13.1. Recommendations
It is recommended to treat all patients with CD4 counts of ≤350 cells/mm3 irrespective of the WHO clinical stage.
(Strong recommendation, moderate quality of evidence)
It is recommended that all patients with WHO clinical stage 1 and 2 should have access to CD4 testing to decide when to initiate treatment.
(Strong recommendation, low quality of evidence)
It is recommended to treat all patients with WHO clinical stage 3 and 4 irrespective of CD4 count.
(Strong recommendation, low quality of evidence)
In making these recommendations, the ART Guideline Review Committee (the “panel”) placed high value on avoiding death, disease progression and the likely risk of HIV transmission over and above cost and feasibility.
13.2. Evidence
The evidence used in formulating recommendations on when to start ART comes from a systematic review: Optimal time of initiation of antiretroviral therapy for asymptomatic, HIV-infected, treatment-naive adults. (2) The review included randomized controlled clinical trials (RCTs) and cohort studies, in which ART initiation was stratified according to CD4 cell count. On the basis of GRADE methodology, the evidence was rated for each of the critical and important outcomes to determine whether or not to change the current WHO guideline.
The recommendations are supported by moderate quality evidence for critical patient and public health outcomes from one unpublished RCT and one post hoc analysis nested in an RCT. In the GRADE evidence profile, pooled data from these two studies provide moderate evidence that starting ART at CD4 levels higher than 200 or 250 cells/mm3 reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. The panel also reviewed large observational data sets from both resource-limited and well-resourced settings that were consistent with data from the RCT, but these did not add to the overall quality of evidence. The panel considered the recommendations to be 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.
Recent modelling and observational data suggest that more than 50% of HIV-infected patients with WHO clinical stage 2 may have a CD4 count of ≤350 cells/mm3. However, considering the uncertain prognostic value of some WHO clinical stage 2 conditions, the panel recommended that HIV-infected individuals with WHO clinical stage 1 and 2 should have access to CD4 testing to decide if treatment should be initiated.
13.3. Summary of findings
Moderate-quality evidence supports strong recommendations for the timing of ART initiation for the critical outcomes of absolute risk of death, disease progression (including tuberculosis), and the occurrence of serious adverse events.
One RCT specifically aimed to determine the optimal time to initiate ART in asymptomatic, treatment-naive, HIV-infected adults. The CIPRA HT-001 (2009) study, a single-centre trial in Haiti, randomized 816 ART-naive participants with a CD4 count of 200-350 cells/mm3, to receive early treatment (start ART within 2 weeks of enrolment) versus standard-of-care treatment (start ART when the CD4 count is <200 cells/mm3 or following the development of an AIDS-defining illness).(3) The median CD4 count at study entry was 280 cells/mm3 in the early treatment group and 282 cells/mm3 in the standard-of-care group. The primary study end-point was survival and the secondary end-point was incident TB. The Data Safety and Monitoring Board (DSMB) recommended cessation of the study after a median follow up of 21 months (1–44 months). Deaths and incident TB occurred in 6 and 18 patients respectively in the early group compared to 23 and 36 patients in the delayed group (mortality HR 4.0, p = 0.0011; incident TB HR 2.0, p = 0.0125). Of the participants in the standard-of-care group, 40% reached a CD4 cell count of <200 cells/ mm3, developed an AIDS-defining illness or died.
Early ART initiation was examined further in one subgroup post hoc analysis (249 participants) nested in a larger RCT. The SMART trial was a multicentre study conducted at 318 sites in 33 high-income and low/middle-income countries, which randomized 5472 participants with CD4 cell counts of >350 cells/mm3 to either a viral suppression strategy (goal of maximal and continuous viral suppression) versus a drug conservation strategy (ART deferred until CD4 was <250 cells/mm3).(4) In a subset analysis of 477 patients who were ART-naive at study entry (n = 249) or who had not received ART for >6 months before randomization (n = 228) and who were randomized to start ART immediately (with CD4 of >350 cells/mm3) or delayed until after CD4 dropped to <250 cells/mm3, there was a reduction of disease progression and serious non-AIDS events when ART was initiated before the CD4 cell count dropped to ≤350 cells/mm3 compared with delaying until the CD4 count was <250 cells/mm3.
In the GRADE profile, pooled data from this RCT and the subgroup post hoc analysis provided moderate evidence that starting ART at CD4 levels higher than 200 or 250 cells/mm3 reduced mortality rates in asymptomatic, ART-naive HIV-infected people. Evidence regarding a reduction in morbidity was less strong because there were few events. The numbers of adverse events were also small.
As the CIPRA-HT001 2009 trial was conducted in a resource-limited setting, the applicability of these results in determining a change in WHO guidelines is high.
The GRADE profile notes that the quality of these data was limited by imprecision (there was only one RCT), indirectness (the SMART data come from a post hoc subset analysis) and reporting bias (there may be other trials which did not conduct or publish similar analyses of potential subsets within the original trials).
The results from the CIPRA HT-001 and SMART trials are consistent with four observational cohort studies from resource-limited and well-resourced countries, which showed that early initiation of ART was associated with reduced morbidity and mortality.(5–8) GRADE tables were not produced for the four observational studies identified in the systematic review as they would not have increased the overall quality of evidence. No trials were identified which evaluated the optimal timing of initiation of ART in people coinfected with hepatitis B, hepatitis C or both.
13.4. Benefits and risks
Benefits
Modelling estimates predict that the initiation of ART for individuals with a CD4 cell count of ≤350 cells/mm3 or with WHO clinical stage 3 or 4 will result in the numbers of people on ART increasing by 49% and a reduction in HIV-related mortality of 20% by 2010-2015.(9) Further modelling data suggest additional transmission benefit from earlier initiation of ART for both sexual transmission and MTCT of HIV providing that there is high treatment coverage and high adherence.(10) Earlier initiation and more time spent on ART may provide impetus to shift to less toxic first-line regimens and reduced prices for newer fixed-dose combinations (FDCs).
Observational and RCT data confirm that there is an increased risk of TB and invasive bacterial diseases as CD4 cell counts decline.(11,12) Conversely, there is a 54% to 92% reduction in TB in individuals receiving ART.(13)
Risks
It is estimated that increasing the threshold for ART initiation can increase ART cost up to 57% by 2010-2015.(9) Broadening the criteria for treatment may result in some persons in urgent need of treatment being displaced by persons for whom treatment would be beneficial but not as urgent. In recommending a higher CD4 count threshold for initiation, a guiding principle is that those most in need of treatment should retain priority access.
Earlier initiation will mean longer exposure to ART (estimated to be 1 to 2 years more) and the possibility of more ART-related side-effects and ARV resistance. It remains unclear if asymptomatic individuals will accept HIV testing or ART. Additionally, the impact of earlier initiation on adherence is uncertain.
13.5. Acceptability and feasibility
In consultations with PLHIV, the benefits of starting ART earlier were recognized and strongly supported. However, concern was voiced about the increased risk of adverse events, resistance to first-line ARVs, drug stock-outs, and unavailability of second-line regimens. While earlier ART initiation will reduce the current disparity between treatment recommendations in resource-limited and well-resourced settings, it will appear to decrease treatment coverage. Ministries and donors may feel under pressure to address immediate increased costs. Feasibility will be enhanced if there is a phased introduction of the higher thresholds, with the speed and completeness determined by the health system's capacity, HIV burden, ART coverage and funding.
13.6. Clinical considerations
Table 8WHO clinical staging of HIV disease in adults and adolescents
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| Clinical stage 1 |
|---|
Asymptomatic
Persistent generalized lymphadenopathy |
| Clinical stage 2 |
|---|
Moderate unexplained weight loss (under 10% of presumed or measured body weight)
Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis)
Herpes zoster
Angular cheilitis
Recurrent oral ulcerations
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections |
| Clinical stage 3 |
|---|
Unexplained severe weight loss (over 10% of presumed or measured body weight)
Unexplained chronic diarrhoea for longer than 1 month
Unexplained persistent fever (intermittent or constant for longer than 1 month)
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis
Severe bacterial infections (e.g. pneumonia, empyema, meningitis, pyomyositis, bone or joint infection, bacteraemia, severe pelvic inflammatory disease)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Unexplained anaemia (below 8 g/dl ), neutropenia (below 0.5 × 109/l) and/or chronic thrombocytopenia (below 50 × 109/l) |
| Clinical stage 4 |
|---|
HIV wasting syndrome
Pneumocystis jiroveci pneumonia
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection (orolabial, genital or anorectal of more than 1 month's duration or visceral at any site)
Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
Extrapulmonary tuberculosis
Kaposi sarcoma
Cytomegalovirus disease (retinitis or infection of other organs, excluding liver, spleen and lymph nodes)
Central nervous system toxoplasmosis
HIV encephalopathy
Extrapulmonary cryptococcosis including meningitis
Disseminated nontuberculous mycobacteria infection
Progressive multifocal leukoencephalopathy
Chronic cryptosporidiosis
Chronic isosporiasis
Disseminated mycosis (histoplasmosis, coccidiomycosis)
Recurrent septicaemia (including nontyphoidal Salmonella)
Lymphoma (cerebral or B cell non-Hodgkin)
Invasive cervical carcinoma
Atypical disseminated leishmaniasis
Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy |
Source: Revised WHO clinical staging and immunological classification of HIV and case definition of HIV for surveillance. 2006.
Table 9Criteria for ART Initiation in specific populations
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| Target population | Clinical condition | Recommendation |
|---|
| Asymptomatic individuals (including pregnant women) | WHO clinical stage 1 | Start ART if CD4 ≤350 |
| Symptomatic individuals (including pregnant women) | WHO clinical stage 2 | Start ART if CD4 ≤350 |
| WHO clinical stage 3 or 4 | Start ART irrespective of CD4 cell count |
| TB and hepatitis B coinfections | Active TB disease | Start ART irrespective of CD4 cell count |
| HBV infection requiring treatment* | Start ART irrespective of CD4 cell count |
- *
The current standard definition of chronic active hepatitis in industrialized countries is mainly based on histological parameters obtained by liver biopsy, a procedure not usually available in the large majority of resource-limited settings. A global definition of chronic active hepatitis for resource-limited settings based on clinical and more simple laboratory parameters is under discussion.
While increased access to CD4 testing is a priority, the lack of a CD4 cell count should not be a barrier to the initiation of ART. For ART programmes in many countries with the highest HIV burden, clinical criteria remain the basis for deciding when to initiate ART. In both resource-limited and well-resourced settings, there is a move towards earlier initiation of ART. However, many people still present for the first time with advanced HIV disease, with a CD4 count of <200 cells/mm3 or with an opportunistic infection.(14,15)
Clinical assessment
Clinical staging is intended for use where HIV infection has been confirmed by HIV antibody testing. It is used to guide decisions on when to start cotrimoxazole prophylaxis and when to start ART. (WHO clinical staging of HIV disease in adults and adolescents) and Annex 21.5 (Diagnostic criteria for HIV-related clinical events in adults and adolescents) provide details of specific staging conditions and the criteria for recognizing them.
For individuals with advanced HIV disease (WHO clinical stage 3 or 4), ART should be initiated irrespective of the CD4 cell count. Both stages 3 and 4 are independently predictive of HIV-related mortality.(16–19) Assessing the need for ART in those with WHO clinical stage 2 presents challenges. Some stage 2 conditions may be considered more indicative of HIV disease progression than others. For example, papular pruritic eruptions (PPEs) typically occur with CD4 counts of <200 cells/mm3, and most physicians would recommend the initiation of ART in the presence of PPEs and the absence of a CD4 count.(20,21) Conversely, recurrent oral ulceration or a fungal nail infection generally would not be considered triggers to start ART. Given the uncertainty with which stage 2 conditions predict mortality and disease progression, HIV-infected individuals with WHO clinical stage 2 should have priority access to CD4 testing to decide if treatment should be initiated. The same recommendation to promote CD4 testing applies to asymptomatic individuals (WHO stage 1). The objective is to identify those with a low CD4 count, are still well, but need to start ART.
Immunological assessment
Expanded provider-initiated testing and counselling (PITC) and voluntary counselling and testing (VCT), together with immunological assessment (CD4 testing), are critical to achieving the goals of earlier diagnosis and starting ART before people become unwell or present with their first opportunistic infection.(22) A CD4 cell count performed at entry into care or prior to ART initiation will guide the decision on when to start ART and serves as the baseline if CD4 testing is used for ART monitoring. ART should be commenced in individuals with a CD4 count of ≤350 cells/mm3. Absolute CD4 cell counts fluctuate within individuals and with intercurrent illnesses. If feasible, CD4 testing should be repeated if a major management decision rests on the value, rather than using a single value. Serial CD4 measurements are more informative than individual values because they reflect trends over time. The total lymphocyte count (TLC) is no longer recommended to guide treatment decisions in adults and adolescents.
Virological assessment
In resource-limited settings, plasma viral load (HIVRNA) measurement is not required before the initiation of ART. However, expanded access to viral load testing is needed to improve the accuracy of diagnosing treatment failure. Earlier detection of virological failure allows both targeted adherence interventions and better preservation of the efficacy of second-line regimens.(23)
