Acute HIV infection: impact on the spread of HIV and transmission of drug resistance

S. Yerlya; S. Voraa; P. Rizzardib; J.-P. Chavef; P. L. Vernazzac; M. Fleppd; A. Telentib; M. Battegaye; A.-L. Veutheyg; J.-P. Bru h; M. Rickenbachi; B. Hirschela; L. Perrina; and the Swiss HIV Cohort Study*

From the University Hospitals of aGeneva, bLausanne, cSt Gallen, dZurich and eBasel, fLa Source Hospital, Lausanne and the gSwiss Institute of Bioinformatics, CMU, Geneva,Switzerland, hAnnecy Hospital, France and the iCoordination and Data Centre, Swiss HIV Cohort Study, Lausanne, Switzerland.

AIDS 2001;15:2287-2292

Objective: To assess the impact of primary HIV infection (PHI) on the spread of HIV and the temporal trends in transmission of HIV drug resistance between 1996 and 1999 in Switzerland.

Methods: Sequencing of the genes for reverse transcriptase (RT) and protease was performed for 197 individuals with documented PHI. Phylogenetic analyses were confronted with epidemiological data.

Results: Significant clustering was demonstrated for 29% of the RT sequences. All these cases occurred closely together in place and time; contact tracing demonstrated transmission at the time of PHI in 30% of them. Genotypic drug resistance was detected in 8.6% of PHI individuals in 1996, 14.6% in 1997, 8.8% in 1998 and 5.0% in 1999. Drug-resistant variants were identified in 11.3% of individuals infected by homosexual contacts, 6.1% by heterosexual contacts, 13% of intravenous drug users and more frequently in men (10.4%) than women (2.6%). Potential factors involved in the recent decrease of transmission of drug-resistant variants include increase of HIV non-B subtypes from 23% in 1996 to 35% in 1999 (only one non-B subtype had resistance mutations) and a steady increase of patients with undetectable viraemia as documented in Swiss HIV Cohort Study (10% in 1996 vs 53% in 1999). editorial note: it's been suggested that the Swiss are better at getting more people under car & in therapy and in success with achieving undetectable viral load. Its suggested that plays an important role in reduced rates.

Conclusions: Phylogenetic and epidemiological analyses underline the impact of PHI in the spread of HIV. Moreover, this study indicates that drug resistance transmission may have decreased recently in Switzerland through the increased frequency of infection with HIV non-B subtypes and the steady increase of patients with undetectable viraemia.

Study population The study included all individuals with documented PHI identified in six AIDS centres of University Hospitals in Switzerland (Basel, Geneva, Lausanne, Lugano, St Gallen and Zurich) and two AIDS Centres of Hospitals close to Geneva (Annemasse and Annecy, France). For each patient, the clinician in charge completed an epidemiological questionnaire labelled with a code number. In the total of 197 individuals infected between January 1996 and January 2000, PHI was documented by evolving HIV antibody response and/or symptoms consistent with an acute retroviral syndrome [25] within 3 months in 70% of individuals and by seroconversion within 12 months of presentation in 30%. Sequence analyses were performed on plasma samples collected at the first visit, before initiation of antiretroviral treatment.

In this large and systematic study, a peak in transmission of antiretroviral drug-resistant variants, reaching nearly 15%, was observed in 1997, followed by decreased prevalence in 1998 (8.8%) and 1999 (5.0%). As in previous studies, genotypic resistance to RT inhibitors was more frequent than to PI [16-22]. The prevalence of transmission of drug-resistant variants was higher in IDU (13%) and in the homosexual group (11%) than in the heterosexual group (6%). The high transmission rate of drug-resistant variants in the first two risk groups is likely because of the initial spreading of HIV-1 infection and, therefore, earlier antiretroviral treatment within these two risk groups. The lower transmission rate observed in the heterosexual risk group is also partially explained by the high percentage of women infected with HIV-1 non-B subtypes (41%).

New guidelines favour a less aggressive strategy for initiation of treatment, based more on CD4 cell counts than on viraemic levels, and treatment interruptions within or outside clinical trials are increasingly popular because of drug adverse events. This obviously leads to an increased number of infectious individuals. Measures to prevent HIV transmission should, therefore, be reinforced. Finally, if mutations conferring multiple drug resistance result in reduced viral fitness [35], the limitations in the replication capacity might also reduce the risk of transmission. The data presented here underline two main points: first, it is not inevitability that transmission of antiretroviral drug resistance will increase, since preventive programmes and treatment availability may decrease it; second, individuals with acute HIV infection are frequently involved in the spread of HIV in a geographical area where newly diagnosed infections decreased over recent years. Hence, the identification of newly infected individuals and contact tracing should be considered as an important public health measure to reduce HIV transmission further.

Eleven (5.8%) individuals harboured variants with mutations associated with resistance to zidovudine and or stavudine (M41L, D67N, K70R, L210W and T215Y/F). The lamivudine-resistant mutation M184V was detected in three (1.6%) individuals and mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors (G190A and/or Y181C) were detected in two (1.1%) individuals. Major mutations associated with PI resistance were detected in 6/176 (3.4%) individuals: the V82A/F mutation was detected in four of these and the L90M mutation in two. In these six individuals, two to five of the minor mutations associated with PI resistance (L10I, K20R, M36I, I54V, L63P, A71T/V and I84V) were also detected.