The editorial staff When to start: guidelines comparison The optimal time to begin antiretroviral therapy remains a critical question for the HIV field, and consensus about the appropriate CD4+ cell count at which to start therapy has evolved in response to emerging data. Experts agree that therapy is indicated at CD4+ cell counts < 350 cell/mm 3 to prevent progression of HIV disease and the risk of opportunistic infection (OI). However, at CD4+ cell counts > 350 cells/mm 3, there is more diversity of clinical opinion over the extent to which benefits might outweigh risks of initiating therapy. In BHIVA 2008 Guidelines, the rationale for treating with antiretroviral drugs in primary HIV infection is as follows: (1) Preservation of specific anti-hiv immune responses that would otherwise be lost, and which are associated with long-term nonprogression in untreated individuals. (2) Reduction in morbidity associated with high viraemia and CD4 depletion during acute infection. (3) Reduction in the risk of onward transmission of HIV. Multiple studies have shown conflicting results of therapy, with varying short-term effects on immunological markers, viral load and CD4 lymphocyte count. However, in order to make a firm recommendation, the results of a randomized prospective study are needed. The Medical Research Council (MRC) SPARTAC study is fully recruited and initial results are anticipated in the next few months. In the meantime, treatment in primary infection (outside a prospective study) should only be routinely considered in those with: - neurological involvement - any AIDS-defining illness - a CD4 cell count persistently <200 cells/ml (i.e. for 3 months or more). In the established HIV infection BHIVA 2008 Guidelines recommendation is that the initiation of therapy should be recommended in all patients with a CD4 count of <350 cells/ml (confirmed on at least one consecutive sample, in the absence of any obvious reason for transient CD4 depletion). Several studies have suggested that CD4 percentage may have a small additional prognostic value independently of the total CD4 cell count, although the data are conflicting. This may prompt deferral of antiretroviral treatment in some patients with CD4 counts <350 cells/ ml but high CD4 percentages, but also may support a decision to start therapy earlier in patients with absolute CD4 counts >350 cells/ml but with low CD4 percentages {e.g. <14%, where Pneumocystis carinii pneumonia (PCP) prophylaxis is indicated; some studies have indicated increased risk of disease progression in patients with CD4 percentages <15 17%}. As detailed above, at CD4 counts >350 cells/ml, multiple cohort studies have suggested that there might be benefits to ART. This is supported by data from the substudy of patients not on therapy at entry to the SMART study. Some of the previous concerns about earlier initiation of therapy have been reduced because of the availability of simpler, less toxic and better tolerated antiretroviral regimens, improved pharmacokinetic profiles and increasing options after virological failure. For the majority of patients, the absolute risk of deferring therapy until the CD4 count is <350 cells/ml is likely to be low, but in a subgroup at particularly high risk of clinical events that may be 253
254 preventable by ART, this is not the case. For all these reasons, in a small number of patients, treatment may be started or considered before the CD4 count is below 350 cells/ml, including the following: - AIDS diagnosis (e.g. Kaposi s sarcoma); any HIVrelated comorbidity; - hepatitis B infection, where treatment of hepatitis B is indicated; - hepatitis C infection in some cases, where treatment for hepatitis is deferred; - low CD4 percentage (e.g.<14%, where PCP prophylaxis would be indicated); - established CVD or a very high risk of cardio vascular events (e.g. Framingham risk of CVD>20% over 10 years). Additionally, it is likely that successful antiretroviral treatment, by reducing viral load, reduces infectivity irrespective of the current CD4 cell count, and this may be taken into account in deciding on the timing of starting treatment, particularly in discordant couples where the infected partner has a high viral load. This is likely to be an issue in a very small number of patients, and it must be stressed that antiretroviral treatment in this context would be an adjunct rather than an alternative to safer sex. In patients who do not have an AIDS diagnosis or coinfection with hepatitis B or C virus, and whose CD4 counts are above 500 cells/ml, the benefits of starting therapy remain unclear, the risk of deferring therapy is low, and we recommend that they consider enrolment in the START study, where this is an option. Whilst it has been clearly shown that HAART improves both short- and long-term prognosis, early initiation of antiretroviral drugs in the setting of comorbidity needs to be balanced against the risks associated with drug drug interactions, overlapping toxicity and the risk of immune reconstitution disease. Despite these potential disadvantages of early introduction of HAART, the recent AIDS Clinical Trials Group (ACTG) 5164 study has suggested that, in the majority of patients presenting with opportunistic disease, ART should be started early (a median of 12 days after starting treatment of the opportunistic infection in the study). This will also allow time for results from resistance tests and human leucocyte antigen (HLA)-B*5701 tests to be available before therapy is started. In patients who present with lymphoma and who are starting chemotherapy, ART should also start immediately. In EACS 2009 Guidelines, in case of Primary HIV infection (PHI), treatment is indicated if: - AIDS defining events - Confirmed CD4 <350/mm3 at month 3 or beyond Treatment should be considered if: - Severe illness/ prolonged symptoms (especially CNS symptoms) If treatment of PHI is considered, patient should be recruited into ongoing clinical trial Treatment optional, as indication relies only on theoretical considerations. In most situations, wait till month 6 (with CD4 and plasma HIVRNA monitoring) and follow criteria for initiation of treatment in chronic HIV infection. Some experts recommend treatment as a tool for prevention of HIV transmission. Duration of treatment: unknown but maybe should be lifelong. Maintain closer follow-up in case of treatment interruption. The recommendations for initiation of therapy in established naive HIV-infected patients are: Symptomatic CDC stage B and C: treatment recommended If OI, initiate as soon as possible Asymptomatic CD4 < 200: Treatment recommended, without delay. CD4 201-350: treatment recommended. CD4 350-500: - Treatment recommended if hepatitis C co-infection, hepatitis B co-infection requiring therapy, HIV-associated nephropathy or other specific organ deficiency; - Treatment should be considered if VL>10 5 c/ml and/or CD4 decline >50-100/mm 3 /year or age BHIVA Guidelines
>50 or, pregnancy, high cardiovascular risk, malignancy. CD4 > 500: - Treatment should generally be deferred, independently of plasma HIV RNA; closer follow-up of CD4 if VL > 10 5 c/ml. - Treatment can be offered if presence of >1 of the above co-morbid conditions (CD4 350-500). Whatever CD4 and Plasma HIV RNA, treatment can be offered on an individual basis, especially if patient is seeking and ready for ARV therapy On 2009 DHHS Panel opinion, randomized controlled trials provide evidence supporting the benefit of antiretroviral therapy in patients with CD4 counts of 350 cells/mm 3 or less. However, such evidence showing benefit for patients with higher CD4 cell counts is not yet available. Based on cumulative observational cohort data demonstrating benefits of antiretroviral therapy in reducing AIDS- and non-aids-associated morbidity and mortality, DHHS now recommends antiretroviral therapy for patients with CD4 count between 350 and 500 cells/mm 3. For patients with CD4 count >500 cells/mm 3, Panel members are evenly divided: 50% favor starting antiretroviral therapy at earlier stages of HIV disease; 50% view initiating therapy at this stage as optional. Panel members favoring earlier initiation of therapy base their recommendation on several recent developments: (1) report from at least one recent cohort study demonstrating survival benefit with initiation of antiretroviral therapy at CD4 count >500 cells/ mm 3 ; (2) growing awareness that untreated HIV infection may be associated with development of EACS Guidelines many non-aids-defining diseases, including cardiovascular disease, kidney disease, liver disease, and malignancy; (3) availability of antiretroviral regimens that are more effective, more convenient, and better tolerated than antiretroviral combinations no longer in use; and (4) increasing evidence that effective antiretroviral therapy reduces HIV transmission. The other 50% of the Panel members feel that current evidence does not definitively demonstrate clear benefit of antiretroviral therapy in all patients with CD4 count >500 cells/mm 3. They also feel that risks of short- or long-term drug-related complications, nonadherence to lifelong therapy in asymptomatic patients, and potential for development of drug resistance may offset possible benefits of earlier initiation of therapy. Thus, pending more definitive supporting evidence, these panel members recommend that therapy in this setting should be optional and considered on a case-by-case basis. Based on the cumulative weight of evidence described above, DHHS recommends that: Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness, or with CD4 count of < 350 cells/mm 3. Antiretroviral therapy should also be initiated, regardless of CD4 count, in patients with the following conditions: pregnancy, HIV associated nephropathy, hepatitis B virus (HBV) coinfection when treatment of HBV is indicated. Antiretroviral therapy is recommended for patients with CD4 counts between 350 and 500 cells/mm 3. The Panel was divided on the strength of this recommendation: 55% of Panel members voted for strong recommendation (A) and 45% voted for moderate recommendation (B). 255
256 For patients with CD4 counts > 500 cells/mm 3, 50% of the Panel members favor starting antiretroviral therapy (B); the other 50% of members view treatment is optional (C) in this setting. Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment, and should understand the benefits and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy based on clinical and/or psychosocial factors. Deferring antiretroviral therapy may be appropriate in some cases. However, several conditions increase the urgency for therapy, including: Pregnancy AIDS-defining conditions Acute opportunistic infections Lower CD4 counts (e.g., <200 cells/mm 3 ) Rapidly declining CD4 counts (e.g., >100 cells/ mm 3 decrease per year) Higher viral loads (e.g., >100,000 copies/ml) HIV-associated nephropathy HBV coinfection when treatment for HBV is indicated In WHO 2009 Guidelines: 1. Start antiretroviral treatment in all patients with HIV who have CD4 count <350 cells/mm 3 irrespective of clinical symptoms. 2. CD4 testing is required to identify if patients with HIV and WHO clinical stage 1 or 2 disease need to start antiretroviral treatment. DHHS Guidelines 3. Start antiretroviral treatment in all patients with HIV and WHO clinical stage 3 or 4 irrespective of CD4 count. In developing these recommendations, the panel placed high value on avoiding death, disease progression and HIV transmission over and above cost and feasibility. The recommendations are supported by moderate quality of evidence for critical patient and public health outcomes from one RCT, the CIPRA-HT001 (a single centre trial in Haiti) and one post hoc analysis nested in a RCT, the SMART trial (a multicentre study in 33 predominantly high income countries). In the GRADE profile, pooled data from these two studies provide moderate evidence that starting ART at CD4 levels higher than 200 or 250 cells/ mm 3 reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. The panel also reviewed large observational data sets from both resource limited and high resource settings which are consistent with data from the RCTs but these did not add to the overall quality of the evidence. The panel considered that starting ART earlier is feasible if introduced in a phased manner, with the speed and completeness determined by health system capacity, HIV burden, ART coverage, equity of access and funding. Considering the uncertain prognostic value of some WHO clinical stage 2 conditions and recent modelling and observational data suggesting that more than 50% of HIV-infected patients with this clinical stage have a CD4 count of <350 cells/mm 3, the panel recommended HIV-infected individuals with WHO clinical stage 1 and 2 should have access to CD4 testing to decide if treatment should be initiated. On 2010 IAS opinion, deciding to start ART requires weighing the benefits of treatment on morbidity
WHO Guidelines and mortality against its risks, including toxicity, resistance, drug interactions, and the costs and inconvenience of lifelong treatment. Sustained viral suppression restores and preserves immunologic function, decreasing opportunistic diseases and mortality. IAS Guidelines The patient must be ready and willing to adhere to lifelong therapy. Advances in ART continue to shift the therapeutic risk-benefit balance to earlier treatment. Improvements in potency, toxicity and tolerability, and pill burden allow for durable viral suppression for most patients. The risks associated with ART have decreased, whereas concerns regarding the risks of long-standing untreated viremia have increased. Uncontrolled HIV replication and immune activation lead to a chronic inflammatory state, resulting in end-organ damage and comorbid conditions not previously thought to be associated with HIV infection. Several studies have shown that the life span of those with HIV infection still falls short of that of the general population, even at higher CD4 cell counts. This life span decrease is related to serious, non- AIDS events attributed to chronic immune activation and the potentially permanent immune damage associated with prolonged immune depletion. In several data sets, non-aids events were associated with elevated levels of viral replication and 257
258 markers of immune activation and coagulation (including D-dimer, interleukin 6, or high-sensitivity C reactive protein). Mortality from non-aids events now exceeds that of AIDS defining opportunistic diseases in individuals receiving effective ART. Patient readiness for treatment is a key consideration when deciding when to initiate ART. There is no CD4 cell count threshold at which initiating therapy is contraindicated. Initiation of therapy is recommended for symptomatic patients with established disease, regardless of CD4 cell count, and for asymptomatic individuals with CD4 cell counts less than or equal to 500/μL. Treatment should be considered for asymptomatic individuals with CD4 cell counts greater than 500/μL. Therapy is recommended regardless of CD4cell count in the following settings: increased risk of disease progression associated with a rapid decline incd4cell count (ie,>100/μl per year) or a plasma HIV-1 RNA level greater than 100 000 copies/ml; older than 60 years; pregnancy (at least by the second trimester); or chronic HBV or HCV coinfec- Italian Guidelines tion, although for patients with HCV genotype 2 or 3 and high CD4 cell counts, an attempt to eradicate HCV may be undertaken before ART is initiated; HIV-associated kidney disease, avoiding drugs with potential adverse effects on the kidney (tenofovir, indinavir, atazanavir), if possible; high cardiovascular risk, modifiable risk factors for cardiovascular disease should be aggressively managed; opportunistic infections, including tuberculosis, with attention to drug interactions and the potential for immune reconstitution inflammatory syndromes; and symptomatic primary HIV infection to prevent rapid progression, to preserve immune function, and to limit ongoing transmission from this highrisk population. Once initiated, ART should be continued, except in the context of a clinical trial. Therapy should be considered where there is a heightened risk of HIV transmission(ie, HIVserodiscordant couples), without supplanting traditional prevention approaches. Risk reduction counseling should be a routine part of care at each patient-clinician interaction.