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London, UK
Following exposure to the HIV virus the majority of individuals who become infected mount an antibody response which is detectable within three to six week. Although a much longer “negative window” i.e. between exposure and producing an antibody response has been recorded in the literature, these cases are very rare.With currently available sensitive tests, it is possible to be certain that individuals who apparently have been exposed but have no antibody response within three months, will not become infected. The ELISA assays have a high degree of sensitivity and specificity but the positive and negative predictive value of the test will depend upon the underlying prevalence of HIV infection. Most false positive tests will be due to transcription errors. It is for this reason that we have a police of two separate tests taken on different days and performed by different ELISA methods before we confirm an HIV positive test. Many countries still use western blot as a confirmatory test. This is expensive and sometimes non-specific.
It is obviously important for preventing transmission, to test blood for HIV prior to transfusion. This also gives some measure of the overall seroprevalence of the condition. We have a confidential system of reporting so that although such individuals donate blood, this is discarded without the need for an HIV test. There are also guidelines about the procedures to take when an individual’s donated blood is found to be HIV positive.
Determination of whether a child is HIV positive is particularly difficult immediately after birth because the IGG antibodies directed against HIV used in the ELISA test crosses the placenta passively at around the time of delivery. While viral culture or a positive HIV PCR test on cord blood available in the United Kingdom. However, PCR is being widely introduced. The importance attached to not incorrectly informing a mother that a child has been infected using PCR technology has led to the sensitivity of this tes being deliberately set at a low level to ensure a high specificity. Most babies produce an IGA antibody within three to six months of birth and these can be detected readily within ELISA assay. The risks of pneumocystis carnii pneumonia and its mortality are particularly high in the first few months of life and many in the UK are moving towards providing prophylaxis for the offspring of all known HIV positive mothers rather than those known to be infected. Despite the low prevalence of HIV in the UK, all mothers are counseled and offered HIV testing during pregnancy. This is less pejorative than “high risk testing” which is inaccurate as women has assumed greater importance because of studies showing the ability to reduce the rate of perinatal transmission, using drug intervention.
Immunological markers
The ability to follow the immunological deterioration which occurs following HIV infection is important for prognosis, for intervention with chemotherapy to prevent opportunistic infections and for trying to decide the optimum period to intervene with antiretroviral therapy. In the UK such monitoring is usually carried out with repeated measurements of the CD4 positive lymphocyte subsets. These have a relatively high degree of variability from day to day and, therefore, we have policy of not taking action on any one result and taking more notice of long term trends rather than sudden changes. We no longer routinely monitor serum neopterin or b-2 microglobulin in addition as this adds little to the information obtained by the CD4 count. Many other much simpler markers of clinical status give almost as much information as a direct measurement of the CD4 count including measurement of the lymphocyte count, erythrocyte sedimentation rate or haemoglobin.
Viral load
It is now, of course, possible to measure the HIV viral load in the plasma. Although this is a composite measure of massive daily production and destruction of virus, it does remain relatively constant over time and is highly predictive of long term outcome within a few months of seroconversion. The ability to differentiate between people at high and low risk of progression is particularly valuable when the CD4 count remains high (greater than 500 cells mm-3). Although the precise values of the viral load remains a matter of debate, a viral load of less than 10, 000 copies is associated with relatively low progression rate compared with those above 50,000 copies who are likely to progress much faster. It seems biologically plausible that those with high viral load should be offered much earlier antiretroviral treatment but this has yet to proven in controlled studies.
Skin Antiretroviral treatment
Considerable improvements in antiretroviral treatment has occurred over the last five or six years and many of us believe that we stand on the threshold of a major breakthrough where long term control of disease may be possible. Three classes of antiviral treatment are currently in use. The nucleoside analogues all act as chain terminators of reverse transcriptase and prevent virus from forming a DNA template which can be incorporated into infected cells. Non nucleoside reverse transcriptase inhibitors (NNRTIs) also act the reverse transcriptase but in a different way, the most obvious difference being the failure to effect the replication of HIV-2. the third class of drugs, proteinase inhibitors, inhibit the unique enzyme shich cleaves the large polypetides that result from transciption of the viral genome. Proteinase inhibitors do not prvent cells becoming infected but inhibit the develoment of viral progeny.
The initial studies in HIV disease use a nucleodide analogue, Zidovudine, and showed that this significantly prolonged life and reduced the risk of opportunistic infections in symptomatic individuals. A subsequent landmark study, Concorde, showe dthat this same drug had no effect if used earlier in asymptomatic individuals. It is now clear that drug failure is related to the develoment of quasi species of virus which are resistant to the drug and many of the patterns of mutations within the RT genome leading to resistance are now known. Unfortunately many drugs which have pronounced effects on HIV in vitro, in vivo lead to very rapid development of resistance, partly because a strong selection pressure, producing preferential growth of pre-existing mutations and partly because the development of de novo mutations at single points in the RT gene because of the very rapid rate of viral turnover. In general every possible viable mutant produced by a single codon mutation in the RT gene is produced daily during HIV viral replication l thus the appearance of virus displaying resistance to most of the M and RTIs and #TC, which require single mutations of the genome, occur very rapidly. Drugs will be effective for much longer if four or five mutations are required within a single genome to produce a resistant or if mutations are required which produce a virus less able to replicate. Thus combinations of drugs which require mutations at different sites to produce resistance, are used together and drugs which require four or five mutations within one genome to induce high level resistance, such as some of the proteinases, are particularly valuable forms of therapy.
Landmark studies recently published show that compared with AZT monotherapy, combination of nucleosides, either AZT and ddI and AZT and ddC increased survival and reduced the incidence of opportunistic infection. A large number of smaller studies showed that using even more drugs in combination were able to produce a greater and sustained effect on the HIV viral load. An important new concept is the attempt to produce a considerable reduction in the rate of viral replication that the viral load falls below detectable limits of a sensitive assay. Such low replication rates are unlikely to be able to produce the complex mutation patterns required to overcome the effect of these drug combinations. This can be achieved with two nucleosides together in about 20% to 30% of patients and in between 70% and 80% with two nucleosides, to which the patient has not been previously exposed, are combined with either an NNRTI or proteinase inhibitor. It appears likely that NNRTIs work best in those who have not previously been exposed to therapy and for this reason, it may be that a triple combination, including one of these drugs, should be used first. The presently available compound, Nevirapine, is associated with rash in a significant proportion of patients but a number of other drugs are at advanced stages of development.
It is clear that proteinase inhibitors are still effective in reducing viral load to below detectable limits if used later in the treatment cascade providing there are still at least two other nucleosides which the patient can be given in addition. Restriction on subsequent nucleosides, after initial therapy, will include the development of cross resistant viral swarms and shared toxicity such as peripheral neuropathy.
The three proteinase inhibitors currently available all have some advantages and disadvantages. Saquinavir is relatively free from toxicity and from drug interaction which are very important in late HIV disease, the only important drug interaction being inablility to use it with strong cytochrome P450 inducing agents such as Rifabutin. The major disadvantage of Saquinavir, however, is in its present formulation it is only poorly bioavailable. However, this problem should be overcome shortly as different preparations come into use. Ritonavir is a highly potent antiretroviral but does strongly both induce and inhibit the cytochrome P450 system and this means there are a number of very complex drug interactions which preclude its use in a proportion of patients. Also there are very serious toxicities which reduce compliance, particularly in the gastrointestinal tract. Indinavir produces less interaction with cytochrome P450 than Ritonavir but it is only absorbed efficiently when on an empty stomach.
It is clear that for long term suppressive theapy to work, compliance must be excellent and this is very difficult to achieve with any known theapy at present. Initiative will be required both for individuals who are themselves using the drug, pharmacists and dietitians to achieve a good compliance rate. It clearly needs to be established by controlled clinical trials that driving the viral load down below detectable limits does result in a considerable improvement in survival.
A number of other new drugs are rapidly entering the HIV field which have further increased the options available to patients already on therapy and for clinicians when deciding what is the optimum therapy to start with. Particularly exciting is a Glaxo-Wellcome product, 1592 which appears to be a potent nucleoside and a new proteinase inhibitor with a novel resistance pattern, Nelfinavir. This drug may not be associated with corss resistance to the other proteinases and, therefore, can either be sequenced first or subsequently in a treatment cascade.