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4CLINICAL GUIDELINES: ANTIRETROVIRAL THERAPY4.1 Preparing people living with HIV for ART 724.2 What to expect in the ˜rst months of ART 744.3 When to start ART .744.4 What to start: ˜rst-line ART 974.5 Monitoring the response to ART and diagnosing treatment failure 1274.6 Monitoring of and substitutions for ARV drug toxicities .1364.7 Key ARV drug interactions 1474.8 What ART regimen to switch to (second- and third-line ART) .150
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724.1 Preparing people living with HIV for ARTBefore people start antiretroviral therapy (ART), health-care providers should initiate a detailed discussion about the willingness and readiness of patients to initiate ART, the antiretroviral (ARV) drug regimen, dosage, scheduling, likely benefits, possible adverse effects and the required follow-up and monitoring visits. In the case of children with HIV, this conversation should directly involve the caregiver and include discussion about disclosing their HIV status. Retesting all people living with HIV before initiating ART is recommended to ensure a correct diagnosis of HIV infection. Initiation of ART should always consider nutritional status, any comorbidities and other medications being taken to assess for possible interactions, contraindications and dose adjustment. The choice to accept or decline ART ultimately lies with the person or his or her caregiver, and if they choose to defer initiation, ART can be offered again at subsequent visits. If the person faces mental health or substance use issues or other potential barriers to ART initiation or adherence, appropriate support should be provided and readiness to initiate ART should be reassessed at regular intervals. Community and peer support can help a person to prepare and make the decision to start therapy. People starting treatment and carergivers should be informed that the first ART regimen offers the best opportunity for effective viral suppression, immune recovery and consequently clinical benefit and that successful ART requires all medications to be taken as prescribed. It is important to acknowledge that there are situations where delays in starting ART can have negative consequences, particularly for people with tuberculosis (TB) or advanced immunosuppression, who are at high risk of death. People should be advised that many adverse effects are temporary or may be treated, and that substitutions can often be made for the ARV drugs associated with adverse effects. In preparation for treatment initiation, it is important to assess the need for psychosocial support to optimize adherence. People receiving ART and caregivers should also be asked regularly about any other medications that are being taken, including herbal remedies and nutritional supplements. People commencing ART should be given advice on safer sex, including condom use and avoidance of other high-risk activities such as sharing of injecting equipment, to prevent transmitting HIV to other people. 4 CLINICAL GUIDELINES: ANTIRETROVIRAL THERAPY
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734.1.1 Accelerated ART initiationGood practice statementEfforts should be made to reduce the time between HIV diagnosis and ART initiation based on an assessment of a person™s readiness. ART initiation is often seen as a non-emergency intervention, and various approaches are used to help prepare people to begin treatment. However, there is increasing recognition of the benefits of accelerated ART initiation, for example, in pregnant women, in order to avoid unacceptably high rates of loss to follow-up after HIV diagnosis. However, concerns remain that accelerated initiation of ART may lead people to start before they are ready, with adverse consequences for adherence and treatment outcomes. Current implementation experience of rapid ART initiation is largely derived from experience with option B+ (lifelong ART for all pregnant and breastfeeding women). Although ART initiation in these programmes is not necessarily on the same day as testing, the majority of women initiate treatment within a short space of time. Of nearly 22 000 women who started ART under option B+ in Malawi, 17% were lost to follow-up six months after ART initiation. Loss to follow-up was highest among women who began ART at large clinics on the day they were diagnosed with HIV (1).A systematic review (2) identified two ongoing studies that evaluated accelerated ART initiation, including treatment initiation on the same day as HIV diagnosis to reduce loss to follow up. The Rapid Initiation of Antiretroviral Therapy to Promote Early HIV/AIDS Treatment in South Africa (RapIT) study randomized individuals to rapid initiation versus standard care (3). Preliminary data showed a relative risk of 1.33 of initiation of ART in 90 days, with a risk difference of 24% (73% in the standard-of-care arm compared to 97% in the rapid initiation arm). The START-Streamlined Initiation trial is examining accelerated ART initiation in Uganda (4). START components include (i) real-time point-of- care CD4 testing, (ii) targeted knowledge transfer to health-care workers and (iii) feedback and reporting to the clinic and providers. Findings from community consultations show that early ART initiation is acceptable, but universal same-day ART initiation following HIV diagnosis is considered to be challenging because of the wide variation in individuals™ understanding of the implications of test results and preparedness to commence lifelong treatment (5). There is a perceived difference in motivation to start ART when sick compared to when healthy. While these guidelines recommend initiation of ART in all people with HIV regardless of CD4 cell count or disease stage, and preliminary data suggest that accelerated ART initiation is possible, the available data are currently inadequate to support a recommendation in these guidelines in favour of same-day or otherwise accelerated ART initiation.
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74The following principles may inform future guidance. Ł Treatment should be started based on a person™s informed decision to initiate ART. Ł Interventions to remove barriers to ART initiation once an individual is diagnosed HIV positive should be implemented. Ł HIV programmes should promote treatment literacy among all people with HIV, including information on the bene˜ts of early treatment, the lifelong commitment required, the risks of delaying treatment and available adherence support. Ł Care providers should be trained to support shared decision-making.Ł Although ART initiation is rarely urgent, it may need to be expedited in certain circumstances, such as serious ill health and for pregnant women in labour whose HIV test result is positive. 4.2 What to expect in the ˜rst months of ARTAlthough ART is a lifelong commitment, the ˜rst months of therapy are especially important. Clinical and immunological improvement and viral suppression are expected when individuals adhere to ART, but opportunistic infections (OIs) and/or immune reconstitution in˚ammatory syndrome (IRIS) may develop, as well as early adverse drug reactions, such as drug hypersensitivity, especially in the ˜rst three months of treatment. ART signi˜cantly decreases mortality overall, but death rates are also highest in the ˜rst three months of ART. These complications are most common when the people starting ART already have advanced HIV disease with severe immunode˜ciency and existing coinfections and/or comorbidities, severely low haemoglobin, low body mass index and very low CD4 cell counts or are severely malnourished (6,7). Poor adherence in this period is also associated with the risk of early treatment failure and rapid development of drug resistance. 4.3 When to start ART4.3.1 When to start ART in adults (>19 years old)RecommendationŁ ART should be initiated in all adults living with HIV, regardless of WHO clinical stage and at any CD4 cell count (strong recommendation, moderate-quality evidence). Ł As a priority, ART should be initiated in all adults with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and adults with CD4 count ˛350 cells/mm 3 (strong recommendation, moderate-quality evidence). Sources : Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: World Health Organization 2015 (http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach Geneva: World Health Organization; 2013 (http://www.who.int/hiv/pub/guidelines/arv2013/download/en).
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75BackgroundSince they were first published in 2002, WHO guidelines on ART have evolved as the body of evidence to support earlier initiation of ART has grown (8). The 2013 WHO ARV guidelines recommended initiating ART for all adults with HIV and a CD4 count at or below 500 cells/mm3, regardless of WHO clinical stage, giving priority to those with severe or advanced HIV disease (WHO clinical stage 3 or 4) or a CD4 cell count at or below 350 cells/mm3 (9). This strong recommendation was based on moderate-quality evidence from three randomized controlled trials (10Œ12) and 21 observational studies (13Œ34), showing that initiating ART at or below a CD4 threshold of 500 cells/mm 3 compared with later initiation reduced the risk of progression to AIDS and/or death, TB and a non-AIDS-defining illness and increased the likelihood of immune recovery. In addition, high-quality evidence from one randomized controlled trial indicated that earlier ART can markedly reduce the risk of sexual transmission to HIV-negative sexual partners in heterosexual couples (11).Mathematical models and ecological studies also suggested that initiating ART earlier could affect HIV incidence at the population level if there is high uptake and sustained HIV testing, ART coverage and retention (35Œ39). For people with certain clinical conditions Œ TB, hepatitis B virus (HBV) coinfection requiring HBV treatment and during pregnancy and breastfeeding Œ and for HIV-serodiscordant couples, the 2013 guidelines recommended initiating ART regardless of WHO clinical stage or at any CD4 cell count. Global ART coverage for all people living with HIV had reached approximately 41% Œ or 15 million people Œ by March 2015 (40). According to the WHO Country Intelligence Database, by June 2014, 60% of the 58 WHO HIV focus countries had adopted the CD4 threshold of 500 cells/mm3 or less for initiating ART and 7% had already moved the CD4 threshold to above 500 cells/mm3 (41). Although the median CD4 count at the time of ART initiation is increasing, it remains significantly lower than 350 cells/mm 3 in almost all settings, including high-income countries (42,43). Late presentation for treatment is associated with high early mortality rates, higher direct health-care costs and poor retention in care (44Œ46). Increasing knowledge of HIV status, strengthening links between testing and care, modifying health systems to manage patient volumes and ensuring optimal long-term retention and adherence remain significant challenges in many settings (47).Rationale and supporting evidenceInitiating ART among all adults living with HIV regardless of WHO clinical stage or at any CD4 cell countSince 2013, evidence and programmatic experience have continued to favour earlier initiation of ART because it results in reduced mortality, morbidity and HIV transmission outcomes. Increasing evidence from systematic reviews and cohort analyses also indicates that untreated HIV infection may be associated with the development of several non-AIDS-defining conditions, including cardiovascular, kidney and liver disease, several types of cancer and neurocognitive disorders (48Œ51), and that initiating ART earlier reduces such events and improves survival. Recent evidence from a large randomized controlled trial also shows that, as demonstrated for heterosexual serodiscordant couples, ART substantially reduces sexual transmission to HIV-negative sexual partners among homosexual couples (52).
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76The recommendation to initiate ART at any CD4 cell count was based on a systematic review with Grading of Recommendations, Assessment, Development and Evaluation (GRADE) evidence pro˜les that assessed the quality and strength of the evidence from one randomized controlled trial (53) and 17 observational studies (18,19,22Œ26,28,30,34,37,54Œ59) reporting clinical, immunological) reporting clinical, immunological and virological outcomes and HIV transmission. In the analysis of data from the single randomized controlled trial (TEMPRANO), moderate-quality evidence (downgraded from high quality because of imprecision) showed that initiating ART at a CD4 cell count above 500 cells/mm 3, in the absence of other treatment indications, leads to less severe HIV morbidity (combined outcome of death, AIDS and severe non-AIDS diseases such as malignancies and bacterial diseases) compared with treatment initiation at a CD4 cell count at or below 500 cells/mm3 (53).Data from another randomized controlled trial (START study), although supportive of the new recommendations, were unpublished at the time of the Clinical Guideline Development Group meeting for these guidelines (60). The START study was planned for completion in 2018, but after an interim analysis in mid-2015, the trials Data Safety Monitoring Board advised immediate dissemination of the findings because of predefined stopping rules. Data from this study could not be incorporated into the systematic review or GRADE table because the comparison groups did not match the review population, intervention, comparator and outcome question (PICO) and therefore could not be considered in relation to the quality of the evidence. Box 4.1 summarizes the study™s key findings. Box 4.1. Strategic Timing of Antiretroviral Treatment (START) study The study enrolled 4685 people with CD4 counts higher than 500 cells/mm 3 at 215 sites in 35 countries. Twenty-seven per cent of the participants were women and approximately half were men who have sex with men. The study examined the rates of serious AIDS-defining illness or death among people who were randomized to receive immediate ART versus deferred ART (until their CD4 count dropped below 350 cells/mm 3). The median baseline CD4 count was 651 cells/ mm 3 in the intervention group that initiated ART at enrolment. In the deferred group, the median CD4 count at ART initiation was 408 cells/mm 3. Follow-up lasted for a mean of 3 years. A total of 86 events (death, serious AIDS events and serious non-AIDS events) occurred among those with later treatment initiation, whereas 41 events occurred among those who started ART immediately, representing a 57% reduction in negative outcomes among those treated early. In both groups, most events occurred when CD4 counts were higher than 500 cells/ mm 3. The study also showed that immediate ART reduced both serious AIDS- related and serious non-AIDS-related events, but the benefit was greater for AIDS events. TB, Kaposi sarcoma and lymphoma Œ the most common AIDS-related events Œ all occurred less frequently in the immediate ART group. Cancer rates (combined AIDS and non-AIDS malignancies) were lower in the immediate ART group, but cardiovascular disease rates were similar between the groups. The occurrence of drug-related adverse events was not significantly different between the two groups. These effects were consistent in countries at different income levels and across geographical regions.
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78Initiating ART among adults with severe or advanced HIV disease or with a CD4 count at or below 350 cells/mm3 as a priorityThe benefits of initiating ART are greatest among individuals with symptomatic HIV disease or those with lower CD4 cell counts. The strength and quality of evidence for this recommendation established in the 2010 WHO guidelines on Antiretroviral therapy for HIV infection in adults and adolescents (65) remains unchanged. Moderate-quality evidence from two randomized controlled trials and several observational studies shows that initiating ART at CD4 counts at or below 350 cells/mm 3 significantly reduces mortality, disease progression and the incidence of OIs, especially TB and non-AIDS- defining conditions (66). Furthermore, several studies and programmatic data suggest that late diagnosis (often defined as a CD4 count at or below 350 cells/mm3) and late treatment initiation are very common, even in high-income settings (67,68).Comparing bene˜ts and harmThe benefits of earlier ART initiation include fewer events caused by severe HIV morbidity and disease progression, improved uptake and initial linkage to care, better immune recovery and decreased HIV transmission. Despite being statistically significant, the comparative outcome differences among study arms with higher baseline CD4 cell counts (e.g. CD4 counts between 350 and 500 cells/mm 3, compared to those with CD4 counts over 500 cells/mm3) were modest. Furthermore, not all observational studies have consistently demonstrated the beneficial effect of initiating ART at a CD4 cell count at or above 500 cells/mm3 on mortality, the incidence of inflammation-related non-AIDS events and ongoing viral replication, compared with initiation at CD4 count at or below 500 cells/mm3. Concerns have also been expressed that, given limited resources, very early treatment could result in some people who urgently need treatment being displaced by those for whom treatment would be beneficial but is less urgently needed. The long-term safety profile of ART and the implications of earlier treatment initiation on drug resistance, toxicity, adherence and retention need to be closely monitored. Follow-up will be needed to evaluate the potential harm and benefits of ART over a lifetime. It is increasingly recognized that, in settings with a high burden of HIV and TB infections, increasing ART coverage is associated with decreasing TB case notifications, and this is likely to improve when ART is started earlier. A modelling study based on national cohort data from four countries in sub-Saharan Africa concluded that programmatic gains and mortality reduction were accrued by eliminating the pre-ART period, suggesting that making treatment available to everyone will strengthen the continuum of care (69).Cost and costŒeffectivenessThe same modelling study indicates that expanding the ART eligibility criterion to above 500 cells/mm3 or regardless of CD4 cell count and linking to HIV care could result in 6Œ14% fewer people dying from HIV-related causes during the next decade (69). In this study, the majority of the impact is caused by programmatic simplification, leading to more people initiating ART in a timely manner and therefore avoiding adverse outcomes during the pre-ART period rather than direct therapeutic benefits. The increased cost of earlier ART would be partly offset by subsequent reduced costs (such as decreased hospitalization and increased productivity) and preventing people from acquiring HIV
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79infection. The modelling suggests that such a change is likely to be costŒeffective in many settings if individuals initiating ART are adherent to treatment and retained in care. Costs will increase significantly but will be far less than if the additional outreach interventions required for maintaining people in pre-ART care are also included. According to estimates by the Joint United Nations Programme on HIV/AIDS (UNAIDS), expanding ART to all people living with HIV is projected to avert 21 million AIDS-related deaths and 28 million new infections by 2030 (70). However, these benefits require high testing uptake, high treatment coverage, sustained adherence and high rates of retention in care. The cost implications at the regional and country levels can also vary and should be further explored, as countries have different levels of current treatment coverage and local cost considerations, depending on their context and resources. Equity and acceptabilityDisclosure of HIV status is essential for accessing adherence support and may be particularly difficult for people who have never been ill. For this reason, initiating ART among adults with severe or advanced HIV disease or with a CD4 count at or below 350 cells/mm3 is recommended as a priority in these guidelines. Additional concerns that mandatory or coercive approaches will be used among at-risk marginalized populations highlight the importance of adequate patient information, informed consent, appropriate health worker training and rights-based legal frameworks to facilitate access. A community-led global consultation examined the acceptability of earlier initiation of ART at a higher CD4 count for people living with HIV, caregivers and service providers and found that earlier initiation was considered acceptable (5). Participants in the consultation emphasized the need for collaborative decision-making with service providers to ensure that the ultimate decision to initiate ART rests with the person living with HIV. Motivation to start and adhere to treatment may be more difficult for people who feel well and have higher CD4 counts than for people who are or have been ill. Stigma and discrimination continue to act as barriers to treatment access and adherence. Critical factors in promoting ongoing engagement in care and adherence include ensuring a stable supply of free or affordable ARV drugs, facilities that are easily accessible and that ensure confidentiality, sympathetic providers and appropriate adherence support. A qualitative literature review showed that acceptability of earlier treatment is greater when people know that treatment reduces mortality risk. Service providers recognize the clinical and preventive benefits of earlier ART and the need for earlier ART initiation for asymptomatic people. Among people living with HIV, acceptance increases when they also have comorbidities or conditions associated with a higher risk of HIV transmission. Issues cited in the literature supported those identified in community consultations (71). Feasibility According to cohort and national programme data, the number of people needing treatment could increase by up to 35% if ART is initiated at any CD4 count rather than at or below 500 cells/mm3 (70). Modelling estimates predict that this increase would be lower, in the range of 7Œ21% over five years, because not all people living with HIV are diagnosed and therefore, unlikely to initiate care and treatment immediately. Country experience has also shown that moving to a higher CD4 threshold for ART initiation may not necessarily lead to a significant immediate increase in the number of people who
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80actually access treatment unless there is also increased uptake of HIV testing, stronger linkage to care, adequate treatment monitoring and sustained adherence support. Late presentation for treatment is still common, with the median CD4 count at ART initiation being below 350 cells/mm3 in the majority of settings, including in high-income countries (66,67).Implementation considerationsRegardless of the epidemic profile and disease burden, priority should be given to people with symptomatic HIV disease or with a CD4 count at or below 350 cells/mm3 who are at high risk of mortality and most likely to benefit from ART in the short term. Initiating ART at CD4 counts above 500 cells/mm 3 may involve the need for additional human, infrastructure and financial resources. Countries have different health system capacity and are at different levels of ART coverage and programme quality. A phased approach to implementation may be needed, especially in settings with a high burden of HIV, low ART coverage, low rates of testing, modest pre-ART care, scarce human resources, limited laboratory capacity, budget constraints and/or competing health priorities. In such settings, equity considerations and giving priority to those who most need treatment should guide implementation (see section 8.2 ﬁDissemination and implementationﬂ).The increased need for ART associated with early initiation may place demands on the health system in some settings, which could increase the risk of drug resistance, such as drug stock-outs, insufficient patient preparation and suboptimal adherence. To maximize the long-term effectiveness of first-line ART regimens and ensure that people are taking the most effective regimen, the scaling up of ART should be accompanied by measures to monitor and improve service quality at the site and programme levels (see sections 6.12 ﬁImproving the quality of HIV care servicesﬂ and 6.13 ﬁProcurement and supply chain managementﬂ).In all settings, continued monitoring will be needed of the long-term safety profile of ARV drugs, and the implications of earlier initiation for drug resistance, toxicity and adherence. It also remains essential to address the structural and social barriers to accessing treatment faced by key populations, such as criminalization, stigma and discrimination (72Œ74).Research gapsSeveral ongoing implementation trials are evaluating the feasibility, acceptability, costŒ effectiveness and impact of immediate treatment for all people living with HIV regardless of CD4 cell count at the population level (SEARCH and MaxART studies) (75,76). Primary outcome results are not expected before 2017 or 2018. Three large randomized trials are examining the population effect of early ART initiation on HIV incidence and mortality (Botswana Combination Prevention Trial, HPTN-071 [PopART] study and 12249 ANRS TasP trial), with results expected after 2016 (77Œ79).Other research priorities include assessing the incidence of short- and long-term severe adverse events as a result of increased exposure to ART, barriers to and enablers of adherence and long-term retention in care, the impact of early initiation of ART on the cascade of care and the magnitude of the prevention benefit, especially among key populations and adolescents.
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814.3.2 When to start ART in pregnant and breastfeeding womenRecommendationART should be initiated in all pregnant and breastfeeding women living with HIV regardless of WHO clinical stage and at any CD4 cell count and continued lifelong (strong recommendation, moderate-quality evidence). Source: HIV and adolescents: guidance for HIV testing and counselling and care for adolescents living with HIV. Geneva: World Health Organization; 2013 (http://www.who.int/hiv/pub/guidelines/adolescents/en). BackgroundProgrammes for the prevention of mother-to-child transmission (PMTCT) were some of the earliest public health interventions that used ARV drugs to reduce the risk of acquisition of HIV. Initially, the regimens recommended by WHO were short courses or single doses of ARV drugs given to the mother and to the infant in the first few days of life. With the scaling up of national HIV programmes from 2003, WHO guidelines made an important shift, recommending that pregnant women living with HIV should be assessed for treatment eligibility and those considered eligible for treatment should be offered lifelong combination ART for their own health, while those who were not eligible should receive short courses of ARV prophylaxis for PMTCT. Although eligibility criteria have changed and the preferred regimens for ART and for PMTCT prophylaxis have evolved, this distinction between treatment and prophylaxis became a fixture of PMTCT programmes. In 2013, the WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (9) recommended that all pregnant and breastfeeding women should be initiated on ART regardless of clinical eligibility. This recommendation was supported by programmatic experience (including from Malawi, which has pioneered universal ART access for all pregnant women), demonstrating that prophylaxis for PMTCT (using different drugs at different times in the course of pregnancy, labour and delivery, as well as long duration of infant prophylaxis while breastfeeding) was more challenging to implement in the field than giving ART to all pregnant women (especially if the ART regimen was a once-daily fixed-dose combination tablet). However, the 2013 WHO guidelines (9) still offered programmes the option to either continue ART lifelong in all women (option B+) or to stop ART after the period of mother-to-child transmission risk in women who did not otherwise meet eligibility criteria (option B). Option B+ was considered to be of the greatest benefit in settings with a high HIV prevalence, high fertility and long duration of breastfeeding, in which initiating ART in all pregnant and breastfeeding women would reduce HIV incidence and prevent HIV transmission in both current and future pregnancies. Following the release of the WHO 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (9), many countries adopted option B+ as the preferred approach for PMTCT programmes in both high- and low-prevalence settings. The 2014Œ2015 Global AIDS Response Progress Report showed that the majority of countries, including almost all the 22 high-priority countries included in
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