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HIV and AIDS

Over the last ten years, the last decade, the number of HIV-infected women has increased worldwide and also in this country. However, the pediatric cases of HIV infection are decreasing because we have been very effective in reducing vertical transmission. However, essentially all the cases of pediatric HIV we see today are due to perinatal transmission. Transfusion of blood products occurred prior to 1985 and we might still see some adolescents who are infected from transfusion.

Intravenous drug use continues to occur and thatís another form of acquisition of infection in the pediatric population, also through sexual contact, primarily in the adolescent group. In the United States, approximately 1,400- 2,000 HIV-infected infants are exposed annually. HIV exposure but not necessarily infected. Not all infants born to HIV-infected women will contract infection. Itís only about one-third of the children, however every single child born to an HIV-infected woman carries maternal antibodies because they cross the placenta. These antibodies persist until approximately 15 months of age.

The rates of perinatal transmission of HIV are the following, and this is actually worldwide: if a woman does not know she has HIV and she has a child, if you donít do anything, no treatment at all, the rate of transmission is 25-30%. However, with treatment - and the initial treatment of pregnant women was with AZT alone, zidovudine alone, transmission rate fell to 8% and now it is less than 4%. So Itís from 4-8% with treatment of the pregnant women who have HIV. Most of the infants who acquire HIV acquire HIV at the time of delivery, labor and delivery.

So what are the risk factors for perinatal transmission? For the infant to become infected? If the mother has an advanced disease, a very high virus load, very decreased CD-4 cell count, then her risk of transmitting to the infant is higher. If she does not have antibodies capable of neutralizing HIV, research studies have shown that also increases the risk of transmission. No treatment, obviously, because then the virus load is not controlled. Also increases substantially the risk of transmission if she acquires HIV while sheís pregnant. There is no neutralizing antibody, immunity will not develop, she will have a very high viremia.

There are several obstetrical factors that play a role in transmission of HIV from mother to infant. Prolonged rupture of membranes is now an established risk factor for increased transmission. Chorion unitas, like with other perinatal infections, also increases the risk of this child being exposed to this virus and also acquiring the disease. Mode of delivery; there was a paper that came out in the New England Journal of Medicine 1994 showing that elective C-section is protective in preventing transmission of HIV. Not an emergency C-section. An elective C-section which occurs obviously without membranes being ruptured.

Clinical presentation in children with HIV infection. A lot has changed over the last 3-4 years because of better drugs to treat HIV, but there is still a small subset of children who do not respond to treatment and who will progress in their disease. When we used to do natural history studies, about 20% of the children would be rapid progressers. Nowadays these are more children who have virologic failure and not responding to treatment. But if you let the disease evolve naturally without any intervention, thatís what you will see. They will develop AIDS within the first two years of life. Then there is another group of children.

Laboratory findings: what could happen in children who have HIV who come to your office? Anemia is common, neutropenia is another common non-specific finding. But most frequent is thrombocytopenia. These children frequently have thrombocytopenia. Hypergammaglobulinemia is extremely frequent. You will do QIgís. The IgG levels will be extremely high, IgM as well, but if you do functional tests these antibodies are not working well. Thatís why they get recurrent infections.

So during pregnancy, if women are diagnosed during prenatal care, at least they should be offered oral AZT. Most people today will give triple therapy to pregnant women as well. It usually consists of two reverse transcriptase inhibitors like AZT or 3TC, and a protease inhibitor or some other drug, at least in this country. And this continues to change every month so it is very hard to update. But the CDC guidelines still indicate that at least oral AZT should be given to these women when they are diagnosed.

Now if women know they are HIV-infected and they get pregnant itís different because you will have to target their virus base and what therapies theyíve had before to avoid resistant strains and so forth. And as I said, new treatment strategies and combination therapies are being developed.

Early diagnosis, as I said before, usually in research centers we try and identify if these infants are positive within the first 48 hours of life. If they have a positive test within 48 hours of life it usually indicates they were infected prior to being born. They had in utero infection. If they were infected at delivery they are usually negative at birth, but they will tend to be positive. Then if you do a PCR by two weeks or by four weeks.

The recommendations per the CDC is that the mother gets AZT during pregnancy. She gets AZT intravenously during labor and delivery and the infant gets six weeks of AZT therapy. This is for all infants born to HIV-exposed women. Once they stop their AZT at six weeks of age, most places are not 100% sure of their diagnosis at that time. So it is recommended that they start prophylaxis for PCP.

How do we treat HIV infection? There are drugs coming out every year but the ones that we currently have available, that you can buy at any pharmacy, we have a category of nucleoside inhibitors of HIV reverse transcriptase, and these include AZT which is the prototype drug. Crossed the blood-brain barrier very well; ddI does not cross the blood-brain barrier as well; ddC which is a very similar drug to ddI. Cross resistance is the rule so if you have resistance to ddI you would never give ddC. Lamivudine, 3TC, which works very well in combination with AZT or in combination with stavudine, which is d4t; d4t also crossed the blood-brain barrier very well. AZT and d4t should not be used together because they are antagonistic in vitro. Abacavir is a new drug.

Protease inhibitors: the most potent drugs, again, for HIV. They have really revolutionized HIV disease in children in that they provoke a very profound suppression of virus load and when used adequately with good compliance they can stop the disease progress altogether and actually help restore immunity. They really have been excellent drugs. The first one to be licensed was ritonavir. For children, the ones with pediatric formulations include ritonavir and nelfinavir and Denavir only comes in capsules. Saquinavir has two forms, itís Fortovase and Invirase. Doses vary but it also only comes in capsules. Amprenavir is a drug that was released last May.

The frequently used combinations: most regimens Ö this is the recommended pediatric guideline. You will use two nucleoside analog reverse transcriptase inhibitors in combination with one protease inhibitor. Or you can use two non-nucleoside reverse transcriptase inhibitors plus one non-nucleoside analog, like for instance: AZT, 3TC, nevirapine. You generally try to use the protease inhibitor because itís a better drug, but if you fear that your patient will not be compliant - that there is a problem with the family - another alternatively acceptable regimen is to use AZT, 3TC, nevirapine. Four drug regimens are also acceptable and they can consist also of two drugs of the class of AZT plus one drug like nevirapine and a protease inhibitor.

Of course the more drugs you give the more toxicity you have. These are the main toxicities of these drugs. AZT causes hematologic toxicity, thatís a primary toxicity, especially anemia or neutropenia. And it is dose related and itís reversible once you stop the drug; ddI rarely can cause pancreatitis; ddC can cause neurotoxicity. The side effects of d4t and 3TC are minimal. Iíve never seen any problem. D4t in my experience has caused some neutropenia even though itís not reported as a side effect, but when we stop the AZT for neutropenia we continue with d4t and the patients often times continue with the neutropenia. Abacavir in 3%, less than 3% of the cases, can cause a fatal hypersensitivity reaction which occurs when you stop the drug and then restart it and re-challenge the patient with this drug later. And thatís a problem. Abacavir by FDA guidelines has to be used, when you use this drug you have to have charts for the patients to fill out and thereís a stricter control because of that. The fatal hypersensitivity reaction is not necessarily a rash. Itís more like a flu-like illness that they have, and you stop the drug then reintroduce them.