Letter from the Publisher

Several major themes were the focus of emphasis at this Fallís conferences and are addressed in this newsletter. The emerging problem of co-infection with hepatitis C and HIV received a great deal of attention. HCV and its treatment is not yet well understood. Is daily dosing of interferon preferable to 3 times per week? Is daily high-dose induction therapy more effective in long-term? Treating HCV in the co-infected person is even less understood, but early studies on this are described below. Early data on once weekly dosing with pegylated interferon were reported and are described below.  Increased attention is being paid to therapeutic drug monitoring (testing drug levels) in evaluating response to therapy. A number of once daily protease inhibitor regimens are being developed, and are described below. There was little new from ongoing studies looking at combining immune-based therapies (Remune, IL-2, vaccines), except for 2 studies described below. But a number of studies are ongoing and results will be available starting next year. Reversing fat redistribution remains unsolved. Structured therapy interuptions continue to receive attention. Many reports in this newsletter were abbreviated from the full versions available on the NATAP web. And, there are additional reports on the site not reviewed here. Information presented at conferences is often preliminary and experimental, and it should be treated that way.

Correlating CD4s with Risk of Developing Opportunistic Infection; Deaths Due to OI Declines by 40%.

Several studies at ICAAC showed the risk of developing an OI is strongly associated with CD4 count. But HIV RNA (viral load) also is a predictor of developing an OI: compared to if VL <400, risk of developing OI increased 1.5 fold if viral load is 20,000 to 55,000, 2.1 fold if 55,000 to 149,000, and 3.1 fold if above 150,000. This association reportedly held true for PCP, MAC, candida esophagus. One study showed changes in these parameters during therapy were associated with a changing risk of death. One study reported that among persons with CD4s >200, high viral load >150,000 conferred an independent risk (RR=3.0) for OIs. OI prophylaxis should be considered if personís CD4 is above 200, if VL is high. However, many individuals with characteristics that would expect progression did not progress. One study reported that although proportion of death due to OI significantly decreased from 70% in early 1980s to 40% in late 1990s, the proportion of deaths due to KS and lymphoma accounted for 12% of those dying due to AIDS related OI and had not declined.

When and with what to begin therapy.  This question received attention at ICAAC and Lisbon. A major emphasis was placed on discussion of these questions at Lisbon. The US Public Health Guidelines suggest considering the initiation of therapy at 500 CD4s, but at Lisbon European researcher, Christine Katlama, suggested it may be preferable to delay until CD4s are 350 due to adherence, side effects, and tolerability concerns. At ICAAC, Chip Schooley felt that there is too much that is unknown about these toxicities (ie, prevalence, clinical significance, relation to therapy) and clinicians should not withhold therapy for an otherwise progressive and fatal illness. Surprisingly, Ian Weller appeared to suggest at Lisbon considering waiting until 200 CD4s. Katlama felt that the major issue with PI-sparing regimens is the lack of data in patients with advanced disease. Biologically speaking some researchers will tell you starting therapy early is preferable in achieving the best initial viral load response, that is expected to lead to a better long-term virologic and consequently clinical outcome. Other researchers are suggesting that if a person isnít going to be adherent, and if their quality of life is significantly affected, delaying the start of therapy may be preferable. This debate actually began at the World AIDS Conference in Geneva. Small studies suggest PI therapy may be more effective in ridding lymph noses & reservoirs of HIV, but NNRTI and triple NRTI regimens also suppress HIV in lymph tissue. There is more limited long term data with PI-sparing than PI regimens. PI data is 2-3 years old, and efavirenz data is 72 weeks. It is generally accepted that the initial virologic response to HAART is better if a person initiates therapy early (500 CD4 or more). A larger proportion of people reduce viral load to undetectable. Sabine Yerly reported at the Resistance Workshop data suggesting the earlier a person is treated, the more likely they are to achieve a more potent viral suppression. The follow-up was 6 months to 2.5 years after starting therapy. Additionally, a study reported at Resistance Workshop by Andrew Phillips (below, on page 18) suggests that if a person has low viral load after 1-2 years following initiating HAART they are likely to remain undetectable for a long period of time, if adherent.

PI sparing (triple NRTIs and NNRTIs) may be easier to tolerate, and thus adhere to: less pills, efavirenz is dosed once daily; NVP twice daily, possibly once daily: Abacavir is 1 pill twice daily. PI therapy appears to cause higher incidence of elevated lipids and glucose. Although individuals whoíve never taken PIs  can develop lipodystrophy it appears to occur more often when PIs are taken.. Is it the mechanism of action of the PI that causes lipodystrophy? Does viral suppression cause lipodystrophy? We donít know.

Resistance Testing. 

Resistance testing is here and will be increasingly used in making treatment decisions. As you may know by now a number of studies have shown that using genotypic or phenotypic testing can help select salvage regimen and improve virologic outcome. Aside from the number of strengths and weaknesses associated with resistance testing, there is concern about variability of results from different labs. For some commercial labs, their ability to interpret results are also variable. Expert advise is needed to interpret results. The NATAP web site conference report on the Resistance Workshop contains comprehensive discussion about resistance testing. The prevalence of transmitting drug resistant virus is a concern. As well, testing may help identify an initial regimen.

The FDA will be reviewing Visible Genetics TrueGene genotypic test for approval in early 2000. Currently, phenotypic testing does not need FDA approval. LabCorpís phenotypic and genotypic tests have been available. Virologicís phenotypic test became commercially available in October/November. Defining cutoffs for phenotypic resistance to certain drugs appears to be important issue. At recent FDA hearing on resistance testing, Doug Mayers said it will be key to establish the cutoffs for resistance to specific drugs. They discussed whether 4-fold resistance was better cutoff than 10-fold resistance, and Doug Richman said he prefers to select drugs for individuals to which they have 4 or less fold resistance. Mellors said future protease inhibitors may have 30-fold cutoffs. Databases are needed to help with utilizing resistance testing, and these databases are being established. Databases can show prior individualsí resistance profile with the regimen they selected and the outcome. Access to this information will be available and is expected to improve treatment selections. The use of testing drug levels is receiving increasing attention and is the subject of studies reported in this issue.

NEW DRUGS. 

A number of new antiviral and immune-based drugs are in development. T-20 (and T-1249), ABT-378, MKC-442, Remune, IL-2 and tipranavir are discussed below. Additionally, DuPont and Agouron are developing NNRTIs which they think, based on very early in vitro data, may not be cross-resistant with currentl NNRTIs. This will have to be confirmed in human studies. PMPA is a once daily nucleotide reviewed below. Adefovir is also a once daily nucleotide but the FDA Antiviral Advisory Committee voted not to recommend approval at this time. Three other new drugs met with development problems this Fall. Both DOTC and FDDA had shown good antiviral activity in early human studies and held forth promise for individuals with NRTI experience and resistance. But both encountered toxicity necessitating interruption of studies. The companies are in discussion with the FDA. Described below in the MKC-442 section is this drugís problematic and unexpected interaction with nelfinavir raising questions about its future use with a PI. DAPD and FTC are new NRTIs in development. Eary data suggest DAPD may be effective against NRTI resistant virus. FTC is taken once daily, likely to be cross-resistant with 3TC, but appears maybe more potent than 3TC. Although it appears as though the development of integrase inhibitors is stalled, Merck may be making some headway. As well, Merck is testing a vaccine candidate in humans. If good results are seen it may be tested in combination with HAART for infected individuals.