STEP PERSPECTIVE, Volume 8, No. 2 - Summer/1996; A Publication of the Seattle Treatment Exchange Project e-mail: step@eskimo.com
Jeffrey T. Schouten, M.D.

Global Epidemiology

KEY ISSUE: By the year 2000, 90% of all cases of HIV infection will be in the developing world. The theme of this year's International AIDS Conference was "One World, One Hope." Almost 15,000 persons from 138 countries attended the IAC: including delegates, PWA's, media representatives, and exhibitors. Many discussions focused on the need to address the AIDS epidemic as a global crisis, and for developed countries to assist in addressing the underlying social conditions of the AIDS epidemic: poverty, inadequate health care resources, and the need to empower women to control their own bodies. Since the beginning of the AIDS epidemic, over 6 million people have died and 5 million children have been orphaned. By the year 2000, greater than 50% of persons infected with HIV will be women and 90% of all persons infected with HIV will be from the developing world.

The World Health Organization estimates that, as of 1996, there are 6 million cases of AIDS , and 17 million people are infected with HIV worldwide. It is estimated that 15% of women of child-bearing age in South Africa are now infected with HIV. By the year 2010, life expectancy in Zambia will fall from 66 to 33, in Zimbabwe from 70 to 40, and in Uganda from 59 to 31. While encouraging data was presented showing a decrease in the rate of HIV infection in Uganda and Thailand, rates of HIV infection are rapidly increasing in India (which does not have an effective HIV prevention program) and Southeast Asian countries. Donna E. Shalala, Secretary of the Department of Health and Human Services stated , "The battle against AIDS is a battle against racism, sexism, poverty and homophobia." Many discussions emphasized the total unavailability due to costs of even the most basic medications to treat people with HIV/AIDS in the developing world, such as prevention for PCP pneumonia. Eric Sawyer, a cofounder of ACT UP NY, reminded the delegates that most people infected with HIV worldwide cannot even get aspirin!

Women and AIDS

KEY ISSUE: There is a global need to empower women to prevent the risk of new HIV infection in women and children, and there is a need to develop microbicidal gels that women can use effectively to prevent HIV infection, while still allowing for pregnancy.

Yvonne Bryson, of the UCLA Children's Hospital, reviewed the factors in maternal-fetal transmission of HIV. HIV transmission may occur in utero (during fetal development), at the time of birth, or by breast feeding. Global transmission rates from mother to infant range from 13% in Europe, to 25% in the US, to 35-40% in Africa. Apparently 30-50% of infants are infected prior to delivery, based on positive HIV Polymerase Chain Reaction (PCR) and cultures at the time of birth.

A factor which influences risk of transmission appears to be duration of ruptured membranes. When these membranes have been punctured for over four hours and the baby has not been born, there is a dramatic increase in the risk of transmission. Risk of HIV transmission is multifactorial, including viral factors (HIV RNA, genotype, and phenotype), immune factors, maternal factors, and fetal-placental factors. Increased risk of transmission is observed with high viral load and low CD4 cell counts. Research continues to determine why 75% of infants born to infected mothers are not infected with HIV. Additionally, over 24 cases are now well-documented where infected children have eliminated the virus from their bodies. The single best predictor of risk of infection appears to be the viral load at the time of delivery. There is still controversy regarding the possible preventive effects of cesarean section versus vaginal delivery. Cesarean section may lower the risk of HIV transmission if there has been prolonged rupture of the membranes. A recent study evaluating vaginal cleansing in Africa at the time of delivery with microbicides failed to show a decrease in risk of HIV transmission.

The ACTG 076 study showed that in women who had not been previously treated with zidovudine (ZDV or AZT) and whose CD4 counts were between 200-500, treatment with ZDV in the third trimester of the pregnancy, intravenous ZDV at delivery, and ZDV administered to the baby, reduced the risk of HIV transmission by 2/3, from 25.5% to 8.3%. The viral load data from this trial was presented at the IAC and it showed that there was a benefit from ZDV therapy at high, medium, and low viral load levels, even though the risk of HIV transmission is lower at lower viral load levels. Based on this data it would appear that all pregnant HIV-positive women may benefit from ZDV therapy. A study in North Carolina showed that the risk of HIV transmission was lowered from 21%, in 1993, to 8.5%, in 1994, due to the use of ZDV in 75% of pregnant HIV-positive women in 1994. However, in the Bronx, only 25% of pregnant HIV-positive women received ZDV in a recent study.

Dr. Bryson stated that the use of ZDV is the standard of care at this time for all pregnant women, but unresolved questions remain concerning the use of double or triple therapy in women with CD4 counts below 200.

Many presenters emphasized the need to increase the number of women in all clinical trials of new antiretroviral drugs. It is thought by some researchers that toxicity and efficacy of drugs may be different in women, and only by including women in these trials will these differences be known.

Viral Dynamics

KEY ISSUE: Recent data has given much better insight into the dynamics of HIV infection, proving that there is no "latent phase," but rather a constant high level of HIV production and infection of new CD4 cells, even in persons with "early infection."

Blocking of HIV replication by combination therapy has lead to new valuable information concerning the rate of HIV replication in the body and the decay of infected CD4 lymphocytes. Dr. David Ho, of the Aaron Diamond AIDS Research Center in NY, summarized his research results which show that there are about 1 billion new viruses produced each day and that the average infected CD4 cells dies in about 1 1/2 days. Thus there is an ongoing very rapid rate of new virus production and many CD4 cells are newly infected every day to replace the infected ones which die very quickly.

It is estimated that less than 1% of the HIV in the blood comes from cells infected more than 2 weeks ago. This is ongoing even in people with stable T-cell counts. Following the initial very high levels of HIV which appear in the blood during the first few weeks of HIV infection, a steady level of HIV is maintained. This level is referred to as the virologic set point. This set point is correlated with risk of progression to AIDS. As discussed below in the viral load section, people with a high viral load after the initial infection have a faster progression to AIDS and death. These observations have corrected the misconception that, after initial infection, there is a "latent" phase during which there is little viral replication.

Studies of lymph nodes show that there is ongoing destruction of lymph nodes by the virus throughout the course of the infection. One of the major justifications for treating HIV infection "early and hard" is to prevent HIV destruction of the immune system. Even with very effective treatment combinations which suppress the level of HIV to non-detectable levels for at least one year, the immune systems of most people do not recover fully.

The rapid production of HIV and death of HIV-infected cells has lead to a better understanding of monitoring the immune system response to therapy. If a treatment regimen is effective in blocking viral replication, then very rapid decreases in viral load levels are observed over a period of 2-3 weeks. If viral load levels remain unchanged after a month, then the treatment is not effective and should be changed. No longer is it necessary to wait until CD4 cells decline before a treatment is known to be ineffective. Dr. Ho strongly believes that, based on the kinetic studies performed in his lab and by others, single drug therapy should not be used (monotherapy) and that treatment should begin early, rather than later, in the course of HIV infection.

Viral Load (HIV RNA)

KEY ISSUE: Viral load is unequivocally the best test for predicting prognosis both after initial infection and later in the course of HIV infection. Five clinical studies have now proven that lowering the viral load with drug therapy correlates with improved clinical outcome.

KEY QUESTION: Will an artificial lowering of HIV RNA render the same outcome as non-progressors (who have very low levels of HIV RNA without therapy)?

John Mellors, of the University of Pittsburgh, presented a large, multicenter study correlating HIV RNA with clinical progression. The study population was based on people enrolled in the Multicenter AIDS Cohort Study (MACS). The viral load was found to be the most important predictor of prognosis. The CD4 cell count also provided predictive information, in addition to the viral load, but was not as accurate a predictor when compared to HIV RNA. People were evaluated based on 5 categories of viral load: <500; 500-3,000; 3,000-10,000; 10,000-30,000; and >30,000 copies/ml. The percentage of persons developing AIDS within 6 years for the 5 HIV RNA groups, respectively, were: 5.4%; 16.6%; 31.7%; 55.2%; and 80%. Overall, 5% of people in the MACS developed AIDS within 3 years, 19% within 5 years, and 12% were AIDS free at 20 years. After 10 years, 5% of the people in the MACS were non-progressors with normal CD4 counts and CD4/CD8 ratios without any therapy. When compared to people with less than 500 virus copies/ml, persons with >30,000 copies/ml had an 18-fold increased risk of death. For people with CD4 counts >750 and viral load less than 500, the risk of progression to AIDS after 9 years was only 3%. For each group of persons with increasing HIV RNA values, there was an increased risk of progression to AIDS and death over time. HIV RNA levels are important predictors of illness throughout the course of HIV infection, not just during the early phase of the infection. The absolute values of HIV RNA measured in the MACS are probably 30% lower than fresh specimens due to storage of the specimens in heparin and freezing, since these samples were collected several years ago.

For the first time, there is now very convincing data that viral load is not only useful for predicting prognosis, but that viral load is also very useful in predicting clinical outcomes of drug therapy trials. Data from the ACTG 175 study was analyzed to correlate changes in viral load with clinical outcome. ACTG 175 compared zidovudine(ZDV), ZDV/ddI, and ZDV/ddC. Viral load was measured with the Roche PCR assay. For each log decrease in viral HIV RNA (10 times decrease) there was a 66% decrease in risk of AIDS or death, and for every log increase in viral load (10 times increase) there was a 6 times increased risk of AIDS or death. Results of the Delta 1 Trial which compared the same drug combinations also confirmed the value of viral load in predicting clinical outcome and benefits of treatment in persons with at least a 1 log (10-fold) decrease in HIV RNA. In a delavirdine study, a decrease in HIV RNA by 1 log (10-fold) correlated with an 80% decrease in disease progression rate. There are now 5 clinical studies which have confirmed that viral load is an important predictor of the clinical benefits of a treatment regimen if the viral load decreases by 1 log (10-fold) or more. These 5 studies are the scientific basis for the recommendations made by Margaret Fischl and others at the IAC that viral load should be used to monitor efficacy of therapy in all patients, and if viral loads are not decreasing after 8-12 weeks by at least 1 log (10-fold), then therapy should be changed, as discussed later in this review.

An important point is emphasized by the MACS study and some of the combination trial results reported below. Quantification of HIV RNA at relatively low levels is important. The Roche PCR assay can measure as few as 500 copies/ ml, while the Chiron bDNA assay has a lower sensitivity limit of 10,000 copies/ ml. As the MACS study data shows, the prognosis of people with viral levels between 500-3,000 is better than those with levels between 3,000-10,000. Chiron has begun to ship version 2.0 of its assay with a lower sensitivity, similar to the Roche PCR assay. So it is important to know which test is being performed. If your HIV RNA level is "non-detectable", it is important to know what that really means. It does not mean that the level is zero, only that the amount of HIV viruses in the circulating blood is below the level that the assay can detect. Likewise, while decreases of greater than 1 log (ten-fold) in clinical trials appear to be correlated with fewer adverse events, such as new illnesses or death, the goal of treatment should be to lower the HIV RNA to non-detectable levels on assays capable of detecting 500 or more viruses/ ml of plasma. More and more trials are beginning not only to report the average decrease in HIV RNA, but also how many persons had non-detectable levels of HIV RNA as a result of the treatment. Comparisons of therapy should primarily be based on the proportion of persons whose viral load (HIV RNA) drops to non-detectable levels and the length of time that decrease is maintained. An image used by one presenter to illustrate the relation of viral load and CD4 cell counts is that HIV infection is like a train on a track, the viral load is the speed of the train and the CD4 cell count represents the distance before AIDS or death occurs.

Several studies were reported at the IAC which studied the effect of immunization and vaccination with influenza vaccine or tetanus vaccine on HIV RNA levels. Vaccination causes a significant increase in HIV RNA levels which usually peak at 2 weeks and return to baseline at 6-7 weeks. This effect should be considered when measuring HIV RNA levels, either for prognosis or to monitor the effect of therapy. In spite of these transient increases, Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, recommends that all HIV-positive persons receive the flu vaccine annually and other recommended vaccines, such as for pneumococcal pneumonia (pneumovax). The transient increase in HIV is probably much less for a vaccination than it is if a person acquires the infection.

Viral Resistance

KEY QUESTION: How do patterns of resistance assist in choosing sequences and combinations of antiretroviral drugs?

Drugs can fail to inhibit HIV replication by several different mechanisms. First, the drug must get inside the cell in which the virus is replicating. So failure to penetrate a tissue compartment, like the central nervous system, or failure to enter a cell will cause drug failure. Second, the drug must reach a critical level in the blood to suppress replication of HIV; failure to absorb the drug or increased clearance of the drug, will lead to suboptimal levels. Third, some drugs require activation by the host's enzymes; therefore, a decrease in these enzymes might lead to drug failure. Fourth, the virus may develop a specific mutation to allow it to reproduce in the presence of the drug. Drug resistance is not the result of a conscious design change by the virus, but rather the result of random mutations which occur whenever the virus divides. One of the challenges in developing effective therapies is that the HIV virus has a very high random mutation rate. Therefore, the longer a person is infected, and the more times the virus divides, the more likely it is to develop a mutation to a specific drug. Thus, the virus can only become resistant to a drug if it is dividing. One of the most encouraging reports at the IAC were that some combination therapies have suppressed all measurable viral replication for at least up to one year. This was observed even in patients who had been on ZDV, prior to the combination drug trial of ZDV, lamivudine (3TC) and indinavir (a protease inhibitor). A drug combination which has the potential to block all viral replication in all tissues in the body has the potential to continue to do so indefinitely, due to the inability of the virus to become resistant if it is not dividing.

Several studies were presented which evaluated the mechanisms of resistance to the protease inhibitors. Resistance to saquainavir does not appear to cause resistance to ritonavir and indinavir. In contrast, resistance to either indinavir or ritonavir causes resistance to the other drug. Indinavir resistance requires 4 amino acid changes to occur, unlike saquinavir, which may be resistant after a single mutation. Resistance will emerge quickly to the protease inhibitors if a person is non-compliant and misses even a few doses. So it is very important to take the drugs as directed to prevent resistance from developing. One report noted that if enough people develop protease inhibitor resistant viruses, it may lead to people becoming infected with strains of HIV that are resistant to the protease inhibitors as well.

Resistance patterns and cross-resistance are important considerations in deciding which drug combinations to use initially and more importantly, which changes to make if a person fails to achieve significant suppression of viral load on a particular combination. Should a new drug be added, should one drug be changed, should all the drugs be changed? These questions can only be answered by considering resistance patterns and mutations.

Immunologic Factors and Therapy

KEY QUESTION: Will recent basic science advances in identifying fusin, a protein necessary for HIV entry into cells, and 3 chemokines, which block HIV entry into CD4 cells, lead to clinically useful immunotherapy?

Robert Gallo, presented the latest findings concerning immunologic factors involved in the infection of cells by HIV. It has been known for a long time that HIV enters the CD4 lymphocytes by attaching to the CD4 receptor on the surface of the cell. In the past year, a second cell surface receptor has been identified which is required for HIV entry into the cell; this new protein is called fusin. New drugs which would interfere with the binding of HIV to fusin are being investigated. Dr. Gallo's lab reported on finding three other substances manufactured by immune cells which appear to block HIV from infecting CD4 cells. These compounds are called chemokines, and the three identified are called rantes, MIP-1a, and MIP-1b. These compounds are produced by CD8 cells, which are known to inhibit HIV replication. Clinical evidence in support of the importance of the chemokines include studies which show that persons who have been exposed to HIV, but are not infected, have high levels of chemokines. Hemophiliacs infused with HIV-infected blood products, who were uninfected, also have high levels of these chemokines. Further investigation may yield compounds which stimulate these chemokines, which may result in prevention of HIV entry into CD4 cells. Dr. Gallo emphasized that immunologic research and therapy needs to be pursued even in the face of the impressive advances in antiretroviral chemotherapy. In most people, even with complete suppression of viral replication, CD4 cells increase only 100-150, and the immune system does not completely recover. Dr. Gallo stated that, "Ultimately, biologic therapy may completely replace chemical therapy."

Several combination antiretroviral drug therapies combining either interleukin-2 or alpha-interferon were presented in the poster sessions. These trials were designed to try to increase immunologic recovery in conjunction with stopping HIV replication. A trial is beginning combining indinavir and interleukin-2 in persons with over 500 CD4 cells to evaluate the possibility of achieving recovery of the immune system when chemotherapy is combined with immunotherapy in early HIV infection. However, at this time, the results of immunotherapy combined with antiretroviral chemotherapy remains unknown. For further details of these trials contact STEP.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI's)

KEY QUESTION: Are initial combinations with NNRTI's as effective as combinations with protease inhibitors?

Two NNRTI's are currently in clinical trials, nevirapine (NVP) (FDA approved in June) and delavirdine (available through compassionate release). Initial clinical trials with the NNRTI's were very disappointing due to the emergence of rapid resistance. In a study reported at the IAC, persons with CD4 counts of 200-600 were randomized to one of three arms: zidovudine(ZDV)/ddI; ZDV/NVP; or ZDV/ddI/NVP. The combination of nevirapine (200 mg/day for 14 days followed by 200 mg twice a day), ddI (400 mg/day), and ZDV (600 mg/day) inhibited viral replication by over 2 logs (100-fold) within one month and resistance did not appear in the majority of the persons over the 10 months of the study. Most significantly, after one year of triple therapy, 60% of persons had non-detectable HIV RNA (with a test that can detect as low as 200 copies of HIV/ml). Another study compared ZDV/ddI with ZDV/ddI/NVP in persons with CD4 counts below 200. This trial is ongoing, but the combination is well-tolerated with acceptable toxicity.

Early reports of delavirdine (DLV) combined with ZDV or ddI showed significant decreases in viral load and increased CD4 cells in both persons with early and advanced HIV infection. Another study compared ZDV to ZDV/DLV, and sustained increases in CD4 cells and 0.5 to 0.6 log decreases in viral load at one year in persons receiving the combination therapy were observed.

Protease Inhibitors and Combination Therapy

KEY QUESTION: Which combinations are the best for both lowering viral load and preventing cross-resistance to other useful drugs?

Scott Hammer, of the Harvard Medical School, reviewed trials comparing zidovudine (ZDV) monotherapy to combination therapy, including ZDV/ddI, ZDV/ddC, ZDV/3TC, and ddI/d4T combinations. All of the trials conducted showed a benefit of the combination therapy compared to ZDV monotherapy. This benefit was evidenced by a decrease in the progression to AIDS and fewer deaths in the group receiving the combination therapy. The combination ddI/d4T caused a sustained 1.3 log decrease in HIV RNA at 52 weeks. A poster at the IAC reported on a trial comparing ZDV/ddI/3TC to d4T/ddI/3TC. At 24 weeks, 90% of the group receiving d4T/ddI/3TC had non-detectable viral load levels. However, this decrease was not maintained after 24 weeks, unlike in the protease inhibitor combinations reported below. For further details of these trials contact STEP.

Clearly, the most impressive data presented at the IAC were the results of combination trials of protease inhibitors and reverse transcriptase inhibitors. These trials have resulted in non-detectable viral levels in up to 80-90% of the patients treated for up to one year. Impressively, the number of persons with non-detectable viral levels appears to be holding steady after one year of therapy.

A large trial of over 1,000 people randomized participants to receive ritonavir (RIT), 600 mg/ twice a day, or placebo, in addition to whatever antiretroviral regimen they were already receiving. The median number of medications participants were receiving was 14, and 1/2 were on either ZDV or d4T. The rest were receiving combinations of antiretrovirals. This study included persons treated with prior antiretroviral therapy. Almost 20% of participants had to discontinue the ritonavir due to intolerance of the solution, which has since been reformulated. However, there was a 50% reduction in disease progression or death in the group receiving ritonavir, which correlated very well with decreases in viral load levels (HIV RNA). Additionally, 60% of persons receiving RIT had non-detectable viral load levels (threshold less than 200 copies/ml), sustained for the 60 weeks of follow-up. CD4 cells increased by 124 above baseline at week 24. These very dramatic decreases in viral load are even more impressive considering that this trial included persons with advanced disease and mimicked "real world" treatment, in that patients were on a variety of antiretroviral drugs in addition to ritonavir.

In another ritonavir study 17 people, with previously untreated HIV infection and CD4 counts of less than 250, received a combination of ritonavir (1200 mg/day), ZDV (600 mg/day), and ddC (2.25 mg/day). Data at 60 weeks of follow-up showed an increase in average CD4 cells from 155 to 337. HIV RNA decreased an average of almost 2 logs (100-fold). The therapy was well-tolerated and the most common side effects were nausea, diarrhea, vomiting, and weakness.

Another equally impressive trial randomized 97 people to one of three regimens: Indinavir (Ind) (crixavan) mono-therapy; zidovudine (ZDV)/3TC; and ZDV (600 mg/day)/3TC (150 mg/ twice a day)/ Ind (800 mg/ three times a day). CD4 counts ranged from 50-400 and all persons had viral load levels at entry of greater than 20,000 copies/ml. Between 80-90% of all people on the triple combination had viral load levels drop to below the non-detectable range (below 500 copies/ml) and maintained those decreases up to one year after initiation of therapy. ZDV/3TC caused a 1.4 log decrease in HIV RNA at 36 weeks, compared to a 1.0 log decrease for Ind monotherapy, and greater than a 2 log decrease for the triple therapy group. The main side effects of indinavir are an asymptomatic increase in indirect bilirubin (a substance regulated by the liver) and mild kidney stones, which are due to drug precipitation in the kidney, and can be avoided by maintaining good hydration (at least 12 8oz glasses of water per day). All of the above studies are continuing to follow patients past one year to determine if resistance to the triple combination will develop. As discussed in the viral resistance section above, long term suppression without resistance is possible if virtually all viral replication in the body is blocked. Until further follow-up and possibly lymph node biopsies are performed, it cannot be said at this time whether or not there continues to be ongoing viral replication in those persons with non-detectable HIV RNA.

Results from an indinavir monotherapy trial were updated comparing three doses: 600mg, 800mg, and 1000 mg every 8 hours. CD4 cells increased an average of 100 in all three groups, and the average decrease in viral load of 2 logs (100 fold) was also the same in all three groups. At the 800 mg dose, over 50% of persons treated had no detectable virus (less than 200 copies/ ml) after 48 weeks of therapy. Most monotherapy protease inhibitor trials show that resistance develops rapidly. However, in this trial at one year follow-up, the virus appears not to have developed resistance. Again the importance of compliance must be emphasized and indinavir requires mutations at several genetic sites before the virus becomes resistant to this drug.

Early results of combination therapy trials of ritonavir (Rit) plus saquinavir (Saq) were presented and showed the therapy to be well-tolerated. This is a very appealing combination because there are different mutations required for HIV to become resistant to both of these drugs. Additionally, saquinavir has low oral absorption and ritonavir significantly increases blood levels of saquinavir. In one trial of ritonavir plus saquinavir, after only 2 weeks, there was a 1.6 log decrease in HIV RNA and an increase of 52 CD4 cells in patients with initial CD4 counts of 100-500. Two dosages were compared, Rit 400 mg BID (twice a day) plus Saq 400 mg BID, versus Rit 600 mg BID plus Aq 400 mg BID. The most common side effects of ritonavir include diarrhea, nausea, and tingling around the mouth. Only 2 out of 65 people had to discontinue the trial due to side effects. In a pilot study of 7 people with AIDS and an average CD4 count of 10, ritonavir and saquinavir were combined at doses of Rit 600 mg BID for one week, at which time Saq 200 mg BID was added, and increased to 600 mg BID at day 15. After 8 weeks, CD4 cells increased from an average of 10 to 39, and viral load decreased by 1 log (10 times). Side effects were minimal in this small pilot trial. Larger trials examining this potent combination are ongoing.

Martin Delaney, of Project Inform, noted that in their experience nausea and diarrhea are problems for many of the people who have taken ritonavir. It is unclear how well-tolerated this drug is outside of the trials discussed above, wherein it appeared to be fairly well-tolerated. One recommendation was to begin ritonavir at less than full dosages for the first week and increase to full dose by week two. This may be of benefit because ritonavir causes an increase in the activity of a liver enzyme which removes ritonavir from the blood, so that at full dose, higher levels in the blood are observed the first week which may contribute to more side effects during that time.

Three new protease inhibitors are in clinical trials, but not yet approved by the FDA. They are nelfinavir, AG1343 (Viracept(tm)) and VX-478 (which has been shown to have high penetration into the central nervous system in animal models). One trial (Nelfinavir Study 510) compared d4T to nelfinavir (NFV)/d4T. NFV was administered in three different dosages: 500, 750, and 1,000 mg three times a day. At 5 months there was a 1.3 log decrease (low dose), 1.7 log decrease (mid dose), and a 1.8 log decrease (high dose) in HIV RNA. d4T alone caused a 0.8 log decrease in viral load. A second study evaluated the triple combination of ZDV (600 mg/ day), 3TC (150 mg BID), and NFV (750 mg three times a day). 12 persons were enrolled on this trial. CD4 counts ranged from 37-557, and HIV RNA was greater than 10,000 in all persons. No one had received prior antiretroviral therapy. Only 1 participant had to discontinue therapy due to side effects, which included diarrhea, nausea, and fatigue. The other 11 persons all have achieved non-detectable viral levels (less than 500 copies/ ml) by the end of 12 weeks of therapy. This trial is ongoing.

A phase II study compared AG1343/d4T to d4T alone. Three doses of AG1343 were compared, 500mg, 750mg, and 1,000mg. All participants had CD4 counts above 200, and viral load levels above 15,000. The mean decrease in viral load in the groups receiving the combination of AG1343 plus d4T was 2.0 logs (100-fold) after 28 days of therapy, compared to a decrease of 0.9 log in the d4T group. The main toxicity in the group receiving the AG1343 was diarrhea. This trial is ongoing and expanding at this time. Another trial compared the combination of AG1343/ZDV/3TC to AG1343/d4T/3TC. At 6 months there was a 2.2 log decrease in viral load in the group receiving d4T, and a 2.9 log decrease in the group receiving ZDV.

There are now 9 approved antiretroviral drugs in the U.S. and several new protease inhibitors and NNRTI's may be approved in the next year. Currently approved drugs are: the nucleoside analog reverse transcriptase inhibitors, ZDV (AZT), ddC, ddI, d4T, and 3TC; the non-nucleoside analog reverse transcriptase inhibitor, nevirapine (accelerated approval program); and the protease inhibitors, saquinavir, indinavir, and ritonavir. Dr. Joep Lange, from the University of Amsterdam, outlined the following basic principles of combination therapy: use drugs with additive or synergistic effects (the drugs would strengthen each other's effectiveness); use drugs without cross-resistance (lack of one mutation which would make the virus resistant to more than one of the drugs); no overlapping toxicity of the drugs (such as avoidance of using 2 drugs which both cause neuropathy); no harmful drug interactions; using drugs which are active in all tissue and cellular compartments (such as using drugs which would penetrate the blood-brain barrier into the central nervous system); using drugs which are easy to take together; and affordability (at least the best results for the money spent).

The first reports of phase I studies (clinical toxicity testing) of a new class of drugs, the integrase inhibitors, were presented at the IAC. The integrase enzyme is an HIV enzyme which enables the viral DNA, which is copied from the RNA, to be incorporated into the DNA of the host cell. This class of drugs would attack the HIV life cycle at a point different than either the reverse transcriptase or protease inhibitors. AR-177 (zintevir) inhibits the integrase enzyme and was well-tolerated in early dose escalation trials (phase I). Efficacy trials (phase II) of this class of drugs should begin later this year or early next year.

Therapy Guidelines and Recommendations

KEY QUESTIONS: Is it time to offer treatment with triple drug combinations as early as possible to everyone? Should the goal of treatment be to lower viral load to undetectable levels in everyone?

John Mellors, of the University of Pittsburgh, outlined the challenges in deciding when to treat and how much to treat. The danger in under-treating is drug resistance, drug failure and disease progression; while the danger of over-treatment is wasted drug and financial resources, increased monitoring costs, and side effects. He recommended that HIV RNA levels be measured twice at baseline, and that the HIV RNA value be used in conjunction with the CD4 and the physical exam to decide when to initiate therapy. He recommended that all patients with over 30,000 copies/ml, regardless of CD4 count, begin on combination therapy. If there is not a 3-10 fold decrease in HIV RNA after 2-4 weeks, then therapy should be changed. The goal should be to get the HIV RNA to a non-detectable level. The HIV RNA level should be monitored every 3-4 months. Dr. Mellors stated that, "Treatments that only partially suppress viremia [viral blood levels] are doomed to failure from resistance."

Margaret Fischl, of the University of Miami, presented her recommendations for individualizing antiretroviral therapy. Patients with HIV RNA levels above 5-10,000 copies/ml should consider beginning antiretroviral therapy, independent of CD4 cell counts. Viral load is very useful in deciding whether or not to begin therapy for people with intermediate CD4 cell counts, between 400-600. She recommended that viral load levels be followed to determine if the treatment is effective and a decrease of at least one log (10 times) should be observed within 8 weeks. The goal of treatment should be to lower the viral load to non-detectable levels. CD4 cells are not an accurate indicator of viral load. In order to achieve the goal of full immunologic recovery, treatment needs to begin early in the course of infection. There is extensive ongoing damage of the lymph nodes during this phase. Later in the infection, CD4 counts only increase 100-150 on average, even when viral replication appears to be completely suppressed. Dr. Fischl also recommended that prophylaxis against opportunistic infections be continued if a person was on prophylaxis before therapy, even if there is a significant increase in CD4 cells as a result of therapy. This is because the new CD4 cells may not be functionally normal CD4 cells, and the person may still be at the same risk for developing opportunistic infections as when the CD4 cells were lower.

Dr. Fischl groups people into low, intermediate, and high risk for progression of disease based on the combination of clinical history, viral load, and CD4 cell counts,. For people in the high risk group (high viral load and low CD4 cells), she recommended that therapy be initiated with either 2 or 3 drug combinations of reverse transcriptase inhibitors and a protease inhibitor. For the intermediate risk group (intermediate viral load and CD4 cells), she recommended the same therapy. For people in the low risk group (lower viral load), she recommended either 2 reverse transcriptase inhibitors, or a reverse transcriptase inhibitor and a protease inhibitor or triple drug therapy. She also stated that people with higher CD4 cell counts and non-detectable viral load may just be monitored every 3-4 months.

Dr. Fischl also discussed the importance of developing a long-term treatment plan when antiretroviral therapy is begun. This plan should include a consideration of which drugs will be added, or deleted, if the initial combination chosen does not lower viral loads levels to non-detectable levels, or at least by 1 log (10-fold). She recommended that clinicians consider changing several drugs in a regimen rather than adding one new drug. This would provide the best opportunity to prevent resistance from developing to the new treatment regimen.

Treatment of Persons Recently Infected With HIV

KEY QUESTION: Should people who have recently been infected be treated with triple drug combinations as soon as they are identified as HIV-positive?

The preliminary results of two ongoing trials which are studying the use of combination antiretroviral therapy shortly after HIV infection were presented at the IAC. (Recent HIV infection is defined by a negative HIV test within the past 6 months prior to infection, or the presence of HIV in the plasma before the initial antibody response has begun.) One trial is being conducted by the Aaron Diamond Research Center in NY and the other at St. Paul's Medical Centre in Vancouver. The scientific support for very early, aggressive therapy is based on the kinetic studies discussed above, as well as studies reported in the past year or two, which showed serious damage to the lymph nodes even during the early asymptomatic phase of HIV infection. It is now known that in most people there is a high level of HIV replication and CD4 death even during the early few years of HIV infection. Therefore, one of the goals of early therapy is to prevent viral replication before the immune system is irreversibly weakened. The damage to the immune system is, to some degree, irreversible, as evidenced by the lack of restoration of a normal immune system when viral replication is almost completely blocked in persons with only moderately compromised immune systems. Also, theoretically, if the treatment is begun when the immune system is healthier, and if the drugs reduced the amount of virus to a very low level, it is possible that the immune system might be capable of eradicating the small number of virus remaining after the treatment.

Another scientific rationale for the early therapy trials is that the virus develops into a more aggressive form in some people over time (the syncytium-inducing (SI) phenotype ). Additionally, the virus has more opportunities to develop mutations to the drugs if it has undergone more replications, as discussed above in the section on viral resistance. Therefore, early therapy might more effectively suppress viral replication for a longer period of time when initiated earlier, rather than later.

Both of the early therapy trials have demonstrated that it is possible to reduce the level of HIV in the plasma to non-detectable levels in almost all persons who are recently infected with HIV. However, the rationale for this therapeutic approach partly depends on whether or not the treatment can eradicate HIV from the body. The majority of people infected with HIV will remain clinically healthy for at least 5-7 years, and 10-12% are clinically healthy 10 years after infection. If everyone were to be treated as soon as they found out they were HIV-positive, the costs would be very great, and unless some of those persons were actually cured, the treatment might be just as beneficial if it were started later in the course of the HIV infection. Persons who are at high risk for rapid progression to AIDS can be identified by viral load levels 2-3 months after infection. The viral load level, as demonstrated by the MACS data presented above, can accurately predict an individual's risk of progression to AIDS over time. It might be more cost effective to treat only persons with high viral load early after HIV infection. The combinations of antiretrovirals used are fairly well-tolerated, but there are some side effects and if the drugs are not taken regularly, even a few missed doses could lead to viral resistance.

Currently, the use of combination therapy in persons recently infected with HIV remains an unresolved issue. However, both of the ongoing trials should have some definitive answers to some of the questions within the next year or two. It is not known at this time whether or not combination antiretroviral therapy should be initiated as soon as possible in all recently infected persons. However, these considerations, should be discussed between the health care provider and the client so they can decide which course of therapy to pursue.

Viral Eradication

KEY QUESTION: Can therapy for 1 to 3 years suppressing viral levels to below detection in the plasma and lymph nodes result in total HIV eradication from the body?

David Ho, of the Aaron Diamond AIDS Research Center in NY, presented an analysis of the rate at which HIV RNA levels decline in the plasma when treated with drug combinations which appear to totally block all viral replication. There is an initial rapid decline in HIV RNA levels the first few days, which is thought to represent the rapid death of CD4 HIV-infected lymphocytes. Then, there is a slower fall in the HIV RNA levels to non-detectable levels over the next several weeks which is thought to represent the death of HIV-infected tissue macrophages (which live longer than HIV-infected CD4 cells). Working with mathematicians from the Los Alamos National Laboratory, Dr. Ho and his colleagues have developed mathematical models which predict that all of the infected cells in the body would die within 30-120 weeks after total suppression of HIV replication. This theory, and it is only a theory, is dependent upon all the drugs getting into every infected cell in all the tissue compartments of the body, so as to prevent replication everywhere in the body. If the virus is replicating, then it has the chance to become resistant to the drugs and escape suppression. Two tissue compartments of serious concern are the central nervous and the testes. It is not known how well the protease inhibitors penetrate the blood-brain barrier. And each protease inhibitor may penetrate at a different rate than the others. Additionally, there may be cells infected with HIV in the body which live for many years. Thus, at any time when therapy is stopped, HIV replication may resume. Herpes is an example of this type of viral infection, where the virus stays dormant in cells in the body for the life of the person.

Studies have also demonstrated that if a person is non-compliant with therapy and misses even a few doses, the virus can rapidly become resistant to the drugs utilized. Researchers from St. Paul's Medical Centre, Vancouver, reported on a group of people with recent seroconversion who were treated with triple drug combinations. One of these people had no detectable HIV RNA in the serum and in a lymph node biopsy after 78 weeks of therapy. However, when treatment was stopped, the level of HIV RNA rose rapidly over a period of only a few weeks. Thus, while David Ho's models and projections are very interesting, there is no scientific proof to the proposition that it is possible to eradicate HIV from the body at this time. However, David Ho's trials will provide some very interesting data on this question within the next 1-2 years, when they begin to stop therapy on some of their participants.

Managed Care Poses a Threat to the Quality of HIV Care

KEY QUESTION: Are managed care plans' cost-cutting efforts to save money on treatment for HIV affecting survival?

Paul Volberding, of the San Francisco General Hospital, spoke very forcefully of his concerns about managed care plans and the quality of care provided to HIV-positive individuals. Dr. Volberding reviewed the study from Seattle, reported in the New England Journal of Medicine, which showed that the survival of persons treated by physicians who treated less than 5 HIV-positive persons a year was significantly less than the survival of persons treated by physicians who treated more than 5 HIV-positive people a year. He stated that this difference in survival was greater than any survival difference between antiretroviral treatments and speculated that people were assigned to inexperienced physicians because the group would save money by providing less care to HIV-positive people. Aggressive, competent care is expensive, even if it saves money in the future by preventing opportunistic infections and keeping people healthier.

The differences in the needs of the average person treated at San Francisco General Hospital currently, compared to 5 years ago, was discussed by Dr. Volberding. The average patient treated 5 years ago was a well-educated, male homosexual who was on one antiretroviral, ZDV, and prophylaxis for PCP. Now, the average patient is a woman, often supporting several children, some of whom may be HIV-positive as well. She may need to be on 3-4 antiretrovirals and prophylaxis for 2 or 3 opportunistic infections. She has need of adequate housing for her children, transportation, nutrition and other social services. Additionally, 5 years ago when a person developed pneumonia they were hospitalized and treated; now the person is treated as an outpatient and sent home with a bag of pills. The AIDS Program at San Francisco General currently treats 3,000 people, of whom only 4% have private insurance. The average CD4 cell count is 278, and they take an average of 8 different oral medications a day. 30% use injection drugs, 33% have a psychiatric disorder, and at least 8% are homeless. However, at San Francisco General Hospital, there are fewer resources to treat people now than there were 5 years ago. Dr. Volberding outlined the status of health care in the U.S., which is evolving to a system where people are referred to as "lives" being "managed" by profit-making companies, funded with private or public resources, with costs "capitated" (physicians receive a fixed amount of money per year to treat each person, regardless of what it actually costs to treat that person, so the incentive is to not spend very much money to treat that person).

Dr. Volberding challenged AIDS activists to pressure managed care plans to provide more resources to treat HIV. In a similar vein, James Curran, the former director of the Centers for Disease Control (CDC), challenged scientists and physicians to become activists to improve federal funding for AIDS research and treatment, and pressure the federal government to adopt sound public health policies. He noted that his greatest disappointment, as director of the CDC, was the failure of the federal government to provide support for sterile needle exchange programs. In many studies presented at the IAC, needle exchange programs were shown to effectively lower the rate of HIV-infection among intravenous drug users.

Dr. Volberding recommended that physicians be required to have specialized training to treat HIV, since it is much more complex today than just a few years ago. He also stated that, "AIDS care should be delivered by the most experienced, trained and committed providers possible, not the least." Perhaps the most important issue in maintaining the quality of care for people with HIV is as Dr. Volberding stated: "The real bottom line in AIDS care is commitment."

These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com
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