Southern African mv Clinicians Society CLINICAL GUIDELINES ANTIRETROVIRAl THERAPY IN ADULTS June 2002 version 3. ClASSES OF ANTIRETROVlRAL AGENTS AND THEIR MECHANISMS OF ACTION THE sour rifq AFR,CA JOUR Al O~ HI MEOICI 'f 2. STANDARD OF CARE Maximally suppressive antiretroviral regimens (highly active antiretroviral therapy - HAARD should be used whenever possible in order to obtain the best clinical results and to prevent resistance. • Single-drug regimens (monotherapy) Monotherapy should not be used in the treotment of HIV infection; however, it continues to play a very important role in the prevention of mother-to-child transmission [MTCD. • Dual-drug regimens Dual therapy is moderately effective, but is unlikely to produce long-term durable benefit in most patients. It is not the standard of care, but is considerably better than no therapy and should be considered in patients unable to afford HAART. This should only be applied to patients who have already developed AIDS. In this setting, dual 'herapy is better than no therapy; otherwise resistance is a major concern if dual nucleoside therapy is prescribed to asymptomatic patients. The efficacy of two-drug combinations [dual therapy) is greater than that of monotherapy, potentially achieving a 1.5 - 1.8 log reduction in viral load. Note that triple combinations are the standard of care. • Triple combinations The combination of three synergistic antiretroviral agents remains the standard of care; substantial reductions in medication prices continue to make triple-drug regimens more affordable. Currently available antiretroviral agents [Table I) inhibit one of two key viral enzymes required by HIV for intracellular viral replication: • reverse transcriptase, which is essential for completion of the early stages of HIV replication, and • protease, which is required for the assembly and maturation of fully in'eetious viral progeny. 1. GOALS OF THERAPY The magnitude of HIV infection in southern Africa and the number of impoverished people who desperately need antiretroviral therapy [ARD but will never receive it is overwhelming, and unparalleled in the history of infectious diseases. Lifetime costs associated with antiretroviral therapy and political intransigence remain the most important obstacles to adequate management of HN infection in many countries, including South Africa, where the availability of finance determines access to therapy. While the Southern African HIV Clinicians Society endorses the right of all HIV-infected adults and children to receive standard of care, it also acknowledges the serious limitations infiuencing the individual's access to effective therapy. The Southern African HIV Clinicians Society endorses the right of all HIV-infected adults and children to receive an optimal standard of care and supports all initiatives that improve access to effective therapy. As knowledge and understanding of the use of antiretroviral therapies is still evolving and new therapeutic agents are becoming available, guidelines are reviewed and updated regularly. The most current version should always be consulted. This is achieved by suppressing viral replication as intensely as possible for as long as possible by using tolerable and sustainable treatment for an indefinite period of time. By doing so, the impact of HIV on the immune system may be minimised and the morbidity and mortality associated with HIV infection can be improved. The primary goals of antiretroviral therapy are: • maximal and durable suppression of viral load • restoration and/or preserva ion of immunological function • improvement of quality of life, and • reduction of HIV-related morbidity and mortality. Effective therapy has been shown to reduce the number of new cells infected by HIV and to impede the ability of the virus to evolve drug resistance. JULY 2002 ------------- TABLE I. ClASSES AND MECHANISMS OF AcnON OF ANTIRETROVlRAL AGENTS Qassification of Enzyme antiretrovil'3l agent Abrev. inhibited Specific action Nucleoside reverse NRTls Reverse Mimics the normal transcriptase inhibitors transcriptase building blocks of HIV DNA Non-nucleoside reverse NNRTls Reverse Directly inhibits transcriptase inhibitors transcriptase reverse transcriptase Protease inhibitors Pis Protease Inhibits late stages of HlV replication THf SOUTHtRN MRICAN JOURNAL Of HIV MfOICINf Protease inhibitors Yes Yes Unknown· No Yes Yes No Yes No No Rare NRTI NNRTI Yes No Yes Yes Yes No Yes No Rare, but Yes potential for anaphylaxis with abacavir Yes Unknown- Yes No Unknown- Yes Unknown- Yes: efavirenz No No No Yes: efavirenz Myelosuppression GI intolerance Pancreatitis Peripheral neuropathy Allergic reaction Side-effect I complication [jpoatrophy lactic acidosis [jpodystrophy Raised cholesterol and triglyceride Insulin resistance Neuropsychiatric manifestations 7. INDICATIONS FOR STARTING ANTIRETROVIRAL THERAPY • Attack the virus at multiple anatomical sites using drugs that can penetrate different cellular and body compartments. • Malt:' darn miuir~ Efavirmz {Stocrinl is teratogt:'flic and shou.ld be: avoidt:'d in womm of chiJd~ring potential unlt:'SS they art:' using aOt:'qllatt:' imramuscu!ar progt:'StOgens and oarrit:'! rontraetp~ and only wht:'ft:' no other antirt:'trovirals art:' ava~ablt. 5tavudint:' (Zt:'rit) and didanosint:' (Vidod art contraindicattti in pregnancy and lactation. Faraliti~ dut to lactic acidosis have been reportro. TABLE Ill. SIDE-Effiffi AND COMPUCATIONS OF ANTlRETROVlRAL AGENTS Drug therapies that do not sufficiently suppress viral replication invariably allow the emergence of resistant viral strains. Resistant virus compromises future therapy for the patient and poses a significant public health challenge as it may be disseminated into the community. Antiretroviral therapy should be deferred until patients are prepared to commit themselves to long-term treatment and to maintaining good adherence to the therapy. All infected individuals. including those on effective antiretroviral therapy, should be viewed as potentially infectious. Adequate counselling about safer sex practices must be provided to encourage prevention of new in ections and reinfection. Generic name Trade name Class of drug Zidovudine (AZT) Retrovir· NRTI Didanosine (ddl) Videx" NRTI Zalcitabine (ddCj Hivid NRTI Lamivudine (3TCj 3TC" NRTI Stavudine (MD Zerir NRTI Abacavir Ziagen" NRTI Nevirapine ViramuneO NNRTI Efavirenz Stocrin NNRTI Nelfinavir Vira-cept" PI Indinavir Crixivan PI Ritonavir Norvir· PI Saquinavir (hard~el Invi-rase PI formulation) Saquinavir (soft-gel Forto-vase PI formulation] Amprenavir Predir· PI lopinavir/ritonavir Kaletra PI • Ava~ablt:' in ~atric foonutations.. TABLE 11. ANTIRETROVIRAL AGENTS CURRENTLY AVAILABLE IN SOUTH AFRICA 5. MAJOR SIDE-EFFECTS AND COMPUCATIONS OF CLASSES OF ANTIRETROVIRAL AGENTS 4. ANTlRETROVIRAL AGENTS CURRENTLY AVAILABLE IN SOUTH AFRICA 6. STANDARD OF CARE Note: Always refer to the most current version of the Guidelines as new treatments regulorly become ovoiloble for clinical use (see Table If). The tolerability of antiretroviral regimens remains one of the important determinants of treatment success. Some of the more common currently recognised side-effects and complications of these agents are listed in Table Ill. The consequences of changing antiretroviral therapy need to be carefully considered before substituting or stopping specific agents. Effective combination therapy should enable the following: • Additive or synergistic antiviral activity. • The delay in, or prevention of. emerging drug-resistant viruses. JULY 2002 ART INTERACTIONS WITH RIFAMPION 8. LABORATORY MONITORING Notes on concomitant tuberculosis Assay Dynamic range Volume required Quantiplex HN- 1 < 50 - > 500000 5 ml EDTA tube RNA 3.) bONA [purple top) AMPICLOR PCR < 400 - > 750 000 200 ~I EDTA plasma HN-l ,1.5 < 50 - > 75000 500 ~I EDTA plasma lCx HIV RNA aT 50 - 1 000 000 200 ~I EDTA plasma 178 - 5000000 500 ~I EOTA plasma NucliSens aT 400 - 10 000 000 200 ~I EDTA plasma 40 - 10000000 500 ~I EDTA plasma THE SOUmqN AHLCAN JOUR AL OF HIV MEDICINE 9.1 Criteria for treatment success • A decline in viral load of at least 1 log from pretreatment levels by 6 - 8 weeks after initiating ART. • A decline in viral load to < 400 RNA copies/m I by 24 weeks after commencemen of therapy. 9. OUTCOMES OF ART 10. INITIAL ANTlRETROVlRAL REGIMENS FOR THE PREVIOUSLY UNTREATED PATIENT • NucliSens, and • LCx. Note: Inadequote patient odherence to the prescribed regimen remains one of the most common reasons for treatment foi/ure. Note: A sustained viral load of < 50 RNA copies/ml is associated with the most durable viro/ogicol benefit. ---------~~--------- ASSAyruBES The article on p. 38 covers anomalies. Monitoring of viral load and CD4+ cell count is covered in full in the article on p. 38. Comparable results are obtained with the first three methods; experience is currently more limited with the LCx assay. It is recommended that the same method be used for sequential testing in an individual patient. 9.2 Criteria indicative of treatment failure These guidelines define virological failure as: • A sustained increase in viral load > 5 000 copies/m!. • A decline in viral load of less than 1 log within 6 - 8 weeks after commencing antiretroviral therapy. • A sustained increase in viral load of> 0.6 log from its lowest point or a return to 50'¥0 of pretreatment value. Several 'actors can infiuence the measure men of HIV viral load. I is strongly recommended that the decision to alter therapy should be based on the results of at least two consecutive viral load measurements performed at least 1 week apart. Initial regimens for treatment-naTve patients should comprise combinations of drugs that are expected to Treatment recommended Treatment Treatment recommended Monitor CD4+ count and commence treatment if the CD4 annual decline is in excess of the expeered 20 - 80 cells/year. or if the CD4 count approaches 200/~1 Defer treatment Treatment Treatment recommended Symptomatic patient Presence of HN-related symptoms, current or previous HIV-associated disease" Primary infection t Asymptomatic patient C04+ count < 2ooJ~1 C04+ count 200 - 350/~1 CD4+ count > 350/~1 NRTls No in eractions Efavirenz Mild reduction in efavirenz levels - some experts increase the dose to 800 mg Nevirapine Moderate reduction in nevirapine levels - limited experience Ritonavir (full dose) No significant interaction Ritonavir + No significant interac ·on saquinavir (both 400 mg bid) All other Pis Marked reduction in PI levels - avoid ~ include A1DS- 10l1J of body weight, unexplain~ dlarrh~ lasting> 1 month, oral candidiasis or oral hairy kukoplakia. tPrimary infection. HAART startro early in primary infection t!:'ads to virat suppr~sion which appears to maintain HIV-spttific immunity in a significant proportion of cases, who b«om!:' slow pr09r~fs with a Jow yiral toad after discontinuing HMRT. Th!:' duration of treatment is uncertain at the present time- • TB should always be managed by public sector TB clinics. • If the patient is already on antiretroviral therapy the regimen should if possible be changed to be compatible with rifampicin. • If the patient's CD4+ count is > 200/~1, commence antiretroviral therapy after completing tuberculosis therapy (provided the patient fulfils the criteria above). • If the CD4+ count is < 200/~1 delay antiretroviral therapy until after the intensive phase of tuberculosis therapy (2 months) unless the patient has other serious HN-related illness or has a very low CD4+ count, in which case antiretroviral therapy should be introduced only once the patient is stabilised on tuberculosis therapy. Four laboratory methods are available for determining viral load: • AMPICLOR PCR • Brancheo DNA JULY 2002 'Teratogenic - should be avoided in womtn of chil~rin9 potential unl~ using adequate: intramuscular ptClgl!Stogens and barrier COl1tra~tives. and only where no other antireuovirals are av.;ilable.. TABLE IV. ANTIViRAl REGIMENS FOR THE PREVIOUSLY UNTREATED PATIENT C.tegory III Ab.c.vir (ABCl C.tegory V Nelfin.vir (NPV) Indin.vir (!DV) Ritonavir [RI\/) Saquinavir [SQV) [soilgel formulation) LopinavirJritonavir combination New agent Stavudind Zidovudinet Lamivudine or zalcitabine Didanosine· or zalcitabine· Abacavir, sravudine or zidovudine or other as determined by resistance testing Determined by resistance testing C.tegory IV Nevir.pine (NVP) Ernvirenz (Ef\/)' Zidovudine Stavudine Didanosine lamivudine Zalcitabine Initial agent Abacavir 9.2 Changing non-nucleoside reverse transcriptase inhibitors (category IV) 'May exhibit reductd activity dut: to crOSHesimnce with lamivudine 13TC1. tMay exhibit cross-resistan~ 9.1 Changing nucleoside reverse inhibitors (categories I, 11 and Ill) (Table V)) TABLE V. CHANGING NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS There is broad cross-resistance between the currently available NNRTls. Resistance to one NNRTI precludes the use of another, unless there are resistance test data to the contrary. Individuals in whom an NNRTI-containing regimen fails may be candidates for an abacavir-containing triple-nucleoside combination (if the viral load is < 55000 RNA copies/ml) or a protease-inhibitor containing regimen. Resistance to one agent of this class effectively results in cross-resistance to all members of drugs in this category (that are currently available in South Africa). Sequential use of these drugs is not recommended. THE SOUTHfRN MRICAN JOURNAL OF HIV MfOI'I'E Changing protease inhibitors (category V) A major reason for failure of regimens that contain pro ease inhibitors is suboptimal pharmacokinetics and inadequate drug exposure as a result of poor adherence (often due to intolerance). This needs to be considered carefully before deciding to introduce an alterna ive PI- containing regimen. Second-line protease inhibitor alternatives may exhibit reduced activity due to extensive cross-resistance within this class of drugs. Pharmacological boosting of protease blood levels can be achieved by combining amprenavir, saquinavir and indinavir with low Category 11 Did.nosine (ddl) lalcit.bine (ddC) Lamivudine [3TC) C.tegory I St.vudine (d4D Zidovudine (AlT) For initiation of ART therapy prescribe two NRTls and an NNRTI (one drug from category I, one from category 11, and one from category IV). If the viral load is < 55 000 copies/ml a third NRTI (from category Ill) may be considered as par of a triple NRTI regimen. In accordance with WHO and UNAIDS recommendations, these guidelines endorse the use of NRTls and NNRTls as first-line therapy. The importance o' adherence must be clearly explained to the patient and reinforced at every visit. Institution of antiretroviral therapy is never an emergency in the setting of established infection. Practitioners should take sufficient time and care to prepare themselves and the patient for an inteNention that may be lifelong. Treatment should only be changed as soon as possible in the following situations: • patient intolerance despite adequate and appropriate inteNention • Significant side-effects • treatment failure, as defined in 9.2 above. achieve the abovementioned treatment goals. These are shown in Table IV. 12. OPTIONS FOR CHANGING THERAPY Particular consideration should be given to those factors that may affect patient adherence, such as the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile. 11. INDICATIONS FOR CHANGING THERAPY Table V contains recommendations for changing therapy when drug resistance emerges; the caveats listed above apply. When virological failure occurs it is essential to change at least two of the drugs in the patient's regimen when possible, The clinician may choose to be guided by genotypic or phenotypic resistance testing. JULY 2002 Chairperson of Adult Guidelines Committee Or Steven Miller Expert Panel Members Steven Andrews, Mark Cotton, Gary Maartens, Des Martin, Steven Miller, Robin Wood, Dave Spencer, Francois Venter International Reviewers Pedro Cahn, David Cooper, Brian Gazzard, Stefana Vella T~E SoUT~tRN AFRICA JOURNAL or ~IV MEDICINE ------------ JULY 2002 Disclaimer: Specific recommendations pravided in this dacument are intended only as a guide to clinical therapy, based on expert cansensus and best current evidence. Treatment decisions for patients shauld be made by their responsible clinicians, with due consideration for individual circumstances. The most current version af this document should always be consulted. 13. TREATMENT DECISION SUPPORT doses of ritonavir. Experience with these combinations is limited and advice on dosing should be sought. For specific advice and assistance in using these guidelines, please contact the Southern African HIV Clinicians Society bye-mail: sahivsoc@iafrica.com