/ 17 August 2012

Clash over HIV drug’s ‘success’

Weighing up the odds: Money spent on a ­prophylactic could be at the expense of providing life-saving ARVs.
Weighing up the odds: Money spent on a ­prophylactic could be at the expense of providing life-saving ARVs.

Truvada, manufactured by the American company Gilead Sciences, is licensed as an antiretroviral treatment for HIV-infected individuals in 93 countries, including South Africa. It is used in combination with other ARVs to suppress the replication of the virus.

But three landmark studies, two of which were conducted in Africa, have shown that daily use of Truvada – which contains two ARVs, tenofovir and emtricitabine – can significantly reduce the risk of HIV-negative people contracting the virus. The American government's iPrEx trial, one of five legs that was conducted in South Africa, found that Truvada reduces the infection risk among gay and bisexual men by 44% on average, if taken once a day. But those participants who were most compliant and took their pills at least nine times out of 10, increased their protection against HIV to 73%.  

Washington University's Partners PrEP study showed an even greater reduction in risk – 75% – of contracting the virus among Kenyan and Ugandan heterosexual "discordant" couples, where one partner was HIV-positive and the other negative.

The TDF2 study by the American government's Centres for Disease Control showed that heterosexual men and women in Botswana are 62% less likely to become infected with HIV if they take a daily Truvada pill.

Prevention method
Last month, the United States's Food and Drug Administration (FDA) approved the registration of Truvada as a formal HIV prevention method, known as pre-exposure prophylaxis (Prep), for people not infected with HIV. This means that HIV-negative people in the US who consider themselves at risk of contracting HIV can legally ask their doctors to prescribe Truvada. Most of those on medical aid will probably also be able to claim the costs of the medication from their medical insurance schemes. Three of the US's largest health insurance companies, Kaiser Permanente, WellPoint and Aetna, have already stated that they will consider covering the costs.

The advantage of taking Truvada is that people are largely protected if they have sex unexpectedly.

But Mitchell Warren, executive director of the US-based HIV lobby group, Avac said: "It is essential to remember that Prep is not a silver bullet as it does not fully protect you against HIV infection. It should be used in combination with other HIV prevention methods, such as condoms."

FDA regulations specify that a Truvada prescription may not be issued for more than three months at a time, and that healthcare providers must confirm that a patient's HIV status is negative before prescribing treatment. If not, an HIV-positive person could become resistant to Truvada, which might be needed later as an HIV treatment.

Given South Africa's high HIV infection rate, some Aids activists are putting pressure on the MCC to follow in the FDA's footsteps quickly.

"South Africa's Medicines Control Council can pave the way for safe and effective use through guidance on the appropriate use of daily Truvada as Prep in different populations and settings as soon as possible," Mitchell said. "Given that some of the Prep trials took place in the country, it's imperative that Gilead Sciences engages with the MCC, just like it did with the FDA."  

To get Truvada registered as a Prep treatment in this country, Gilead has to submit available scientific evidence of its efficacy to the MCC, which will decide whether it is sufficient.

Open and willing
MCC chairperson Professor Peter Eagles would not confirm or deny whether the council had received an application from Gilead. "I would prefer it if you direct this question to the company," he said.  

Gilead spokesperson Cara Miller said there are no plans to file for registration, but added: "Gilead is open and willing to discuss with international health authorities and ministries of health the potential for enabling access to Truvada for Prep."

Some scientists, such as Professor Linda-Gail Bekker of the Desmond Tutu HIV Centre at the University of Cape Town, are hoping that Truvada will be an approved Prep treatment in South Africa within a year. Although the MCC has said it would increase staff numbers to speed up approval processes, the council sometimes takes up to five years to register medicines.

South Africa is the only African country with guidelines for Prep treatment, drawn up by the HIV Clinicians' Society. Designed for gay men, they were published in the Southern African Journal of HIV Medicine in June. Bekker, who co-chaired the guideline committee, said work should begin on an addendum that would expand guidelines to ensure safe use in heterosexuals. "The reality is that some South Africans, particularly in the private sector, are using Truvada as a Prep treatment already. Nothing prevents doctors from prescribing it off-label at the moment, as it's already available for a different use," she said.

Although Mitchell said that the unregulated, off-label use of Truvada could be dangerous as the MCC would have little control over its use, Eagles said that the MCC would consider assisting with formulating "relevant and appropriate guidelines" should it be approached to do so.

Risk compensation
Health Minister Aaron Motsoaledi said that he was not yet satisfied with the available scientific evidence concerning Truvada, and that potential risks associated with its use by HIV-negative people needed further assessment: "There are many concerns that I heard about at the HIV conference [in Washington, DC] and I'd like those to be addressed before we make a decision about Truvada."

Two studies with HIV-negative women as subjects, the FemPrEP and Voice studies, were stopped early after preliminary results indicated that the research was unlikely to demonstrate that daily doses of tenofovir, one of the ARVs contained in Truvada, or Truvada itself, reduced participants' chances of contracting HIV. When blood was analysed to determine whether subjects had taken their pills, only 38% of FemPrEP participants had detectable levels of Truvada in their blood, indicating that drug adherence was low and, therefore, the study was severely compromised.

Mitchell said: "Having a condom in your pocket does not protect you against HIV. You have to get the condom from your pocket and put it on to your penis. Similarly, you have to get a Truvada pill from the container to your mouth for it to be effective."   

Other studies are being conducted to determine whether it is possible to take Truvada only a few times a week and still be protected against HIV. (See "Danger of the window period").

Other concerns about Prep include that it could divert resources from ARV treatment for HIV-infected people, particularly in Africa, where many HIV-infected patients who need treatment are not receiving it. A month's daily dose of Truvada in South Africa costs about R475.

Some researchers are also concerned that Prep could result in "risk compensation" – it could encourage users to take more risks. But, for Mitchell, the issue is relatively simple. "If we can expand the menu of HIV prevention by adding another [safe] option, we have to do that as it will result in fewer infections."

Mia Malan works for the ­Discovery Health Journalism Centre at ­Rhodes University

Danger of the window period

Because immune systems need time to produce the antibodies that fight an HIV infection and which reveal the presence of the virus, there is a window period during which a person might be HIV positive but test HIV negative.

During this period, which can last between two and 12 weeks, although the average is 25 days, the virus replicates quickly. Starting pre-exposure prophylaxis (Prep) during this stage is dangerous because the amount of antiretrovirals (ARVs) being taken is too low to fight the large amount of HIV effectively.

Truvada contains only two types of ARVs. Effective HIV treatment requires at least three different types of ARVs.

Truvada, as a Prep treatment, is also unlikely to have been used for long enough to have produced  a high enough level of protection. This could lead to the virus becoming resistant to Truvada, leading to a resistant HIV strain, which could be passed on to others for whom Truvada would be ineffective as HIV treatment. Therefore people who use Prep should be tested regularly for HIV.