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Two AIDS vaccine trials announced for the developing world
Progress in HIV-1 therapy continues on upward track ood progress in the treatment of HIV-1 infection was evident at the 6th Conference on Retroviruses and Opportunistic Infections (Chicago, IL, USA; Jan 31–Feb 4). R Gullick (New York, NY, USA) and colleagues reported sustained suppression of serum HIV-1 RNA to fewer than 50 copies/mL in 67% of the 33 patients who were randomly assigned more than 3 years ago to the zidovudine, lamivudine, and indinavir arm of the Merck 035 study. This good news, however, was tempered by increasing awareness of the difficulties associated with the long-term use of drug regimens containing protease inhibitors. Very high levels of medication compliance, in excess of 80%, may be needed to prevent the development of drug resistance and maximise the duration of response, warned S Vella (Rome, Italy). Variable drug pharmacokinetics leading to sub-therapeutic drug concentrations may also be a problem. Preliminary results from T Kakuda (Minneapolis, MN, USA) and co-workers indicated that this can be ameliorated by carefully controlling the plasma concentration of drugs. The frequency, cause, and reversibility of metabolic complications associated with the long-term use of protease inhibitors—including lipodystrophy syndrome—remain to be established. However, much attention was given to these recently recognised problems in Chicago. L Ruiz (Barcelona, Spain) and colleagues have begun studies on patients who had been successfully treated with regimens containing protease inhibitors, but who then developed mild to moderate adverse metabolic effects.These patients were randomly allocated to continued therapy or switched to a regimen
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containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) but no protease inhibitor. Early results suggest that there may be some reversal of the metabolic abnormalities, but until the impact of switching to a protease-inhibitor-free regimen on the control of HIV-1 replication is known, the practice cannot be strongly recommended. A growing body of evidence supports the use of regimens without protease inhibitors for initial therapy. K Tashima (Providence, RI, USA) and coworkers reported encouraging results for regimens consisting of two nucleoside reverse transcriptase inhibitors and an NNRTI. Early favourable results were also presented for triple-nucleoside therapy with zidovudine, lamivudine, and abacavir. And findings from the Atlantic Study showed comparable antiretroviral activity for stavudine plus didanosine combined with indinavir, nevirapine, or lamivudine. Despite these encouraging results, in most studies more than 30% of patients on initial therapy have persistently detectable plasma HIV-1 RNA after 48 weeks of therapy. This underscores the need for more potent but easier-to-comply-with regimens. Along these lines, the M97-720 Study Group reported that the new protease inhibitor ABT-378/ritonavir was well tolerated and suppressed plasma HIV-1 RNA to fewer than 50 copies/mL in 89% of patients after 24 weeks. There were also several reports showing continued success of simplified regimens, once daily regimens, and directly observed therapy. Lasting immunological benefit for up to 2 years was reported for some patients on triple-drug regimens, despite detectable HIV-1 RNA loads. The final outcome for these patients
Two AIDS vaccine trials announced for the developing world On Feb 9, Thailand’s Ministry of Public Health authorised large-scale clinical testing of an experimental AIDS vaccine. According to UNAIDS, this will be the first such trial in the developing world. The Thai trial will involve 2500 volunteers at risk of HIV-1 infection because of injecting-drug use. Volunteers will be given the AIDSVAX B/E vaccine, developed by Vax Gen (Brisbane, CA, USA). This vaccine, a preparation of gp120, is also being tested in 5000 US volunteers at risk of HIV-1 infection through sexual transmission, but the vaccine to be used in Thailand has been altered to take into account the prevalent HIV-1 strains found there. On Feb 8, Pasteur Mérieux Connaught announced the start of a phase I HIV-1 vaccine trial in Uganda. The trial, sponsored by the US National Institute of Allergy and Infectious Diseases, will involve 40 healthy volunteers in Uganda, 20 of whom will be given ALVAC-HIV (vCP205). This canarypox -based vaccine ex presses HIV-1 gp120, gag, and protease. Jane Bradbury
remains uncertain, and optimism should be restrained because persistent viral replication in the presence of drugs may allow evolution of cross-resistance to available and investigational drugs, warned B Larder (Stevenage, UK).
Several investigators reported that viral rebound is often associated with resistance to only one of the drugs in the triple regimen. Frequent monitoring of HIV-1 RNA permits the identification of virological failure caused by resistance to one drug, a finding that strongly argues for regular monitoring of plasma HIV-1 RNA during therapy. In addition, in a prospective study in treatment-experienced patients there was a greater response in HIV-1 RNA loads when changes in therapy were based on the results of resistance testing. Finally, several reports confirmed the transmission of drug-resistant HIV-1. For example, S Wegner (Rockville, MD, USA) reported that up to 6% of seroconverters carry virus resistant to at least one drug. Taken together, these data argue for the use of resistance testing to guide therapy in naïve and treatment-experienced patients. F Lori (Washington DC, USA) reported anecdotal cases in which intermittent, sequential discontinuations of antiretroviral therapy produced progressively longer times to rebound of plasma HIV-1 RNA, but this potentially hazardous practice should be discouraged pending evaluation in clinical trials. By contrast, there is abundant clinical and laboratory evidence of immune reconstitution with effective antiretroviral therapy. Several preliminary reports indicated that discontinuation of primary prophylaxis may be safe in selected patients, such as those with a sustained CD4 increase to more than 200 cells/mL and an HIV-1 RNA decrease to less than 50 copies/mL. Julio Montaner, John Mellors
THE LANCET • Vol 353 • February 13, 1999
565
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containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) but no protease inhibitor. Early results suggest that there may be some reversal of the metabolic abnormalities, but until the impact of switching to a protease-inhibitor-free regimen on the control of HIV-1 replication is known, the practice cannot be strongly recommended. A growing body of evidence supports the use of regimens without protease inhibitors for initial therapy. K Tashima (Providence, RI, USA) and coworkers reported encouraging results for regimens consisting of two nucleoside reverse transcriptase inhibitors and an NNRTI. Early favourable results were also presented for triple-nucleoside therapy with zidovudine, lamivudine, and abacavir. And findings from the Atlantic Study showed comparable antiretroviral activity for stavudine plus didanosine combined with indinavir, nevirapine, or lamivudine. Despite these encouraging results, in most studies more than 30% of patients on initial therapy have persistently detectable plasma HIV-1 RNA after 48 weeks of therapy. This underscores the need for more potent but easier-to-comply-with regimens. Along these lines, the M97-720 Study Group reported that the new protease inhibitor ABT-378/ritonavir was well tolerated and suppressed plasma HIV-1 RNA to fewer than 50 copies/mL in 89% of patients after 24 weeks. There were also several reports showing continued success of simplified regimens, once daily regimens, and directly observed therapy. Lasting immunological benefit for up to 2 years was reported for some patients on triple-drug regimens, despite detectable HIV-1 RNA loads. The final outcome for these patients
Two AIDS vaccine trials announced for the developing world On Feb 9, Thailand’s Ministry of Public Health authorised large-scale clinical testing of an experimental AIDS vaccine. According to UNAIDS, this will be the first such trial in the developing world. The Thai trial will involve 2500 volunteers at risk of HIV-1 infection because of injecting-drug use. Volunteers will be given the AIDSVAX B/E vaccine, developed by Vax Gen (Brisbane, CA, USA). This vaccine, a preparation of gp120, is also being tested in 5000 US volunteers at risk of HIV-1 infection through sexual transmission, but the vaccine to be used in Thailand has been altered to take into account the prevalent HIV-1 strains found there. On Feb 8, Pasteur Mérieux Connaught announced the start of a phase I HIV-1 vaccine trial in Uganda. The trial, sponsored by the US National Institute of Allergy and Infectious Diseases, will involve 40 healthy volunteers in Uganda, 20 of whom will be given ALVAC-HIV (vCP205). This canarypox -based vaccine ex presses HIV-1 gp120, gag, and protease. Jane Bradbury
remains uncertain, and optimism should be restrained because persistent viral replication in the presence of drugs may allow evolution of cross-resistance to available and investigational drugs, warned B Larder (Stevenage, UK).
Several investigators reported that viral rebound is often associated with resistance to only one of the drugs in the triple regimen. Frequent monitoring of HIV-1 RNA permits the identification of virological failure caused by resistance to one drug, a finding that strongly argues for regular monitoring of plasma HIV-1 RNA during therapy. In addition, in a prospective study in treatment-experienced patients there was a greater response in HIV-1 RNA loads when changes in therapy were based on the results of resistance testing. Finally, several reports confirmed the transmission of drug-resistant HIV-1. For example, S Wegner (Rockville, MD, USA) reported that up to 6% of seroconverters carry virus resistant to at least one drug. Taken together, these data argue for the use of resistance testing to guide therapy in naïve and treatment-experienced patients. F Lori (Washington DC, USA) reported anecdotal cases in which intermittent, sequential discontinuations of antiretroviral therapy produced progressively longer times to rebound of plasma HIV-1 RNA, but this potentially hazardous practice should be discouraged pending evaluation in clinical trials. By contrast, there is abundant clinical and laboratory evidence of immune reconstitution with effective antiretroviral therapy. Several preliminary reports indicated that discontinuation of primary prophylaxis may be safe in selected patients, such as those with a sustained CD4 increase to more than 200 cells/mL and an HIV-1 RNA decrease to less than 50 copies/mL. Julio Montaner, John Mellors
THE LANCET • Vol 353 • February 13, 1999
565