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CROI 2005: Boston, Mass.; Feb. 22-25, 2005

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The Body Covers: The 12th Conference on Retroviruses and Opportunistic Infections
Problems With Drug Resistance Persist in the Prevention of Mother-to-Child Transmission in the Developing World

February 24, 2005

Prevention of mother-to-child transmission (PMTCT) is critical for slowing down the epidemic in the developing world. While we have had dramatic success with PMTCT in developed countries where drug cocktails are available throughout a woman's pregnancy and where breastfeeding can be avoided to prevent transmission, the same options are not readily available to the developing world. We need research such as this to identify the benefits and drawbacks of various simple and economically feasible prophylactic regimens being tried to prevent both transmission at birth and during breastfeeding.

Because of both the cost and social stigma that is associated with formula feeding in the developing world and, of course, the health benefits of breast milk in countries with poor sanitation, breastfeeding -- even with its 10%-15% HIV transmission risk -- will continue to be practiced by most mothers in poor countries.

HIVNET 012, which showed that the administration of single-dose nevirapine (NVP, Viramune) to mother and infant decreased HIV transmission to breastfed infants by 41%, as compared to zidovudine (AZT, Retrovir), remains the sentinel study in this field.1,2 Many key questions remain unanswered, however. Will the high rates of drug resistance seen in mothers receiving these regimens be seen in those of their children who are infected during breastfeeding? Will this diminish treatment options for these infants in the future?

Viral resistance in children exposed to these regimens is a potential problem for those who acquired HIV either at birth or during breastfeeding. This study sought to evaluate the extent of the problem as part of the SIMBA (Stopping Infection from Mother to child via Breastfeeding in Africa) study conducted in Uganda and Rwanda. This multi-center trial by Marina Giuliano et al looked at the safety and efficacy of lamivudine (3TC, Epivir) and nevirapine in preventing postnatal transmission of HIV.

The mission of the trial Giuliano presented at CROI was 2-fold: 1) to evaluate the presence of resistance mutations in children who were diagnosed with HIV while receiving antiretroviral prophylaxis to prevent breastfeeding-associated transmission and 2) to evaluate baseline resistance in mothers at the time of delivery.

All the enrolled pregnant women received zidovudine + didanosine (ddI, Videx) from 36 weeks gestation to 1 week post-partum. Four hundred four infants of HIV-infected women were enrolled in SIMBA from July 2001 to August 2002 and randomized 1:1 to receive nevirapine syrup (2 mg/kg/day for the first 14 days, then 4 mg/kg/day thereafter) or lamivudine syrup (4 mg/kg/day for the first 14 days, then 8 mg/kg/day thereafter) from 24 hours after birth for the duration of breastfeeding (up to 6 months of age) or until they were confirmed HIV infected by 2 consecutive tests.

For this study, analyzed samples were collected from infants at a median time of 2 weeks after the first detection of HIV. Samples were collected from mothers at enrollment, prior to the administration of the study drug and again at delivery. The TruGene phenotyping kit was used to ascertain the presence of resistance mutations.

Thirty infants acquired HIV: 7% through early transmission (within 4 weeks of delivery) and only 1% through late transmission (4 weeks to 6 months after delivery). Twenty-six infants were able to be evaluated, with 13 having received lamivudine and 13 nevirapine. Twenty children had their first HIV-positive test at birth, 5 at week 3, and 1 at week 6.

The genotype samples evaluated were the first available after the infant's initial positive HIV test (median 2 weeks after the start of prophylaxis for the lamivudine group and 6 weeks after prophylaxis initiation for the nevirapine group). The second resistance tests were done on samples drawn after discontinuation of prophylactic drugs for the infant (median of 5 months after discontinuation of prophylaxis for the group on lamivudine and 6 months after for the nevirapine group). HIV-1 subtypes A and D were primarily seen in the study cohort. Genotype samples drawn at the time of delivery were available from 30 of the women who transmitted HIV to their babies.

Nine out of 13 (67.2%) of the infants taking lamivudine had the M184V/I mutation present in their first genotype sample. However, this mutation faded rapidly and was no longer present in the samples collected 3-6 months later. Twelve of 13 (92.3%) of the infants who were taking nevirapine had non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations (9 Y181C, 3 G190A, 2 K103N, 1 Y188H, 1 V106A) with 3 children having multiple mutations. The NNRTI mutations persisted in all samples drawn after discontinuation of prophylaxis.

Two mothers in the lamivudine group had resistance mutations present at both study enrollment and delivery (1 had the K103N mutation and the other had M41L). These mutations were present and persistent in all of their infants' viral genotype samples. Two mothers in the nevirapine group had baseline resistance mutations -- one had V108I and one G190A. Only V108I persisted in both infant samples. In the 22 mothers tested at delivery, no resistance mutations associated with the prophylactic zidovudine and didanosine being received were found.

Giuliano identified several potential problems with this study. The number of infected infants in this study is small, with most infected around the time of delivery. Drugs were received for at least 14 days, even if the infants were infected at birth, so the need for easy, inexpensive and readily available tests to identify these infants may be critical to preventing resistance from inappropriate receipt of single-agent prophylactic regimens.

The amount of resistance seen in this study was higher than in other studies done in this area, so larger trials are needed to confirm this finding. The significance of the reversion to wild-type virus in the lamivudine-treated infants, but not the infants treated with nevirapine, is of unclear significance since mutations revert at varying rates and lamivudine-resistant virus may reoccur with future lamivudine therapy in these children. That virtually all the infants taking nevirapine developed persistent NNRTI resistance is worthy of further research.

The following key question still needs to be answered: As these children mature, will their treatment options be limited or can clinical benefit still be derived from this drug class?

HIVNET 012 showed similar NNRTI resistance patterns (K103N in mothers and Y181C in infants), however, in that trial the majority faded by 12 months or so. Longer follow-up may be useful for comparison in this cohort.3 The many issues surrounding nevirapine toxicity continue to muddy the waters.

Decreasing Resistance in Infants and Mothers

Several other presentations at CROI looked at combination prophylactic regimens aimed at decreasing the risk of resistance in infants and mothers. Chaix et al (Abstract 72LB) reporting on the ANRS DITRAME Plus study from Abidjan, Côte d'Ivoire, studied the effects of the addition of zidovudine and lamivudine from 32 weeks gestation to 3 days post-partum to single-dose nevirapine at delivery in 329 mothers.

In this study, the infants received zidovudine for 7 days post-delivery with single-dose nevirapine on day 2. This study found a 6-week HIV transmission rate of 4.7%, with genotyping showing only 1 of the 16 infected children to have nevirapine and lamivudine mutations and 3 children to have lamivudine mutations.

Ngo-Giang-Huong et al (Abstract 802) found an 8% nevirapine resistance rate in non-breastfed infants who were exposed to single-dose nevirapine or placebo plus 1-6 weeks of zidovudine at birth, with the mothers having all received single-dose nevirapine plus zidovudine for varying durations pre-partum.

Approximately 500,000 women have received single-dose nevirapine at delivery since the results of HIVNET 012, with 9%-14% transmission rates in various trials. As these mothers and infants live longer, healthier lives and repeat pregnancies occur, the possibility of the persistence of resistance from single-dose or short-course regimens becomes a critical question.

Effectiveness of Single-Dose Nevirapine in Second Pregnancies

Martinson et al (Abstract 103) presented preliminary data from an ongoing study looking at the effectiveness of single-dose nevirapine in a second pregnancy. Data from 6 weeks post-delivery was available for 77 case mothers who were being exposed a second time to single-dose nevirapine in 13 clinics in Soweto, South Africa. They were matched to 140 controls who were receiving single-dose nevirapine for the first time. No other antiretroviral therapy was given to any of the study participants.

Only 2 of the women receiving single-dose nevirapine for the second time had evidence of baseline resistance and none of the women transmitted HIV to their infants. However, a trend towards effect of past single-dose nevirapine experience existed, with 10.7% of cases transmitting HIV to their infants versus 3.8% of controls, for an adjusted odds ratio of 2.3. Maternal viral resistance rates 6 weeks post-delivery were similar -- 45.1% for cases and 54.8% for controls. Final data from this trial may prove to be a significant piece in the puzzle.

The risk of viral resistance must be balanced by the dramatic decrease in HIV transmission rate associated with use of these relatively easy and inexpensive regimens. Clarifying the issues of efficacy, toxicity, cost and resistance that surround PMTCT in the developing world is crucial to controlling the pandemic in the developing world.

While Giuliano's CROI presentation, which looked at a relatively inexpensive regimen for PMTCT delivered in the context of breast feeding -- which will continue to be a transmission risk in the developing world -- is an important contribution, larger studies in varied settings are needed to validate her findings and explore the long-term consequences of resistance for mothers and infants.

Footnotes

  1. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. September 4, 1999;354(9181):795-802.

  2. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. September 13, 2003;362(9387):859-868.

  3. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS. October 19, 2001;15(15):1951-1957.
Reference


Authored by: M Giuliano, C Galluzzo, E Germinario, R Amici, M Pirillo, L Bassani, J Vyankandondera, F Mmiro, P Okong, S Vella

Affiliations: Inst Superiore di Sanita, Rome, Italy; Ctr Hosp de Kigali, Rwanda; Mulago Hosp, Kampala, Uganda; St Francis Hosp, Nsambya, Kampala, Uganda



  
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