Antiretroviral therapy in children, women and intravenous drug users
Brian A. Boyle, MD, for HIVandHepatitis.com
The Monday afternoon plenary session at the 5th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland concerned antiretroviral therapy in different populations.
This session presented an opportunity to evaluate and discuss the unique problems with HAART encountered by children, women and those patients who have a history of using or are still actively using intravenous drugs. The somewhat informal and less pressured atmosphere of the 5th International Congress allows for good give and take between the presenters and the audience, and some of the questions from the audience were remarkably revealing and insightful regarding the difficulty many patients and providers have with antiretroviral (ARV) therapy, especially in these populations.
ARV Therapy in Children
The first presenter was Carlo Giaquinto from Italy. He did an outstanding job of covering his topic “Antiviral therapy of children: Review of the issues”. Dr. Giaquinto started with the good news. Several studies reflect the remarkable progress that has been made in treating HIV-infected children, with mortality rates declining from 5.4% in 1995 to 1% in 1998 . Further, while it is unclear whether children may have some defects in antigen presentation and cytokine production, children clearly appear to have an increased ability to recover immunologically from the damage caused by HIV. In one study, HAART-treated children had significantly higher increases in naive CD4+ and CD8+ cells then generally seen with adults, and that this is likely related to the presence of a functional thymus .
Dr. Giaquinto went on to state, however, that other studies, including PENTA 7, have not been as encouraging. In that trial, only 25% of the naive, newly-infected children started on HAART were less than 50 copies/mL at the end of 24 weeks. Dr. Giaquinto stated that while the reasons for this low success rate were certainly multi-factorial, that major contributors were poor adherence and poor pharmacokinetics, especially related to the nelfinavir. The bottom line for children is the same as for adults: Immunologic recovery and virologic control are dependent upon adherence to a potent antiretroviral regimen that achieves and maintains drug levels adequate for durable virologic suppression.
Pharmacokinetics is a critical issue in the populations discussed during this plenary, since most of the dosing schedules are based upon adult males. Dr. Giaquinto urged that further information be collected regarding the effects of age, surface area, weight, absorption, metabolism and other issues involved in achieving adequate drug levels. The data is clear that insufficient drug levels, especially due to the variability of levels achieved with PIs, may be a reason many patients fail therapy, and this may be especially true in children .
Adherence is a particularly difficult issue in children. It depends not only on the child taking the medication, but also on the parent/caregiver giving the medication. Children dislike taking medications and parents/caregivers frequently become burned out by the constant struggle of forcing the medications on the child. Dr. Giaquinto outlined several factors which may influence HAART adherence in children including the characteristics of the ARV drug given (e.g., dosing schedule, number and size of pills, taste of liquid or powder formulations, food interactions), the duration of therapy, the age of the child, fears regarding disclosure, diagnosis awareness and clinical stage.
He proposed that until further research addresses pharmacokinetic, toxicity, and tolerability issues regarding the use of antiretrovirals (ARVs) in children, clinicians should start with the easiest and simplest potentially effective regimen, that the regimen should have “forgiving” pharmacokinetics regarding late or missed doses if possible and that the clinician should work to educate both the child and the parent/caregiver regarding the necessity of ARV therapy and collaborate with them to maximize adherence. As a final thought, he mentioned a consideration of a structured treatment interruption, but unless the child is newly-infected, the chance of success, as most of the adult trials reflect, in chronic infection is small.
ARV Therapy in Women
Danielle Mercey from London discussed “Antiviral therapy in women”. She started by saying that the data was still unclear in women, as it is in all populations, regarding when therapy should be started. She pointed out, however, that in many women this issue is moot since they are not diagnosed as having HIV until they have relatively advanced HIV disease. She cited studies that found that more than one third of newly diagnosed women had a CD4+ cell count less than 200 cells/mm3 at the time of diagnosis and that in her clinic in London the median CD4+ cell count of newly-diagnosed women is 220 cells/mm3 and one-third have an AIDS diagnosis. She suggested that some inroads could be made by increased testing during gynaecologic and antenatal visits, since many women are seen there, but admitted that this is clearly not an adequate solution by itself. Further, additional funding for educational efforts regarding the benefits of testing and safer sex are necessary so women know how to avoid infection and get tested if they have a high-risk encounter.
Treatment discrepancies also abound when treatment rates between men and women are examined. Some of this may be related to clinician decisions, but Dr. Mercey contends that part of this discrepancy is related to women being less optimistic regarding ARV therapy and having a higher level of misconceptions regarding the benefits, risks and side effects of that therapy. Thus, clinicians should work harder to educate female patients and not accept, on face value and without further discussion, a decision not to start ARV therapy.
The issue of viral load discrepancy between men and women was discussed briefly. Dr. Mercey does not think that the differences are significant enough to warrant separate guidelines for women at this point. I am not sure I entirely agree and I think there is mounting evidence that indicates that a woman with one-half the viral load a man has may be at equal risk for progression [4, 5]. It may be premature to call for gender specific guidelines at this point, but clinicians and patients should certainly be aware of this data when making the decision about when to start therapy.
There is a significant need for further information about the use of ARVs in pregnancy, and Dr. Mercey took a relatively unpopular stand by advocating that some consideration should be given to deferring ARV therapy during pregnancy due to the risk of developmental and congenital abnormalities in children exposed to ARVs in utero. I think most clinicians still believe that the best data indicates that the risk and consequences of HIV infection outweighs the risk of these potential abnormalities [6, 7], but most would also agree that the degree of risk is not entirely clear .
Most clinicians believe this is an issue of which the mother should be informed and that she should have the ultimate right to accept or reject ARV medications for preventing maternal-foetal spread. Another issue which needs further data is whether to stop antiretrovirals during the first trimester of pregnancy. Currently, most clinicians do so to prevent foetal developmental problems, despite some evidence that this may adversely affect viral control later in the pregnancy , which may have implications for both mother and foetus.
Dr. Mercey discussed some of the reasons women may have more difficulty with ARV therapy. One problem is limited information regarding the pharmacokinetics of these agents in women, especially the need for dose adjustment for weight, and this may contribute to the high rate of side effects women encounter with NFV-related abdominal pain, IDV-related nephrolithiasis, and NVP-related rash. Finally, women find some of the body shape changes particularly disturbing and this may affect their willingness to take or stick with certain therapies. Several women in Dr. Mercey’s clinic were greatly disturbed when their families mistook their visceral fat accumulation for a pregnancy, and it does not take much thought to realize what kind of effect this would have on a woman’s willingness to continue ARV therapy.
Dr. Mercey then spent some time discussing adherence (she used the term “compliance”) in women. While most studies do not show female gender to be an independent risk for nonadherence, there are special issues surrounding adherence in women due to their busy lives that may involve work and caring for children, a higher likelihood of depression and lack of social/family supports. One woman from the audience made the observation that many of us have seen in our clinics: She is very supportive with helping her husband remain adherent to his ARV regimen, whereas her husband provides virtually no help to her. Frequently, getting medical treatment is one more burden piled on top of many other burdens and Dr. Mercey suggested that simple, forgiving regimens with convenient clinic visits, appropriate social supports for family, financial and disclosure issues, and treatment of depression may help with maximizing adherence in women.
ARV Therapy Among Intravenous Drug Users (IDU)
Fiona Mulcahy of Dublin discussed “Antiviral therapy and management of HIV in intravenous drug users.” She started her talk by saying that since most intravenous drug users (IDUs) are excluded from clinical trials, that there is very limited data regarding ARV therapy in this population and that many clinicians, due to perceived adherence issues, may inappropriately withhold ARV therapy . Dr. Mulcahy outlined the many psychosocial issues confronting IDUs including high rates of homelessness, unemployment, educational deficits and poor HIV knowledge. She urges that clinicians make an extra effort to correct these issues, where possible, however, she urges that the abilities of each patient be assessed individually regarding his or her ability to adhere and that clinicians do not automatically withhold HAART from IDUs.
Further, concerns regarding the increased metabolism of methadone by various antiretrovirals need to be addressed. In that regard, her data indicates that efavirenz (EFV) and nevirapine (NVP) decrease methadone levels on average about 50-60% (although there is wide variability in this effect) and that up to 75-86% of patients experience some withdrawal symptoms after days 7 to 10 of therapy with these antiretrovirals. This delay in withdrawal symptom onset is due to the time required for enzyme induction by EFV or NVP and it is Dr. Mulcahy’s impression that symptoms which occur before that date are more likely to be related to ARV side effects than withdrawal. NFV, ritonavir (RTV) and ABT-378/r (Kaletra) also may cause significant enzyme induction and methadone reduction and Dr. Mulcahy urges clinicians to assess patients for methadone withdrawal shortly after starting those regimens as well.
Methadone also affects ARV levels. These may be clinically significant regarding zidovudine (ZDV) (area under the curve (AUC) increased 40% by methadone), didanosine (ddI) (AUC decreased 60% by methadone), and to a limited extent stavudine (d4T) (AUC decreased 18%). As one questioner pointed out, some data indicates that the methadone related increase of ZDV may cause increased side effects and withdrawal from treatment and the methadone related decrease of ddI might cause virologic failure.
Another issue that directly affects many IDUs is hepatitis C co-infection. Dr. Mulcahy feels the data indicates relatively aggressive treatment of co-infected patients, but continues to have concerns regarding potential interactions of ribavirin (RBV) with certain antiretrovirals, especially ZDV.
Most studies do not indicate that the RBV/ZDV interaction is clinically significant, I think most clinicians would agree that treatment of hepatitis C co-infection is appropriate if inflammation or fibrosis are present on liver biopsy; however, patient hesitance regarding injecting interferon (IFN) three times a week, especially patients with a history of IDU, and IFN side effects remain an obstacle. Hopefully, with the advent of pegylated IFN, which allows for once a week dosing of IFN, the problems surrounding this issue will diminish, but it is still not an easy task to get IDUs to start and stay on hepatitis C therapy.
Dr. Mulcahy discussed clinical guidelines for improving the care of HIV-infected IDUs. High on her list was getting IDUs into a methadone maintenance program since her data indicates that this is associated with increased adherence and long-term ARV success. She also urged clinicians to consider linking drug therapy programs with ARV treatment and using directly observed therapy where possible as these may also contribute to antiretroviral success.
Providing the patient with frequent, careful medical and psychosocial follow-up with constant reinforcement of the need for ARV treatment and the ability of the clinician to manage ARV-related side effects and potential toxicities are also keys to success in this population.
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