Clinical guidelines for antiretroviral management of HIV disease. Origins and history of the HIV epidemic

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1 Clinical guidelines for antiretroviral management of HIV disease Origins and history of the HIV epidemic Both known species of HIV, viz. HIV-1 and HIV-2 originated in Africa (HIV-1 from Central Africa and HIV-2 from West Africa) as zoonotic infections from primate hosts. Human infection is thought to have been facilitated during the slaughtering of primates for the bush meat trade. About 65% of the global total of HIV infection is located in sub-saharan Africa, with South Africa having the highest number of persons, 5 to 6 million, living with HIV. 1 HIV-1, which is found through out the world and is responsible for the majority of cases of HIV infection, has been subdivided into 10 subtypes A to J (also known as clades or genotypes); within the South African context, reference to HIV implies HIV-1 subtype C. 2 (See Table I.) Antiretroviral management Worldwide, six classes of antiretroviral agents are available. Each class exhibits a different mechanism of action. 1. Nucleoside reverse transcriptase inhibitors (NRTIs) The structures mimic natural nucleosides. After phosphorylation by cellular enzymes, they are preferentially incorporated into new viral DNA where they inhibit elongation of the DNA chain, thus halting viral replication. 2. Nucleotide reverse transcriptase inhibitors (NtRTIs) Act like NRTIs. 3. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) These act by binding to the DNA cellular enzyme reverse transcriptase (RT), thus interfering with its activity 4. Protease inhibitors (PIs) Prevent the production of infective virions by directly impacting on the infected cell pool 5. Fusion inhibitors (FIs) [Not currently available in South Africa] Table I: Comparison of global and sub-saharan African estimates of the HIV/AIDS epidemic as of December Number of people living with hiv, 2008 People newly infected with HIV, 2008 AIDS-related deaths, 2008 Global Nadine Butler, MPharm, PhD School of Pharmacy, University of the Western Cape Sub-Saharan Africa 33.4 million 22.4 million 2.7 million 1.9 million 2.0 million 1.4 million These drugs prevent the fusion of HIV to human cells. 6. Integrase inhihitors [Not currently included in South African treatment guidelines] Prevent insertion of the HIV DNA into the human DNA genome. In the late 1980s, Zidovudine (AZT) was the first antiretroviral drug used clinically. AZT belongs to the nucleoside reverse transcriptase inhibitor (NRTI) class. As resistance developed rapidly, the clinical benefits were not sustained. Combination therapy with two NRTI drugs was introduced in the early 1990s; although benefits were of longer duration, resistance also developed. In the mid 1990s the phrase highly active antiretroviral therapy (HAART) was coined to describe the combination of two NRTIs with the more powerful protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Provided that high levels of adherence to HAART regimens are achieved, viral replication is suppressed, viral mutations do not occur and resistance does not develop. HIV infection has thus come to be considered as a chronic disease, requiring longterm management. National strategic plan In 2007, under the auspices of the South African National AIDS Council (SANAC), the South African government, in conjunction with civil society, developed a 5-year National Strategic Plan (NSP) to address the challenges of HIV/AIDS as well as other sexually transmitted infections. The two main objectives of the NSP were, by the end of 2011, to reduce the number of new HIV infections by half, and to provide comprehensive treatment, care and support to 80% of persons needing this. Two further initiatives have been an HIV Counselling and Testing Campaign (HCT) and an expanded treatment programme. The HCT campaign has a target of testing 15 million people by June The expanded treatment programme has a target of all of the more than public health facilities around the country being able to initiate patients on antiretroviral therapy by the end of facilities were enrolling patients at the end of 2009; this number had increased to 814 by July SAPJNovDec10pp42-49.indd 42 12/3/ :33:26 AM

2 GUIDELINES Treatment guidelines for HIV management in adults and adolescents The first national ART guidelines for South Africa were published in 2004, as part of a comprehensive plan for the care, management and treatment of HIV and AIDS. This was the first time that South Africa had included ARV treatment to the existing range of intervention policies. 4 An updated version of the guidelines, based on new information and evidence, for the management of HIV-infected adolescents and adults in South Africa has been published in The guidelines contain recommended ART regimens, as well as laboratory and clinical monitoring at diagnosis, initiation of ART and during treatment. There is a focus on the integration of HIV management with other health services such as tuberculosis (TB) prevention and treatment, maternal and child health, sexual and reproductive health, and access to contraceptives. 5,6 Treatment guidelines for infants and children have been published separately. 7 These 2010 guidelines have been developed to specifically address the need for strengthening the capacity of both the public and private sectors to deliver quality integrated HIV/AIDS health and wellness services. In order to ensure timely initiation of ARVs, for both treatment and prevention, and to reduce levels of unnecessary drug toxicities, the following specific objectives were identified: To prioritise ARVs for Patients with CD4 counts < 200 cells/mm 3 or with severe HIV disease, irrespective of CD4 Patients co-infected with TB/HIV Pregnant women with CD4 350 cells/mm 3 for lifelong ART and CD4 > 350 cells/mm 3 for prophylaxis To ensure access to ART within 2 weeks in pregnant women, those with low CD4 counts, very ill patients and those with MDR-TB or XDR-TB To standardise first and second line therapy for children, adolescents and adults in both the public and private sectors To reduce the use of stavudine To expand the use of fixed-dose and co-packaged formulations To enable nurses to initiate ARVs for treatment and prevention To enable PHC facilities to initiate, manage, monitor and refer patients The focus on early initiation of treatment, i.e. before patients become ill because of their weakened immunity, is justifiable for many reasons. People living with HIV would have an opportunity to stay healthier and live longer. Estimates are that implementation of the guidelines could result in HIV-related mortality being reduced by 20% as opportunistic infections can also be reduced. Since ART in effect reduces the level of virus in the body, prevention benefits also accrue, since the infected person is less likely to pass on the virus to sexual partners. 7 These guidelines largely follow the latest WHO HIV treatment recommendations, particularly regarding the phasing out of the use of stavudine as part of first-line therapy, due to pronounced side effects of peripheral neuropathy, fat loss in the limbs and face (lipoatrophy) and life-threatening hyperlactataemia and lactic acidosis. However, whereas the WHO guideline recommends that all patients be initiated on ART when their CD4 counts drop to below 350 cells/mm 3, the South African guidelines retain the 200 cells/ mm 3 criterion, except for four distinct groups of patients. 8 Note: healthy persons have a CD4 count of cells/mm 3. In the guidelines, reference is made to WHO clinical staging of disease. The WHO system is based on clinically apparent HIVassociated symptoms, described as Stages 1 to 4, corresponding to a clinical picture of asymptomatic, mildly symptomatic, advanced symptoms and severe disease, respectively. The CD4 counts associated with these 4 stages are > 500, , and < 200 cells/mm 3, respectively. 9 (See Table II.) The guidelines specify clearly which patients are eligible to receive ART. (See Tables III and IV.) A distinction is made Table II: Classification of ARV drugs Class Drug Abbreviation Nucleoside reverse transcriptase inhibitors (NRTIs) Nucleotide reverse transcriptase inhibitors (NtRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Zidovudine Lamivudine Emtricitabine Stavudine Abacavir Didanosine Tenofovir Nevirapine Efavirenz AZT 3TC FTC d4t ABC ddl TDF NVP EFV Protease inhibitors (PIs) Lopinavir/Ritonovir LPV/r Table III: Standardised National Eligibility Criteria for starting ART regimens for adults and adolescents 6 Eligible to start ART Require fast track Not yet eligible for ART CD4 count 200 cells/mm 3 irrespective of clinical stage CD4 count 350 cells/mm 3 In patients with TB/HIV Pregnant women WHO stage IV irrespective of CD4 count MDR/XDR-TB irrespective of CD4 count Pregnant women eligible for lifelong ART Patients with very low CD4 (< cells/mm 3 ) WHO stage IV, CD4 count not yet available MDR/XDR-TB Transfer to a wellness programme for regular follow-up and repeat CD4 testing 6-monthly Advice on how to avoid HIV transmission to sexual partners and children Initiate INH prophylaxis if asymptomatic for TB Contraceptives and annual Pap smear 43 SAPJNovDec10pp42-49.indd 43 12/3/ :33:26 AM

Table IV: Standardised National Eligibility Criteria for starting ART regimens for infants and children 5 Eligible to All children < 1 year of age start ART Children 1 5 years with clinical stage 3

requiring fast-tracking, i.e. who should receive ART within two weeks of being eligible, and all other patients, who should receive ART within two months of either clinical staging or the

Any medical contraindications would first be identified.

regimen with no side effects Contraindication to TDF: renal disease Failing on a d4t or AZT-based 1st line regimen Failing on a TDF-based 1st line regimen Failing any 2nd line regimen the importance

) Since TB is such a common co-morbid condition with HIV, all patients should be screened for TB.

blood-stained Fever Night sweats Unexplained weight loss Loss of appetite, malaise, tiredness Shortness of breath, chest pains New palpable lymphadenopathy ART treatment should be continued

3 Table IV: Standardised National Eligibility Criteria for starting ART regimens for infants and children 5 Eligible to All children < 1 year of age start ART Children 1 5 years with clinical stage 3 or 4 or CD4% 25% or absolute CD4 count < 750 cells/mm 3 Children between 5 to 15 years with clinical stage 3 or 4 or CD4 count 350 cells/mm 3 Require fast track between those patients designated as requiring fast-tracking, i.e. who should receive ART within two weeks of being eligible, and all other patients, who should receive ART within two months of either clinical staging or the determination of a qualifying CD4 count. When ART eligibility criteria have been satisfied, a multidisciplinary team should assess whether the patient is ready for this treatment. Any medical contraindications would first be identified. In addition, whether the patient understands the following should be assessed: their HIV status the need for ART All new patients needing treatment, including pregnant women Currently on d4t based regimen with no side effects Contraindication to TDF: renal disease Failing on a d4t or AZT-based 1st line regimen Failing on a TDF-based 1st line regimen Failing any 2nd line regimen the importance of adherence and the link between adherence and treatment outcomes (specifically, decrease in viral load) need for commitment to regular scheduled visits (See Tables V VII.) Since TB is such a common co-morbid condition with HIV, all patients should be screened for TB. If two or more of the following are present, TB is suspected: Cough > 2 weeks Long-standing cough due to chronic obstructive airway disease should be excluded Sputum production which may be blood-stained Fever Night sweats Unexplained weight loss Loss of appetite, malaise, tiredness Shortness of breath, chest pains New palpable lymphadenopathy ART treatment should be continued throughout TB treatment. Table V: Standardised National ART regimens for adults and adolescents 6 1st Line TDF +3TC/FTC + EFV/NVP For TB co-infection EFV is preferred. For women of child-bearing age, not on reliable contraception, NVP is preferred d4t +3TC + EFV/NVP AZT +3TC + EFV/NVP TDF +3TC/FTC + LPV/r AZT +3TC + LPV/r Specialist referral 2nd Line Salvage Remain on d4t if well tolerated. Early switch with any toxicity. Substitute TDF if at high risk of toxicity (high BMI, low Hb, older female) Intensive adherence management indicated. If viral load remains high after 3 months, switch Table VI: Standardised National ART regimens for infants and children 5 1st Line All infants and children < 3 years ABC +3TC + LPV/r For TB co-infection EFV is preferred. Children 3 years ABC +3TC + EPV Remain on d4t if well tolerated. Early switch with any toxicity. Substitute TDF if at high risk of toxicity (high BMI, low Hb) Currently on d4t-based regimen with no side-effects Children > 3 years Failed ABC + 3TC + ETV Failing on a AZT or ddl-based regimen Can continue AZT + ddl + LPV/r ABC +3TC + LPV/r 2nd Line Substitute once lipodystrophy suspected Failing on LPV-based regimen Refer Specialist advice necessary and/or hospital referral Infants under 3 years failing 1st line Refer Specialist advice necessary and/or hospital referral Failing any 2nd line regimen Children < 1 year of age Clinical Stage 4 MDR or XDR-TB Specialist referral Salvage 44 SAPJNovDec10pp42-49.indd 44 12/3/ :33:32 AM

4 WOMEN INFANTS Table VII: Standardised National ART and ARV regimens for HIV positive pregnant women and their infants 6 Regimen Comment Eligible for lifelong ART TDF + 3TC/FTC + NVP Start lifelong ART within 2 weeks Currently on lifelong ART Continue ART Substitute EFV with NVP if in first 12 weeks of pregnancy Contraindication to TDF Not eligible for ART Unbooked and presents in labour Mother on lifelong ART Mother on PMTCT Mother did not get any ARV before or during delivery Unknown maternal status (orphaned or abandoned) AZT + 3TC + NVP AZT from 14 weeks Single dose NVP + AZT 3 hourly in labour TDF + FTC single dose after delivery Single dose NVP + AZT 3 hourly in labour TDF + FTC single dose after delivery NVP at birth then daily for 6 weeks irrespective of feeding NVP at birth then daily for 6 weeks, continued as long as any breastfeeding NVP as soon as possible and daily for 6 weeks, continued as long as any breastfeeding NVP immediately Test with rapid HIV test +ve: continue NVP for 6 weeks -ve: discontinue NVP The guidelines contain extensive information regarding the monitoring of HIV patients at various stages, viz. when initially diagnosed as HIV +ve, during routine follow-up visits, when ART eligibility criteria fulfilled, and when actually on ART. (See Tables VIII and IX) Adherence Adherence is the cornerstone of successful ART and is logically an area of HIV management where pharmacists are most likely to be involved. HIV/AIDS is now considered a chronic, manageable condition. Factors such as the stage at which ART is initiated, the particular therapeutic regimen, and the level of support that a patient receives, all contribute to the success of treatment. While these factors are doctor or other-driven, adherence to the regimen is largely patient-driven. Less than optimal adherence levels can lead to treatment failure, as measured by detectable viral load (> 50 copies/ml). Other implications of non-adherence are: Development of resistant strains of HIV Decreased CD4 counts Possible cross-resistance to other drugs in the same class (particularly NNRTIs and PIs) Increased risk of disease progression Limited options for following other regimens Increased costs of second line and salvage regimens Increased costs as a result of treating opportunistic infections Trauma as a result of treatment failure Self-blame by the patient and loss of confidence in ART Assess ART eligibility Stop NVP at 6 weeks if formula fed Assess ART eligibility for mother within 2 weeks Follow-up 6 week lab detection HIV test It is obvious that adherence levels of less than 95% would be associated with poor therapeutic outcomes. Note: 95% adherence means being late or missing one dose in 20 or, in terms of current dosing schedules, one dose in a 10-day cycle. (See Table X) The reasons for patient non-adherence are many and varied, and it is not necessarily true that health care providers and patients have the same perceptions of these. A study from the USA showed that doctors perceived the number of doses to be the most important reason for non-adherence while patients listed meal instructions as the most likely to cause them to delay or miss doses. 2 Some practical strategies that could be implemented to try to improve patient adherence to ART are: Make sure the dosing schedule fits the patient s life Define dosing instructions precisely, for e.g. twice daily means taking the drug every 12 hours at the same times every day or an empty stomach means no food for two hours before taking the prescribed drug and at least half an hour after dosing Organise the patient to divide doses on a daily basis by using pillboxes or small pill containers Explain the importance of being organised where routine may be disrupted Advise use of timers (cell phone alarms work well) Explain the what if situations Forgetting doses Vomiting pills 46 SAPJNovDec10pp42-49.indd 46 12/3/ :33:32 AM

5 GUIDELINES Table VIII: Standardised National Monitoring for adults and adolescents with HIV 5 AT INITIAL DIAGNOSIS OF HIV ACTIVITY Check HIV result Clinical staging if HIV +ve Ask if pregnant or planning to conceive Do the CD4 count Hb** or FBC*** if available PURPOSE Ensure national testing algorithm followed Assess eligibility for ART or fast-tracking Identify women needing ART or ARV for PMTCT* Identify TB/HIV co-infected Identify eligibility for ART or ARVs if pregnant Detect anaemia or neutropenia AT ROUTINE FOLLOW-UP VISITS Check that CD4 count has been done in the last 6 mo. WHO clinical staging Assess eligibility for ART Identify TB/HIV co-infection IF ELIGIBLE F ART Serum Creatinine and clearance if starting on a TDF-based regimen Refer if estimated creatinine clearance is < 50 ALT # if starting on a NVP-based regimen If ALT raised do HepBSAg ## and avoid NVP Hb or FBC if available if starting on an AZT-based regimen Refer to doctor if < 8 g/dl ON ART Clinical stage CD4 at 6 mo, 1 yr on ART and then every 12 mo VL $ at 6 mo, 1 yr on ART and then every 12 mo ALT if on NVP and develops rash or symptoms of hepatitis FBC at 1, 2, 3 and 6 mo if on AZT Creatinine at 3 and 6 mo, then every 12 mo if on TDF Fasting cholesterol and triglycerides at 3 mo if on LPV/r Monitor response to ART Identify problems with adherence Identify NVP toxicity Identify AZT toxicity Identify TDF toxicity Identify LPV/r toxicity * PMTCT = Prevention of mother to child transmission; ** Hb = haemoglobin; *** FBC = full blood count; # ALT = Alanine transaminases; ## HepBSAg = Hepatitis B surface antigen; $ VL = viral load Table IX: Standardised National Monitoring for infants and children with HIV 5 AT INITIAL DIAGNOSIS OF HIV AT ROUTINE FOLLOW-UP VISITS ACTIVITY Check HIV result Document weight and height Do the CD4 count Hb* or FBC** if available Check that CD4 count has been done in the last 6 mo. WHO clinical staging PURPOSE Ensure national testing algorithm followed Monitor growth Assess eligibility for ART Identify TB/HIV co-infected Identify eligibility for ART or ARVs Detect anaemia or neutropenia Assess eligibility for ART Identify TB/HIV co-infection IF ELIGIBLE F ART Serum Creatinine if starting on a TDF-based regimen Refer if estimated creatinine clearance is < 50 ALT # if starting on a NVP-based regimen If ALT raised do HepBSAg and avoid NVP Hb or FBC if available if starting on an AZT-based regimen Refer to doctor if < 8 g/dl Clinical stage Monitor response to ART CD4 at 6 mo, 1 yr on ART and then every 12 mo Identify problems with adherence ON ART VL ## at 6 mo, 1 yr on ART and then every 12 mo ALT if on NVP and develops rash or symptoms of hepatitis Identify NVP toxicity FBC at 1, 2, 3 and 6 mo. If on AZT Identify AZT toxicity Creatinine at 3 and 6 mo, then every 12 mo if on TDF Identify TDF toxicity Fasting cholesterol and triglycerides at 3 mo if on LPV/r Identify LPV/r toxicity * Hb = haemoglobin; ** FBC = full blood count; # ALT = Alanine transaminases; ## VL = viral load 47 SAPJNovDec10pp42-49.indd 47 12/3/ :33:33 AM

Table X: Relationship between non-adherence to ART and viral suppression 2 Adherence rate % Patients with undetectable viral load > 95% 81% 90-95% 64% 80-90% 50% 70-80% 25% < 70% 6% Provide a 24 hour

Treatment Helpline Direct Encourage the patient to keep a drug diary, recording all doses and side effects Encourage the patient to make and keep follow-up appointments for blood tests and to collect

In conclusion, ART, with its demonstrable positive therapeutic outcomes, has changed the approach to the management of HIV +ve patients.

6 Table X: Relationship between non-adherence to ART and viral suppression 2 Adherence rate % Patients with undetectable viral load > 95% 81% 90-95% 64% 80-90% 50% 70-80% 25% < 70% 6% Provide a 24 hour support number, for e.g. Treatment Helpline Direct Encourage the patient to keep a drug diary, recording all doses and side effects Encourage the patient to make and keep follow-up appointments for blood tests and to collect prescriptions Provide written information as it is possible that patients forget much of what is said during a consultation. In conclusion, ART, with its demonstrable positive therapeutic outcomes, has changed the approach to the management of HIV +ve patients. ART failure is invariably the result of non-adherence to the prescribed regimens. All health care providers involved in ART should therefore pay special attention to educating patients on the importance of adherence, and the recognition of and response to side effects, to integrating ART regimens into the patients daily routines, and assessing adherence levels at all visits.r Contd from p. 41 References 1. The South African National HIV Prevalence, HIV Incidence, Behaviour and Worms A Review Communication Survey HSRC Press, Cape Town HIV/AIDS Management Course for Healthcare Professionals 4th ed. Foundation saginata for Professional (beef Development tapeworm) 2010 infects man through cattle. Taenia 3. AIDS Epidemic update. Joint United Nations Programme on HIV/AIDS (UNAIDS) Taenia and World solium Health (pork Organization tapeworm) (WHO), uses pigs Available as an at intermediate host. 4. National Antiretroviral Treatment Department of Health 5. The The South lifecycles African Antiretroviral are similar, Treatment but there is an important Accessed variation 27 July 2010 with 6. Taenia solium. If the eggs of pork tapeworm are eaten pdf. Clinical for the Management of HIV and AIDS in Adults and by another human or are regurgitated by the original host, the Adolescents. Accessed 27 July 2010 eggs 7. can hatch in the human host s gut and larvae can reach the intestines for and the Management form cysticerci. of HIV in Cysticercosis children. 2nd ed may Accessed cause a 27 July 2010 variety 8. of problems such as epilepsy and fluid on the brain. en/print.html More than five million people receiving HIV treatment: WHO advises earlier treatment among people with HIV. Accessed 27 July 2010 D. 9. latum (fish tapeworm) is passed to humans Antiretroviral when therapy they eat for raw HIV or undercooked infection in adults freshwater and adolescents fish. Recommendations for a public health approach. Accessed 27 July WHO Case Definitions of HIV for Surveillance and People Revised with Clinical tapeworm Staging infections and immunological are often Classification asymptomatic. of HIV-related If symptoms Disease in are Adults present and Children. they may include abdominal pain, diarrhoea, 2B7781C612E6.asp. weight loss, weakness South Africa and updates nausea. HIV treatment guidelines. Ac July 2010 Diagnosis usually is made when a piece of the worm is found in the stool. 1,2,3,4,5 Treatment People with worm infections should seek medical help for diagnosis and treatment. Anthelmintics are medications to treat and to deworm patients. (See Table I on previous page.) Prevention Most worm infections may be prevented with strict adherence to hygiene. Avoidance of contaminated water, and thorough washing of hands and foods is important. Contaminated water should not be used for drinking, bathing or cleaning food. Regular de-worming reduces transmission of worms, and reduces the possibility of severe infections and symptoms. 3 Conclusion Worm infections affect millions of people worldwide. The breakdown of sanitation and lack of clean water aids the transmission of these diseases. Education and adherence to good hygiene procedures can minimise these problems.r References 1. Protozoa and Helminths. Accessed 10/8/ Worms. Accessed 9/8/ Albrich J. Helminths and Anthelmintics. SA Pharmacist s Assistant. Spring Parasitic Worms (Helminths). Accessed 10/8/ Berkow R. (editor) The Merck Manual of Medical Information Merck Research Laboratories. 6. Leder K. Ascariasis. UptoDate.com Accessed August Leder K. Enterobius and trichuriasis. UptoDate.com Accessed August Macpherson G. (editor) Black s Student Medical Dictionary A&C Black Publishers Limited. 9. Weller P.F. Cutaneous larva migrans (creeping eruption). UptoDate.com Accessed August MIMS 48(10) October SAPJNovDec10pp42-49.indd 48 12/3/ :33:35 AM

THE SOUTH AFRICAN ANTIRETROVIRAL TREATMENT GUIDELINES 2010

THE SOUTH AFRICAN ANTIRETROVIRAL TREATMENT GUIDELINES 2010 The South African Antiretroviral Treatment Guidelines 2010 Goals of the programme Achieve best health outcomes in the most cost-efficient manner