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Personal Practice Indian Pediatrics 2000;37: 1328-1340 |
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Human Immunodeficiency Virus Infection |
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Infection with the Human Immuno-deficiency Virus (HIV) is now a major public health problem for both developing and developed countries as it has dramatically increased the global burden of disease. The devastating consequences of this pandemic would have health implications for the next many decades. Guestimates suggest that life expectancy at birth in some of the African countries which was just 44 years in the early 1950s and which had risen to as much as 59 years in the early 1990s, may again drop to near 45 years over the next decade or so because of the ill-effects of HIV infection and the acquired immunodeficiency syndrome (AIDS). The effects on children would be equally pathetic because it is believed that the accrued beneficial effects from all child health related programs may be anulled by HIV/AIDS(1-3). According to data provided by UNAIDS, by end of 1999 the total number of people living with HIV/AIDS stood at 33.6 million of whom as many as 16 million were women and children below 15 years of age. The number of people newly infected with HIV in 1999 was 5.6 million of whom 2.3 million were women and 570,000 were children. About half of all people who acquire HIV infection do so before they turn 25 years of age and many of them die within the next 10 years or so, that is at a time when their economic productivity is at its peak. Many African countries have lost significant proportions of their workforce to HIV with grave conse-quences to the national exchequer(1). It must be noted that while children can be ‘infected’ with HIV just as adults are, they can also be significantly ‘affected’ by HIV while remaining uninfected themselves. By the end of 1999, the pandemic had left behind a cumulative total of 11.2 million ‘AIDS orphans’ – a term used to identify children who have lost their mother to HIV/AIDS before the age of 15. Many of these maternal orphans have also lost their father. It is believed that more children have been orphaned because of HIV/AIDS than there are people who have developed AIDS. For every child who contracts the infection, the number ‘affected’ is at least 5 times higher(1-4). It is unfortunate that HIV infection continues to be highly stigmatized in India. Children affected by or infected with HIV are discriminated against and often denied open access to health care. Majority of our hospitals do not have appropriate manage-ment protocols in place to look after the needs of such children. It is tragic, but nevertheless true, that many hospitals actually turn away HIV infected patients or deny them facilities which would be by right theirs had their HIV status not been known. Health is not a priority area for many developing countries and the governments feel overwhelmed when faced with a crisis of such unprecedented proportions. However, if one goes by the experience of Brazil and Argentina (both of which can be termed as developing countries), provision of appro-priate counselling and treatment facilities (which include anti-retroviral drugs) is not only economically feasible within the constraints of their health budgets but also perhaps cost effective in the long run(5).
"A child is not a miniature adult" – this adage is as appropriate for HIV/AIDS as it is anywhere else. Unlike adults, where the primary route of transmission of HIV is sexual, majority of infected children acquire the disease from their mothers at the time of birth. In India, however, a small proportion (say 10-15%) of children continue to acquire the infection through transfusion of blood/blood products– this proportion is likely to fall down considerably over the next few years as blood bank screening procedures are further refined. Most perinatal transmissions occur at or near the time of birth which raises the theoretical possibility of initiating treatment in an infected infant from day one of life itself, provided the requisite diagnostic tests are available. In other words, it is possible to treat ‘primary’ HIV infection in children–a situation which is extremely difficult to define precisely in adults(6). The perinatal transmission rates vary from 13-42% and are twice as high in Africa as in Europe(7). With the advent of use of anti-retroviral drugs in pregnant women with HIV, along with other measures, these rates would fall down considerably(8-13). A baby who has acquired the infection perinatally, poses considerable diagnostic problems for the physician because the usual laboratory tests (i.e., HIV IgG) are meaningless in view of the passive transfer of maternal IgG antibodies across the placenta. The clinical behavior of HIV infection in children is also very different from that in adults. Children tend to have a more rapidly downhill course, have more of bacterial and less of opportunistic infections and tend to develop Kaposi’s sarcoma very rarely. Lypmphoid interstitial pneumonia (LIP) is characteristically seen only in children(14,15). Monitoring of a pediatric patient while on anti-retroviral therapy (ART) is qualitatively very different from an adult. The CD-4 T-lymphocyte counts in infants are much higher (Table I) than in adults and show a progressive decline with age. The cut-off levels of CD4 T-lymphocytes for starting prophylactic therapy for opportunistic infec-tions are, therefore, considerably higher than adults(16-19). HIV RNA levels in infants who are perinatally infected may often be higher than those observed in adults with HIV infection. Children may, therefore, take that much longer to show a comparable decline in RNA copy number(20-22). Further complete suppression of infection to a level where the viral RNA is undetectable is achieved much less often in children as compared to adults, inspite of being on equally potent triple drug regimens. The long term effects of ART are much less clearly defined in children. In adults, it has been clearly shown that ART is more effective in treatment naive patients, as prior exposure to zidovudine or other nucleoside reverse transcriptase inhibitor (RTI) regimens may foster selection of drug resistant strains of the virus. A peculiar situation therefore arises in perinatally acquired infections where the fetus has been exposed to zidovudine and other antiretroviral drugs in the context of maternal treatment or prevention of perinatal transmis-sion. The therapeutic regimen selected for a given child should take these facts into consideration(4,23-26).
A commonly used classification system is given in Tables I and II(4,27). A child should be labelled to have AIDS only in the presence of a precise defining illness/condition. Such conditions are often very difficult to define in the developing country set-up where the laboratory back-up may be totally inadequate. It may be noted that from the patient’s point of view this classification is to some extent only of academic interest because the decision to start specific ART is now not based on the precise categorization as it hitherto was. All infected children (and adults) should be offered ART irrespective of their symptom status or immunological dysfunction so as to preempt further deterioration(4).
The laboratory diagnosis of HIV infection is based on identification of antibodies to viral proteins, detection of viral antigens, detection of viral nucleic acids or culture of the virus. The commonly used tests are as follows: (i) HIV IgG elisa - is the usual screening test and detects IgG antibodies. Before declaring a patient to be seropositive, the test should be repeated using a different test principle (along with a rapid test) and only if all the tests so performed are positive should the patient be declared to have the infection. Babies below 18 months of age can have a passive transfer of IgG antibodies and may have false positive HIV ELISA. The currently available kits detect both HIV 1 and 2 and the sensitivity is over 99.5%. HIV IgG ELISA is the only test which is necessary for routine patient care in developing countries. (ii) Western blot - detects antibodies to the various proteins and glycoproteins separated on an electrophoretic strip. Presence of antibodies to any two of the following antigen groups is taken as a positive test: p24, gp 41, gp 120/160. Western blots are prohibitively expen-sive and, in the developing country context, need not be done for routine diagnostic purposes. (iii) HIV p24 antigen - detectable before the development of antibodies but has a rather poor sensitivity. (iv) DNA PCR - amplifies proviral DNA and is an extremely sensitive method for early diagnosis of infection. (v) Quantitative viral RNA - is a measure of the ‘viral load’ and is somewhat pre-dictive of the rate of CD 4 cell depletion. The test can be carried out using signal amplification (bDNA technology), target amplification (PCR) or nucleic acid sequence based amplification (NASBA). The test is expensive with each assay costing Rs. 8-10,000. (vi) HIV culture - is cumbersome and diffi-cult to perform in most laboratories and the results are not available till at least 2-4 weeks. In babies born to HIV seropositive mothers diagnostic tests ( p24 antigen, DNA PCR and HIV RNA assay) should be performed at 48 hours and at 2, 6 and 18 weeks. Early diagnosis is essential because identification of infection during the first few weeks of life allows the clinician to initiate ART or intensify the ongoing prophylactic regimen for prevention of perinatal trans-mission. Cord blood samples should never be used for diagnostic purposes because of the risk of contamination with maternal blood. An infant cannot be declared infected unless 2 of the 3 above mentioned tests are found to be positive on blood samples obtained at 2 different occasions(4,28-31).
Every child with HIV infection in whom ART is contemplated should be regularly followed up to look for any signs of clinical deterioration. Laboratory tests (CD4 counts and quantitative HIV RNA) should be performed regularly but are often difficult to carry out in our set-up because of the expenses involved. CD4 counts are age-dependent (Table I) and may decrease transiently following minor illnesses or after vaccinations(4,16-18). HIV RNA copy number is dependent on the assay method used with the inter-assay difference being as much as two fold (0.3 log 10). PCR based assays are more sensitive than bDNA based tests, but are technically more complex and less easily reproducble(4,19,32). Unlike adults, the predictive value of HIV RNA copy number with disease progression in children is less clearly established(4,33-35).
A. Principles
B. Drugs Available A large number of anti-retroviral drugs are available to the clinician (Table III). HIV infection is now considered to be a ‘chronic manageable condition’ rather than a ‘rapidly fatal illness’. Prolonged survival is a distinct reality with the advent of triple drug therapy. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first drugs to be used for treatment of HIV infection and are also the least expensive. A combination of 2 NRTIs along with a protease inhibitor (PI) or a non-nucleoside analogue reverse trans-criptase inhibitor (NNRTI) is the preferred initial therapy. ddc is believed to be less powerful than ZDV, ddI or 3TC. ZDV and d4T should not be used together (Table III).
NNRTIs are being increasingly used in HIV treatment protocols even in children. Unlike most other anti-retroviral drugs, NNRTIs are not associated with significant side-effects and do not have restrictions associated with intake of food. Further they need to be taken only once or twice daily and this improves patient compliance. They also freely cross the blood brain barrier. PIs have been in use for more than five years now. Nelfinavir and ritonavir were the first PIs to receive FDA approval for use in children. The major problems associated with PIs relate to the expense of therapy and poor patient compliance because of associated side-effects. Most PIs have restrictions related to intake of food and have significant drug-interactions, the most notable of these being with other anti-retroviral drugs and anti-tubercular medications(37). A number of disturbing and bizarre side-effects have recently been reported in patients on long-term therapy on this group of drugs. These include obesity (protease paunch!), lipo-dystrophy, gynecomastia, hyperglycemia, hyperlipidemia and perianal abscesses (tails!). It is these side-effects which preclude the continued use of PIs in upto 20-30% of patients(4,23). C. What to Start? Any one of the following combinations may be started:
We prefer using a combination of ZDV and 3TC. Other acceptable NRTI combina-tions include ZDV + ddI/ddC or d4T + 3TC/ddI. The role of dual PI based combinations (in addition to 2 NRTIs) as initial therapy is yet to be clearly defined, but may be considered in patients with advanced HIV disease. The only PI which is easily available in India is saquinavir but this is the least powerful of all the PIs. D. When to Change ART may need to be changed under the following circumstances:
E. What to Change to? The striking short-term benefits of triple drug combination therapy should not preclude the fact that treatment is very expensive (Rs. 11,000 per month with a NNRTI based regimen and Rs.13,000 per month with a PI based regimen for an adult), therapeutic regimens are associated with lot of side-effects and the long-term efficacy (say beyond 3-5 years) is not clearly known. Whenever a decision is made to change a given regimen, atleast 2 drugs (preferably all 3) should be replaced. While the NRTIs can be replaced by other drugs from the same class, the same does not hold true for the PI or NNRTI because of significant cross-resis-tance amongst other drugs of these classes. In effect, therefore, it means that a PI based regimen needs to be replaced with an NNRTI based regimen and vice-versa. E. Is There a Role for Dual/Mono NRTI Therapy? Theoretically, any child who requires ART should be given triple drug therapy. However, the cost of this therapy turns out to be prohibitive and very few of our patients are able to afford it. In such situations we do offer dual NRTI therapy (e.g., with ZDV and 3TC) as it results in significant clinical improve-ment and virological and immunological recovery and improves the overall quality of life, albeit for a short term. Development of resistance is a risk associated with such therapy but in children this is to some extent acceptable because under normal circum-stances children, unlike adults, would not pass on such resistant strains to other individuals. We never use monotherapy now a days(38-41). F. Prevention of Perinatal Transmission Prevention of perinatal transmission of HIV has been one of the big success stories of HIV treatment. In 1994 the joint French-American placebo controlled double blind trial (ACTG 076) of ZDV therapy showed that administration of the drug (100 mg five times a day) during the second and third trimesters of pregnancy followed by an intravenous bolus of 2 mg/kg at start of labour and 1 mg/kg/hour thereafter, and oral administration (2 mg/kg/every 6 hours) to the neonate for 6 weeks resulted in a 66% decrease in the rate of perinatal transmission if breastfeeding was not allowed. Subsequent trials conducted in Thailand (breastfeeding not allowed) and in Ivory Coast and Burkina Faso (breastfeeding allowed) have shown that even much shorter courses of ZDV (given for 2-4 weeks before delivery) have resulted in a significant decrease in rates of peri- natal transmission (by 38-50%). The cost of such short course ZDV regimens is obviously much less than the original ACTG 076 regimen. An even more promising regimen is the one pertaining to single dose nevira-pine (2 tablets of 200 mg each) along with a dose given to the newborn baby (2 mg/kg within 72 hours of birth), which resulted in a 50% reduction in perinatal transmission. It is now clear that if in addition to administration of antiretroviral drug the mother undergoes an elective Cesarean section along with douching of the birth canal with virucidal agents, the perinatal trans-mission rates can be brought down to almost negligible levels (say 1-5%). This is indeed a big change from the perinatal transmission rates of 12-43% reported in early nineties(7-12,42-44). G. Prophylactic Therapy Prophylaxis against opportunistic infections is indicated whenever there is significant immunodeficiency. The most important opportunistic infection is with the fungus Pneumocystis carinii for which cotrimoxazole is the preferred drug and definite guidelines(4) are available for its use in children (Table III). The dose is approximately 1-2 mg/kg/day of trimethoprim given at bed-time. Cotrimoxazole perhaps also provides some protection against other bacterial infections which are common in developing countries. Rigid application of the guidelines for cotrimoxazole prophylaxis based on the child’s CD4 counts is difficult in our country because of the costs involved in performing the test. Prophylaxis against Mycobacterium tuberculosis and fungal infections is given only when there is a specific indication (e.g., contact with an open case of tuberculosis; or culture proven systemic fungal infection). Routine use of isoniazid for all patients with HIV infection is not an acceptable clinical practice.
H. General Care Although majority of our children are unable to afford specific ART, there is still a lot that one can do for them. Incidental infections (e.g., pneumonia, diarrhea, pyo-derma) should be aggressively managed with appropriate antimicrobials. If the condition does not settle down, hospitalization may become necessary. Tuberculosis is especially common and may have unusual modes of presentation–the clinician, therefore, has to have a high index of suspicion. We follow the usual immunization schedule in HIV infected children, but inactivated polio vaccine may be preferred to oral polio vaccine. The former, however, is not easily available in India. One should not unnecessarily withhold other live vaccines (e.g., BCG, measles) from such children because the accrued benefits far outweigh the associated risks, specially in developing countries. The immunodeficiency associated with HIV is quantitatively and qualitatively different from that of a child having severe combined immunodeficiency, a syndrome in which live vaccines are strictly contraindicated. Nutritional rehabilitation is an important aspect of management of such children and requisite efforts must be put in to ensure an adequate intake of food items that are inexpensive and culturally acceptable. The results of such interventions are often very gratifying.
As the number of HIV infected patients increases it is inevitable that hospital accidents, due to needle-stick injuries and cuts with scalpels/other sharps involving hospital personnel who deal with them, would also show an increase. At our hospital we encounter 2-4 such accidents every year. The risk of seroconversion following a needle stick injury is believed to be 3/1000. The site of exposure should be washed with water and detergent and a virucidal agent should be applied. All individuals who have had such accidental pricks/cuts or who have had mucocutaneous exposure to biological fluids (say over the conjunctiva) should be offered counselling and advised to take a course of ZDV and 3TC for at least 4 weeks, preferably longer. Further, an ELISA test should be performed soon after exposure and repeated thereafter at 6 weeks and 6 months. In situations where the chances of transmission are very high (e.g., patient with high viral load and inoculation involving a hollow bevelled needle) indinavir should be administered along with ZDV and 3TC. Needless to say such accidents are best prevented. One must incorporate stringent precautions (universal precautions) in day to day clinical care. All biological samples must be considered potentially infected. Gloves should be worn during venepunctures and while setting up drips. We use bleaching powder for disinfection of soiled bandages, bed linen, etc.
Triple drug therapy is by no means a panacea as far as treatment of HIV infection is concerned. There is a significant number of patients (say 20-40%) who have to dis-continue such therapy due to intolerable side-effects (specially with PIs), treatment related toxicity or treatment failure. A number of new approaches are being tried in such situations. These include use of integrase inhibitors (e.g., AR 177) and fusion inhibitors (e.g., T-20). The latter group of drugs prevent fusion of HIV with target cells. Adefovir, a nucleotide analogue, has also shown promising results and is believed to be unique because HIV does not easily develop resistance to it. Even amongst the conventional groups of AR drugs, exciting developments are taking place. Newer NRTIs (e.g., emtricitabine), NNRTIs (DMP 961, DMP 963, AG 1549) and PIs (e.g., AG 1776, ABT 378) are in the stage of trials and may turn out to be clinically useful. Further, chemokines have been isolated which interfere with co-receptors involved in HIV infection (e.g., CCR5, CXCR4). Benz-amide comopunds interfere with zinc finger proteins which are necessary for viral packaging and replication. Although curative therapy of HIV infection is still a distant mirage, overall there is far more optimism today than was the case in early nineties.
Treatment guidelines for HIV are changing rapidly and regimens which are state of the art today may be considered obsolete within a year. A number of websites are available which provide regular updates. These include http://www.aegis.com/; http://www.aegis.com/areas.html; http://www.tele port.com/celinec/aids.shtml; http://www.crit papth.org/aric; http://www.hivatis.org; http://www.bcpwa.org; http://www.aidsnyc.org/nat.ap; http://www.catie.ca; http://www.aidsnyc.org/network; and http://www.jri.org/infoweb/treatment/library/beta.
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