"Throw everything at the virus with your second-line
combination," Dr Mike Youle of the Royal Free Centre for HIV Medicine told a NAM
forum on salvage therapy held at the University of London Union on November
30th.
At the forum, Dr Youle outlined his controversial approach
to treating HIV. If a person’s current combination of three or four drugs,
including a protease inhibitor or a non-nucleoside, does not suppress viral load
to below 400 copies, he advocated using at least five new drugs. This, he said,
gives a person the best chance of driving HIV to undetectable levels.
"If you don’t make a dramatic stab at halting virological
failure, the problem will get worse as you fail successive regimens," Dr Youle
said. According to current thinking, if viral load can be kept at below 50
copies per millilitre of blood, disease progression and AIDS are less likely to
occur.
Dr Youle proposed a ‘backbone’ combination of ddI,
efavirenz, ritonavir (100 mg), indinavir (800 mg) and hydroxyurea. 3TC/d4T may
also be added, or nelfinavir/saquinavir may be used instead of
ritonavir/indinavir.
He presented preliminary results of a study of this
combination conducted at the Royal Free. Participants had viral loads over
10,000 and decreasing CD4 counts after at least six months on a
protease-containing regimen. Most participants had one month off treatment
before commencing the multi-drug combination and the mean viral load at baseline
was over 750,000.
Fifty-two people have completed six months of treatment on
the multi-drug combination, and early results are "relatively impressive"
according to Dr Youle, although he cautioned that we don’t know what will happen
in the long-term.
At six months, 44 people had viral loads below 400, of whom
12 were below 50. Ultra-sensitive tests were done when a person had two results
below 400 using the standard assay. Two people, both of whom had previously
taken nevirapine, had little benefit. Three people had good responses but
decided to stop treatment and all now have viral loads over 1 million. Another
person achieved undetectable viral load and then had viral rebound; after adding
3TC/d4T, they again achieved viral load below 400. One other person experienced
severe lipid problems and had to alter their regimen.
Dr Youle said that similar aggressive treatment strategies
are being used at a number of centres around the world and he criticised
conservative approaches to treatment failure in the UK.
But will this multi-drug approach prevent AIDS after five or
ten years? Mathematical modelling has predicted that to prevent HIV disease
progression in the long-term, viral load needs to be suppressed to less than one
copy per millilitre of blood. This suggests that a multi-drug strategy may not
prevent disease progression in people whose viral load is between 50 and 400.
Despite his belief that the multi-drug approach is the best strategy at the
moment, Dr Youle acknowledged that "Current drugs are not proven to be effective
in the long-term".
Pros and cons of protease inhibitors
He said the main concern with this multi-drug combination is
lipid abnormalities and body fat changes primarily associated with the use of
protease inhibitors. "Almost everybody on protease inhibitors will get physical
changes at some stage. Length of treatment and stage of disease prior to therapy
appear to be key factors determining who develops these changes. It is one of
the most depressing new aspects of 1998," Dr Youle told the forum.
Dosing ritonavir at 100mg twice daily and indinavir at 800
mg twice daily may reduce the incidence and severity of lipid abnormalities, Dr
Youle said. He challenged the assumption that two protease inhibitors have a
stronger anti-HIV effect than one but noted that the benefit of two protease
inhibitors was increased drug levels in the blood.
Dr Youle was a little cautious about protease-sparing
regimens as a salvage strategy, particularly for people who have had high viral
loads and low CD4 counts (e.g. below 50). He said that protease inhibitors stop
the production of new HIV from cells that have been infected with HIV for a
long-time. In contrast, the other two classes of anti-HIV drugs, NRTIs and
NNRTIs, stop the infection of new immune cells. Therefore, a protease-sparing
regimen may prevent the infection of new cells, but cells that are already
infected can continue to produce new HIV, giving rise to the possibility of drug
resistance and viral rebound.
Drugs in the pipeline
"You want to make your best decision today without cutting
out future options, " Dr Youle said. In choosing a drug, a person needs to
consider whether or not resistance to this drug will reduce their chance of
benefiting from other, better drugs currently in the pipeline. He questioned the
wisdom of widespread use of expanded access programs, suggesting that the UK had
perhaps benefited from limited access to new drugs prior to marketing. He said
that sometimes the first drug of a class to be developed and marketed (e.g. hard
gel saquinavir) does not prove to be the best drug of its class and early use
may compromise benefits to all but the sickest patients.
In his presentation, Dr Youle described some drugs in the
pipeline: abacavir, lodenosine, efavirenz, MKC 442, adefovir, amprenavir, ABT
378 and tipranavir. He highlighted that ABT 378 and tipranavir both need to be
taken with ritonavir to be viable treatment options, and that ritonavir looks
like a major culprit in causing lipid abnormalities which may increase the risk
of pancreatitis, heart disease and diabetes. However, it is presently unclear
whether the tiny amounts of ritonavir used in combination with ABT 378 and
tipranavir will cause lipid abnormalities. Nevertheless, the possible benefits
of these drugs in future, long-term treatment strategies was
questioned.
Serious kidney problems have emerged from trials of the
nucleotide adefovir. Dr Youle said that a number of deaths may have been
associated with adefovir and that the kidney damage caused by adefovir may be
irreversible in some cases. Another nucleotide called bis POC PMEA, under
development by the same pharmaceutical company, may prove to be a better
treatment than adefovir, Dr Youle said.
Long-term and future treatment strategies
While strongly advocating his multi-drug approach to HIV to
reduce viral load to undetectable levels, Dr Youle acknowledged that treatment
strategies and his own views are constantly changing as new research emerges. He
said that new approaches to treating HIV may replace the current aim of reducing
viral load to undetectable levels through constant treatment with anti-HIV
drugs.
Pulsing or cycling of anti-HIV drugs, where a person may
take a combination for a limited period (e.g. nine months) and then stop or
cycle to a new combination, is one possible future strategy. Another approach
may be to force drug resistance so that HIV mutates a great deal. The theory is
that HIV will become unfit and cause much less damage to the body. However, some
experts contend that forcing resistance may improve the fitness of HIV and that
such a treatment strategy would fail.
There is some evidence that the rate of viral load decline
in the first few weeks on treatment will predict the overall outcome of a
combination. If this theory is proven to be correct, a person will know within a
month whether or not their treatment is likely to fully suppress HIV.
Multi-drug regimens are known to produced dramatic declines
in viral load within the first few weeks of therapy. Dr Youle said that it may
be logical to take many available agents initially and then reduce to four or
five drugs, although this strategy and particular combinations would need to be
tested in large-scale studies.
Prevention issue
The transmission of drug-resistant virus is a key issue for
treatment and prevention education, according to Dr Youle. Although there are
now many options for people who have not previously taken treatment, the
effectiveness of particular drugs may be negligible if a person acquires a
drug-resistant strain of HIV. "Getting HIV in 1998 is very different than
getting HIV in 1992," Dr Youle said, "because HIV caught now is likely to be
less amenable to suppression with currently available agents."