Drug-resistant HIV puts pressure on industry

This new strain potentially makes a mockery of current AIDS treatments that can be administered. Patients with a high degree of some drug resistance can usually find a second or third line drug therapy regimen for effective treatment. However this new case highlights just how far the pharmaceutical industry has to go in order to find an effective cure.

Health officials in New York said the strain of three-class antiretroviral-resistant HIV, or 3-DCR HIV, did not respond to three classes of anti-retroviral medication, and also appeared to shorten the interval between HIV infection and the onset of AIDS.

While drug resistance is increasingly common among patients who have been treated for HIV, cases of 3-DCR HIV in newly diagnosed, previously untreated patients are extremely rare. The combination of this pattern of drug resistance and rapid progression to AIDS may not have been diagnosed previously.

Strains of 3-DCR HIV are resistant to three of the four available types of antiviral drugs that are most commonly prescribed: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors.

This strain also caused a rapid onset of AIDS, which usually occurs more than ten years after initial infection with HIV. In this patient's case, onset of AIDS appears to have occurred within two to three months, and at most 20 months, after HIV infection.

The New York City resident, who was not named, was a man in his mid-40s, who had reported feeling unwell in late October and November. Subsequent positive ELISA and Western Blot (HIV tests) documented in mid-December confirmed the diagnosis. The individual then progressed to a diagnosis of highly drug-resistant AIDS by mid-January. Ordinarily, it has taken up to ten years for an untreated individual to progress from HIV infection to an AIDS defining illness and diagnosis.

Officials also said he frequently used the stimulant drug crystal methamphetamine. Officials fear increasing abuse involving crystal meth in the city may help lead to more unsafe sex through loss of inhibitions.

Dr Antonio Urbina, medical director of HIV education and training, at St. Vincent's Catholic Medical Centre said: "The rapidly growing crystal meth epidemic in New York city continues to play a significant role in facilitating the transmission of HIV. In light of the emergence of this virulent new strain, health care providers must be especially vigilant in recognising the signs and symptoms of crystal methamphetamine use in their patients."​

However, some Aids specialists outside New York have cast doubt on the alarm, saying that the man's immune system may already have been compromised, according to an article in the New York Times (NYT) newspaper.

Robert Gallo, a co-discoverer of the Aids virus, told the NYT the combination may be just chance.

"It can be the patient, not the virus that is rare,"​ he said.

Even if the virus proves less virulent than was initially suspected, the latest discovery serves as a wake-up call to the fact that a virus exists that is resistant to a significant number of drugs.

More evidence in scientific literature about the detailed structure and molecular basis of the virus in this case is needed before being it can be considered to be more virulent. Other questions that need investigating, includes seeing whether substance abuse increases a person's susceptibility to disease.

Currently there is a range of marketed antiretrovirals for the treatment of HIV, the majority of which were launched between the years 1990 to 2000. These are slowly being replaced by products with lower pill burden, higher potency and less incidence of adverse side effects. Those candidates with efficacy against resistant strains or novel having mechanisms of action now dominate the pipeline.

Inside an infected cell, HIV produces new copies of itself, which can then go on to infect other healthy cells within the body. The more cells HIV infects, the greater its impact on the immune system (immunodeficiency). Antiretroviral drugs slow down the replication and, therefore, the spread of the virus within the body, by interfering with its replication process in different ways.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) reduce an enzyme called reverse transcriptase by preventing the process that replicates the virus's genetic material. HIV needs reverse transcriptase to generate new copies of itself.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) also interfere with the replication of HIV by binding to the reverse transcriptase enzyme itself. This prevents the enzyme from working and stops the production of new virus particles in the infected cells.

Protease Inhibitors (PIs) inhibit the digestive enzyme protease that is needed in the replication of HIV to generate new virus particles. It breaks down proteins and enzymes in the infected cells, which can then go on to infect other cells. The protease inhibitors prevent this breakdown of proteins and therefore slow down the production of new virus particles.

Other drugs that inhibit other stages in the virus's cycle (such as entry of the virus and fusion with an uninfected cell) are currently being tested in clinical trials.

A recent market report by Datamonitor's suggests that by 2012, global product sales could amount to just under $12 billion (€9.2 billion), approximately double the value recorded for 2003 ($5.76 billion).

Within the HIV pipeline, around a third of candidates are classified as entry inhibitors/others. Datamonitor predicts that in 2012, 16 per cent of total sales revenue could be derived from these novel compounds. Candidates such as the CCR5 (a chemokine receptor on the cell surface) antagonists SCH-D (Schering-Plough​), GW873140 (GlaxoSmithKline​), UK-427, 857 (Pfizer​) and the CD4 inhibitors such as BMS-488043 (Bristol Myers Squibb​) presently appear safe and orally available, but more importantly, are being developed by major players

As well as novel HIV antiretrovirals, second generation NRTIs, NNRTIs and PIs are also being developed with a focus on efficacy against resistant HIV strains observed in patients failing first-line therapies. In addition, two new combination products, Ziagen (abacavir) /Epivir (lamivudine, 3TC) and Viread (tenofovir) /Emtreva ((emtricitabine) are predicted to contribute an additional $770 million in 2012 replacing revenue lost from GlaxoSmithKline's Combivir (lamivudine/zidovudine) and Trizivir (abacavir + AZT + 3TC).

Companies with no existing HIV market experience are currently developing more than half of the HIV pipeline with the greatest compound diversity. Despite this, Datamonitor predicts that only 30 per cent of revenue ($3.5 billion) will be derived from these new players in 2012 should their clinical development plans be successful. Schering-Plough and Tibotec-Virco are the most noticeable new entrants