New HIV Prevention Technologies – HIV Vaccines


The promise of an effective HIV vaccine has always been just over the horizon, but more than 20 years after the identification of HIV,
vaccines remain far from implementation.

The two large HIV vaccine studies till date have shown no protective
effect.The latest is the Merck’s trial which not only showed that the
tested vaccine could not prevent HIV infection but also highlighted
some other findings:

1) The trial participants who received the vaccine showed the highest
risk of HIV infection in individuals who had had adenovirus infection
in the past. Adenoviruses most commonly cause respiratory illness.
they could also cause various other illnesses such as infection of
the GIT, eyes and skin depending on the type. Symptoms of respiratory illness caused by adenovirus infection range from the common cold syndrome to pneumonia and bronchitis

2)the trial also showed that the trial participants who had signs of
adenovirus infection, and were uncircumcised were at four times
greater risk of HIV infection if they received the vaccine compared
to circumcised men who had the adenovirus infection and were in the
placebo group. A vaccine study is still ongoing in Thailand and should be concluded in June 2009. A phase IIb HIV vaccine study known as the PAVE 100 study is still being planned to begin in 2008. While we have dissapintment in the field, more studies are still needed in order to improve understanding of the strengths and limitations of various HIV vaccines designs.

For the future, vaccine approaches would focus more on basic research without precluding clinical research. Currently, investment in
vaccine research comes overwhelmingly from the public sector and
foundations. Only one private company (Merck) has invested more than $10 million annually in vaccine research. Companies cite the current scientific uncertainty and the lack of incentives for conducting
phase II studies and investigating process development as barriers to entry to the field

Prevention of Mother to Child Transmission (PMTCT)

Mother to child transmission remains a major means of HIV
transmission. HIv can be transmitted from the mother to the child
through 3 routes:

1. During pregnancy when the mother goes through trauma that may
cause a tear in the placenta and allow direct contact between the
mother and the child’s blood. This should not happen normally. This
route of transmission for HIV infection from mother to child is quite
low

2. At delivery. When delivery is not taken carefully and the child is
exposed to contact with the mother’s vaginal fluid which is infected
with the virus, or the mother’s blood.ideally, HIV infected pregant
mothers should be slated for caserean section so as to further reduce this possibility

3. After birth through breast milk. This is the most common route of
infection. The breastmilk contains HIV virus. the virus could infect
the child through the gut. the gut contains a lot of CD4 cells and
therefore HIV infection can easily occur in the gut when exposed to
the virus. Often times, HIV infected mothers are advised not to
breastfeed. When they opt too for a number of different reasons, they are advised to breastfeed exclusively (breastfeed the child strictly on breastmilk only) before weaning off the child. Exclusive
breastfeeding is however recommended where replacement infant feeding is not acceptable, feasible, affordable, sustainable and safe

The use of prophylactic Amtiretroviral regimen to reduce the rate of
HIV transmission from mother to child has improved over the past ten years. Current WHO guidelines recommend a short-course regimen ideally consisting of AZT for the mother from week 28 of pregnancy, single dose nevirapine at the onset of labour, and AZT/3TC for 7 days after delivery. The infant should also receive a single dose of nevirapine at delivery, and AZT/3TC for 7 days. Mothers with CD4 cell counts below 350 should be considered for antiretroviral therapy. Despite the proven effectiveness of ARV to reduce rate of Mother to child transmission of HIV infection, mirage of logistic problems prevent the effective use of this innovation include the ineffectiveness of health systems. Less complex regimens are recommended where the health system cannot deliver this level of care, but even the delivery of single-dose nevirapine – the least effective regimen – has posed significant problems for health systems in sub-Saharan Africa. Detailed analysis of programme delivery in Zambia, for example, has shown that only one in three women diagnosed HIV-positive actually took nevirapine at delivery. But then only 30% of woment actually take an HIV test!

No recent analysis of potential technological improvements to PMTCT
programs has been carried out . Ongoing studies are investigating the efficacy of HAART (a ARV treatment regimen consisting of at least 3 drugs) and the safety and efficacy of tenofovir (a type of ARV).

Interpreting the results of HIV prevention trials (2)

Clinical Trial Results Are Valuable. This is because:
1. They can tell us which products are not studying anymore

2. They can point to the kinds of changes that could be made to
improve other clinical trial design

3. They may yield beneficial information about behavioral and
cultural practices that affect HIV transmission and the results we
get from clinical trials; and

4. They provide valuable information about how prevention trials can
be better managed.
Understanding Clinical Trial Results:
Prior to a clinical trial, studies of the product to be tested are
done in the lab and in animals. Small size, medium size and large
size animals are used when testing the product. the right animal is
also used. For example, when testing microbicides, the rabbit
vaginal is used because this is the most sensitive vaginal and if it
does not harm the rabbit vaginal, it may not harm the human vagina.
Doing a microbicide animal study using a donkey may therefore be
wrong.

After animal studies, there are also other phases of studies:
1. Phase I which looks at the safety of the product or drug in very
few people

2. Phase II which looks at the safety of the drug and also tries to
test if the drug can do what it is meant to do in an ideal
condition. This is known as an ‘efficacy’ study

3. Phase III which looks at the safety of the drug and also tries to
see if the drug or product can do what it is meant to do under
normal conditions

Eg – Ampicillin is an antibiotics that went through animal, phase I,
II and III clinical trials. It was found to be able to treat similar
human infections in animals. It was found safe in phase I studies.
In phase II studies, It was shown to produce good results when taken
every 6 hours for 7 days. In phase III studies, it was shown that if
people miss the every 6 hours once in a while, or use it for less
than 7 days (for 3-5 days) it can still be effective. For this
reasons, the drug went throuh further development.
What is a successful clinical trial:
A clinical trial could end in any of the phases. A phase III trial
could be end because:

1. There is proof that the product can work to prevent HIV infection
e.g. male circumcision

2. That there is no proof that th drug is working e.g. carraguard

3. That the product or drug is causing harm eg making people very
sick or causing more HIV infectione.g. N9

4. When the results are not clear and there is no evidence that it
would be clearer with ontinued study e.g. SAVVY
An HIv prevention Clinical Trial would be considerd Successful if:

1. The research plan is conducted as stated in the study protocol.

2. The study is done using the right method

3. The trial provides further information to the HIV prevention field

4. Trial participants are informed and educated about HIV, the
purpose and outcome of the study.

5. The health of participants is protected

6. Trial is continuously monitored at defined intervals by the right
persons who know what they should be looking out for

7. Participants and the community are engaged with the research
process in an ethical, respectful and efficient manner.

8. The trial participants did not abscond from the trial and so at
least 85% of those that started the trial stayed till the end. This
reduces bias

9. The study results are communicated to participants, their
communities and other stakeholders.

10. A plan to ensure trial participants and or the study community
has access to study products in the case of a positive result.

Interpreting the results of HIV prevention trials (3) – So far so…

In the lats two years, the world had received the results of a
number of HIV prevention trials. Specifically, the following trials
have produced no evidence of effect, or a trend towards harm:

• CONRAD phase III study of cellulose sulphate (UsherCell)
microbicide halted after interim analysis showed higher rate of HIV
infection in UsherCell group (the Family Health International study
of cellulose sulphate, a trial also conducted in Nigeria – was also
halted not because there was harm but due to the fact that the
CONRAD study was stopped).

• MIRA female diaphragm and lubricant study completed, but no
evidence of protective effect.

•HSV-2 suppression therapy which were completed but no evidence of protective effect.

•Population Council phase III study of Carraguard microbicide
completed, but no evidence of protective effect.

•The 0.5% concentration PRO 2000 arm abandoned in the MDP
(Microbicides Development Program) phase III study due to futility

•STEP proof of concept study of Merck’s Ad5 HIV vaccine halted after
interim analysis showed lack of protective effect. There was a
tendency towards more harm

Although these studies have not provided a prevention technology for further development, they have demonstrated the ability of multiple sponsors to run large trials of prevention technologies, and
generated important information that will contribute to the design
of future studies.

The only positive results in the past two years from HIV prevention
phase III trials have come from adult male circumcision studies
which shows that circumcision reduces the rate of HIV infection IF
and WHEN the study site heals at least 6 weeks before commensing
sex. The need and importance of healing was evident from the results of a negative signal observed a study of male circumcision in HIV- positive men which showed a trend towards a higher rate of HIV
infection in sexual partners of circumcised men when compared to
partners of men who were not circumcised.

Has the field failed so far?
In the field of drug development, there are evidence to show that
when 10,000 potential drugs are found to possibly work in the
laboratory, it takes an average of 6.5years for ONLY 250 of these
compounds to show that it can actually do something in animals. Of
the 250 compunds, only 5 makes it through to phase III over a 7 year period. And of the five, only 1 makes it for drug approval after a 1.5year period. On the whole, it takes about 15 years to develop a
product even WHEN all the needed information is available.

The HIV prevention field has so far not deviated from the norm of
drug development even moreso in the light of the many unknown that plaques the research field. All trials have informed the planning
and implementation of the next trial in such a way as to improve the
care and protection of trial participants. The field is also more
responsive to community concern.

Has the field failed so far? The moderator lookd forward to your
sharing your views and perception on this. Happy discussion.

Could vaginal microbicides protect men more so than women?

In the July 15, 2008 issue of the Proceedings of the National Academy of Sciences (http://www.pnas.org), Dr. Sally Blower and her colleagues report that mathematical models of real-world use of ARV-based vaginal microbicides predict that men may actually derive greater long-term protection against HIV infection than women. There are a lot of assumptions and unknowns in these models, including questions of microbicide efficacy and adherence, condom use, and drug resistance. But even if ARV-based microbicides turn out to be only partially effective, these models predict that large numbers of at-risk men and women will be protected if these products are widely available and used.

One question that remains unanswered, however, is whether the widespread use of an ARV-based microbicide could select for drug resistant strains of HIV. The women enrolled in current or planned trials of ARV-based candidate microbicides likely are at low risk of developing drug resistance. Trial participants will be screened monthly for HIV infection, and will stop using a candidate microbicide immediately if they become infected. These women will be tested frequently to see if they develop drug-resistant virus, and arrangements will be made to ensure they have access to effective drugs. However, as the Blower model suggests, even if an ARV-based candidate microbicide does not seem to select for drug resistant virus during phase II and phase III safety and effectiveness trials, drug resistance could be a long-term problem once the product is widely available and used by women who undergo much more infrequent HIVcounselling and testing. Thus, it will be important to couple the widespread introduction of ARV-based microbicides with increased counselling, education, HIV testing, and drug resistance monitoring for at-risk individuals.

To learn more about ARV-based microbicides and HIV drug resistance, see the GCM fact sheets entitled “ARV-based Microbicides: The Promise and The Puzzle” and “Understanding HIV Drug Resistance.” These and other basic GCM fact sheets and materials are available for free download at http://www.global-campaign.org/download.htm.

HSV-2 treatment does not reduce the risk of HIV infection

As we first reported in the April 18, 2008 issue of GC News, although number of studies have shown that herpes simplex virus type 2 (HSV-2) infection is associated with an increased likelihood of acquiring HIV, treating people who have HSV-2 doesn’t reduce their risk of HIV infection. In the June 21st issue of the Lancet, Dr. Connie Celum and her colleagues at the University of Washington present the results from the second large-scale clinical trial designed to test whether treating HSV-2 can help prevent HIV infection among high-risk individuals. They found no evidence of a protective effect.

In the accompanying editorial, Drs. Ronald Gray and Maria Wawer of Johns Hopkins University argue that these findings call into question current prevention policies that focus on control of sexually transmitted diseases to lower transmission of HIV, stating: “It is time to reassess [this] hypothesis and to adjust prevention policy accordingly.”