(Last updated: March 5, 2015; last reviewed: March 5, 2015)
OverviewThe decision about when to initiate combination antiretroviral therapy (cART) in asymptomatic HIV-infected older children and adolescents continues to generate controversy among HIV experts. Aggressive therapy in the early stages of HIV infection has the potential to control viral replication before HIV can evolve into diverse and potentially more pathogenic quasispecies. Initiation of therapy at higher CD4 T lymphocyte (CD4) cell counts has been associated with fewer drug resistance mutations at virologic failure in adults.1 Early therapy also slows immune system destruction and preserves immune function, preventing clinical disease progression.2,3 Ongoing viral replication may be associated with persistent inflammation and development of cardiovascular, kidney, and liver disease and malignancy; studies in adults suggest that early control of replication may reduce the occurrence of these non-AIDS complications.2,4-6 Conversely, delaying therapy until later in the course of HIV infection, when clinical or immunologic symptoms appear, may result in reduced evolution of drug-resistant virus due to a lack of drug selection pressure, improved adherence to the therapeutic regimen due to perceived need when the patient becomes symptomatic, and reduced or delayed adverse effects of cART. Because therapy in children is initiated at a young age and will likely be life-long, concerns about adherence and toxicities are particularly important.
Treatment Recommendations for Initiation of Therapy in Antiretroviral-Naive, HIV-Infected Infants and Children
|Recommend Urgent Treatmenta||Combination Antiretroviral Therapy (cART) Should Be Initiated Urgently in All HIV-Infected Children with any of the Following:
Age <12 Months:
|Recommend Treatmentb||cART Should Be Initiated in HIV-Infected Children Aged ≥1 Year with any of the Following:
|Consider Treatmentb||cART Should Be Considered for HIV-Infected Children Aged ≥1 Year with:
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
a Within 1–2 weeks, including an expedited discussion on adherence
b More time can be taken to fully assess and address issues associated with adherence with the caregivers and the child prior to initiating therapy. Patients/caregivers may choose to postpone therapy, and on a case-by-case basis, providers may elect to defer therapy based on clinical and/or psychosocial factors.
c CD4 counts should be confirmed with a second test to meet the treatment criteria before initiation of cART.
d To avoid overinterpretation of temporary blips in viral load (which can occur, for example, during intercurrent illnesses), plasma HIV RNA level >100,000 copies/mL should be confirmed by a second level before initiating cART.
Infants Younger Than 12 Months
The Children with HIV Early Antiretroviral Therapy (CHER) Trial, a randomized clinical trial in South Africa, demonstrated that initiating triple-drug cART before 12 weeks in asymptomatic perinatally infected infants with normal CD4 percentage (>25%) resulted in a 75% reduction in early mortality, compared with delaying treatment until the infants met clinical or immune criteria.16 Most of the deaths in the infants in the delayed treatment arm occurred in the first 6 months after study entry. A substudy of this trial also found that infants treated early had significantly better gross motor and neurodevelopmental profiles than those in whom therapy was deferred.17 Because the risk of rapid progression is so high in young infants and based on the data in young infants from the CHER study, the Panel recommends initiating therapy for all infants <12 months regardless of clinical status, CD4 percentage, or viral load (Table 5). Before therapy is initiated, it is important to fully assess, discuss, and address issues associated with adherence with an HIV-infected infant’s caregivers. However, given the high risk of disease progression and mortality in young HIV-infected infants, it is important to expedite this assessment in infants younger than 12 months.
The risk of disease progression is inversely correlated with the age of a child, with the youngest infants at greatest risk of rapid disease progression. Progression to moderate or severe immune suppression is also frequent in older infected infants; by 12 months, approximately 50% of children develop moderate immune suppression and 20% develop severe immune suppression.18 In the HIV Paediatric Prognostic Markers Collaborative Study meta-analysis, the 1-year risk of AIDS or death was substantially higher in younger children than in older children at any given level of CD4 percentage, particularly for infants younger than <12 months.19 Unfortunately, although the risk of progression is greatest in the first year of life, the ability to differentiate children at risk of rapid versus slower disease progression by clinical and laboratory parameters is also most limited in young infants. No specific “at-risk” viral or immunologic threshold can be easily identified, and progression of HIV disease and opportunistic infections can occur in young infants with normal CD4 cell counts.19
Identification of HIV infection during the first few months of life permits clinicians to initiate cART during the initial phases of primary infection. Data from a number of observational studies in the United States and Europe suggest that infants who receive early treatment are less likely to progress to AIDS or death than those who start therapy later.2,20,21 A study of 195 South African children initiating cART aged <24 months found that infants treated by 6 months achieved target growth milestones more rapidly than children who initiated therapy between 12 and 24 months.22 Several small studies have demonstrated that, despite the very high levels of viral replication in perinatally infected infants, early initiation of treatment can result in durable viral suppression and normalization of immunologic responses to non-HIV antigens in some infants.23,24 In infants with sustained control of plasma viremia, failure to detect extra-chromosomal replication intermediates suggests near-complete control of viral replication.25 Some of these infants have become HIV seronegative. Although there is a single case report of a period of remission in an HIV-infected child treated with a cART regimen initiated at age 30 hours, discussed below, current cART has not been shown to eradicate HIV infection in perinatally infected infants because of persistence of HIV in CD4 lymphocytes and other cells.26-28
The report of a prolonged remission in an HIV-infected child in Mississippi generated discussion about early initiation of cART in newborn infants with high-risk HIV exposure. This newborn, born to a mother who did not receive antenatal or perinatal cART, was treated with a three-drug cART regimen at ages 30 hours through 18 months, after which cART was discontinued against medical advice. Intensive follow-up evaluations showed no evidence of virologic rebound for more than 2 years following discontinuation of cART, at which time viremia recurred and cART was restarted.29 This experience has prompted increasing support for initiation of treatment in the first weeks of life, as soon as the diagnosis is made. However, because of limited safety and pharmacokinetic data and experience with antiretroviral (ARV) drugs in infants <2 to 4 weeks, drug and dose selection in this age group is challenging (see What to Start and Specific Issues in Antiretroviral Treatment for Neonates). If early treatment is initiated, the Panel does not recommend empiric treatment interruption.
Virologic suppression may take longer to achieve in young children than in older children or adults.30,31 Possible reasons for the slower response in infants include higher virologic set points in young infants, inadequate ARV drug levels, and poor adherence because of the difficulties in administering complex regimens to infants. With currently available drug regimens, rates of viral suppression of 70% to 80% have been reported in HIV-infected infants initiating therapy at <12 months.2,32,33 In a 5-year follow-up study of 40 HIV-infected children who initiated treatment at <6 months, 98% had CD4 percentage >25% and 78% had undetectable viral load with median follow-up of 5.96 years.2 More rapid viral suppression in young infants may also be important in reducing the long-lived HIV reservoir; a study of 17 HIV-infected infants initiating lopinavir/ritonavir-based cART before 6 months demonstrated that time to the first HIV viral load <400 copies/mL was correlated with the size of the long-lived HIV reservoir (i.e,. the resting memory CD4 cell pool).34 In addition, in the Pediatric HIV/AIDS Cohort Study/Adolescent Master Protocol (a cross-sectional study of 144 perinatally infected youth with long term viral suppression) found a lower proviral reservoir in those who achieved virologic control at <1 year versus 1 to 5 years versus >5 years of age (4.2 vs. 19.4 vs. 70.7 copies/million peripheral blood mononuclear cells, respectively).35
Information on appropriate drug dosing in infants younger than 3 to 6 months is limited. Hepatic and renal functions are immature in newborns undergoing rapid maturational changes during the first few months of life, which can result in substantial differences in ARV dose requirements between young infants and older children.36 When drug concentrations are subtherapeutic, either because of inadequate dosing, poor absorption, or incomplete adherence, ARV drug resistance can develop rapidly, particularly in the setting of high levels of viral replication in young infants. Frequent follow-up and continued assessment and support of adherence are especially important when treating young infants (see Adherence).
Finally, the possibility of long-term toxicities (e.g., lipodystrophy, dyslipidemia, glucose intolerance, osteopenia, mitochondrial dysfunction) with prolonged therapy is a concern.37
Children Aged 1 Year and Older
In general, disease progression is less rapid in children aged ≥1 year,18 however, children with stage 3-defining opportunistic infections (see Revised Surveillance Case Definition for HIV Infection at http://www.cdc.gov/mmwr/pdf/rr/rr6303.pdf and Table 7) are at high risk of disease progression and death. Given the high risk of disease progression and mortality with severe HIV disease, the Panel recommends urgent treatment (i.e., within 1–2 weeks) for all such children, regardless of immunologic or virologic status. In these cases, the clinical team should expedite a discussion on adherence and provide increased, intensive follow-up in the first few weeks to support the children and families. Children aged ≥1 year who have mild to moderate clinical symptoms (see Table 7) or who are asymptomatic are at lower risk of disease progression than children with more severe clinical symptoms.38 In these children, more time can be taken to fully assess, discuss and address issues associated with adherence with the caregivers and the children prior to initiating therapy. In asymptomatic children, consideration of CD4 count and viral load may be useful in determining the need for therapy.
In adults, the strength of recommendations to initiate cART in asymptomatic individuals is based primarily on risk of disease progression, as determined by baseline CD4 cell count.7 In adults, both clinical trial and observational data support initiation of treatment in individuals with CD4 counts <350 cells/mm3. In HIV-infected adults in Haiti, a randomized clinical trial found significant reductions in mortality and morbidity with initiation of treatment when CD4 counts fell to <350 cells/mm3, compared with deferring treatment until CD4 cell counts fell to <200 cells/mm3.8 In observational data in adults, a collaborative analysis of data from 12 adult cohorts in North America and Europe on 20,379 adults starting treatment between 1995 and 2003, the risk of AIDS or death was significantly less in adults who started treatment with CD4 counts 200 to 350 cells/mm3 compared with those who started therapy at CD4 counts <200 cells/mm3.39 A prospective observational cohort study of 468 adults found that initiation of cART within 4 months of infection resulted in the highest likelihood and fastest rate of recovery of CD4 counts when compared with initiation between 4 and 12 months or more than 12 months post-infection. Furthermore, starting cART at lower CD4 counts, defined as <500 cells/mm3, as compared with higher CD4 counts, was associated with a significant reduction in CD4 recovery.40
The Cochrane Collaboration41 published a review on the effectiveness of cART in HIV-infected children aged <2 years based on data from published randomized trials of early versus deferred cART.16,42 The authors concluded that immediate therapy reduces morbidity and mortality and may improve neurologic outcome, but that data are less compelling in support of universal initiation of treatment between ages 1 and 2 years.
The Pediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) trial was designed to investigate the impact on AIDS-free survival and neurodevelopment of deferral of cART in children aged >1 year.43 This multicenter, open-label trial randomized 300 HIV-infected children aged >1 year (median 6.4 years) to immediate initiation of cART or deferral until the CD4 percentage was <15%. The median baseline CD4 percentage was 19% (IQR 16% to 22%) and 46% of children in the deferred group started cART during the study. AIDS-free survival at week 144 was 98.7% (95% CI 94.7–99.7) in the deferred group and 97.9% (CI 93.7–99.3) in the immediate therapy group (P = 0.6), and immediate cART did not significantly improve neurodevelopmental outcomes.44 However, because of the low event rate, the study was underpowered to detect a difference between the two groups. This study population likely had a selection bias toward relatively slowly progressive disease because it enrolled children who had survived a median of 6 years without cART. The limited enrollment of children aged <3 years poses restrictions on its value for recommendations in that age group.
A secondary analysis of a randomized controlled trial addresses the comparative efficacy of starting versus deferring treatment at higher CD4 thresholds in HIV-infected adults. The HPTN 052 trial randomized 1763 HIV-serodiscordant couples to initiate ARV treatment either on entry into the study (median CD4 counts of 442 IQR 373–522 cells/mm3) or after a decline in CD4 count to <250 cells/mm3 or with onset of an AIDS-related illness (median CD4 count 230 [IQR 197–249] cells/mm3). New-onset AIDS events and tuberculosis occurred more frequently in the delayed versus early treatment group (P = 0.031 and 0.018, respectively), thus showing a benefit to starting cART early, when the CD4 count is over 400 cells/mm3.9 Two observational studies in adults—the ART Cohort Collaboration (ART-CC) and North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)—also suggest a higher rate of progression to AIDS or death in patients deferring treatment until the CD4 count is <350/mm3 compared with patients starting cART at CD4 counts of 351 to 500 cells/mm3.10,11 The NA-ACCORD study demonstrated a benefit of starting treatment at CD4 cell counts >500 cell/mm3 compared with starting cART at CD4 cell counts below this threshold;10 however, the ART-CC cohort found no additional benefit for patients starting cART with CD4 cell counts >450 cells/mm3.11 In a third observational study of 5,162 patients with CD4 cell counts between 500 and 799 cells/mm3, patients who started cART immediately did not experience a significant reduction in progression to AIDS or death (HR: 1.10, 95% CI: 0.67 to 1.79) or death alone (HR: 1.02, 95% CI: 0.49 to 2.12), compared with those who deferred therapy.13 There are no similar observational data analyses for HIV-infected children.
In children, the prognostic significance of a specific CD4 percentage or count varies with age.19,45 In data from the HIV Paediatric Prognostic Markers Collaborative Study meta-analysis, derived from 3,941 children with 7,297 child-years of follow-up, the risk of mortality or progression to AIDS per 100 child-years is significantly higher for any given CD4 count in children ages 1 to 4 years than in children aged ≥5 years (see Figures A and B and Tables A and B in Appendix C: Supplemental Information). Data from the HIV Paediatric Prognostic Markers Collaborative Study suggest that absolute CD4 cell count is a useful prognostic marker for disease progression in children aged ≥5 years, with risk of progression similar to that observed in adults (see Table B in Appendix C: Supplemental Information).19,46 For children ages 1 to <5 years, a similar increase in risk of AIDS or death is seen when CD4 percentage drops below 25% (see Table A in Appendix C: Supplemental Information).
Because the CD4 percentage is more consistent than the naturally declining CD4 cell count in the first years of life, it has been used preferentially to monitor immunologic status in children aged <5 years. However, an analysis of more than 21,000 pairs of CD4 measurements from 3,345 children aged <1 to 16 years in the HIV Paediatric Prognostic Markers Collaborative Study found that CD4 cell counts and percentages were frequently discordant around established World Health Organization (WHO) and the Pediatric European Network for Treatment of AIDS (PENTA) thresholds for initiation of cART (14% and 21%, respectively).47 Furthermore, CD4 cell counts were found to provide greater prognostic value over CD4 percentage for short-term disease progression for children aged <5 years as well as in older children. For example, the estimated hazard ratio for AIDS or death at the 10th centile of CD4 cell count (compared with the 50th centile) was 2.2 (95% confidence interval [CI]) 1.4, 3.0) for children ages 1 to 2 years versus 1.2 (CI 0.8, 1.6) for CD4 percentage. Recently, the CDC has issued an updated HIV infection staging classification based on age-specific CD4 values, indicating a preference for CD4 count over CD4 percentage in all ages (see Revised Surveillance Case Definition for HIV Infection at http://www.cdc.gov/mmwr/pdf/rr/rr6303.pdf).
The level of plasma HIV RNA may provide useful information in terms of risk of progression, although its prognostic significance is weaker than CD4 count.45 Several studies have shown that older children with HIV RNA levels ≥100,000 copies/mL are at high risk of mortality48-50 and lower neurocognitive performance;51 similar findings have been reported in adults.52-54 Similarly, in the HIV Paediatric Prognostic Markers Collaborative Study meta-analysis, the 1-year risk of progression to AIDS or death rose sharply for children aged >1 year when HIV RNA levels were ≥100,000 copies/mL (see Figures D and E and Table A in Appendix C: Supplemental Information).45 For example, the estimated 1-year risk of death was 2 to 3 times higher in children with plasma HIV RNA 100,000 copies/mL compared with 10,000 copies/mL and 8 to 10 times higher with plasma HIV RNA >1,000,000 copies/mL. Therefore, the Panel recommends that children of all ages with HIV RNA levels >100,000 copies/mL initiate cART.
As with data in adults, data from pediatric studies suggest that improvement in immunologic parameters is better in children when treatment is initiated at higher CD4 percentage/count levels.31,55-60 In a study of 1,236 perinatally infected children in the United States, only 36% of those who started treatment with CD4 percentage <15% and 59% of those starting with CD4 percentage 15% to 24% achieved CD4 percentage >25% after 5 years of therapy.61 Younger age at initiation of therapy has also been associated with improved immune response and with more rapid growth reconstitution.22,31,55,61,62 In addition, the PREDICT Study demonstrated improved height z-scores in the early treatment arm compared with no improvement in the deferred arm.43 Given that disease progression in children aged ≥5 years is similar to that in adults,46 and observational data in adults show decreased risk of mortality with initiation of therapy when CD4 cell count is <500 cells/mm3,10,11 most experts feel that recommendations for asymptomatic children in this age range should be similar to those for adults. However, there are no conclusive pediatric data to address the optimal CD4 cell count threshold for initiation of therapy in older children; additional research studies are needed to answer this question in children more definitively. The Panel has moved to endorse initiating cART in all HIV-infected adults regardless of CD4 cell count, using varying strengths of evidence to support different CD4 cell count thresholds7 and incorporating compelling data demonstrating that cART is effective in preventing secondary transmission of HIV. However, prevention of sexual transmission of HIV is not a significant consideration for children aged <13 years. Comparative studies on the impact of treatment versus treatment delay at specific higher CD4 cell counts have not been performed in children, and observational adult studies have produced conflicting results.10,11,14 Drug choices are more limited in children than in adults and adequate data to address the potential long-term toxicities of prolonged cART in a developing child are not yet available. Some studies have shown that a small proportion of perinatally infected children may be long-term nonprogressors, with no immunologic or clinical progression by age 10 years despite receiving no cART.63-65 Medication adherence is the core requirement for successful virologic control, but achieving consistent adherence in childhood is often challenging.66 Incomplete adherence leads to the selection of viral resistance mutations but forced administration of ARVs to children may result in treatment aversion or fatigue, which occurs among many perinatally infected children during adolescence.67 The relative benefits of initiating cART in asymptomatic children with low viral burdens and high CD4 cell counts must be weighed against these potential risks.
The Panel recommends that cART be urgently initiated in all children younger than aged 12 months, and in those aged 12 months or older who have Centers for Disease Control and Prevention (CDC) Stage 3-defining opportunistic illnesses or Stage 3 CD4 counts (Tables 6 and 7).
The Panel also recommends that children aged 12 months or older with the following findings initiate cART:
The evidence for this recommendation is strongest for children with CD4 cell counts <350 cells/mm3. For children with CD4 cell counts 350 to 500 cells/mm3, the recommendation is based on observational data in adults, hence the evidence base is not as strong; this recommendation should not prohibit research studies in children designed to answer this question more definitively.
The Panel also recommends consideration of treatment for all children aged 12 months or older with no or mild symptoms and CDC Stage 1 CD4 counts (Tables 6 and 7), although the strength of recommendation is lower because of limited data.
Patients/caregivers may choose to postpone therapy, and, on a case-by-case basis, providers may elect to defer therapy based on clinical and/or psychosocial factors. Note that the Panel’s recommendations which permit optional deferral of therapy for healthy children older than 1 year are different from the 2013 WHO guidelines, which recommend initiation of therapy for all children younger than 5 years, reflecting different approaches in resource-limited settings.
In general, except in infants younger than age 12 months and children with advanced HIV infection, cART does not need to be started urgently (i.e., within 1–2 weeks). Before initiating therapy, it is important to take time to educate caregivers (and children, as appropriate) about regimen adherence and to anticipate and resolve any barriers that might diminish adherence. This is particularly true for children age 5 years and older, given their lower risk of disease progression and the higher CD4 cell count threshold now recommended for initiating therapy.
If therapy is deferred, the health care provider should closely monitor a child’s virologic, immunologic, and clinical status every 3 to 4 months (see Clinical and Laboratory Monitoring). Factors to consider in deciding when to initiate therapy in children in whom treatment was deferred include:
Table 5. Indications for Initiation of Antiretroviral Therapy in HIV-Infected Children
Table 5 provides general guidance rather than absolute recommendations for individual patients. Factors to be considered in decisions about initiation of therapy include risk of disease progression as determined by CD4 percentage or count and plasma HIV RNA copy number, the potential benefits and risks of therapy, and the ability of the caregiver to adhere to administration of the therapeutic regimen. Urgent treatment should be initiated within 1 to 2 weeks, including an expedited discussion on adherence. In non-urgent settings, more time can be taken to fully assess and address issues associated with adherence with the caregivers and the child prior to initiating therapy. Patients/caregivers may choose to postpone therapy and, on a case-by-case basis, providers may elect to defer therapy based on clinical and/or psychosocial factors.a
|<12 Months||Regardless of clinical symptoms, immune status, or viral load
||Urgent treatment (AI for <12 weeks of age; AII for ≥12 weeks)|
|1 to <6 Years||CDC Stage 3-defining opportunistic illnessesb||Urgent treatment (AI*)
|CDC Stage 3 immunodeficiency:d CD4 <500 cells/mm3||Urgent treatment (AI*)|
|Moderate HIV-related symptomsb||Treat (AII)|
|HIV RNA >100,000 copies/mLc||Treat (AII)|
|CD4 cell countd 500–999 cells/mm3||Treat (AII)|
|Asymptomatic or mild symptomsb and CD4 cell countd ≥1000 cells/mm3
||Consider Treatment (BIII)|
|≥6 Years||CDC Stage 3-defining opportunistic illnessesb||Urgent treatment (AI*)|
|CDC Stage 3 immunodeficiency:d CD4 <200 cells/mm3||Urgent treatment (AI*)|
|Moderate HIV-related symptomsb||Treat (AII)|
|HIV RNA >100,000 copies/mLc||Treat (AII)|
|CD4 cell countd 200–499 cells/mm3||Treat (AI* for CD4 cell count <350 cells/mm3 and AII* for CD4 cell count 350–499 cells/mm3)
|Asymptomatic or mild symptomsb and CD4 cell count ≥500 cells/mm3||Consider treatment (BIII)|
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = data from randomized controlled trials in children; I* = data from randomized trials in adults with accompanying data in children from nonrandomized trials or observational cohort studies with long-term clinical outcomes; II: data from well-designed nonrandomized trials or observational cohort studies in children with long-term clinical outcomes; II* = data from well-designed nonrandomized trials or observational cohort studies in adults with long-term clinical outcomes with accompanying data in chidren from smaller non-randomized trials or cohort studies with clinical outcomes data; III = Expert opinion
a Children in whom cART is deferred need close follow-up. Factors to consider in deciding when to initiate therapy in children in whom treatment was deferred include:
b Table 7
c To avoid overinterpretation of temporary blips in viral load (which can occur during intercurrent illnesses, for example), plasma HIV RNA level >100,000 copies/mL should be confirmed by a second level before initiating cART.
d Laboratory data should be confirmed with a second test to meet the treatment criteria before initiation of cART.
|Stage||Age on Date of CD4 Test|
|<1 Year||%||1 to <6 Years||%||≥6 years||%|
a The stage is based primarily on the CD4 count; the CD4 count takes precedence over the CD4 percentage, and the percentage is considered only if the count is missing. If a Stage 3-defining opportunistic illness has been diagnosed (Table 6), then the stage is 3 regardless of CD4 test results.
Source: Centers for Disease Control and Prevention: Revised Surveillance Case Definition for HIV Infection—United States, 2014. MMWR 2014;63(No. RR-3):1-10.
|Mild HIV-Related Symptoms|
|Children with two or more of the conditions listed but none of the conditions listed in Moderate Symptoms category
|Moderate HIV-Related Symptoms|
|Stage-3-Defining Opportunistic Illnesses In HIV Infection|
a Only among children aged <6 years.
b Only among adults, adolescents, and children aged ≥6 years.
c Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy and HIV wasting syndrome, are described in the following references: