resistance to drugs, and the ARV formulary in Nepal.
Treatment failure on a triple NRTI regimen is more easily managed because two important drug classes (NNRTIs and PIs) will have been spared. Thus a boosted PI + NNRTI +/-alternative NRTIs (e.g. ddI and/or TDF) can be considered if drug availability permits.
Patients on a failing second-line regimen with no new ARV options should continue on a tolerated regimen.
Note: Didanosine and Abacavir are no longer part of recommended second-line regimens due to increased cost and complexity. In addition, ABC cross resistance is common after ZDV or d4T use in first-line. However ddI and ABC should continue to be available in Nepal for the use in triple NRTI combinations and other circumstances where standard NRTIs are contraindicated.

VIII. Monitoring of HIV Drug Resistance
Individual HIV drug resistance (HIVDR) testing to guide treatment is not recommended.
Monitoring should be Done Using: "Early Warning Indicators" for HIV drug resistance targeted at ART facilities, which are designed to alert programme managers to programmatic factors that are likely to be associated with poor outcomes of ART.
Monitoring surveys to assess the emergence of HIVDR and associated factors in cohort (s) of treated patients 12 months after ART initiation in sentinel ART sites. Reintroduction of Nevirapine Using Dose Escalation. Because nevirapine is an inducer of the drug-metabolizing hepatic enzymes, administration of full therapeutic doses of nevirapine without a 2-week, low-dose escalation phase will result in excess plasma drug levels and potentially increase the risk for toxicity. Therefore, in a patient who has interrupted treatment with nevirapine for more than 2 weeks, nevirapine should be reintroduced with a dose escalation period of 200mg once daily for 14 days, then a 200mg twice-daily regimen.
Discontinuation of Lamivudine or Tenofovir in Patients with Hepatitis B Coinfection. Patients with hepatitis B coinfection who are receiving one or both of these NRTIs may experience an exacerbation of hepatitis upon drug discontinuation

X. Antiretroviral Therapy in Pregnancy
ARV regimens given for treatment to pregnant women should preferably include drugs shown to be effective in reducing mother-to-child transmission. First-line treatment regimens in pregnant women should include ZDV whenever possible. The combination of ZDV/3TC has been recommended as the first choice for use in pregnancy. If hemoglobin monitoring is not possible or baseline hemoglobin is low, use TDF in place of ZDV in pregnancy. There is potential increased risk of lactic acidosis with the combination of d4T/ddI in pregnant women, so this combination should be avoided. NVP is the choice NNRTI for use in pregnancy, but should not be prescribed with CD4 over 250. EFV is contraindicated in the first trimester of pregnancy. PIs have been associated with the development of glucose intolerance and even diabetes mellitus in non-pregnant individuals. Among PIs, Lopinavir/ritonavir is the first choice PI for use during pregnancy. Antiretroviral therapy should be started as soon as possible in pregnancy. ART should not be stopped during first trimester due to risk of viral rebound and decline in CD4, risking maternal disease progression and increasing transmission.

Prevention of Mother-to-Child Transmission (MTCT) of HIV
The area for PMTCT of HIV is one of the most rapidly evolving in all of HIV care. Please refer to the most up-to-date version of Nepal National Guidelines. Note: ART is even more urgent in the case of pregnant women, given the potential to decrease HIV transmission to the infant and potential NVP resistance issues from short course ARVs. Pregnant women needing ART should start ART as soon as possible.

NATIONAL ANTIRETROVIRAL THERAPY GUIDELINES
The Standard Life-long ART Regimen in Pregnancy is: ZDV + 3TC + NVP This should be used in those women eligible by the above criteria. Efavirenz can be used after the first trimester of pregnancy and may be preferred in women with higher CD4 counts. NVP should not be used in those with CD4 over 350 and only used with caution in those between 250 and 350 due to risk of liver toxicity. All pregnant women taking NVP need close monitoring of liver function. If close liver function monitoring is not possible, consider using EFV instead of NVP after the first trimester, for those with CD4 over 250. Note: Due to increased chance of NVP induced hepatotoxicity, EFV is preferred after the first trimester in women with: CD4 between 250 and 350 unless LFTs can be monitored closely.
CD4 over 350 (regardless of lab capabilities) Other options for the third ARV in this group include Abacavir or Lopinavir/ritonavir Substitute TDF for ZDV if anemic or unable to monitor haemoglobin.

Antiretroviral Prophylaxis for Mother and Baby (When Mother does Not Yet Need ART)
The risk of HIV transmission to the baby can be reduced to 5% or less, if the mother takes ARVs during the antenatal period and with careful management of the delivery and provision of ARVs to both mother and baby after delivery and to mother throughout breastfeeding.
Recommended PMTCT Prophylactic Short-term Triple Antiretrovirals All HIV positive pregnant or lactating women should be seen at the ART clinic. All those not yet eligible for life-long ART should be offered short term triple antiretroviral prophylaxis starting from as early as 14 weeks of pregnancy (or when first seen, if later in pregnancy). The mother should take triple antiretrovirals during the second and third trimester of pregnancy (from 14 weeks) and for one year postpartum while breastfeeding her baby. Antiretrovirals should be stopped one week after breastfeeding cessation, usually at 12 months of age.  All HIV-exposed infants should receive daily nevirapine from as soon as possible after birth to 6 weeks of life (regardless of what the mother received).

Breast-feeding
Breastfeeding, in particular exclusive breastfeeding, is the ideal way to feed infants and it should be protected, promoted and supported. Beyond sound nutrition, it protects against common childhood infections. However, it is one of the routes for mother-to-child HIV transmission. Nepal experts agree with WHO in the promotion of breastfeeding along with the use of antiretroviral prophylaxis as the ideal way to feed infants of HIV-infected women in Nepal.

Breastfeeding is Now Recommended for HIV-exposed Babies Until 12 Months of Age
Mothers should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter, and continue breastfeeding for the first 12 months of life while taking triple ARV prophylaxis throughout.
12 months of breastfeeding gives the maximum survival benefit of breastfeeding.
Mothers take ARVs to reduce the risk of transmission during the entire duration of breastfeeding. After 12 months of age, the survival benefits of breastfeeding decreases. Breastfeeding should then only stop once a nutritionally adequate and safe diet without breast milk can be provided.

Breastfeeding Cessation
HIV-infected mothers should stop breastfeeding gradually within one month. Mothers should continue triple ARV prophylaxis for one week after breastfeeding is fully stopped. Stopping breastfeeding abruptly is not advisable.
Research shows that rapid and abrupt cessation breastfeeding is associated with adverse consequences for the infant such as growth failure and increased prevalence of diarrhoea.
Breast milk viral load is also known to spike with rapid cessation of breastfeeding, so there is chance of increased transmission if the child is fed again.

ARV Prophylaxis During Breastfeeding
Mothers should continue triple ARV drugs until one week after all exposure to breast milk has ended.
If a mother is taking an NNRTI (most commonly EFV), the NNRTI should be stopped one week after breastfeeding cessation and the two NRTI ARVs continued for an additional one week. This is to decrease the chance of NNRTI resistance, which is more likely when all three drugs are stopped together.
All women with HIV should be offered contraception at 6 weeks postpartum. If adequate contraception can not be assured, EFV should be changed to either ABC or LPV/r while the NRTI backbone is continued. EFV is teratogenic in the first trimester of pregnancy and must be avoided in any woman with a chance of another pregnancy.
If a breastfeeding mother stops triple ARVs for whatever reason, provider should consider giving the baby daily NVP until one week after breastfeeding cessation according to the following dosing table.

Prong 2 of PMTCT: HIV/ART and Family Planning Options
To avoid unintended, unplanned pregnancies among HIV positive couples, careful reproductive health and family planning counseling is essential for all people living with HIV.
Condoms: Male (or female) condoms are the only contraceptive method that can provide "dual protection" against STIs and HIV, and are therefore always recommended where one or both partners are infected with HIV. Breast feeding is recommended for all babies of HIV-infected mothers for 12 months.
Exclusive breast feeding is recommended for all infants of HIVinfected woman for the first six months.
After 6 months, culturally appropriate complimentary foods (weaning) is started and mother is advised to stop breast feeding as early as possible.
Babies should continue to breastfeed while adding complementary feeds from 6 to 12 months.

Babies of HIV-infected mothers should stop breastfeeding at about 12 months of life, if it is safe to do so.
Conditions for safe replacement feeding should be assessed prior to 12 month postpartum weaning.
Breastfeeding should be stopped gradually over 1 month ARV prophylaxis should be continued until 1 week after all breastfeeding stops. Women who do not yet require ART for their own health can stop triple ARV prophylaxis then.
If a child is diagnosed as HIV-infected, the mother should be encouraged to continue breastfeeding the child until at least 2 years of age.

XI. Tuberculosis and Antiretroviral Therapy
The life time risk of someone with latent TB developing TB disease in an HIV negative individual is 5-10% whereas PLHIV have up to a 50% risk. Therefore managing TB among HIV infected individuals is one of the major responsibilities of the ART clinician.

Intensified Case Finding
As TB is one of the most common opportunistic infection among the HIV infected people, all clients diagnosed HIV positive in VCT centers and all HIV positive people visiting ART centers should be screened for TB using a standard screening process.

Screening Questions for Active TB:
Does patient currently have any of the following: If "Yes" to any of the 4 questions, further TB investigation is needed.
Ask the client to report immediately if any of the above mentioned symptoms occur.

Isoniazid Preventive Therapy (IPT)
IPT refers to taking 6 months of isoniazid daily for latent TB infection regardless of CD4 cell count or ART status.

Identifying Those in Need of IPT:
Perform TB screening for all new HIV infected clients at their first visit with 4 TB screening questions, a full initial history and physical examination. Repeat screening should take place at 3 monthly intervals for all PLHIV.
Anyone answering "yes" to any of the four screening questions should be sent for investigations as needed.
If there are any signs of active TB or any concerns about unexplained illness, do NOT offer IPT, but refer client to TB doctor or supervising doctor as appropriate.
All PLHIV without active TB or other unexplained illness are offered IPT with appropriate counseling.

Initiating IPT:
Explain the IPT program to the client and assess predicted adherence to 6 months of Isoniazid.
Cotrimoxazole and ART should not be started at the same time as IPT.
Those with liver disease, active alcohol use, jaundice, habitual treatment defaulter and prior Isoniazid resistance should be excluded.

DOTS is not needed for IPT
IPT Regimen: Isoniazid 300 mg daily for 6 months. If available, Vitamin B6 25 mg (pyridoxine) should be given together with IPT for 6 months.

Follow-up Visits While on IPT:
Client must be seen every month for adherence check, side effect check and medication refill.
Ask about symptoms of breakthrough TB at each visit. If any occur, evaluate for TB.
See latest Nepal IPT guidelines for more details.

Patterns of HIV-related TB
Pulmonary TB (PTB) Even in HIV-infected patients, PTB is still the commonest form of TB. The presentation depends on the degree of immunosuppression. The table below shows how the clinical picture, sputum smear result and CXR appearance often differ in early and late HIV infection.

TB Treatment in HIV
Effective treatment and control of TB is a central priority when developing treatment strategies for co-infected patients. Tuberculosis treatment following the DOTS strategy should be initiated promptly in diagnosed cases of TB. All PLHIV with TB need ART. Suggestions for timing of initiation of ART for TB patients in different situations is given in following table: Patients already receiving ART when they develop TB should adjust the regimen to be compatible with TB treatment. Following completion of antitubercular therapy the ART regimen can be continued or changed depending upon the clinical and immunologic status of the patient.
Second line ART and TB-coinfection: Drug choices: Use of Rifabutin in TB-HIV co-therapy.
The HIV pandemic has led to a resurgence of tuberculosis and the challenge of TB-HIV co-therapy for patients on second-line ART is well recognized. Management of co-infected patients has shown that TB can be cured with standard antituberculosis regimens, including the use of rifampicin-based TB treatment for 6 months. Preliminary evidence and experience has confirmed recommendations in WHO guidelines that for most patients, especially those with CD4 counts < 100 cells/mm 3 , HIV treatment should not be delayed, but should be started or continued along side TB treatment. It is expected that many patients will fail first-line ART with active TB; and TB will develop in patients on second-line therapy. However, because of well recognized drug-drug interactions, it is difficult to use Rifampicin with any boosted PI-based regimens. For patients who need antituberculosis treatment in Nepal and who need a boosted PI, the only option is: Substitute rifabutin for rifampicin in the anti-TB regimen and maintain the standard PI-based ART regimen. Dose of rifabutin when used with boosted PI is 150mg three times a week.

XII. Hepatitis C Co-infection and ART
Hepatitis C patients should be monitored by following ALT regularly. If ALT is elevated, check full liver function tests. If transaminases are >5 times the upper limit of normal, carefully evaluate for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute viral hepatitis A or B infection, hepatobiliary disease, or alcoholic hepatitis); short-term ART interruption may be required.
Rarely, PLHIV may access Hepatitis C treatment in Nepal. Concurrent treatment of both HIV and HCV is feasible but may be complicated by pill burden, drug toxicities, and drug interactions such as the following: Didanosine should not be given with ribavirin because of the potential for drug-drug interactions leading to life-threatening ddI-associated mitochondrial toxicity including hepatomegaly/steatosis, pancreatitis, and lactic acidosis Zidovudine should be avoided with ribavirin when possible because of possible anemia. If no alternatives, ribavirin dose reduction is necessary.
Drug-induced liver injury from ART is more common in HIV /HCV coinfection.
Stavudine (with or without didanosine) and nevirapine are the ARVs most likely to cause liver injury. Immune Reconstitution Inflammatory Syndrome is a spectrum of clinical signs and symptoms resulting from the restored ability to mount an inflammatory response associated with immune recovery. It can present with the signs and symptoms of a previously subclinical and unrecognized opportunistic infection, as a paradoxical worsening of treatment response several weeks into therapy, or as an autoimmune disease in the context of immune recovery on ART. Typically, IRIS occurs within two to twelve weeks of the initiation of ART, although it may present up to 24 weeks after ART initiation. The incidence of IRIS is estimated to be 10%-32% of adults initiating ART. There is a higher risk in those starting ART with lower CD4 counts.

XIII. Hepatitis B Co-infection and ART
The syndrome can be characterized by fever, lymphadenopathy, worsening pulmonary lesions (on X-ray examination), expanding central nervous system (CNS) lesions, elevation of hepatic enzymes (Hep B co-infection), skin lesions or signs of autoimmune diseases. Sometimes, a brief course of corticosteroids may be required to reduce inflammation for severe respiratory or CNS symptoms. Prednisolone (or prednisone) at 0.5 mg/kg/day for five to ten days is suggested in moderate to severe cases of IRIS. Steroid doses have to be adjusted upwards when using together with microsomal enzyme enhancers like Rifampicin.

XV. Cotrimoxazole Prophylaxis in Adults
All PLHIV should be evaluated for possible need for Cotrimoxazole prophylaxis, even in areas without ART accessibility, or in the time that they are preparing for ART initiation. Cotrimoxazole has been proven to prevent morbidity and mortality in PLHIV and is a very important component of a complete package of care for HIV.
Cotrimoxazole Prophylaxis should be Given to: HIV infected adults with CD4 count <350 cells/mm 3 All adults who have had an episode of PCP All adults with symptomatic HIV disease or Clinical stage 2, 3 or 4 The Regimen is: 1 DS tablet (160TMP/800SMX) every day OR 2 SS tablets (80TMP/400SMX) every day

Continue Cotrimoxazole Prophylaxis as Follows:
Lifelong, if not on ART If on ART the CD4 is >350 on two consecutive samples 6 months apart, Cotrimoxazole can be discontinued.
Stop prophylaxis for severe cutaneous reactions, such as Stevens-Johnson syndrome, renal and/or hepatic failure, and severe hematological toxicity.

Timing of Cotrimoxazole Prophylaxis in Relation to ART Initiation:
Since the most common initial side effect of cotrimoxazole and antiretroviral therapy (especially nevirapine and efavirenz) is rash, it is recommended to start cotrimoxazole prophylaxis first and to initiate antiretroviral therapy two weeks later if the individual is stable on cotrimoxazole and has no rash. Do NOT start Cotrimoxazole and ART at the same time.

For Cotrimoxazole Intolerance, Consider The Following Alternatives:
Dapsone 100 mg once daily is the first choice.

OR
In cases of non-life-threatening adverse reactions, stop treatment for two weeks; then re-challenge the client with cotrimoxazole in a gradually increasing dose of an oral suspension of cotrimoxazole. After desensitization under surveillance, up to 70 percent of clients may again tolerate cotrimoxazole. 1. Follow-up of clients on Cotrimoxazole prophylaxis every month.
Monitor for toxicity, clinical events and adherence.
Lab tests of hemoglobin and white blood counts, only as indicated.
2. Adherence counseling on Cotrimoxazole can be useful to help prepare clients for ART in the future and problem-solve barriers to medication adherence.

XVI. Post Exposure Prophylaxis (PEP) of HIV
Post Exposure Prophylaxis (PEP) is currently the only way to reduce the risk of HIV infection in someone exposed to the virus. It refers to the use of antiretroviral medications to help prevent HIV transmission. The rationale is that ARVs given immediately after exposure can stop the virus from disseminating in the body and establishing infection.
The majority of occupational exposures do not lead to HIV infection. The risk of HIV transmission following skin puncture from a needle or other sharp object that was contaminated with a blood from a person with "documented" HIV infections is about 0.3%. The risk of HIV transmission is less with injuries sustained with solid bore (e.g. suture) needles than with hollow bore (e.g. blood drawing) needles. Similarly, the smaller the size of hollow bore needle, the less risk of HIV transmission. There have been rare reports of health workers who have become infected by exposure of mucous membrane (of eyes, nose or mouth) or abraded (broken) skin to HIV-infected material; the risk is estimated to about 0.09%. HIV is not transmitted through healthy intact skin.

First Aid Immediately after Potential Exposure:
The aim of first aid is to reduce contact time with the source person's blood, body fluids or tissues and to clean and decontaminate the site of the exposure.
If the skin is broken following an injury with a used needle or sharp instrument, the following is recommended.
Do not squeeze or rub the injury site.
Wash the site immediately using soap or a mild disinfectant solution that will not irritate the skin.
If running water is not available, clean the site with a gel or other handcleaning solution, whatever is customarily available.
Do not use strong solutions, such as bleach or iodine, to clean the site as these may irritate the wound and make the injury worse.
After a splash of blood or body fluids on broken skin, the following is recommended: Wash the area immediately.
If running water is not available, clean the area with a gel or other handrub solution, whatever is customarily available.
Do not use strong disinfectants.

NATIONAL ANTIRETROVIRAL THERAPY GUIDELINES
After a splash contacts the eye, do the following: Irrigate the exposed eye immediately with water or normal saline.
Sit in a chair, tilt the head back and have a colleague gently pour water or normal saline over the eye, pulling the eyelids up and down to make sure the eye is cleaned thoroughly.
If contact lenses are worn, leave these in place while irrigating the eye, as they form a barrier over the eye and will help protect it.
Once the eye has been cleaned, remove the contact lenses and clean them in the normal manner. This will make them safe to wear again.
Do not use soap or disinfectant on the eye.
After a splash contacts the mouth, do the following.
Spit the fluid out immediately.
Rinse the mouth thoroughly, using water or saline, and spit again. Repeat this process several times. The decision to start PEP is made on the basis of degree of exposure to HIV and HIV status of the source from whom exposure has occurred (source patient). Decisions should be made based in part on information about the source, including ART, response to therapy, including viral load, and any data on HIV resistance testing. Decisions should not delay initiation of PEP, and modifications can be made after information is obtained. If the HIV status of the source is not known, HIV testing of the source could be done after necessary counseling. In any case, if the risk is high, PEP should be started immediately. If the HIV test results of the source are found to be negative, PEP can be discontinued. Specific recommendations for PEP are given in the two tables below, one for percutaneous injuries and the second for exposures to mucous membranes or non-intact skin.

Drug Selection for PEP
There are two types of regimens recommended for PEP. They are the basic regimen of two drugs combination and expanded regimen of three drugs as given below: Regimens for PEP

DRUG COMBINATIONS (EXPANDED REGIMEN)
2 nucleosides (as above) + LPV/r Alternative to ZDV is TDF, in the case of anemia.
Alternatives to LPV/r include: ATV/r, SQR/r and FosAPV/r, if available.
Note: NVP should not be used for PEP due to risk of hepatotoxicity.
If PEP is given, the exposed person should have a baseline Hemoglobin test, if Zidovudine is used as part of PEP.
HIV Antibody testing (rapid or ELISA) should be used to monitor for seroconversion, and test should be performed at baseline and at 3 and 6 months post exposure.
Testing for other bloodborne diseases-such as hepatitis B and Cis also important; depending on the nature of the risk and the local prevalence, if testing is available.

Counseling for HIV Post-exposure Prophylaxis
In the process of seeking informed consent for HIV post-exposure prophylaxis, people who have been exposed to HIV must be made fully aware of the following: The risk of acquiring HIV infection from the specific exposure; What is known and not known about the efficacy of PEP; The importance of taking a HIV test and of receiving appropriate post-test counseling (although testing may be delayed if necessary); The possibility that they might already be infected with HIV will need to be assessed if they have not already had an HIV test; People already living with HIV should be referred for treatment of their infection, and if they had started PEP the medicine should be stopped when the diagnosis is confirmed; People with discordant rapid HIV test results should be offered PEP while waiting for pending laboratory-based confirmatory testing; PEP medication will be discontinued if their initial HIV test is positive: this medication could increase the risk of drug resistance among people already infected; The importance of adhering to medicine; What to do if they forget or vomit a dose (see ART adherence section) The duration of the course of medicine (four weeks); The common side effects that may be experienced while taking PEP medicine; That they can stop taking PEP medicine at any time, but if they do so, they will probably not get the full benefit of PEP, if the source to which they were exposed was HIV positive; PEP medicine can be taken during pregnancy and may protect the mother from getting HIV infection after exposure; That continuing to breastfeed while taking PEP is safe, although if women get infected by HIV while breastfeeding, the risk of transmitting HIV through breastfeeding is higher at the early stage of infection in the absence of ARVs. All women in Nepal should exclusively breastfeed their infants for the first 6 months of life with continued breastfeeding until 12 months (if HIV infected or at least 2 years (if HIV negative).

PEP Following Sexual Assault
There are no available data about the use of PEP following rape. But if the risk of transmission of HIV is considered to be present, PEP, as used for health workers after occupational exposure, can be used taking into account various factors, including drug toxicity and adherence, as discussed above. PEP for the victim of rape can be made available if required.
PEP for Non-occupational Exposure Other Than Rape: For non-occupational exposure other than rape, clinician will decide on a case-by-case basis whether PEP should be provided. It should not be provided in the case of chronic HIV exposure or cases of "recreational exposure". Provider may decide to provide PEP in some cases, such as an episode of condom breakage in a discordant couple.

Where should PEP be Available in Nepal?
Drugs for PEP should be made available in every hospital so that treatment can be immediately initiated. Further management must be decided by an expert as soon as possible.
Starter packs of between 2 and 5 days of ARVs can be placed in other medical facilities with linkages to full PEP packages. These can be prescribed under the condition that the client return to see a designated provider for complete risk assessment and to collect the rest of the 28 days of medicine. This helps prevent large wastage due to expiry of unused PEP packs. 1. HIV antibody testing continues to be the backbone; however it is of more limited use in children aged <18 months, who may still be carrying passively transferred maternal HIV antibodies.
All infants born to HIV infected mothers will test antibody positive at birth.
However, children over 12 months of age have usually lost maternal antibody. If ELISA is positive after 12 months of age, there is a 96% chance the child is HIV-infected.
All HIV-exposed infants should undergo virologic testing at 6 weeks of age, if available.
All exposed infants should be tested at 9 months during the time of measles vaccination. Those tested positive should be referred to sites where DNA PCR tests are available for early infant diagnosis.
2. Virological tests are needed to confirm HIV infection in children less than 18 months of age.
DNA PCR is the most common virological test for definitive diagnosis in infants (qualitative).
RNA PCR (quantitative) also called Viral Load is most commonly used to follow response to ART.
Virological tests become positive much earlier than antibody tests.
If tested at 6 weeks almost all infants infected intrauterine and peripartum will be positive.
Recently, Dried Blood Spot (DBS) has been found to be reliable for DNA PCR sample collection and allows finger or heel-stick collection along with ease of transportation of the sample to a central laboratory from other parts of the country.

II. Antiretroviral Therapy (ART) in Infants and Children
The advent of potent antiretroviral therapy has dramatically reduced rates of mortality and morbidity and has improved the quality of life of infants and children living with HIV although it does not provide a cure. As a result HIV is now perceived as a manageable chronic illness.   III. Immunization of Children Exposed/Infected with HIV

Indications for Starting ART in HIV-
The majority of children with maternally transmitted HIV infection acquire the infection during or shortly after birth. Early in life they are immunologically normal and only later without specific treatment do they develop progressive immunodeficiency.
All children who have been exposed to HIV should be fully immunized according to age. Because most children who are HIV-infected do not have severe immune suppression during the first year of life, immunization should occur as early as possible after the recommended age to optimize the immune response.
BCG and live attenuated vaccines (including influenza, Japanese encephalitis, measles, mumps, rubella, typhoid, varicella and yellow fever) should not be given to children with severe immunodeficiency.

XVIII. Antiretroviral Therapy in Injecting Drug Users
Initial Evaluation Care for HIV-positive injecting drug users (IDU) must address substance use and substance dependence, psychological and social issues, and medical complications associated with injecting drug use and HIV.

Evaluation of Substance Use and Dependence
Standardized assessment tools should be used for screening and initially evaluating substance use and dependence. Any screening or assessment must be voluntary and fully informed, with explanation of why the service needs to understand the individual's substance use and associated problems. Under-reporting use of illicit substances is common, so all patients should be screened for substance use and dependence Patients who admit to substance use should be examined further, as should those who do not but present with clinical signs or symptoms of drug use, including injections. It is crucial to assess drug dependency, as it has implications for patient management strategy.
Typically a substance use and dependence assessment includes a complete history of substance use and treatment and a physical examination. A substance use and treatment history will include: Initial evaluation should be followed by treatment of opportunistic infections and other conditions as indicated.

Psychosocial Assessment
Mental health comorbidities are common among IDUs with HIV. Some estimates suggest that between 25% and 50% of drug users also have a comorbid mental health problem.
A thorough psychosocial assessment should be undertaken at initial evaluation, focusing on:

Interactions between ARVs and Methadone/Buprenorphine
Methadone and buprenorphine are the most common drugs prescribed for Opioid Substitution Therapy (OST). Significant interactions with some of the most commonly used ARVs.
AZT and Methadone AZT does not change methadone levels in the bloodstream. Methadone significantly increases the blood concentration of AZT (43%). Watch for possible increases in AZT toxicity: anaemia, myalgia, bone marrow suppression, fatigue, headache and vomiting.

EFV and Methadone
Efavirenz (EFV) can significantly decrease the concentration of methadone in the blood by 60%, and can cause methadone withdrawal. withdrawal can be delayed and possibly not seen until 2-3 weeks after starting the EFV. May require a methadone dose increase of 50%.

NVP and Methadone
Nevirapine (NVP) can significantly decrease the blood concentration of methadone (46%). Methadone withdrawal is common. withdrawal can be delayed and possibly not seen until 2-3 weeks after starting NVP. May need a methadone dose increase of approximately 15%.

PIs and Methadone
PIs can induce or inhibit CYP3A.
PIs can induce CYP3A causing faster metabolism of other drugs. This will decrease blood levels of PIs. Faster metabolism of methadone may cause withdrawal.
PIs can inhibit CYP3A causing slower metabolism of other drugs. This will increase blood levels of PIs. Slower metabolism of methadone may cause toxicity.

OPIOID SUBSTITUTION TREATMENT
All the PIs and EFV can increase levels of cisapride and non-sedating antihistamines (aztemizole, terfenedine), which can cause cardiac toxicity. Coadministration is not recommended.   (A booklet with about 12 copies of the above made for each patient for monitoring is recommended).

Early Warning Indicators
On-Time ARV Pick-Up (EWI 4a)-Measures the proportion of patients who have picked up all their prescribed ARV drugs on time for two consecutive drug pick-ups after a baseline pick-up.
Retention on ART at 12 months-Measures the proportion of adults and children known to be alive and on treatment 12 months after initiation of ART This data is collected for all patients on ART (i.e. a census of all patients on ART at a site/region/country level) hence no sample size calculation is necessary. This measurement of retention can be incorporated into EWIs.

Suggested Target:
Poor Performance <75% Fair Performance 75-84% Desirable Performance >85% ARV drug supply continuity-number of months (or bi-monthly periods) in the designated year in which there were no stock-out days of any ARV drug routinely used at the site.
Modification to the definition above by including "bi-monthly periods" to be consistent with current reporting in Nepal about ARV stock to NCASC Suggested Target: 100% ART prescribing practices-Measures the proportion of patients initiating ART at the site who are prescribed, or who initially pick up from the pharmacy, an appropriate first-line ART regimen.
The definition of an appropriate first-line regimen is dictated by the NCASC in the ART guideline, about what constitutes appropriate first-line therapy. In addition to assessing prescribing practices per the country recommendations of appropriate first-line, the data can also be analysed in the context of which regimens are most predictive of the development of HIVDR (i.e. whether any mono-or dual-therapy is being prescribed or picked-up).

ANNEX VIII
National ART Programme Monitoring 1. Monitoring and Evaluation of the ART Programme with the increasing access to antiretroviral treatment (ART), a strong monitoring system is required at facility, district, provincial, national and international levels.
At Facility Level, The Objectives of Programme Monitoring are to: Support patient management by regularly recording and storing of key individual information for lifelong care and follow-up; Facilitate an accurate patient tracking system to identify those missing or lost to follow-up; and Support drug supply management at the facility.
At All Levels, Programme Monitoring will Help to: Document the progress in equitable access to HIV care and ART programmes; and Identify the successes and gaps over time and modify the programmes accordingly.
2. ART Program Performance Indicators at national/ international levels

ART program performance indicators at national level
The following indicators, based on the monitoring and evaluation framework were developed for national programmes to demonstrate progress in scaling up ART programmes: Monitoring and evaluation framework