Several groups have presented new drug resistance transmission data in adult seroconverters, adult partner pairs and mother and child pairs at recent meetings, including the 8^th Conference on Retroviruses and Opportunistic Infections (8^th CROI). These include data from three large national cohorts.

Acute Infection
Yerly et al. presented data from the Swiss cohort for the years 1996 to 2000 (Abstract 754) [1]. According to their findings, genotypic drug resistance among HIV seroconverters rose from 8.6% in 1996 to 14.6% in 1997, but then declined to 8.8% in 1998, to 5.0% in 1999 and, again, to 4% in 2000. Drug-resistant virus was detected in 11.3% of MSM, 6% of heterosexual transmissions (mainly clade non-B) and 13% of IVDU. Nucleoside resistance (mainly AZT and/or 3TC resistance) was detected in 5.8% of isolates, NNRTI resistance in 1.1% and PI resistance in 3.4%. Clusters of infected patients were detected for 29% of the isolates sequenced.

Chaix et al. presented data for 121 acute seroconverters enrolled in the French ANRS primary infection cohort in 1999 (Abstract 755) [2]. Overall 12 of 121 patients (10%) had evidence of drug resistance. NRTI resistance (mainly AZT and/or 3TC resistance) was detected in 6% of isolates, NNRTI resistance in 4% and PI resistance in 3%. Multidrug resistant (MDR) virus was detected in 1.6% of newly infected patients. No significant changes in the rate of transmission of drug-resistant virus were seen between 1996 and 1999. Drug resistant virus was only detected in transmissions of clade B virus.

Little et al. presented data from 394 treatment-naive, newly infected patients detected in nine North American cities (Abstract 756) [3]. Resistance in this cohort was defined as phenotypic resistance with an IC₅₀ for a drug greater than 10-fold above a wild-type reference HIV strain. From 1995 to 1998, 3.5% of all isolates had evidence of drug resistance: 2.7% had NRTI resistance, 1.3% had NNRTI resistance, 0.4% had PI resistance and 0.4% had MDR virus. Rates of drug resistance in newly infected patients rose during 1999-2000 to 14% of all HIV isolates: 8.3% NRTI resistance, 7.1% NNRTI resistance, 8.2% PI resistance and 5.8% MDR virus. Rates were even higher for a small number of HIV isolates from HIV seroconverters in 2000, with 7% NRTI resistance, 15% NNRTI resistance and 7% PI resistance. The reasons for a rising incidence of primary HIV drug resistance in North America and a falling rate in Switzerland was not clear although an increasing percentage of HIV infections in Europe are caused by non-clade B HIV-1.

Adult Partner Pairs
Previous reports of transmission of AZT-resistant virus suggested that drug-resistant virus was less transmissible than wild-type, drug sensitive virus. Hecht et al reported genotypic resistance data pertaining to HIV isolates from 11 partner pairs from San Francisco (Abstract 87) [4]. Virus from two source patients had NRTI mutations (T69D and M184V). Both were transmitted. One source patient had virus with the pan-NNRTI resistance mutation, K103N, which was transmitted. While no source patients had virus with primary PI resistance mutations, three source patients had four secondary mutations, all of which were transmitted. This study from the HAART era demonstrated no evidence that drug-resistant virus was selected against during primary infection since all 10 mutations in RT and protease of virus from source patients were transmitted to their partners.

Perinatal Transmission
Bauer et al. presented data from the Women and Infants Transmission Study (WITS) cohort on 36 mothers harboring HIV with AZT resistance mutations and 45 mothers with wild type virus at term (Abstract 711) [5]. Factors associated with AZT resistance at term included AZT use prior to pregnancy, viral load (log₁₀ plasma HIV RNA copies) and CD4 count at delivery. In this study of AZT monotherapy to prevent perinatal transmission of HIV, 20% of mothers transmitted HIV to their infants. HIV was transmitted by six of 11 (55%) mothers whose virus had AZT IC₅₀ >0.1 µM, compared to 16 of 46 (36%) mothers who did not transmit HIV to their infants. Increasing levels of AZT resistance were significantly associated with increased perinatal transmission.

In another study, Eshleman et al presented data on 95 HIV-infected women and 20 HIV-infected infants from the HIVNET-012 study of single-dose nevirapine prophylaxis against maternal-infant HIV transmission in Uganda (Abstract 516) [6]. 18 percent (17/95) women had genotypic evidence of nevirapine resistance at week 6. HIV isolates from 5 of these women at 12 to 18 months after delivery had reverted to wild type virus. Nevirapine resistance mutations were detected in 9/20 infants (45%) at 6 weeks after delivery. Virus had reverted to wild type in 3/7 infants in samples obtained 14 to 16 weeks post delivery. Isolated virus from mother-infant pairs demonstrated different drug resistance mutations suggesting independent evolution of drug resistance in the mothers and infants rather than transmission of drug resistant virus.

And lastly, Cunningham et al. presented data from PACTG 316, in which single-dose nevirapine was administered during delivery to women with detectable virus who were on a non-NNRTI containing antiretroviral regimen (Abstract 712) [7]. The trial was closed to accrual in June 2000 due to low rates of transmission in the placebo arm of the trial after 1,052 women had been enrolled. Viral isolates from 104 women (51 on NVP and 53 women on placebo) were evaluated. Genotypic evidence of NRTI and PI resistance was common at delivery. At six weeks post partum, NVP resistance was detected in virus from 5/46 women (11%) who had plasma HIV RNA > 400 copies/mL. One mother, who received efavirenz after delivery, developed a K103N mutation. No follow-up data on the mothers or infants are available at this time.

Taken together, these findings emphasize the need to optimize antiretroviral therapy to maximally suppress plasma HIV RNA in mothers at term. In countries where antiretroviral therapy is not available, nevirapine monotherapy can significantly decrease perinatal transmission and nevirapine resistance will revert to wild type in the absence of drug pressure. In countries where HAART is routinely available, every effort should be made to combine nevirapine with additional drugs to maximally suppress HIV replication. Simply adding nevirapine (or efavirenz in the non-pregnant patient) to a failing antiretroviral regimen will rapidly select for NNRTI resistance that often does not revert in the face of continuing drug selection pressure. The risk/benefit of simply adding nevirapine to a failing HAART regimen at term is uncertain and may jeopardize the mother’s ability to successfully control her own HIV infection in the future.

References

Yerly S, Race E, Vora S, et al. HIV Drug Resistance and Molecular Epidemiology in Patients with Primary HIV Infection. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 754.
Chaix ML, Harzic M, Masquelier B, et al. Prevalence of Genotypic Drug Resistance among French Patients Infected during the Year 1999. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 755.
Little SJ, Routy JP, Daar ES, et al. Antiretroviral Drug Susceptibility and Response to Initial Therapy Among Recently HIV-Infected Subjects in North America. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 756.
Hecht* FM, Kahn JO, Warmerdam M, Webb M, Digilio L, Lee KH, and Grant RM. Transmission of Specific Antiviral Resistance Mutations within Partner Pairs. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 87.
Bauer G, Pitt J, Colgrove R, Welles S. Phenotypic Zidovudine (ZDV) Resistance and Perinatal HIV-1 Transmission. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 711.
Eshleman SH, Mracna M, Guay L, et al. Selection of Nevirapine Resistance (NVPR) Mutations in Ugandan Women and Infants Receiving NVP Prophylaxis To Prevent HIV-1 Vertical Transmission (HIVNET-012). 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 516.
Cunningham CK, Britto P, Gelber R, Dorenbaum A, Mofenson L, Culnane M, Sullivan JL, and the PACTG 316 Team. Genotypic Resistance Analysis in Women Participating in PACTG 316 with HIV-1 RNA >400 Copies/ml. 8^th Conference on Retroviruses and Opportunistic Infections. 2–4 Feb 2001, Chicago, IL. Abstract 712.