Marys Medicine

Hiv therapy i.cdr

Universita di Padova HIV Therapy Course I
2,255 HIV positive women gave birth in the UK during the year ending June 2001 (Institute of Child Health, London).
In the last few years, the use of antiretroviral drugs during pregnancy has reduced the risk of vertical transmission dramatically. Nonetheless, new problems have emerged - particularly in the clinical management of children undergoing antiretroviral polytherapy (side effects, compliance etc.).
Children are treated by specialist paediatric AIDS centres. However, collaboration with non-specialist centres and with General Practitioners is essential. This course is intended for:
the monitoring of antiretroviral therapy.
—hospital paediatricians and infectious diseases specialists who, while not working in At the end of the course the doctor will
specialist paediatric AIDS centres, treat be able to:
children with HIV infection; —recognise the different types of —doctors, including paediatricians, who antiretroviral drugs, follow up children with HIV infection at an understand the basic interpretation of the outpatient level. principal laboratory tests, —identify possible side effects of the The objective of the course is to improve
the treatment management of HIV positive —relate to the parents of the child, with children born of seropositive mothers and particular regard to the treatments already being treated by a specialist administered and methods for improving paediatric AIDS centre. The course will focus on the improvement of treatment —check that the doses administered are management with antiretroviral drugs, and Given the peculiarities of paediatric AIDS (family pathology, social problems, risk of the child
being left an orphan etc.), the course will also deal with the psychological and social
that the doctor should take into account when choosing and managing treatment.
—AZT, ZDV: zidovudine — NFV: nelfinavir —ARV: antiretroviral —APV: amprenavir —ddI: didanosine —ABT378: lopinavir/ritonavir —d4T: stavudine —PI: protease inhibitors —3TC: lamivudine —NRTI: nucleoside reverse transcriptase —ddC: zalcitabine —ABC: abacavir —NNRTI: non-nucleoside reverse —NVP: nevirapine transcriptase inhibitors —EFV: efavirenz —VL: viral load —DLV: delavirdine —STI: structured treatment interruptions —SQV: saquinavir —OI: opportunistic infections —IDV: indinavir —HAART: highly active anti retroviral —RTN: ritonavir Universita di Padova HIV Therapy Course I
General considerations for ARV

In the last few years considerable progress has been made:
—in the standardisation of virological techniques to monitor viral load (and
therefore the rate of viral replication), by determining the plasma concentration of HIV-RNA. —in the availability of drugs which significantly reduce the rate of HIV
replication. Various studies have shown that the rate of viral reproduction correlates
directly with the fall in the CD4 lymphocyte count and consequent disease progression
(Figures 1-2).
FIGURE 1 Progression of viral and immunological markers during HIV infection.
Source: Recreated from NEJM - Pantaleo et al. 328(5):327 Figure 1
FIGURE 2 Link between the initial viral load and the evolution of the disease
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In particular, combinations of a number of drugs (Highly Active Anti Retroviral Therapy; HAART) have changed the natural history of HIV infection considerably, both in adults (Figure 3) and children (Figures 4-5). FIGURE 3 Mortality and the use of Antiretrovirals in the case of patients with less than
100 CD4/mm .
FIGURE 4 Kaplan-Meyer Estimates of Cumulative Survival Probabilities
by Birth Cohort and Calendar Period.
Source: De Martino et all for the Italian Register for HIV Infection in Children /
JAMA 2000; 284:190-197
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FIGURE 5 AIDS progression before and after 1997.
Source: PENTA 1
The number of cases of AIDS has diminished considerably in Western countries where patients have access to combination treatment (Figures 6-7). FIGURE 6 HIV infections and AIDS cases in UK.
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FIGURE 7 Viral and immunological response (CD4) to therapy.
Change in human imunodeficiency virus (HIV) RNA and CD4 T cell count over 96 weeks in patients meeting a definition of complete virologic responders, partial responders and transient responders. Figure shows median CD4 changes (A) and median HIV RNA changes (B). The number of patients evaluated at each time point is shown.
Source: JID 2000; 181; 949
Perinatal HIV infection differs appreciably to that in an adult from a clinical,
virological and immunological point of view
, because the infection is developing in
a person whose immune system is still developing. This can substantially influence
treatment decisions for a child with HIV infection.
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The disease can develop more rapidly in a child than in an adult, and may be characterised - at least until adolescence (Figure 8) - by greater neurological effects and a lower incidence of cancers. Prior to 1993 the leading cause of AIDS in HIV-infected children younger than two was Pn. carinii. Since 1993 the introduction of Pn. carinii pneumonia prohylaxis, with co-trimoxazole in the neonatal period, has reduced the impact of this OI, and reduced the mortality of infected children (Figure 9). [1] FIGURE 8 Comparing natural history of HIV infection in children versus adults.
faster progression primary opportunistic infections (rare cases of reactivation) interstitial lymphocytic pneumonia frequency of bacterial infections progressive encephalopathy slow growth rare Kaposi sarcoma FIGURE 9 Average survival of infants after PCP/CMV infection, before and after 1993
(introduction of prophylaxis - UK). Source: Williams, AJ et al., AIDS 15:335-339
Progression of viraemia in the neonatal period is similar to that of acute infection in the adult (Figure 1). Viral loads are very high in the first months; these fall at 3-4 years (Figure 10).
FIGURE 10 Evolution of HIV -RNA level (log) with IC 95%.
Source: PENTA 1 trial; AIDS 1988
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In short, the immune system of a child, whether HIV is present or not, is characterised by a substantially immature immune system with great variability in CD4 lymphocyte values in the first 2 years of life (range 800 - 6000 cell/ml) and a working thymus. This is reflected by a particular susceptibility to infection (in the first year OI are also possible with "normal" CD4 values) on one hand, and in immunological reconstitution, secondary to antiretroviral treatment on the other, characterised by a greater increase in CD45+RA+(naive) lymphocytes compared to CD45+RO+ (Figure 11).
FIGURE 11 Characteristics of immunological reconstitution.
Source: TREC Response to Antiretroviral Therapy in HIV-infected Children
in the PENTA 5 Trial - A De Rossi et al. - Poster 807-W
Problems peculiar to children, such as the different significance of viral load and the variability in the CD4 lymphocyte count, call for caution when antiretroviral treatment is initiated. This variability in CD4 values and viral load (Figure 10) make the criteria applied in starting antiretroviral treatment for adults difficult to apply to children.
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Most antiviral drugs used in clinical practice or in trials are available in paediatric formulation (Tables 6-7). TABLE 6 Antiretroviral drug available in paediatric formulations: NRTI and NNRTI.
Clinical Trials
Abacavir (syrup) Efavirenz (susp) TABLE 7 Antiretroviral drug available in paediatric formulations: PI.
Clinical Trials
However, the low solubility of antiretroviral drugs means that these preparations are not easy to administer to children, particularly infants. A consequence of this is the difficulty of conducting pharmacokinetic studies in infants to define the optimum dosages needed to maintain the drugs at concentrations that inhibit viral replication. It is known that the kinetics of a drug depend on how it is metabolised, and thus on the age and the weight/body surface area ratio of the child (cfr. Drug dosages). Taking these drugs poses further problems in early childhood. For example, not only do the preparations often taste horrible, but having to take them persistently several times daily can give rise to confidentiality issues for a child at school. For adolescents there are specific and challenging problems. Frequently these relate to the difficulty of adhering to complex treatment regimes. Parents are often reluctant to impose the treatment regimes on their children due to the difficulty of informing their child of the diagnosis of HIV-1. During treatment with PI, significant metabolic changes may occur (lipodystrophy, "buffalo hump" etc.), which can change a child's physical appearance, and are an important factor in reduced compliance in adolescents.
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The peculiarities of HIV-1 infection and the difficulties inherent in the treatment of children (particularly in the case of poly-chemotherapy) increase the risk that a sub-therapeutic dose is given. This increases the risk of developing resistant and particularly aggressive viral strains. Treatment compliance must therefore be evaluated very carefully when planning the choice of drugs and the timing of - or adaptations to - the treatment regime. The first drugs that the child is likely to receive will be antiviral, and so beginning anti-retroviral treatment has enormous psychological impact on both the child and the parents. Therefore it is important that when starting or changing the treatment, detailed discussions are held with the parents and the child. The type of treatment, possible side effects and the importance of compliance should be discussed carefully. This discussion should clarify which therapeutic approach gives the highest chance of success. Providing psychological and social support for the family and the child often helps.
Treatment strategies able to reduce the burden of long term antiretroviral treatments have been explored for several years. Administration of powerful poly-chemotherapy for a few months, followed by less aggressive treatment, has been shown to be ineffective in adults in terms of reducing viral replication rate. Protocols are being studied that foresee the structured treatment interruption (STI) in patients with VL < 50 copies/ml. This approach, which has an undeniable importance in improving the quality of life of individual patients, is based on objective criteria relating to the particular individual: —A patient who is being treated with HAART and in whom complete suppression of viral replication (VL <50 c/ml) has been achieved. The increase in viral load resulting from treatment interruption would stimulate the specific anti-HIV immune response, and as a consequence lead to improved control of viral replication. —A patient with therapeutic failure and multiple resistance to antiretroviral drugs. Interruption of treatment would select for "wild" type viral strains, which present greater "fitness", but are more sensitive to treatment (Figure 12). FIGURE 12 Structured treatment interruption (STI) may be associated
with increased levels of viral strains responsive to medication.
For children, the possibility of interrupting treatment without compromising effectiveness would have an enormous impact on the treatment strategies adopted.
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Mini Quiz 1
Question 1:
Is there a correlation between an increase in viral load, diminution in CD4 lymphocytes
and the progression of the disease?
Question 2:
Do the guidelines for adults suggest initiating antiretroviral treatment in all HIV positive
When to initiate treatment
There are currently no studies that indicate the best moment for initiating
antiretroviral treatment
, in children or in adults.
Recently the guidelines for the treatment of adults were modified, and the approach
advised is less aggressive than that used previously
. In fact it has been shown
that the risk of progression is relatively low in patients with CD4>350/mm3 and with
viral load < 55,000 copies / ml (RT-PCR)
( [2], while the side effects
(particularly metabolic) in the medium-long term of HAART can be significant.
Treatment of the primary infection is generally advised for adults: this can limit the initial replicative peak of the virus during the acute phase of the infection, thereby improving the prognosis of the disease. However, the lack of data relating to: —the duration of treatment during the acute infection, —the consequent risk of side effects, —the consequent risk of a deterioration in quality of life, should be taken into consideration in deciding whether to initiate treatment early. The most recent American guidelines for the treatment of the infection in the
paediatric age range ( [3]
advise initiating antiretroviral treatment:
—within the first 12 months in all children with a documented HIV infection, —in all symptomatic children (Category A,B,C of the CDC classification), —in all children with serious and moderate immunological deficits (category 2 and 3 of the CDC classification), ( [4], —in children that are asymptomatic and with a good immune situation, if the evaluation of viral load suggests it. Universita di Padova HIV Therapy Course I
In Europe the approach to treatment is less aggressive than that in America
and around 20% of infected children do not receive any treatment [5-14].
The advice is to initiate treatment in children who are symptomatic or have a viral load > 100,000 copies/ml and CD4 < 15% (conditions associated with an unfavourable prognosis). In children with a lower viral load and with a higher CD4 count (compared to the normal values for their age) the advice is: careful monitoring of the progress of clinical and laboratory parameters combined with case by case evaluation of the best moment to initiate treatment. There is a also a relationship between the viral load value (Table 8), CD4 lymphocytes (Figure 7, Table 9) and the progression of the disease [6][7]. Thus there are both advantages and disadvantages in starting treatment early, and these must be considered with great caution (Figure 13). TABLE 8 Association of baseline HIV RNA quartile by age at entry with risk of disease
progression or death during study follow up among HIV-infected children enrolled in Approximate qualites
with disease
with disease
of baseline
of patients
HIV RNA (copies/mL)*
Age<30 Months at Entry +
<1,000-150,000 500.001-1,700,000 Age>30 Months at Entry ++
<1,000-15,000 Source:
Sleasman JW Immune reconstitution after ritonavir therapy
in child human immunodeficiency virus infection involving lymphocyte lineages.
J Pediatr 134: 597-606
Choen Stuart JW et al.(1998): Early recovery of CD4 T lymphocytes in children
on highly active antiretroviral therapy. Dutch Study group for children with HIV
infection. AIDS 12: 2155-2159
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TABLE 9 Association of baseline CD4+ T-lymphocyte percentage with long-term risk
of death in human immunodeficiency virus (HIV) infected children.
Sleasman JW Immune reconstitution after ritonavir therapy in child human immunodeficiency virus infection involving lymphocyte lineages. J Pediatr 134: 597-606Choen Stuart JW et al.(1998): Early recovery of CD4 T lymphocytes in children on highly active antiretroviral therapy. Dutch Study group for children with HIV infection.
AIDS 12: 2155-2159 FIGURE 13 Early initiation of HAART.
improved prognosis (especially some infants do not need therapy for babies born to a mother undergoing treatment during negative impact on QOL in the long allows normal immune system toxicity in both short and long term difficulty obtaining correct dosage eradication of infection risk of resistance (low adherence, PK) re-establishes a set point after decreased therapeutic options weak specific immune reaction Universita di Padova HIV Therapy Course I
Although the American guidelines suggest treating all unweaned babies [4] as soon as the infection is diagnosed, early treatment has been studied by several authors [8][9][10]. The results have been strongly contrasting, and most of the children did not have suppression of viral replication (VL < 50 copies/ml) after 6 months of treatment (Figure 14).
FIGURE 14 Therapy during the first year of life.
Age at initiation
VL (C/ml)*
12 in Rx with 4 drugs (including NNRTI) n=18 (12)
Levy et al
ZDV, 3TC, ddI or Funk et al
Lyell et al
ZDV, 3TC, ABC, NVP (patients with AIDS) (*) At 24 weeks
Lyall, EGH et al,Fifth International Congress on Drug Therapy in HIV Infection;
Glasgow Oct 2000: P212
Scott, ZA, Faye, A et al, Eighth Conference on Retroviruses and Opportunistic
Chicago Feb 2001:169, 678
Various hypotheses have been put forward for this "lack of success" of the treatment. Possible explanations include: —the difficulty of administering drugs (for example NFV suspension) due to the nature of their formulations, —possible under-dosage due to the variability of metabolism in the first months of life, —the possibility that viral strains present are resistant to the pharmacological combinations used. The initiation of treatment in the first months of life also raises significant questions, to which it is not easy to give an answer. If a child responds to treatment, one would not expect to continue the treatment in the long term. In this case, theoretically possible options (which must clearly be evaluated within the framework of clinical studies) may be the administration of a vaccine or a structured interruption of the treatment. On the other hand, in the case of a lack of response to the treatment, it is not clear if it would be better to suspend the treatment or change the treatment regime used. Universita di Padova HIV Therapy Course I
In any case, at the moment at which it is decided to initiate antiretroviral treatment, some very important and inter-dependent issues are for consideration: —convincing the parents of the child to initiate treatment, —the possibility of obtaining good adherence to the treatment in the long term, —the pharmacokinetic data available for the combinations proposed, —the availability of formulations that may be successfully administered to the child, —treatment that may be received by other members of the nuclear family. Only a decision that takes account of all of these aspects will be likely to produce a good result.
Mini Quiz 2
Question 3:
Is the functionality of the thymus in the first two years of life inferior compared to
Question 4:
Does antiretroviral treatment initiated in the first 6 months of life lead to the eradication
of the virus?
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Drugs with which to start treatment
When antiretroviral HIV treatment is started for an unweaned baby or child, a
combination therapy of more than one drug
must always be used, irrespective of
the presence of symptoms and their severity.
In general, the treatment regime selected should be that which most guarantees: — the greatest suppression of viral replication, — a sustained increase in the number of CD4 lymphocytes, — an improved clinical prognosis. Furthermore, in choosing a treatment regime these following aspects should also be taken into consideration: — dosage, — toxicological profile, — pharmacological interactions, — the fact that the patient is a child, — the availability of adapted formulations, — age, — school attendance. When treatment is being considered for a child younger than two years old, it is advisable to check which drugs may have been previously taken by the mother during pregnancy and by the newborn baby in the perinatal period to prevent vertical transmission [13] ( Treatment with antiretrovirals causes the selection and expansion of drug-resistant viral variants. Although it seems that these variants are not necessarily transmitted by the mother to the child, it is nevertheless reasonable to initiate treatment using a treatment combination not used previously.
Although the drugs used to start treatment are broadly the same for both symptomatic and asymptomatic children, the choice of treatment must take into consideration the child's clinical status (cfr. Table 1). TABLE 1 Suggested criteria for drugs to be used for the initiation
of antiretroviral treatment based on the clinical conditions of the child [5] Clinical stage
Treatment combinations advised
2NRTI + PI combo CD4 < 15% and VL >100.000 with stable clinical situation 2NRTI + NNRTI 2NRTI Evaluate the general conditions, CD4 and the viral load.
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A child who is asymptomatic or has
mild symptoms (cat. A/B)

The treatment combinations advised for starting treatment are presented in Figure 15.
FIGURE 15 Medication combinations to be used at the start of therapy.
The development of resistant viral strains is less frequent with PI than with NNRTI, and therefore treatment combinations containing PI may be better than those with NNRTI. Moreover, they are easy to administer and well tolerated in children. The advantages and disadvantages of the various treatments (cfr. Table 2) can have a different importance to different patients, and therefore the choice of treatment to be used must be made after having carefully evaluated the particular characteristics of the child and family. TABLE 2 Advantages and disadvantages of the different classes of drugs.
Effectiveness well documented Poor tolerability and containing from a clinical, virological and difficulty in taking > for use in case of PI, but NOT immunological point of view. difficult adherence. therapeutic failure. Lasting benefits in spite of Metabolic changes (*) in Cross-resistance possible sudden rise in viral the medium-long term. load. Multiple mutations necessary for development of resistance. Blocks the HIV cycle at two levels (RT and PI). Few side effects (lack of those Rapid appearance of Minor interactions Conserve PI for containing linked to PI). Easier to use and resistance (one mutation tolerate than PI. therapeutic failure. Cross-resistance with the entire class of NNRTI. Facility of use and good "Clinical" effectiveness Few problems and Conserve the PI to NNRTI, NO tolerability (compared to PI). unknown in the medium- Lack of side effects linked to PI long term. Limited long- and NNRTI and NNRTI, Resistance to 1 term virological therapeutic failure. NRTI does not imply cross- effectiveness in patients Cross-resistance resistance to the entire with high viral load > limited to within 100,000 copies/ml at the initiation of treatment. (*) It has not been shown that any side effects attributed to treatment with protease
inhibitors, for example lipodystrophy, are closely associated with the use of regimes
containing PI. Lipodystrophy has also been found sporadically in patients being treated
with NRTI and in patients not receiving antiretroviral treatment. The effects of ritonavir,
the principal inhibitor of CYP450, may be reduced using combinations of one or more
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Recently, the Penta 5 study [11] showed that treatment with two NRTIs, including ABC, is not inferior to treatment that includes PI (Figures 16-17-18, Tables 10-11). These combinations, therefore, may be considered in particular situations, such as in completely asymptomatic children in whom there may be problems with treatment compliance when three drugs are used. FIGURE 16 PENTA 5 - Population studied.
Gibb, DM et al,Fifth International Congress on Drug Therapy in HIV Infection;
Glasgow Oct 2000: PL6.8 PENTA 5 Trial
FIGURE 17 Variations in the level of HIV-RNA (logistical regression).
Gibb, DM et al,Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: PL6.8PENTA 5 Trial Universita di Padova HIV Therapy Course I
FIGURE 18 Variations in the level of HIV-RNA (logistical regression).
placebo 24
Gibb, DM et al,Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: PL6.8; PENTA 5 Trial TABLE 10 Percentage of babies with VL 50 c/ml - 400 c/ml in 24 and 48 weeks.
Overall p Adjusted p*
(*) correct data for the use of NFV, HIV-1 RNA at the beginning of the therapy, CD4%
and age (logistical regression)
Source: Gibb DM for the PENTA 5 Executive and the PENTA Steering Committee.
A randomised trial evaluating three NRTI regimens with and without nelfinavir
in HIV-infected children: 48-week follow-up from PENTA 5 trial.
Fifth International Congress on Drug Therapy in HIV Infection;Glasgow Oct 2000: PL6.8
TABLE 11 Percentage of babies with VL 50 c/ml - 400 c/ml in 24 and 48 weeks.
Adjusted p*
(*) correct data for the use of NFV, HIV-1 RNA at the beginning of the therapy,
CD4% and age (logistical regression)
Source: Gibb DM for the PENTA 5 Executive and the PENTA Steering Committee.
A randomised trial evaluating three NRTI regimens with and without nelfinavir
in HIV-infected children: 48-week follow-up from PENTA 5 trial.
Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: PL6.8
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Nucleoside reverse transcriptase inhibitors (NRTI)
Recommended NRTI combinations (on the basis of data gathered on adults and in paediatric trials) are: —ZDV + 3TC —ZDV + ddI —d4T + 3TC —d4T + ddI —ZDV + ABC —3TC + ABC —(ZDV + ddC) All of these NRTI combinations probably have comparable effectiveness, with the sole exception of those containing ABC (in particular ABC + 3TC), which seem to be more effective than the others in reducing viral replication (Table 10, Figure 18). Due to the highly negative predictive value of encephalopathy in HIV-1 [14], it is advisable to insert into the combination at least one drug that has a good ability to cross the blood-brain barrier (ZDV, d4T or ABC). However, the following combinations, for reasons of cross-resistance, antagonism or superimposition of toxicity, are not advised: —d4T + ZDV, —ddC + ddI, —ddC + d4T, —ddC + 3TC. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
If it is decided to combine a NNRTI with two NRTIs, a choice may be made between: —Efavirenz (EFV) —Nevirapine (NVP) In adults, the combination of 2 NRTIs with EFV or NVP has shown itself to be as effective as the combination of 2NRTI with PI in reducing viral replication and in guaranteeing a good immunological response (Table 12). TABLE 12 Effectiveness of different HAART regimes in ART-naive patients after
48 weeks of treatment (ITT)*.
%<50 c/ml
(*) ITT = Intention to Treat (Analysis)
Source: Atlantic Study
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In children - although there is not much data - combinations containing NNRTI are used a great deal, due to the ease of administration (by syrup) and the dose schedule (once or twice a day). [5] EFV is a drug which is administered once a day, and which is therefore used a great deal, in combination with 2 NRTIs, as an initial treatment in children of school age. However, the lack of information on dosage and pharmacokinetics in children under two years of age makes its use in this age band inadvisable. Protease inhibitors (PI)
For children, the use of combinations containing PI leads to a reduction in viral load of the order of log2. However, the viral load only falls below 50 copies/ml after 48 weeks of treatment in 40% of cases. [5].
If it is decided to initiate combination treatment containing PI, the following drugs are currently available: —Nelfinavir (suspension and tablets) —Indinavir (capsules) —Amprenavir (tablets) —Saquinavir/Fortovase (gel capsules) —Ritonavir (syrup and gel capsules) —Lopinavir/Ritonavir (ABT378) While NFV, IDV and APV may be used as a single PI, but always in combination with drugs from other classes (NRTI or NNRTI), it is advisable to use RTN and SQV in combination with another PI. RTN and SQV at standard doses are poorly tolerated over long periods of time (high risk of metabolic complications): they present management difficulties due to their various interactions with other drugs commonly prescribed to HIV positive patients. Nevertheless, RTN and SQV have been shown to be very useful since at low doses they can increase the minimum concentration (Cmin) of other PI (Figure 19). An increase in Cmin allows the plasma levels of a drug to be constantly maintained above the threshold for inhibiting viral replication (Figure 20), thereby increasing the potency of the treatment.
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FIGURE 19 Indinavir + Ritonavir (078) Twice Daily PK Mean Plasma Indinavir
Concentration Over Dosing Interval Using IDV/RTV 800/100 mg and 400/400 mg q12h FIGURE 20 Basic pharmaceutical principles.
Although treatment with a combination of two PIs may prove successful for a good proportion of children [12], there is an increased risk of metabolic changes and of burning out an effective treatment option (the treatment is also effective in non-naive children). Thus the suggestion for now is to steer away from using lopinavir/ritonavir or other PI combinations when initiating treatment in asymptomatic or moderately symptomatic children. Universita di Padova HIV Therapy Course I
A child with significant
symptoms (cat. B/C)

If antiretroviral treatment needs to be initiated in children who have already developed significant symptoms or have severe immunodeficiency (classes 2-3) and a high viral load, use treatment combinations guaranteeing maximum effectiveness in reducing viral replication. Combinations containing 2 NRTIs associated with more than one PI, with or without a NNRTI, should therefore be considered. The choice of drugs must take into account any other ongoing treatments and prophylaxes, thus avoiding cross-toxicity as far as possible (Tables 13-14-15). Other factors which may be present in sick children and which may influence the taking and absorption of drugs (chronic candidosis, cachexia, anorexia, chronic diarrhoea, etc.) must also be considered.
TABLE 13 Toxicity of antiretroviral drugs (NRTIs).
Most important side effects
Zidovudine (Retrovir) Neutropenia, anaemia, nausea, headache, myopathy - AZT, ZDV Didanosine (Videx) Pancreatitis (dose related), peripheral neuropathy (dose related), diarrhoea and abdominal pains, abnormal electrolytes, pigmentation of the retina (rare) Zalcitabine, (Hivid) Headache, gastro-intestinal problems, peripheral neuropathy, rare pancreatitis in children, hepatic toxicity, ulcers in the airways Stavudine, (Zerit) Peripheral neuropathy and pancreatitis (rare) Lamivudine, (Epivir) Headache, abdominal pains, pancreatitis, peripheral neuropathy, neutropenia, increased hepatic functioning values – all effects rare. Occasional rash. Abacavir, (Ziagen) 3%-5% may develop hypersensitivity reactions, fever, indisposition, mucositis + rashes, generally in the first 6 weeks. Interrupt the treatment and do not resume it. References: SPC (Summary of Product Characteristics)
TABLE 14 Toxicity of antiretroviral drugs (NNRTIs).
Most important side effects
Rash 5%-10%. The medication can be continued Nevirapine (Viramune) for as long as there are no signs of Stevens-Johnson Syndrome - if this appears therapy should be stopped. Efavirenz (Sustiva, Stocrin) Rash, toxicity of SNC, somnolence, nightmares. Delavirdine (Rescriptor) Drug interactions Headache, tiredness, rash. SPC (Summary of Product Characteristics) Universita di Padova HIV Therapy Course I
TABLE 15 Toxicity of antiretroviral drugs (PIs).
Most important side effects
Nausea, hyperbilirubinemia (10%), nephrolithiasis Indinavir (Crixivan) (4%), anaemia, abnormal lipid and glucose Gastro-intestinal problems, paraesthesia, headache, Ritonavir (Norvir) increased liver enzymes, increased haemorrhage, diabetes, abnormal lipid and glucose metabolism. Saquinavir (Fortovase, Rash, headache, gastro-intestinal problems, spontaneous haemorrhage, abnormal lipid and glucose metabolism. Nelfinavir (Viracept) Mild diarrhoea, vomiting, rash, diabetes (rare), abnormal lipid and glucose metabolism (rare). Amprenavir (Agenerase) Gastro-intestinal problems, abnormal lipid and glucose metabolism. Pancreatitis, elevated levels of total cholesterol and Lopinavir + Ritonavir (Kaletra) triglycerides, nausea, diarrhoea, abdominal pain, rash, headache and asthenia. References: SPC (Summary of Product Characteristics)
Once a treatment regime has been started, it should generally be continued - even during episodes of serious illness.
Mini Quiz 3
Question 5:
Is it advisable to administer ZDV as monotherapy to a child with slight symptoms?
Question 6:
Is one of the principal advantages of the administration of treatment with NNRTI the
inhibited appearance of viral strains resistant to these drugs?
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Drug dosages
Dosages of the principal antiretrovirals commonly used in children are set out in tables 3, 4 and 5: Table 3: Nucleoside reverse transcriptase inhibitors (NRTI);
Table 4: Non-nucleoside reverse transcriptase inhibitors (NNRTI);
Table 5: Protease inhibitors (PI).
TABLE 3 Dosages of the principal antiretroviral drugs in the paediatric age range.
Nucleoside reverse transcriptase inhibitors (NRTIs).
360 mg/m2/day (BID) 200mg/m2 x 3/day (neurological patient) 2 mg/kg x 4/day (newborn baby) 1.5 mg/kg x 4/day (premature) 200 mgx3 or 300 mg x 2/day (adolescent) Didanosine (Videx) 180-240 mg/m2/day (OD or BID) - ddI 50 mg/m2 x 2/day (newborn baby) > 60 kg ® 200 mg/day (BID) or 400 mg/day (OD) Zalcitabine (Hivid) 0.03/Kg/day/TID - ddC Stavudine (Zerit) 2 mg/kg/day (BID) 40 mg x 2/day (> 60 kg) Lamivudine (Epivir) 8mg/kg/day (BID) (child) - 3TC 300 mg/day (BID) (adult) Abacavir (Ziagen) 16 mg/kg/day (BID) - ABC 300 mg/day (BID) SPC (Summary of Product Characteristics) TABLE 4 Dosages of the principal antiretroviral drugs in the paediatric age range.
Non-nucleoside reverse transcriptase inhibitors (NNRTI).
Efavirenz (Sustiva, Stocrin) 15-20 Kg 250 mg 20-25 Kg 300 mg 25-33 Kg 350 mg 33-40 Kg 400 mg >40 Kg 600 mg Nevirapine (Viramune) 5 mg/kg/day x first 14 days 120-200 mg/m2 x 2/day Source: SPC (Summary of Product Characteristics)
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TABLE 5 Dosages of the principal antiretroviral drugs in the paediatric age range.
Protease inhibitors (PI).
Saquinavir (Invirase, Fortovase) 300 mg/m2 x 3/day 600 mg/m2 x 3/day (adolescent) Ritonavir (Norvir) 400 mg/m2 x 2/day 600 mg x 2/day (adolescent) Indinavir (Crixivan) 500 mg/m2 x 3/day 800 mg x 3/day (adolescent) Nelfinavir (Viracept) 130-150mg/kg/day, TID (up to 1250mg/day) 10 mg/kg x 3/day (newborn baby) 750 mg x 3/day (adolescent) Amprenavir (Agenerase) 17mg/kg x 3/day (child) - for syrup 20 mg/Kg x 2/day (< 50 Kg) 1200 mg x 2/day (> 50 Kg) Lopinavir + Ritonavir (Kaletra) 10-15 Kg 1.75 ml x 2 /day 20-25 Kg 2.25 ml x 2/day 30-40 Kg 3.5 ml x 2/day > 40 Kg 5 ml x 2/day > 12 years 3 capsules x 2/day (*) PIs dosages change in case of using them in combination with RTV and/or EFV
SPC (Summary of Product Characteristics);
PENTA 7 Trial (for NFV)
For some antiretroviral drugs there are no paediatric preparations (syrup or suspension) to allow dosage to be adapted to variations in weight. This has limited the possibility of carrying out pharmacokinetic studies on newborn babies and children in general.
Pharmacokinetic studies have been conducted on newborn babies treated with ZDV, 3TC, NVP and NFV. In the first months of life, clearance of NFV is very rapid and its variability is extreme. The recommended dose is therefore 150 mg/kg BID [10]. During puberty, hormonal changes take place that can theoretically influence the
metabolism of drugs, and this is linked to protein and hepatic metabolism. This is
especially important for those drugs with a limited therapeutic index
Although there is no data of any kind on how to modify drug dosage during adolescence,
the USA guidelines [2] on antiretroviral treatment in adults/adolescents suggest
the following outline, in accordance with the Tanner classification:

according to paediatric guidelines Classes III - IV careful monitoring of toxicity and adaptation of dosage according to adult guidelines Correct answers to Mini Quizes:
Mini Quiz 1
Mini Quiz 2
Mini Quiz 3
Universita di Padova HIV Therapy Course I
1. Williams AJ, Duong T, McNally LM, Tookey PA, Masters J, Miller R, Lyall EGH, Gibb DM: Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection. AIDS 15:335-339 2. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and 3. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection 4. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994; 43 (RR-12): 5. Sharland M, Gibb D, Giaquinto C on behalf of the Penta Steering Committee: Current evidence for the use of paediatric antiretroviral therapy - a PENTA analysis. Eur J Pediatr (2000) 159: 649-656 6. Sleasman JW, Nelson RP, Goodenow MM, Wilfred A, Balser M, Suckerman J, Pizzo PA, Mueller: Immune reconstitution after ritonavir therapy in child human immunodeficiency virus infection involving lymphocyte lineages. J Pediatr 134: 597-606 7. Choen Stuart JW, Slieker WA, Rijkers GT, Geelen SP, Scherpbier HZ, Hartwig NG, Roos MT, Meecker B, Noest E, Boucher CA, Suirr MH, de Boer R (1998): Early recovery of CD4 T lymphocytes in children on highly active antiretroviral therapy. Dutch Study group for children with HIV infection. AIDS 12: 2155-2159 8. Lyall EGH, Head S, Walters MDS, Tudor-Williams G: Baby cocktail!- A palatable four drug combo for HIV infected infants. Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: P212 9. Scott ZA, Chadwick EG, Catalina MD, McManus M, Yogev R, Palumbo P, Britto P, Sullivan JL, Luzuriaga K, PACTG 345 Investigators: HIV-1-Specific CD8+ T Cells in Vertically Infected Infants: Early Responses and the Effects of Antiretroviral Therapy. Eighth Conference on Retroviruses and Opportunistic Infections; Chicago Feb 2001:169 10. Faye A, Compagnucci A, Saidi Y for the PENTA 7 Executive Committe. Evaluation of Toxicity, Tolerability and Antiviral Activity of Early d4T + ddI + Nelfinavir (NFV) Therapy in HIV-1 Vertically Infected Infants: 24-Week Preliminary Results from the PENTA 7 Study. Eighth Conference on Retroviruses and Opportunistic Infections; Chicago Feb 2001: 678. 11. Gibb DM for the PENTA 5 Executive and the PENTA Steering Committee. A randomised trial evaluating three NRTI regimens with and without nelfinavir in HIV-infected children: 48-week follow-up from PENTA 5 trial. Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: PL6.8 12. Cahn P, Renz C, Deetz C, Xu Y, Saez-Llorens, Violari A, Gomez P, Handelsman E, Pelton S, Ramilo O, Chadwich E, Arpadi S, Allen U, Bertz R, Sun E: ABT-378/ritonavir (ABT-378/r) in HIV infected children Fifth International Congress on Drug Therapy in HIV Infection; Glasgow Oct 2000: P225 13. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States 14. Italian Register for HIV Infection in Children Italian guidelines for antiretroviral therapy in children with human immunodeficiency virus-type 1 infection.
Acta Paediatr 88: 228-32, 1999. Universita di Padova HIV Therapy Course I
Dr. Carlo Giaquinto
Coordinator of Paediatric European Network for Treatment of AIDSAssociate – Department of Paediatrics of Padua University 1982 Graduation of Medical and Surgical Faculty at Padua University
1983 Clinical Fellow in Paediatric Infectious disease, Institute of Child Health, London
1986 Specialization in Paediatrics in Padua University
1986 Fellow at Immunology Department, Albert Einstein College of Medicine, New York.
1988-1993 Associate doctor, Department of Paediatrics of Padua University ULSS-21.
Since 1989 Professor at Paediatrics School in Padua University.
Since 1993
Associate doctor, Department of Paediatrics of Padua University ULSS-21 1996-1997 WHO-World Health Organization, Geneva, consultant for the Program of
Management of Paediatric Diseases
Since 1985 Scientific coordinator of Paediatric AIDS Centre in Padua for research projects in
the areas II-III-IV-V-VI-VII-VIII-IX, research programmes 1 and 2 of AIDS project– Superior
Institute for Health (in charge Prof. F. Zacchello)
1986 Promoter (together with Prof. C.S.Peckham) of Collaborative European Study regarding
natural history of HIV infection in paediatric age group
1989 WHO consultant for paediatric AIDS, specially in matters regarding breast feeding and
1990-1994 Member of Executive Committee (as Italy's representative) within Paediatric
European Network for Treatment of AIDS (PENTA) of European Union. European coordinator of
research project PENTA 2.
1991 Beneficiary of financing in domain 5 of the project SIDA-ISS and of the project of
antiretroviral therapy of the Superior Institute of Health.
Since 1992 Member of Executive Committee of the European Forum of Children and
Families Affected by HIV/AIDS, concerted action of European Union. 1993-1999 Project
Coordinator for the concerted action of Paediatric European Network for Treatment of AIDS of
European Union (63 European paediatric centres). 1995-1996 Beneficiary of financing within
the project AIDS and it's social aspects, Superior Institute of Health (projects 1°-2°-3°)
Since 1995 Coordinator of the project Organization of a network to ensure assistance to
families affected by HIV, within the programme Europe Against AIDS (EU).
Since 1995 Coordinator of PENTA Project, financed by European Community within the
programme BIOMED II.
1996-1997 World Health Organization, UNAIDS, Geneva, consultant for project
WHO/UNICEF: training course on management of childhood diseases.
Since 1996 Scientific advisor of Moschino Foundation, Project SMILE.
Since 1997 Member in National Committee for Fight Against AIDS and other infectious
diseases, Ministry of Health.
Since 1997 Coordinator of project Sunflower Smile Day Clinic Network in Romania, financed
by Romanian Angel Appeal, Romanian Ministry of Health , world Bank, Franco Moschino
Universita di Padova HIV Therapy Course I
1998-1999 Project coordinator and President of the project "A good model of alternative
family assistance for HIV/AIDS affected children", within European Union's programme
"Europe against AIDS".
Since 1998 Member of Committee for Therapeutic Solidarity Funds, financed by French
Ministry of Health and European.
Since 1998 Coordinator of project Pedianet: data base build-up in order to be used by
paediatricians in Italy.
Since 2000 Project coordinator and President of the project "Implementation of strategies to
prevent mother to child transmission of HIV among immigrants in Europe: evaluation of the
knowledge and the needs of immigrants women in Europe", part of European Union's
programme "Europe against AIDS".
Publications and conferences
He held over 150 seminaries, conferences and speeches in different Italian universities and abroad, as well as during International congresses. Author of three monographies of paediatric AIDS.
He published: 90 articles in international journals72 articles in National journals and different chapters in English and Italian books120 papers at congresses with published results Prof. Ruggiero D'Elia
Associate Professor of Infectious Diseases, University of Padua. In charge of the Service for Pediatric Infectious Diseases in Immunodepressed Patients, Dept. of Pediatrics, Padua.
1962 Degree in Medicine and Surgery
1963 Accreditation to practice the profession
1964 Specialisation in Pediatrics
1967 Specialisation in Cardiology
1976 Specialisation in Neonatology
1983 Specialisation in Infectious Diseases
1963 Temporary assistant of human anatomy - Pavia
Pediatric assistant - Pediatric Clinic, Padua Pediatric assistant - Pediatric Clinic, Padua since 1972
University Assistant - Pediatric Clinic, Padua 1971 University Teacher of Clinical Pediatrics - Padua
1978 Assistant Professor of Infectious Diseases during Infancy - Padua
1980 Associate Professor of Infectious Diseases - Padua
Director of the Clinical Pediatric Department of Treviso General Hospital, accredited with the University of Padua Universita di Padova HIV Therapy Course I
Professor, Course of Infectious Diseases in Infancy for 5th year medical Professor, Course of Infectious Diseases, basic teaching, obligatory, for 4th year medical students, University of Padua Teaching of Infectious Diseases/Clinical Immunology at the following specialisation schools at the University of Padua: Pediatrics, Neonatology, Gynecology, Obstetrics, Hygiene —Practical and theoretical teaching of specialisation students, trainee physicians and other health sector personnel —Speaker/moderator at numerous national and European infectiology and chemotherapy —Consultancy for the Veneto Region for problems associated with vaccination, pediatric AIDS monitoring and microbial resistance to antibiotics programmes Member of the following scientific associations
—Società Italiana di Pediatria —Società Italiana di Malattie Infettive — Italiana di Infettivologia Pediatrica —Società Europea di Malattie Infettive Pediatriche (ESPID) —Società Europea di Ematologia e Immunologia Pediatrica (ESPHI) —Società Americana di Microbiologia —Società Internazionale dell'Ospite Immunocompromesso (IHS) —Società Internazionale di Malattie Infettive —Chairman of the European Society for Pediatric Infectious Disease (ESPID), 1987-88 and Organiser of the VI Annual Meeting of the Society in Padua (1988). Experience in countries in and outside Europe
—LAUSANNE, Department of Pediatrics, 1973, one month —ZURICH, Department of Pediatrics, 1975, one month —LONDON, Institute of Child Health-Hospital of sick children, 1976, one month —MUNICH (Germany) Department of Pediatrics and Infectious Diseases, 1981, 4 months —UNITED STATES: Experience of one week in each: —BALTIMORE, Johns Hopkins, Department of Infectiology and Immunology —BETHESDA, National Institutes of Health, National Cancer Institute —PHILADELPHIA, Children Hospital, Department of Infectiology —NEW YORK, Cornell University —BOSTON, Children Hospital and Boston City Hospital, Department of Infectiology 247 publications in pediatric and infectious diseases journalsAUTHOR of chapters in books on pediatrics and pharmacologyAUTHOR of the book:"SORVEGLIANZA E CONTROLLO DELLE INFEZIONI OSPEDALIERE" in collaboration with L.Diana, 1985.
Universita di Padova HIV Therapy Course I
Dr. Vania Giacomet
1991 Degree in Medicine and Surgery, University of Padua
1991 Accreditation to practice the medical profession, University of Padua
1995 Diploma of Specialisation in Pediatrics, University Pediatric Clinic, Ferrara
Since 1995
Clinical and research activities at the Department of Pediatrics, University of 1998 Coordination of a project for the prevention of HIV infection at state schools in Padua
Course in Epidemiology and Data Analysis at the "Mediterranean School of Medical Statistics and Clinical Epidemiology", Fontane Bianche (Siracusa) Since 1998
Sits on the Infectious Diseases Examination Board and conducts practical pediatric exercises for students on the Degree Course in Medicine and Surgery at the University of Padua 1999 National coordinator of the study to assess adherence to antiretroviral therapy in
pediatric age at a number of the most important pediatric HIV centre in Italy
Co-supervisor for three Degree in Medicine dissertations at the University of Padua —In the Department of Pediatrics, Padua, performs the following activities —clinical and research activities as part of the Ministry of Health and Institute of Health AIDS —clinical and research activities as part of the European Collaborative Study, Prospective Study of children born to seropositive mothers —clinical and research activities as part of PENTA (Pediatric European Network for Treatment Experience in countries in and outside Europe
—LONDON, The Hospital for Sick Children, Department of Infectious Diseases, 1994, 1997 —LONDON, Medical Research Council, 1997 —BENGHAZI (Libya) Children Hospital, 1998, 3 weeks —LONDON, Medical Research Council - HIV Clinical Trials Units, 2000, 1 month Has taken part as speaker in a number of national and international congresses in the field of pediatric infectiology.


Chin. Phys. B Vol. 24, No. 1 (2015) 014704 TOPICAL REVIEW — Magnetism, magnetic materials, and interdisciplinary research Surface modification of magnetic nanoparticles in Chu Xin(储 鑫), Yu Jing(余 靓), and Hou Yang-Long(侯仰龙 Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing 100871, China (Received 4 November 2014; published online 9 December 2014)


CHAPTER 17 Hydrocephalus in Neurocysticercosis and Other Parasiticand Infectious Diseases S. CAVALHEIRO*, S.T. ZYMBERG, P.D. TEIXEIRA, M.C. DA SILVA The cestode species are the most common parasites infection by T. solium. Colli et al. reported that 2.7% that affect the central nervous system (CNS). Five of hospital admissions for neurological diseases in