Main article: Clinical Care Options discussion on mother-to-child transmission

For this special issue of HATIP, we are grateful to Clinical Care Options (http://clinicaloptions.com/) for granting permission to reprint part of their comprehensive coverage of the recent 3^rd International Conference on HIV Pathogenesis and Treatment, held in Rio de Janeiro, Brazil, in July 2005. CCO convened 7 expert panels to discuss and debate new data on key therapeutic issues presented in Rio, including the following analysis of studies of intervention to prevent mother-to-child transmission and access to treatment in resource-constrained settings by Michel Kazatchkine, MD, James McIntyre, MD, and Charles van der Horst, MD.

Free CME credit (or a certificate of participation) for this discussion is available on the CCO site, on successful completion of the online post-test and evaluation. The CCO site also includes Capsule Summaries of all the most important individual studies discussed by the panel, as well as downloadable PowerPoint slides for you to use in your own presentations.

Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC. This program is approved for AMA PRA category 1 credit. CCO’s online coverage of the Rio meeting was supported by educational grants from Bristol-Myers Squibb, Gilead Sciences, Roche, Tibotec Therapeutics, and Trimeris. Copyright © 2005 Clinical Care Options, LLC. All rights reserved.

Discussants:

Michel Kazatchkine, MD

Ambassador on AIDS and Transmissible Disease

Ministry of Foreign Affairs
Paris, France

Charles van der Horst, MD

Professor of Medicine
University of North Carolina School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, NC

James McIntyre, MD

Executive Director
Perinatal HIV Research Unit
University of Witwatersrand
Johannesburg, South Africa

James McIntyre:

At the 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment, our group presented new data from the Treatment Options Preservations Study (TOPS) (http://www.clinicaloptions.com/HIV/Conference%20Coverage/Rio%202005/Capsules/TuFo0204.aspx).[1] This study randomized antepartal HIV-positive women and their newborn infants, who were not breastfed, to receive single-dose nevirapine at delivery or to receive single-dose nevirapine at delivery plus fixed-dose zidovudine/lamivudine for either 4 or 7 days postpartum. The objective of the study was to test whether the addition of nucleoside reverse transcriptase inhibitors (NRTIs) would reduce the incidence of HIV transmission and nevirapine resistance in both mother and infant. The hypothesis was that declining nevirapine levels may cause nevirapine resistance in the presence of a significant viral load and that the addition of dual-NRTI therapy may keep the level of virus below that associated with development of resistance.

After an interim analysis of trial data demonstrated a significant reduction in the rate of mother-to-child transmission (MTCT) in the nevirapine plus zidovudine/lamivudine arms compared with the nevirapine-only arm, the nevirapine-only arm was terminated, but recruitment to the nevirapine plus zidovudine/lamivudine arms continued. The findings we presented at this meeting represent new data on a larger group of mothers exposed to zidovudine/lamivudine plus nevirapine.

We continue to find no significant difference in the rate of development of resistance related to the duration of exposure to zidovudine/lamivudine (4 days vs 7 days). Sixty percent of mothers in the single-dose nevirapine group exhibited evidence of nevirapine resistance 6 weeks postpartum, compared with 12% of mothers in the 4-day zidovudine/lamivudine group and 10% of mothers in the 7-day zidovudine/lamivudine group.

Among the infants, the overall transmission rate measured at Week 6 was 10.5%. The rate of nevirapine resistance was low, with 2 of 21 infected infants demonstrating resistance at birth, and an additional 5 infants in the nevirapine-only arm developing resistance by Week 6.^[2] No infants in the nevirapine plus zidovudine/lamivudine arms acquired nevirapine resistance in the weeks postpartum.

Questions have been asked about why only 4 or 7 days of zidovudine/lamivudine treatment had such a good protective effect when detectable levels of nevirapine may linger for up to 21 days. Indeed, the reduction in the incidence of maternal nevirapine resistance from 60% to 10% with 7 days' treatment is more than we expected. I think we are witnessing the effect of reduction in viral load to < 400 copies/mL in both the 4-day and 7-day zidovudine/lamivudine groups, when assayed at Week 2. We do not have specimens taken between 2 and 6 weeks postpartum so it is not clear how long the duration of undetectable viral load persists. It may be that the reduction in viral load is prolonged beyond 7 days as a result of lamivudine treatment, which has a much longer half-life than zidovudine. It is also not clear how persistent low levels of nevirapine may affect viral replication in these patients.

Charles van der Horst:

Data presented at the 12th Conference on Retroviruses and Opportunistic Infections earlier this year indicated that the development of resistance mutations is driven not by the persistent low levels of nevirapine, but by the high levels of nevirapine in the presence of high viral load at the beginning of the study period.[3] That's the key point. The effect of the addition of zidovudine/lamivudine is protection from the development of resistance mutations when both nevirapine concentration and viral load are greatest, not when nevirapine levels are low.

Michel Kazatchkine:

We have seen this phenomenon in adult clinical practice as well. When an HIV-infected adult initiates a regimen containing nevirapine and experiences intolerance or rash early in treatment, he or she often develops resistance to nevirapine despite short exposure to it because it is present at high levels with accompanying high viral load.

Charles van der Horst:

Viral load is the key. If we hypothesize that the error rate of reverse transcriptase is about 10% in each replication cycle, and 100,000 copies/mL of the virus exist, then many more mutations will be generated at this high viral load than if, say, only 5000 copies/mL of the virus are present.

James McIntyre:

This suggests that extending antiretroviral treatment beyond 21 days may not be effective in further reducing the amount of resistance. The Ditrame Plus study, which showed an extremely low rate of nevirapine resistance (1.1%) at Week 6, is also consistent with this hypothesis.[3] In this study, women had received zidovudine plus lamivudine from week 32 prior to delivery and for three days postpartum, and, therefore, had low viral loads before they were given nevirapine.

Charles van der Horst:

Our research group in Malawi has been encouraged to extend zidovudine/lamivudine treatment beyond 7 days. I'm concerned about doing that because I think it will generate an additional problem. During this time, while mothers are being treated with dual-NRTI therapy only, viral load in the mother will probably increase, and the M184V lamivudine resistance mutation may well develop in that scenario.

James McIntyre:

The other interesting aspect of the TOPS study was the reduction in detectable resistance in the 10% of children who were infected. Among children who received zidovudine/lamivudine as well as single-dose nevirapine, there was no detectable resistance noted at 6 weeks. However, detection of resistance may be a function of the test used.

Additional data were presented by Sarah Palmer at the 14^th International HIV Drug Resistance Workshop using real-time polymerase chain reaction (PCR) techniques.^[4] That work showed that when one uses a more sensitive technique to detect resistance, it is possible to show that genotypic resistance is not completely eliminated but, nevertheless is reduced. Nevirapine resistance mutations were detected using real-time PCR in 75% of women who received nevirapine only, compared with 27% of women who also received zidovudine/lamivudine.

Charles van der Horst:

Another poster that we should mention in the context of single-dose nevirapine and MTCT was a presentation looking at the timing of nevirapine dosing in HIVNET 024.[5] The data showed that timing variations in either mother or infant dosing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women who received nevirapine less than 2 hours before delivery, early nevirapine administration to the infant (within 4 hours of birth) was not associated with lower rates of MTCT when compared with later administration (4 hours or longer after birth). It was possible to administer the infant dose up to 72 hours postpartum without impairing the protective effect against MTCT.

 

 

Treatment response in mothers previously exposed to single-dose nevirapine

James McIntyre:

Marc Lallemant's group has previously presented data showing that women exposed to single-dose nevirapine who subsequently received antiretroviral treatment for their own health exhibited a poorer virologic response to therapy than women who did not receive single-dose nevirapine, although clinical and immunologic outcomes were not significantly different.^[6,7] At this meeting, 12- and 18-month follow-up from the same study were presented within an expert talk.^[8] I found Lallemant's data reassuring. There had been a presumption that the rate of virologic response would continue to deteriorate over time, but Lallemant showed that response at either 12 months or 18 months was very similar to that seen at 6 months.

Additional reassuring data on response to treatment after nevirapine use were presented from the MTCT Plus program in Abidjan, Cote d'Ivoire.^[9] However, 60% of women in that study had been on a zidovudine/lamivudine regimen before delivery, so a low rate of nevirapine resistance was expected.

Michel Kazatchkine:

The Abidjan study, unfortunately, did not report resistance or virologic response data, but it did show that the increase in CD4+ cell counts, which is associated with important clinical benefit, was similar in women who were preteated with nevirapine and in those who were not.

James McIntyre:

It was reassuring to me that the results of these studies suggest that the effect of nevirapine exposure on subsequent treatment outcome does not seem to be marked. It is, of course, always better to avoid the selection of nevirapine resistance than to allow it to happen. However, for the many women who start antiretroviral treatment after exposure to single-dose nevirapine, it seems that responses to therapy are reasonable.

The remainder of the expert discussion, available at the CCO Web site, covers:

• HIV-Exposed but Uninfected Infants
• Scaling Up Preventative MTCT Programs
• Male Partner Counseling
• Male Circumcision as an HIV Prevention Measure
• Adverse Pregnancy Outcomes
• Tuberculosis Coinfection

To read the discussion, view capsule summaries of the data, and complete the post-test and evaluation, visit

http://clinicaloptions.com/HIV/Conference%20Coverage/Rio%202005.aspx

References

1. McIntyre JA, Martinson N, Gray GE, et al. Single dose nevirapine combined with a short course of Combivir for prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and infant resistant virus. Program and abstracts of the 3^rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract TuFo0204.

2. Gray GE, McIntyre JA, Martinson N, et al. NNRTI-resistant mutations in HIV-infected infants following single dose nevirapine (sd-NVP) are reduced by the addition of short course zidovudine and 3TC.Program and abstracts of the 3^rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract TuPe5.4P01.

3. Chaix ML, Dabis F, Ekouevi D, et al. Addition of 3 days of ZDV+3TC postpartum to a short course of ZDV+3TC and single-dose NVP provides low rate of NVP resistance mutations and high efficacy in preventing peri-partum HIV-1 transmission: ANRS DITRAME Plus, Abidjan, Côte d'Ivoire. Program and abstracts of the 12^th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 72LB.

4. Palmer S, Boltz V, Maldarelli F, et al. Short-course Combivir (CBV) single dose nevirapine reduces but does not eliminate the selection of nevirapine-resistant HIV-1: improved detection by allele-specific PCR. Antivir Ther. 2005;10:S5. Abstract 3.

5. Chi BH, Wang L, Read JS, et al. Timing of maternal and infant nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024. Program and abstracts of the 3^rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract TuPp0405.

6. Jourdain G, Ngo-Giang-Huong N, Tungyai P, et al. Exposure to intrapartum single-dose nevirapine and subsequent maternal six month response to NNRTI-based regimens. Programs and abstracts of the 11^th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. Abstract 41LB.

7. Jourdain G, Ngo Giang Huong N, Le Couer S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004;351:229-240.

8. Lallemant M. Response to therapy after prior exposure to nevirapine. Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract TuFo0205.

9. Bedikou G, Viho I, Tonwe-Gold B, et al. 6-month immunological response with HAART containing nevirapine in HIV-infected women post exposure to single dose of nevirapine for PMTCT. The MTCT-plus Initiative in Abidjan, Cote d'Ivoire (2003-2005). Program and abstracts of the 3^rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract MoOa0203.

News headlines

High incidence of TB after ART started, MSF reports

http://www.aidsmap.com/en/news/6F10822E-7E9D-4740-AEFD-92131F44B2D4.asp
Medecins Sans Frontieres’ treatment programmes in resource-limited countries are seeing high rates of TB in people after they begin taking antiretroviral therapy, according to a presentation from the group at last week’s 36^th Union World Conference on Lung Health in Paris.

Vitamin D boosts anti-TB immunity, now being tested as add-on to TB therapy

http://www.aidsmap.com/en/news/5442DEBA-9C00-432E-A26C-BF11BDC438A0.asp?hp=1
Sunlight was considered an essential element of tuberculosis (TB) control in the pre-antibiotic era because ultraviolet light and heat kill mycobacteria. TB sanatoria were designed to let in light, and even today TB wards are recommended to have large external windows for good ventilation and sunlight exposure.

Blood concentrations of efavirenz predict who will develop central nervous system side-effects

http://www.aidsmap.com/en/news/92700721-A585-497B-8392-ED8CC7749DCA.asp?hp=1
Spanish researchers have found that patients who have been taking long-term antiretroviral therapy including the non-nucleoside transcriptase inhibitor (NNRTI) efavirenz (Sustiva) are much more likely to develop neuropsychological side-effects if they have high blood concentrations of efavirenz.

Stigma and myths still harming TB fight

http://www.aidsmap.com/en/news/F1064B98-5293-4636-85F0-14D07AA15DD2.asp?hp=1
Stigma and misinformation about TB are still major barriers to TB screening and treatment in some countries, the 36th International Conference on Lung Health heard last week in Paris. Without dispelling some of the myths about TB and its treatment, national programmes are unlikely to identify people with latent infection because many do not consider themselves to be at risk, and so the chances of catching people before they reach the infectious stage of active, smear-positive TB are lessened. This in turn prevents a country from containing its TGB epidemic.

An HPV vaccine - what it might really mean

http://www.aidsmap.com/en/news/3429199D-5FE5-4795-B0E6-CD957617C160.asp?hp=1
As far as the mainstream media is concerned there is now a "100% effective" vaccine against the two strains of the human papilloma virus (HPV) that cause most cases of cervical cancer. It is not quite that simple.

How do TB clinic practices obstruct good HIV care?

http://www.aidsmap.com/en/news/E232AB03-D6EE-461D-BBF5-6ED6C7688BC8.asp?hp=1
Researchers from Kenya report that tuberculosis (TB) clinic practices provide a major obstacle to the provision of good HIV care, despite the fact that national TB programes throughout Africa and Asia are being urged to integrate HIV care with TB care. The findings, drawn from a survey of TB clinics in two districts of Kenya, reflect practice in many countries, and were presented to last week's International Conference on Lung Health in Paris.

BCG vaccine causing disease in HIV-positive children

http://www.aidsmap.com/en/news/07A66C8F-0653-4600-A5BA-4F812C3A343F.asp?hp=1
BCG vaccination against tuberculosis can cause local or systemic disease in HIV-positive children, and doctors should be more vigilant for signs of complications associated with the vaccine, South African researchers reported last week at the 36th World Conference on Lung Health in Paris.

Side-effects major reason UK patients switch from first-line therapy, BHIVA audit finds

http://www.aidsmap.com/en/news/D225AEAD-0E1C-425C-B8F7-6324ECE54A53.asp?hp=1
An audit of UK patients who switch from their first- to second-line anti-HIV therapy has found that toxicity was the main reason for switching therapy. In addition, one in four patients who changed regimens due to virological 'failure' did not obtain a resistance test result before switching therapy. The results were presented at last week's British HIV Association (BHIVA) conference, held in central London, and are now available for download from BHIVA's clinical audit website. The audit also found that some patients with virological 'failure' remained on therapy with detectable viral loads for long periods before switching.

CD4 cell count below 250 associated with shorter treatment break

http://www.aidsmap.com/en/news/F76BCC68-235B-41A6-B13F-D5C3311D7A44.asp?hp=1
A lowest ever CD4 cell count between 200 - 250 cells/mm3 is associated with faster reinitiation of therapy in patients who took a break from antiretroviral therapy, according to a Canadian study published in the November 15th edition of the Journal of Infectious Diseases (now available online). The investigators also found that the presence of specific HIV genotypes, which studies before the availability of effective anti-HIV therapy had shown to be a predictor of rapid loss of CD4 cells, were associated with a shorter duration of treatment interruption.

Hepatitis C found more frequently in semen of men coinfected with HIV/HCV

http://www.aidsmap.com/en/news/66CC79E7-7D38-4DE3-B27F-05FB368E5690.asp?hp=1
Hepatitis C virus is found significantly more frequently in the semen of men who are coinfected with HIV than in the semen of men who are only infected with hepatitis C (HCV), according to research published in the November 4th edition of AIDS. Sexual transmission of hepatitis C virus has recently been observed in HIV-positive gay men and the investigators write, "our results partly illustrate how the recent increase in sexually transmitted hepatitis C virus in homosexual men could arise."

Timing variations don’t affect nevirapine’s impact on mother-to-child transmission

http://www.aidsmap.com/en/news/1D0EAA91-5541-4CC1-A8E7-396B12B67016.asp?hp=1
Variations in the timing of nevirapine (Viramune) dosing for both mother and infant don’t have a significant impact on the effectiveness of nevirapine in preventing mother-to-child transmission, according to an analysis published in the November 4th edition of the journal AIDS. Mothers who took the drug less than two hours before delivery were no more likely to pass on the virus than women who had taken it more than four hours before delivery, and as long as infants received their dose within 72 hours of delivery, it didn’t seem to matter when they - or their mothers - actually took the drug.

Parasitic worm infections increase risk of mother-to-child HIV spread

http://www.aidsmap.com/en/news/6D2E1DC5-E249-4BF8-A390-84CDDF063A47.asp?hp=1
Treating helminth (parasitic worm) infections in pregnant women with HIV might reduce the rate of mother-to-child HIV transmission, researchers from Kenya and the United States suggest in a report published in the November 4th edition of the journal AIDS.

Cheaper female condom will increase access in Africa

http://www.aidsmap.com/en/news/E33913EF-0A68-462D-AD2E-80BB89D819DB.asp?hp=1
Women in sub-Saharan Africa will soon benefit from a cheaper version of the female condom, enabling them to negotiate safer sex with their male partners.

Zimbabwe teachers urge free ARVs as AIDS thins their ranks

http://www.aidsmap.com/en/news/9F37FC59-39BA-4772-B79A-CC766F0BA5DB.asp?hp=1
Teachers in Zimbabwe have urged the government to provide free AIDS treatment after a survey revealed the profession was struggling with the highest infection rates in the country.

Scans show specific patterns of brain damage in patients with AIDS

http://www.aidsmap.com/en/news/05081148-B30C-4A41-9BA8-81AC63683809.asp?hp=1
Patients with AIDS have specific patterns of brain damage in regions that control motor, language and sensory functions, according to a study of brain scans published on 10th October in the online version of The Proceedings of the National Academy of Sciences of the USA.

Fish oil can reduce triglyceride levels in HIV patients

http://www.aidsmap.com/en/news/8BFCCB2F-3ACA-457E-9FEE-AE09544989E4.asp?hp=1
Fish oil can significantly reduce triglyceride levels in HIV-positive people taking antiretroviral therapy, according to a small US study published in the November 15th edition of Clinical Infectious Diseases. An accompanying editorial calls the study "important" and states, "fish oil therapy looks like it is as good as other possible therapies."

Survey of medical education needs of physicians and healthcare workers in Africa

HATIP subscribers and readers working in Africa are invited to take part in a survey of medical education needs relating to HIV treatment. The survey is collecting information on HIV/AIDS physician education programmes in Africa. Your responses to the survey will help develop effective education programmes in the future. The survey should take about 10 minutes of your time. Thank you in advance for taking time out of your busy schedule to participate.

Links to the survey:

English

http://www.surveymonkey.com/s.asp?u=208671193094

Français

http://www.surveymonkey.com/s.asp?u=96352123934

Português

http://www.surveymonkey.com/s.asp?u=223411239386